Cerebral Blood Flow in Migraine John Edmeads, M.D., F.R.C.P. (C), F.A.C.P. Department of Neurologic Sciences, Sunnybrook Medical Centre; and Department of Medicine, University of Toronto, Toronto (Dr. Edmeads). Reprint requests to: Department of Neurologic Sciences, Sunnybrook Medical Centre, 2075 Bayview Avenue, Toronto, M4N 3M5, Canada (Dr. Edmeads). Presented in part at the 19th Annual Meeting of the American Association for the Study of Headache, June 18, 19, 1977, San Francisco, Calif. Accepted for publication: 6/28/77 SYNOPSIS Cerebral blood flow has seldom been measured during attacks of migraine and cluster headache. The literature is reviewed and five cases studied in our laboratory are described. The results of these studies confirm Wolff's hypothesis that cerebral blood flow is decreased during auras and increased during headaches. However, the distribution in time and space of the blood flow changes do not always correlate with the clinical features of the attack. Autoregulation of cerebral blood vessels may be impaired in aura and headache, and this may be a factor in intensifying and prolonging attacks. (Headache 17: 148-152, 1977) The concept that migraine headaches are produced by vascular congestion within the head originated with Willis1 in the seventeenth century. In 1872, Latham2 postulated "defective blood supply to one side of the brain from contraction of cerebral arteries" as the cause of migrainous visual auras. These speculations were not tested in the laboratory until forty years ago. The tambour experiments of Graham and Wolff3 established that migraine headache is related to increased pulsations of extracranial vessels, but the state of the intracranial circulation during headache was not clarified. However, Wolff hypothesized that "headache-is an epiphenomenon-the painful dilatation, chiefly of some branches of the external carotid artery, is incidental to dilatation of branches of the internal carotid artery".4 From other experiments in which migraine auras were abolished by cerebral vasodilators5 Wolff drew support for the concept that auras are associated with intracranial vasoconstriction and cerebral ischemia. It has been pointed out6,7 that these experiments did not actually measure cerebral circulation in migraine, and, therefore, the conclusions must be viewed as hypotheses only. This paper examines the impact of cerebral blood flow measurements in migraine on Wolff's vascular theory. INHALATION CEREBRAL BLOOD FLOW STUDIES In 1967 O'Brien, using a radioactive xenon inhalation technique, made the first cerebral blood flow measurements in patients during a migraine attack.8 In this technique the patient breathes a mixture of 133Xe and air for five minutes on a closed circuit system, saturating his tissues. Xenon inhalation is then stopped, and the desaturation curve produced by arterial washout is followed over a period of forty minutes by two scintillation counters placed on either side of the head. The half-life of the fast component of the washout curve is an index of the cerebral cortex perfusion rate. Patients with migraine were studied early in the headache and again when headache-free. A mean decrease in flow of twenty percent during the headaches was present, with no asymmetry between the hemispheres even in those patients with unilateral headaches. There was "no notable change" in paCO2 or blood pressure.8 In 1971, in a larger series, O'Brien reported that patients who had cerebral blood flow measured during a headache showed a small mean increase of 8%. Those measured during the aura showed a greater mean reduction of 23%.9 Patients studied during the aura10 had bilateral reduction in blood flow which was not limited to the small area of cortex directly related to the symptoms, and which could outlast the symptoms of the aura. Inhalation techniques for measuring cerebral blood flow are non-invasive and can measure simultaneously flow through both hemispheres. They do require at least twenty minutes, making
it difficult to study the sequential and rapidly changing phases of a migraine attack. More important is the inability of the technique to isolate the intracranial from the extracranial circulation. This is a major drawback in migraine, a condition associated with marked differences between intracranial and extracranial vascular function during attacks. INTRACAROTID CEREBRAL BLOOD FLOW STUDIES The intracarotid xenon technique11,12 or modifications thereof, have been used in measuring regional cerebral blood flow (rCBF) during attacks of migraine. In this method, a fine polyethylene catheter is inserted precutaneously high into the internal carotid artery and a bolus of 2-3 millicuries of 133Xenon in saline is injected. The rate of Xenon washout from the carotid circulation reflects the cerebral blood flow; washout curves are monitored by 16 to 254 extracranial probes positioned over the injected hemicranium. The rCBF values are calculated from the initial slope of the washout curves, which largely measure cortical blood flow, and are expressed as ml of blood per 100 Gm of brain per minute. This technique is invasive and limited to migraine patients undergoing clinically indicated carotid angiography. These are usually patients with atypical migraine. Therefore, the validity of extrapolating results from these cases to patients with common migraine can be questioned. This technique also has the disadvantage of measuring only flow through the carotid system of one hemisphere, but it is highly accurate, quick (each determination takes only several minutes; serial studies in the same attack are possible), and the portion of the cerebral circulation being measured can be defined. In 1969 Skinhoj and Paulson13 reported rCBF to be profoundly reduced in one patient during an aura. Angiography during the aura was normal, suggesting that any spasm present was in vessels too small to be visualized angiographically. In another patient, rCBF was increased during a migraine headache. In 1973 Skinhoj14 reported rCBF measurements in four patients during auras, and in another six patients during headache. During auras marked reduction of rCBF was found in all, at times to levels critical for oxygenation of the brain. The reduction was not uniform throughout the hemisphere. One patient showed the phenomenon of "kinked curves", indicating compartments with very slow and fast flow rates within the same small areas of brain. Angiograms during the aura did not show spasm; two of four angiograms showed reflux of contrast material into the basilar artery. Five of six patients measured during a headache showed increased rCBF. The one who did not was hyperventilating, and cerebral blood flow could have been reduced by the hypocapnia. Patients with headache had decreased bicarbonate and increased lactate in CSF, indicating acidosis. Skinhoj hypothesized that the vasoconstriction and ischemia of the aura produced cerebral hypoxia and lacticacidosis, which led to compensatory vasodilatation. He echoed Wolff's postulate5 that "the stage of painful vasodilatation is an attempt on the part of the organism to restore the cranial circulatory homeostasis". Wolff, however, attributed the compensatory vasodilatation to neural impulses in hypoxic brain rather than to metabolic changes. In 1973 another patient15 showed marked reduction of rCBF and impaired cerebral vasomotor reactivity during a migraine aura. The rCBF was to less than half normal values and was uniform throughout the hemisphere, even though the aura could be localized clinically to a small area of cortex. The paCO2 was low (28 mm Hg) because the patient was hyperventilating. Inhalation of CO2, with a rise in paCO2 to 38 mm Hg, produced no increase in rCBF. Three and a half months later, when the patient was asymptomatic, rCBF was normal, and showed normal reactivity to changes in paCO2. Intramuscular ergotamine failed to alter rCBF during the aura or during asymptomatic periods in the studies. Mathew et al16, using a gamma camera to monitor washout curves, measured rCBF in twenty-four migraine patients in 1976. In thirteen rCBF studies were done during a headache; in another three, during the aura. The clinical data are insufficient to permit detailed clinicopathologic correlation. Overall figures indicate that flow was lower than normal during auras, higher than normal during headaches, and normal between attacks. OBSERVATIONS IN OUR LABORATORY Using an intracarotid 133Xenon technique with sixteen extracranial probes, rCBF was measured in four patients with migraine and one with cluster headache.
Case 1: An 18-year-old woman afforded a unique opportunity to measure cerebral blood flow in the same attack through the aura, the headache phase, and relief of the headache after ergotamine.17 For two years she had attacks which began with numbness in the right hand, spreading to involve the entire right side of the body; sometimes a flickering right hemianopia was present. After several minutes, throbbing left-sided headache occurred which persisted for several hours. Angiography was done because of increased frequency of attacks and their unchanging localization. She developed the aura as the left internal carotid artery was catheterized. The first rCBF measurement was done immediately and showed a uniformly low flow rate. The mean value was 38 ml per 100 gm per minute, compared to a normal value of 64±9, (values in our laboratory are corrected to a paCO2 of 40 mmHg using the formula of Olesen et al12). Fifteen minutes later, after the aura faded and headache appeared, a second rCBF study was done. This showed a uniform rise above normal with a mean value of 82 ml per 100 gm per min. Ergotamine tartrate 0.5 mg was then injected intramuscularly and fifteen minutes later, with the headache almost completely gone, a third rCBF study showed persistent elevated flow rate (mean value 91 ml per 100 gm per min.). Finally a left carotid angiogram showed reflux of contrast medium into the basilar artery. Case 2: A 25-year-old man had rCBF studies two days after complete clinical subsidence of a severe attack of cheirooral migraine. As a child he had had a succession of brief but intense headaches. He was then well until age 25 when he presented with the abrupt onset of expressive dysphasia and weakness of the right hand and face. These cleared in four hours, but were followed by throbbing left temporal headache and vomiting which persisted for the rest of the day. On the first day, after the aura had cleared but while the headache was present, a technetium glucoheptonate brain scan demonstrated diminished density of isotope in the distribution of the left middle cerebral artery; a second scan seventeen seventeen days later was normal. On the day after the attack, with the patient clinically normal, an electroencephalogram showed a left frontotemporal delta focus; a second tracing two weeks later was normal. Two days after the headache rCBF studies were done. The probe overlying Broca's area recorded a flow value twenty percent higher than the mean flow in adjacent parts of the hemisphere. Hyperventilation, with paCO2 decreasing to 21 mmHg, showed a fall in rCBF in the hyperperfused area which was, however, only half that in adjacent areas. This indicated focal impairment of reactivity of vessels to changes in paCO2. Angiography, after the rCBF studies, was normal. The patient had later attacks of ergotamine-responsive hemicrania, sometimes preceded by transient neurologic deficits. Case 3: A 38-year-old man had rCBF studies during a visual aura, and after relief of headache by ergotamine. After the age of five years he had recurrent left occipital headaches preceded by shimmering bilateral central scotomata. Angiography was done because of recent onset of coital cephalalgia. During catheterization of the left internal carotid artery he developed his usual aura and the first rCBF measurement was normal (54 ml per 100 gm per minute). The aura cleared fifteen minutes later and his left occipital headache began. Ergotamine 0.25 mg was given intramuscularly and the headache disappeared in ten minutes. A second rCBF study was unchanged. The angiogram was normal. Case 4: A 24-year-old man had rCBF studies during a hemicranial headache. Just before entering the laboratory he complained of flashing lights in the left eye. These cleared in two minutes, and left hemicranial headache occurred. rCBF was measured 16 minutes and again 31 minutes after the onset of headache and results were normal. Ergotamine 0.5 mg was injected intramuscularly immediately after the second flow study and a third determination, 25 minutes later, while the patient was headache-free, was also normal. Angiography was normal. Case 5: A 32-year-old man had rCBF studies during a cluster headache, and after the administration of ergotamine.18 Left carotid angiography excluded a lesion. Ten minutes after the angiogram (normal) he developed severe left retro-orbital pain, and ten minutes later the first rCBF study was done. This was in the upper range of normal (67 ml/100 gm/min). Ten minutes after that, or twenty minutes after the start of headache, a second rCBF with hyperventilation showed normal reduction in response to lowered paCO2. Three minutes later, or twenty-three minutes after the start of the headache, 0.75 mg of ergotamine was injected intramuscularly. The third rCBF study was done ten minutes after ergotamine injection, thirty-three minutes after the start of the headache, when the pain was much less severe. This clearly showed increased flow to 78 ml/100 gm/minute. DISCUSSION Changes in cerebral blood flow during aura: Almost all patients who have been studied during an aura have had reduction of cerebral blood flow. The one exception is our case 3, in whom rCBF was normal. In this patient the aura was probably due to
dysfunction of the occipital cortex which is supplied by the vertebrobasilar system, but our technique measured flow though the carotid system. This result may thus reflect sampling limitations of the intracarotid method. Failure of angiography to show narrowing of vessels despite reduced flow suggests that the vasoconstriction causing hypoperfusion must be in the arterioles, which are not visualized in angiograms. One patient19 in whom transient non-filling of vessels was noted on in angiograms done during an aura, did not have concomitant rCBF measurements. Other mechanisms of reduced cerebral perfusion, such as increased blood viscosity or platelet sluding, have not been adequately explored. However produced, the decrease in blood flow may be sufficient to impair oxygenation of the brain, and biochemical changes consistent with cerebral hypoxia have been found in the CSF of migraineurs.14,20 During an aura the cerebral blood vessels may be incapable of dilating in response to increased paCO215, and this failure could be a factor in prolonging cerebral hypoxia and producing the symptoms of the aura. Though the symptoms are usually focal, the reduction in cerebral blood flow during the aura often is not. The intracarotid technique, which measures flow through one hemisphere, only demonstrated that the reduction of flow may be diffuse in that hemisphere. The inhalation studies indicate that flow through both hemispheres may be reduced during an aura and some of the inhalation data10, and the technetium brain scan in our case 2 suggest that the reduction in blood flow may outlast the clinical aura. Changes in cerebral blood flow during headache: Nearly all migraine patients and the one cluster patient, studied during headache, had increased cerebral blood flow. The normal rCBF in one patient during headache was attributed to vasoconstriction caused by hyperventilation.14 We believe the normal rCBF in our case 4 was due to sampling artifact. The increased cerebral blood flow during the headache phase is probably a compensatory response to the hypoxia of the aura, mediated by metabolites. However produced, the hyperperfusion of the headache has many of the characteristics of the hypoperfusion of the aura. The distribution of the increased rCBF does not always correlate with the location of the headache. Patients with headache confined to one temple may have hyperperfusion of the entire ipsilateral hemisphere; indeed, inhalation studies suggest that the increased blood flow is often bilateral even in strictly unilateral headaches. Reactivity of the presumably dilated arterioles to changes in paCO2 may (Case 2) or may not (Case 5) be impaired. Failure of vasoconstriction in response to a falling paCO2 may prolong the hyperperfusion and, indirectly, the headache. The pain of headache may increase cerebral metabolism,21 in turn increasing cerebral blood flow through persistent vasodilatation, completing a vicious circle which prolongs the headache. However, the persistence of focal or diffuse hyperperfusion after the pain abated either spontaneously (Case 2) or after ergotamine (Cases 1 and 5) indicates that in at least some patients other factors must be sought to account for the prolonged vascular change. CONCLUSIONS For practical therapeutics, the observation that ergotamine does not affect cerebral blood flow, even when it has clearly been effective in abolishing headache,22 is important. The immunity of the intracranial circulation to ergotamine23 suggests that the traditional prohibition of this drug for patients with severe vasoconstrictive auras24 may be unnecessary, and that these patients may now receive the benefits of early treatment. The theoretic implications of the blood flow studies are far-reaching. Clearly, they provide evidence for Wolff's hypothesis of the vascular etiology of migraine. Perhaps, more important, blood flow studies indicate that this hypothesis, while correct, is incomplete. The unexpected finding of frequent discrepancies between spatiotemporal distribution of blood flow and the distribution of symptoms, and of the disordered cerebral vasoreactivity during attacks, may serve as points of departure for further research into the mechanisms of migraine. REFERENCES 1.
Willis, Thomas: Practice of Physick. London, 1684. (Quoted in Knapp, R. D.: Reports from the past. Headache 3:112-122, 1963.)
2.
Latham P: Clinical lectures on nervous or sick headaches. Brit Med J 1:305-306; 336-337, 1872.
3.
Graham JR and Wolff HG: Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiat 39:737-740, 1938.
4.
Wolff's Headache and Other Head Pain. 3rd ed. (Revised by DJ Dalessio) p. 293. New York Oxford University Press, 1972.
5.
Op cit: 231-235.
6.
Sacks OW: Migraine, the Evolution of a Common Disorder. Berkeley, University of California Press, 1970.
7.
Schiller F: The migraine tradition. Bull Hist Med 49:1-19, 1975.
8.
O'Brien MD: Cerebral cortex perfusion rates in migraine. Lancet 1:1036, 1967.
9.
O'Brien MD: Cerebral blood flow changes in migraine. Headache 10:139-143, 1971.
10.
O'Brien MD: The relationship between aura symptoms and cerebral blood flow changes in the prodrome of migraine. Proc Int Headache Symposium, Elsinore. Dalessio DJ, Dalsgaard-Nielsen T, and Diamond S. (eds). Basle. Sandoz. 1971.
11.
Lassen NA and Ingvar DH: The blood flow of the cerebral cortex determined by Krypton 85. Experientia 17:42-43, 1961.
12.
Olesen J, Paulson OB and Lassen NA: Regional cerebral blood flow in man determined by the initial slope of intra-arterially injected 133Xe. Stroke 2:519-540, 1971.
13.
Skinhoj E and Paulson OB: Regional blood flow in internal carotid distribution during migraine attack. Brit Med J 3:569-570, 1969.
14.
Skinhoj E: Hemodynamic studies within the brain during migraine. Arch Neurol 29:95-98, 1973.
15.
Simard D and Paulson OB: Cerebral vasomotor paralysis during migraine attack. Arch Neurol 29:207-209, 1973.
16.
Mathew NT, Hrastnick F and Meyer JS: Regional cerebral blood flow in the diagnosis of vascular headache. Headache 15:252-260, 1976.
17.
Norris JW, Hachinski VC and Cooper PW: Changes in cerebral blood flow during a migraine attack. Brit Med J 3:676-677, 1975.
18.
Norris JW, Hachinski VC and Cooper PW: Cerebral blood flow changes in cluster headache. Acta Neurol Scand 54:371-374, 1976.
19.
Dukes HT and Vieth RG: Cerebral arteriography during migraine prodrome and headache. Neurology 14:636-639, 1964.
20.
Welch KMA, Chabi E, Nell JH, et al: Biochemical comparison of migraine and stroke. Headache 16:160-167, 1976.
21.
Ingvar DH: Pain in the brain-and migraine. Hemicrania 7:2-6, 1976.
22.
Hachinski VC, Norris JW, Cooper PW and Edmeads JG: Ergotamine tartrate and cerebral blood flow. Canad J Neurol Sci 2:333, 1975.
23.
Edmeads J, Hachinski VC and Norris JW: Ergotamine and the cerebral circulation. Hemicrania 7:6-10, 1976.
24.
Edmeads J: Management of the acute attack of migraine. Headache 13:91-95, 1973.
it difficult to study the sequential and rapidly changing phases of a migraine attack. More important is the inability of the technique to isolate the intracranial from the extracranial circulation. This is a major drawback in migraine, a condition associated with marked differences between intracranial and extracranial vascular function during attacks. INTRACAROTID CEREBRAL BLOOD FLOW STUDIES The intracarotid xenon technique11,12 or modifications thereof, have been used in measuring regional cerebral blood flow (rCBF) during attacks of migraine. In this method, a fine polyethylene catheter is inserted precutaneously high into the internal carotid artery and a bolus of 2-3 millicuries of 133Xenon in saline is injected. The rate of Xenon washout from the carotid circulation reflects the cerebral blood flow; washout curves are monitored by 16 to 254 extracranial probes positioned over the injected hemicranium. The rCBF values are calculated from the initial slope of the washout curves, which largely measure cortical blood flow, and are expressed as ml of blood per 100 Gm of brain per minute. This technique is invasive and limited to migraine patients undergoing clinically indicated carotid angiography. These are usually patients with atypical migraine. Therefore, the validity of extrapolating results from these cases to patients with common migraine can be questioned. This technique also has the disadvantage of measuring only flow through the carotid system of one hemisphere, but it is highly accurate, quick (each determination takes only several minutes; serial studies in the same attack are possible), and the portion of the cerebral circulation being measured can be defined. In 1969 Skinhoj and Paulson13 reported rCBF to be profoundly reduced in one patient during an aura. Angiography during the aura was normal, suggesting that any spasm present was in vessels too small to be visualized angiographically. In another patient, rCBF was increased during a migraine headache. In 1973 Skinhoj14 reported rCBF measurements in four patients during auras, and in another six patients during headache. During auras marked reduction of rCBF was found in all, at times to levels critical for oxygenation of the brain. The reduction was not uniform throughout the hemisphere. One patient showed the phenomenon of "kinked curves", indicating compartments with very slow and fast flow rates within the same small areas of brain. Angiograms during the aura did not show spasm; two of four angiograms showed reflux of contrast material into the basilar artery. Five of six patients measured during a headache showed increased rCBF. The one who did not was hyperventilating, and cerebral blood flow could have been reduced by the hypocapnia. Patients with headache had decreased bicarbonate and increased lactate in CSF, indicating acidosis. Skinhoj hypothesized that the vasoconstriction and ischemia of the aura produced cerebral hypoxia and lacticacidosis, which led to compensatory vasodilatation. He echoed Wolff's postulate5 that "the stage of painful vasodilatation is an attempt on the part of the organism to restore the cranial circulatory homeostasis". Wolff, however, attributed the compensatory vasodilatation to neural impulses in hypoxic brain rather than to metabolic changes. In 1973 another patient15 showed marked reduction of rCBF and impaired cerebral vasomotor reactivity during a migraine aura. The rCBF was to less than half normal values and was uniform throughout the hemisphere, even though the aura could be localized clinically to a small area of cortex. The paCO2 was low (28 mm Hg) because the patient was hyperventilating. Inhalation of CO2, with a rise in paCO2 to 38 mm Hg, produced no increase in rCBF. Three and a half months later, when the patient was asymptomatic, rCBF was normal, and showed normal reactivity to changes in paCO2. Intramuscular ergotamine failed to alter rCBF during the aura or during asymptomatic periods in the studies. Mathew et al16, using a gamma camera to monitor washout curves, measured rCBF in twenty-four migraine patients in 1976. In thirteen rCBF studies were done during a headache; in another three, during the aura. The clinical data are insufficient to permit detailed clinicopathologic correlation. Overall figures indicate that flow was lower than normal during auras, higher than normal during headaches, and normal between attacks. OBSERVATIONS IN OUR LABORATORY Using an intracarotid 133Xenon technique with sixteen extracranial probes, rCBF was measured in four patients with migraine and one with cluster headache.
Case 1: An 18-year-old woman afforded a unique opportunity to measure cerebral blood flow in the same attack through the aura, the headache phase, and relief of the headache after ergotamine.17 For two years she had attacks which began with numbness in the right hand, spreading to involve the entire right side of the body; sometimes a flickering right hemianopia was present. After several minutes, throbbing left-sided headache occurred which persisted for several hours. Angiography was done because of increased frequency of attacks and their unchanging localization. She developed the aura as the left internal carotid artery was catheterized. The first rCBF measurement was done immediately and showed a uniformly low flow rate. The mean value was 38 ml per 100 gm per minute, compared to a normal value of 64±9, (values in our laboratory are corrected to a paCO2 of 40 mmHg using the formula of Olesen et al12). Fifteen minutes later, after the aura faded and headache appeared, a second rCBF study was done. This showed a uniform rise above normal with a mean value of 82 ml per 100 gm per min. Ergotamine tartrate 0.5 mg was then injected intramuscularly and fifteen minutes later, with the headache almost completely gone, a third rCBF study showed persistent elevated flow rate (mean value 91 ml per 100 gm per min.). Finally a left carotid angiogram showed reflux of contrast medium into the basilar artery. Case 2: A 25-year-old man had rCBF studies two days after complete clinical subsidence of a severe attack of cheirooral migraine. As a child he had had a succession of brief but intense headaches. He was then well until age 25 when he presented with the abrupt onset of expressive dysphasia and weakness of the right hand and face. These cleared in four hours, but were followed by throbbing left temporal headache and vomiting which persisted for the rest of the day. On the first day, after the aura had cleared but while the headache was present, a technetium glucoheptonate brain scan demonstrated diminished density of isotope in the distribution of the left middle cerebral artery; a second scan seventeen seventeen days later was normal. On the day after the attack, with the patient clinically normal, an electroencephalogram showed a left frontotemporal delta focus; a second tracing two weeks later was normal. Two days after the headache rCBF studies were done. The probe overlying Broca's area recorded a flow value twenty percent higher than the mean flow in adjacent parts of the hemisphere. Hyperventilation, with paCO2 decreasing to 21 mmHg, showed a fall in rCBF in the hyperperfused area which was, however, only half that in adjacent areas. This indicated focal impairment of reactivity of vessels to changes in paCO2. Angiography, after the rCBF studies, was normal. The patient had later attacks of ergotamine-responsive hemicrania, sometimes preceded by transient neurologic deficits. Case 3: A 38-year-old man had rCBF studies during a visual aura, and after relief of headache by ergotamine. After the age of five years he had recurrent left occipital headaches preceded by shimmering bilateral central scotomata. Angiography was done because of recent onset of coital cephalalgia. During catheterization of the left internal carotid artery he developed his usual aura and the first rCBF measurement was normal (54 ml per 100 gm per minute). The aura cleared fifteen minutes later and his left occipital headache began. Ergotamine 0.25 mg was given intramuscularly and the headache disappeared in ten minutes. A second rCBF study was unchanged. The angiogram was normal. Case 4: A 24-year-old man had rCBF studies during a hemicranial headache. Just before entering the laboratory he complained of flashing lights in the left eye. These cleared in two minutes, and left hemicranial headache occurred. rCBF was measured 16 minutes and again 31 minutes after the onset of headache and results were normal. Ergotamine 0.5 mg was injected intramuscularly immediately after the second flow study and a third determination, 25 minutes later, while the patient was headache-free, was also normal. Angiography was normal. Case 5: A 32-year-old man had rCBF studies during a cluster headache, and after the administration of ergotamine.18 Left carotid angiography excluded a lesion. Ten minutes after the angiogram (normal) he developed severe left retro-orbital pain, and ten minutes later the first rCBF study was done. This was in the upper range of normal (67 ml/100 gm/min). Ten minutes after that, or twenty minutes after the start of headache, a second rCBF with hyperventilation showed normal reduction in response to lowered paCO2. Three minutes later, or twenty-three minutes after the start of the headache, 0.75 mg of ergotamine was injected intramuscularly. The third rCBF study was done ten minutes after ergotamine injection, thirty-three minutes after the start of the headache, when the pain was much less severe. This clearly showed increased flow to 78 ml/100 gm/minute. DISCUSSION Changes in cerebral blood flow during aura: Almost all patients who have been studied during an aura have had reduction of cerebral blood flow. The one exception is our case 3, in whom rCBF was normal. In this patient the aura was probably due to
dysfunction of the occipital cortex which is supplied by the vertebrobasilar system, but our technique measured flow though the carotid system. This result may thus reflect sampling limitations of the intracarotid method. Failure of angiography to show narrowing of vessels despite reduced flow suggests that the vasoconstriction causing hypoperfusion must be in the arterioles, which are not visualized in angiograms. One patient19 in whom transient non-filling of vessels was noted on in angiograms done during an aura, did not have concomitant rCBF measurements. Other mechanisms of reduced cerebral perfusion, such as increased blood viscosity or platelet sluding, have not been adequately explored. However produced, the decrease in blood flow may be sufficient to impair oxygenation of the brain, and biochemical changes consistent with cerebral hypoxia have been found in the CSF of migraineurs.14,20 During an aura the cerebral blood vessels may be incapable of dilating in response to increased paCO215, and this failure could be a factor in prolonging cerebral hypoxia and producing the symptoms of the aura. Though the symptoms are usually focal, the reduction in cerebral blood flow during the aura often is not. The intracarotid technique, which measures flow through one hemisphere, only demonstrated that the reduction of flow may be diffuse in that hemisphere. The inhalation studies indicate that flow through both hemispheres may be reduced during an aura and some of the inhalation data10, and the technetium brain scan in our case 2 suggest that the reduction in blood flow may outlast the clinical aura. Changes in cerebral blood flow during headache: Nearly all migraine patients and the one cluster patient, studied during headache, had increased cerebral blood flow. The normal rCBF in one patient during headache was attributed to vasoconstriction caused by hyperventilation.14 We believe the normal rCBF in our case 4 was due to sampling artifact. The increased cerebral blood flow during the headache phase is probably a compensatory response to the hypoxia of the aura, mediated by metabolites. However produced, the hyperperfusion of the headache has many of the characteristics of the hypoperfusion of the aura. The distribution of the increased rCBF does not always correlate with the location of the headache. Patients with headache confined to one temple may have hyperperfusion of the entire ipsilateral hemisphere; indeed, inhalation studies suggest that the increased blood flow is often bilateral even in strictly unilateral headaches. Reactivity of the presumably dilated arterioles to changes in paCO2 may (Case 2) or may not (Case 5) be impaired. Failure of vasoconstriction in response to a falling paCO2 may prolong the hyperperfusion and, indirectly, the headache. The pain of headache may increase cerebral metabolism,21 in turn increasing cerebral blood flow through persistent vasodilatation, completing a vicious circle which prolongs the headache. However, the persistence of focal or diffuse hyperperfusion after the pain abated either spontaneously (Case 2) or after ergotamine (Cases 1 and 5) indicates that in at least some patients other factors must be sought to account for the prolonged vascular change. CONCLUSIONS For practical therapeutics, the observation that ergotamine does not affect cerebral blood flow, even when it has clearly been effective in abolishing headache,22 is important. The immunity of the intracranial circulation to ergotamine23 suggests that the traditional prohibition of this drug for patients with severe vasoconstrictive auras24 may be unnecessary, and that these patients may now receive the benefits of early treatment. The theoretic implications of the blood flow studies are far-reaching. Clearly, they provide evidence for Wolff's hypothesis of the vascular etiology of migraine. Perhaps, more important, blood flow studies indicate that this hypothesis, while correct, is incomplete. The unexpected finding of frequent discrepancies between spatiotemporal distribution of blood flow and the distribution of symptoms, and of the disordered cerebral vasoreactivity during attacks, may serve as points of departure for further research into the mechanisms of migraine. REFERENCES 1.
Willis, Thomas: Practice of Physick. London, 1684. (Quoted in Knapp, R. D.: Reports from the past. Headache 3:112-122, 1963.)
2.
Latham P: Clinical lectures on nervous or sick headaches. Brit Med J 1:305-306; 336-337, 1872.
3.
Graham JR and Wolff HG: Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiat 39:737-740, 1938.
4.
Wolff's Headache and Other Head Pain. 3rd ed. (Revised by DJ Dalessio) p. 293. New York Oxford University Press, 1972.
5.
Op cit: 231-235.
6.
Sacks OW: Migraine, the Evolution of a Common Disorder. Berkeley, University of California Press, 1970.
7.
Schiller F: The migraine tradition. Bull Hist Med 49:1-19, 1975.
8.
O'Brien MD: Cerebral cortex perfusion rates in migraine. Lancet 1:1036, 1967.
9.
O'Brien MD: Cerebral blood flow changes in migraine. Headache 10:139-143, 1971.
10.
O'Brien MD: The relationship between aura symptoms and cerebral blood flow changes in the prodrome of migraine. Proc Int Headache Symposium, Elsinore. Dalessio DJ, Dalsgaard-Nielsen T, and Diamond S. (eds). Basle. Sandoz. 1971.
11.
Lassen NA and Ingvar DH: The blood flow of the cerebral cortex determined by Krypton 85. Experientia 17:42-43, 1961.
12.
Olesen J, Paulson OB and Lassen NA: Regional cerebral blood flow in man determined by the initial slope of intra-arterially injected 133Xe. Stroke 2:519-540, 1971.
13.
Skinhoj E and Paulson OB: Regional blood flow in internal carotid distribution during migraine attack. Brit Med J 3:569-570, 1969.
14.
Skinhoj E: Hemodynamic studies within the brain during migraine. Arch Neurol 29:95-98, 1973.
15.
Simard D and Paulson OB: Cerebral vasomotor paralysis during migraine attack. Arch Neurol 29:207-209, 1973.
16.
Mathew NT, Hrastnick F and Meyer JS: Regional cerebral blood flow in the diagnosis of vascular headache. Headache 15:252-260, 1976.
17.
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