Correspondence
Spreading Cerebral Hypoperfusion during Migraine Headache
N Engl J Med 1995; 332:1516-1518June 1, 1995
- Article
To the Editor:
The report by Woods et al. (Dec. 22 issue)1 on spreading oligemia as demonstrated by positron-emission tomography (PET) during a spontaneous episode of migraine confirms previous observations made on the basis of conventional studies of cerebral blood flow, as discussed by Olesen in the accompanying editorial.2 It is a giant step, however, to conclude that this observation can be equated with “spreading depression,” which is primarily an observation in experiments with animals. Besides, one could ask how spreading depression leads to the clinical features of migraine — specifically, pain, the most important symptom. What is the clinical correlate of spreading depression? The patient described by Woods et al. did not have any neurologic symptoms or signs despite widespread changes on the PET scan. Could this be explained on the basis of ischemia alone that was not severe enough to cause functional compromise, rather than spreading neuronal inhibition, in which case one would have expected more noticeable neurologic manifestations? Other factors, such as neurogenic inflammation, a lowered pain threshold, and vasodilatation (as discussed by Olesen) may play a part in an explanation of the clinical syndrome of migraine.
2 ReferencesN. Vijayan, M.D.
University of California School of Medicine, Sacramento, CA 958191
Woods RP ,Iacoboni M ,Mazziotta JC . Bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med 1994;331:1689-1692
Full Text | Web of Science | Medline2
Olesen J . Understanding the biologic basis of migraine. N Engl J Med 1994;331:1713-1714
Full Text | Web of Science | Medline
To the Editor:
I reported measurements of cerebral blood flow in the early stages of a migraine attack in 1967, using the xenon-133 inhalation technique.1 A summary of data on a series of seven patients studied in the prodromal and early stages of headache was published in 1971.2 These observations showed that cerebral blood flow is reduced in the prodromal or aura phase of a migraine attack and — a controversial observation at the time — that this is a generalized phenomenon, not strictly a focal event, as previously assumed, since there were bilateral reductions in flow in patients with unilateral aura.
I also demonstrated that the reduction in flow continued into the headache stage, indicating that the headache was not due to cerebral vasodilatation and explaining the concurrence of aura with headache in some patients. I observed a small increase in flow later in the headache stage in an additional 10 patients and noted that if this was a reactive hyperemia, it suggested that all migraine attacks have a vasoconstrictive phase, even if it is not clinically evident, a view disputed by others and discussed by Woods et al.
The mean reduction in flow was 20 percent in the seven patients during the prodrome, which is the same as the reduction reported by Woods et al., and I also concluded that this was an underestimate of the peak reduction. In the patient described by Woods et al., the reduction in blood flow persisted for at least 11/ 2 hours, during which time there were no symptoms of aura, apart from some difficulty in focusing clearly about 45 minutes after the onset of the attack. This finding confirms my observation, made more than 20 years ago, that the reduced flow persists into the early part of the headache stage and supports my view that the migrainous aura is the incidental clinical expression of a more widespread phenomenon and that vasoconstriction occurs in patients with “common migraine” who do not have a clearly defined aura or prodrome.
2 ReferencesMichael D. O'Brien, M.D.
Guy's Hospital, London SE1 9RT, United Kingdom1
O'Brien MD . Cerebral-cortex-perfusion rates in migraine. Lancet 1967;1:1036-1036
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O'Brien MD . Cerebral blood changes in migraine. Headache 1971;10:139-143
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To the Editor:
Woods et al. and Olesen support the notion that Leão's spreading depression accounts for symptoms of migraine attacks. There are, however, several points against this hypothesis. First, the phenomenon was originally described in anesthetized animals.1 Lauritzen2 recently noted that spreading depression does not occur in conscious rats. Patients are acutely conscious, even fearful, during the aura and the whole migraine episode. Second, Leão described a band rippling across the cortex, whereas in the study by Woods et al. and in previous studies, whole cortical areas have shown increasing degrees of hypoperfusion. Third, the depression in animals persists for 1 to 3 minutes, whereas in migraine hypoperfusion of 120 to 240 minutes has been demonstrated. Fourth, Leão's band of depression is immediately succeeded by intense hyperemia, with arteries dilating by 50 to 100 percent and veins becoming “as scarlet as arteries.”1 In migraine, Leão found that eventually after two to six hours patchy regions of increased flow sometimes developed in cortical regions which were previously hypoperfused. Finally, Leão's spreading depression has not been seen in patients, including nearly 1000 patients who underwent needling of the cortex in Penfield and Jasper's study of epileptic foci,3 and has not been reported by numerous observant neurosurgeons who daily traumatize the brain.
3 ReferencesJ.N. Blau, M.D.
National Hospital for Neurology and Neurosurgery, London WC1N 3BG, United Kingdom1
Leao AAP . Spreading depression of activity in the cerebral cortex. J Neurophysiol 1944;7:359-390
Web of Science2
Lauritzen M . Pathophysiology of the migraine aura: the spreading depression theory. Brain 1994;117:199-210
CrossRef | Web of Science | Medline3
Gloor P . Migraine and regional cerebral blood flow. Trends Neurosci 1986;9:21-21
CrossRef | Web of Science
To the Editor:
Dr. Olesen's review of research on the biologic basis of migraine is intriguing, but I was puzzled by his concluding admonition that we “acknowledge that migraine is a neurobiologic, not a psychogenic, disorder.”
Although one could argue that all human experience is ultimately neurobiologic, I wonder whether Dr. Olesen wishes to discount a psychogenic role in how migraine is experienced. The research he cites provides a glimpse into the neurobiology of migraine but certainly does not exclude the possibility of a role for psychogenic factors. Does he believe that we should close the door on trying to understand the psychogenesis of migraine at a time when we are learning more about the influence of psychogenic factors on other biologic processes?
Darius Rastegar, M.D.
1605 Park Ave., Baltimore, MD 21217Author/Editor Response
The authors reply:
To the Editor: Contrary to O'Brien's early findings, subsequent studies with substantially superior spatial resolution have only rarely demonstrated bilateral hypoperfusion in migraine or hypoperfusion in migraine without a typical migraine aura.1 Our observation should be regarded as an interesting exception, not the rule, with respect to these issues.
As Blau indicates, spreading depression is associated with a narrow band of hyperperfusion that is located at the leading edge of a broad brand of hypoperfusion.2,3 Blood-flow measurements in unanesthetized animals have shown that the band of initial hyperperfusion during spreading depression can be as narrow as a few millimeters and may involve a flow that is only 50 percent above the base-line value.3 Given the resolution and signal-to-noise characteristics of our scanner, our ability to detect such increases with a single blood-flow measurement is marginal at best. Transient hyperperfusion, which has occasionally been detected immediately before the onset of spreading hypoperfusion in other studies of migraine,1 may have resulted from a fortuitous acquisition of data before areas of hypoperfusion developed.
The hypoperfusion phase of spreading depression in animals lasts an hour or longer.2 It is the depression of electrical activity that lasts only a few minutes. Our scanner should easily detect the resulting broad band of hypoperfusion moving steadily and concentrically across the brain surface. Images acquired at 15-minute intervals can identify new areas of hypoperfusion but cannot establish exactly when during the preceding 15 minutes any given area first became involved. This effect of discrete temporal sampling accounts for the fact that entire cortical areas appear to have become involved simultaneously rather than sequentially.
Our data clearly demonstrate spreading hypoperfusion during migraine. The potentially complex relation between this hypoperfusion and the symptoms of aura and pain in patients with migraine is an important area of active research.1,2,4 To our knowledge, spreading depression is the only documented cause of spreading hypoperfusion in animals, and we have been unable to formulate any plausible hypothesis other than spreading depression to explain our findings. Despite assertions by others to the contrary, Jasper unambiguously stated that he had seen spreading depression during surgery in human beings.5 The true value of the spreading-depression model of migraine will rest on the validity of the predictions that it brings to clinical practice. If the model eventually fails in this respect, any alternative model will still have to explain the spreading pattern of hypoperfusion that we and others have observed.
5 ReferencesRoger P. Woods, M.D.
Marco Iacoboni, M.D., Ph.D.
John C. Mazziotta, M.D., Ph.D.
UCLA School of Medicine, Los Angeles, CA 900951
Olesen J ,Friberg L ,Olsen TS , et al. Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann Neurol 1990;28:791-798
CrossRef | Web of Science | Medline2
Lauritzen M . Pathophysiology of the migraine aura: the spreading depression theory. Brain 1994;117:199-210
CrossRef | Web of Science | Medline3
Duckrow RB . A brief hypoperfusion precedes spreading depression if nitric oxide synthesis is inhibited. Brain Res 1993;618:190-195
CrossRef | Web of Science | Medline4
Moskowitz MA ,Nozaki K ,Kraig RP . Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms. J Neurosci 1993;13:1167-1177
Web of Science | Medline5
Bures J ,Buresova O . The use of Leão's spreading cortical depression in research on conditioned reflexes. In: Jasper HH, Smirnov GD, eds. The Moscow Colloquium on Electroencephalography of Higher Nervous Activity. Electroencephalogr Clin Neurophysiol 1960;13:359-376
Author/Editor Response
I accept Dr. Rastegar's view that psychological mechanisms influence basic neural mechanisms and that the distinction between psychogenic and neurobiologic mechanisms is not as sharp as was previously believed. On the basis of recent developments in our understanding of the biologic mechanisms of migraine, I suggest that migraine is determined primarily by genetic and other nonpsychogenic mechanisms. This in no way rules out the possibility that psychosocial factors influence the expression of the disease and may lead to periods of exacerbation. Research on these aspects of migraine remains important, but whether we like it or not, doctors tend to view diseases with an established biologic basis differently from those without such a basis.
Dr. Blau repeats his previous criticisms of the hypothesis that cortical spreading depression is the pathophysiologic mechanism of the migraine aura. Many of his points have already been publicly debated, but I will respond to them briefly. First, cortical spreading depression can easily be elicited in conscious animals.1 Second and third, it has been shown repeatedly that in the wake of spreading depression, regional cerebral blood flow remains depressed in large areas of the brain for long periods (e.g., more than one hour in rats) and the reduced flow is followed by delayed hyperperfusion, as in migraine.2 Fourth, the band of hyperperfusion is probably too narrow to be picked up by current imaging techniques for brain blood flow.3 Finally, I do not know how “observant neurosurgeons” would be able to observe spreading depression. It may also easily have been missed by investigators who were not specifically looking for it. Indirect evidence of the existence of cortical spreading depression in humans was documented by Welch and associates in magnetoencephalographic studies,4 and the phenomenon has been demonstrated in human-brain slices.5
The many similarities between cortical spreading depression and migraine with aura have been discussed extensively. The theory is further supported by the study of Woods et al. At present, all we need is direct electrophysiologic confirmation of the occurrence of cortical spreading depression during a migraine aura.
5 ReferencesJes Olesen, M.D.
University of Copenhagen, DK-2600 Glostrup, Denmark1
Bures JO, Buresova O, Krivanek J. The mechanism and applications of Leão's spreading depression of electroencephalographic activity. Prague, Czech Republic: Academia, 1974.
2
Fabricius M ,Lauritzen M . Transient hyperemia succeeds oligemia in the wake of cortical spreading depression. Brain Res 1993;602:350-353
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Olesen J ,Larsen B ,Lauritzen M . Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol 1981;9:344-352
CrossRef | Web of Science | Medline4
Welch KM ,Barkley GL ,Tepley N ,Ramadan NM . Central neurogenic mechanisms of migraine. Neurology 1993;43:Suppl 3:S21-S25
Web of Science | Medline5
Avoli M ,Drapeau C ,Louvel J ,Pumain R ,Olivier A ,Villemure JG . Epileptiform activity induced by low extracellular magnesium in the human cortex maintained in vitro. Ann Neurol 1991;30:589-596
CrossRef | Web of Science | Medline
