- Email: [email protected]
MIGRAINE: A VASOMOTOR INSTABILITY OF THE MENINGEAL CIRCULATION
1136 attack it is apparent that he tissues, and feeling cold:
Dogma Disputed
too was aware
of pallor, lax
"His face is occasionally red, but usually pale, sallow... The tone of the skin is usually poor, with evident wrinkles and folds, but there may be ’puffiness’ or edema of the face, as well as elsewhere. His extremities are usually cold, he complains of
MIGRAINE: A VASOMOTOR INSTABILITY OF THE MENINGEAL CIRCULATION*
feeling chilly..."
Wolff? dismissed Kunkle’s observationthat the Valsalva manoeuvre can accentuate migraine headache and the implication that migraine headache must arise intracranially. Wolff3 maintained that the migraine pain arises solely from extracranial arteries:
J. N. BLAU National Hospitals for Nervous Diseases, Queen Square, London WC1, and Maida Vale, London W9
The current view that the migraine aura arises from spasm of the major cerebral arteries and the ensuing headache from extracranial arterial vasodilatation is examined and refuted. It is proposed that the headache is due to stimulation of nociceptive nerve-endings in the walls of meningeal vessels (arterioles, venules, and particularly the dural venous sinuses); and that the aura arises from calibre changes in meningeal vessels that penetrate the outer cortex, resulting in localised inhibition or excitation. It is suggested that there are two types of migraine patients— vasodilators and vasoconstrictors.
Summary
INTRODUCTION
MIGRAINE pathogenesis is bedevilled by contradictions : thus Wilks’ observed that digital compression of his own carotid artery temporarily relieved his migraine pain, whereas Du Bois Reymond2 noted facial pallor and a constricted superficial temporal artery during his attacks. The current view on migraine pathogenesis is that of, Wolff,3 who summarised 30 years’ experimental evidence in support of the hypothesis that the aura is due to constriction of one of the major cerebral arteries and that the headache is caused by excessive pulsations of the extracranial arteries, specifically the supraorbital, superficial temporal, or occipital vessels. A succinct rebuttal of this hypothesis is given by Friedman.44 .
"Vasodilatation alone, however, cannot explain the painful phase of migraine. Most patients during an attack of migraine turn pale and feel cold, phenomena associated with vasoconstriction rather than vasodilatation. Further, headache is usually aggravated by coughing, straining, or applying the Valsalva test; from this we can infer that a venous component is involved."
"Thus the amplitude of the pulsations of the superficial branches of the external carotid artery closely parallels the intensity of the headache, and reduction in the intensity of the headache is intimately associated with decrease in amplitude of the pulsations. In fact, headache ends when the amplitude of these arteries in sufficiently decreased, whether by means of
ergotamine, epinephrine, or pressure." The crucial piece of evidence on which Wolff’s hypothesis stands or falls is, I suggest, his own tambour recordings of the superficial temporal artery9 (see accompanying figure). It is clear from the tracing that 36-72 h before the onset of migraine-i.e., when the patient is symptom-free-the arterial pulsations are of the same magnitude as when the headache is graded "7+" on a 0-10 scale. The conclusion is inescapable that on this evidence there is no relationship between the temporal-artery pulsation and the presence or absence of headache. Furthermore, as mentioned earlier, attempts to reproduce these tracings have not been successful.5 At the time when carotid angiograms were carried out after the neurosurgeon had dissected the carotid bifurcation under local anaesthesia, Northfieldlo injected histamine into the internal carotid artery of 5 patients, inducing ipsilateral headache. In the same 5 subjects histamine injected into the external carotid artery produced "no headache at all". In summary, the points against extracranial arterial dilatation as a cause of migraine headache are: 1. Clinical features of facial pallor, lax subcutaneous tissues, and patient feeling cold. 2. Wolff’s own tambour recordings during a pain-free period, 36-72 h before an attack.
-
Heyck5 emphasised that tissues of the face and scalp. become lax during attacks, and he was unable to repeat Wolff’s tracings of the superficial-temporal-artery pulsations. These contradictions should at least lead us to question the extracranial hypothesis. There is -a further, intellectual, difficulty in accepting that spasm of one group of vessels followed by vascular dilatation in another territory can account for one and the same attack. ’
Tunis and Wolff’s temporal-artery and during a migraine.
PATHOGENESIS OF HEADACHE IN MIGRAINE
Examination
andRefutation of Wolff’s Extracranial
Hypothesis From Wolff’s6
description
of the
migraineur
in
pulse-wave tracing before
-
an
*Based on a paper presented at a migraine workshop held in November, 1977, at the Wellcome Trust, London.
Note the amplitude of pulse-waves at 36-72 h before and during a "7+" headache: they are the same height. Hence extracranial vasodilatation is unrelated to the headache. (Reproduced, with permission, from M. M. Tunis and H. G. Wolff, Archs Neurol. Psychiat., Chicago, 1953,70, 551. Copyright 1953, American Medical Association.)
1137
Heyck’s failure to reproduce Wolff’s tracings. 4. Histamine injected into the internal carotid artery produced ipsilateral headache, but no headache was experienced when histamine was injected into the external carotid artery in the same patients. 3.
Points in Favour of an Intracranial Origin of Migraine 1. The
symptom-complex of headache, vomiting, and photophobia.-In temporal arteritis when the superficial arteries are inflamed, headache is prominent but gastrointestinal symptoms and photophobia are absent. In meningitis, however, headache, vomiting, and photophobia are cardinal symptoms and signs. By analogy, the headache phase of migraine mimics meningitis’ rather than giant-cell arteritis. 2. Variation
in
intracranial venous pressure.Coughing, sneezing, and bending down, each of which raises the intracranial venous pressure, potentiate the pain in the majority of migraineurs. This observation is derived from case-histories taken between attacks and has not been confirmed in patients during attacks. Furthermore, the Valsalva manoeuvre, which similarly affects the intracranial venous pressure, increases the headache briefly when the subject stops breath-holding.48 The pain mechanism here could be sudden pressure changes in the intracranial venous sinuses or the . effect of increased systemic blood-pressure on intracranial blood-flow. It is noteworthy that the dural venous sinuses have a liberal supply of nociceptive nerve-endings along their whole intracranial course, thus differing from the intracranial arteries, in which pain nerve-endings are restricted to the first few centimetres of origin at the base of the brain. 11 accentuation.-Most patients lie still during attacks because sudden head movement inthe head pain. Jolt accentuation arises intra-
3. Jolt migraine creases
cranially, being a feature of lumbar-puncture headache12 (which is caused by a disturbance of intracranial hydrodynamics) and histamine-induced headache. 13 That histamine headache arises intracranially was proved ingeniously by Pickering,13 who raised the pressure in a pneumatic cuff wound round the top of the head enough to occlude the superficial circulation; the headache was unaffected. 4. Histamine headache simulating migraine.-Von Storch 14 found that histamine headache simulated migraine pain in 33 out of 37 migraineurs. Injections of 0.015-2 mg of histamine induced intense headaches that could persist for hours or days-and with higher doses white and silver light flashes were experienced in the central field of vision.I5 It is not suggested that histamine causes migraine, but this evidence supports the view that migraine is primarily a vascular headache arising inside the skull. 5. Evidence from ocular and conjunctival vessels.Vessels to the optic fundus derive solely from the internal carotid artery through the ophthalmic artery, whereas the conjunctival circulation is an anastomosis of branches from the internal and external carotid arteries. I suggest that the conjunctival vasculature reflects the mcningeal circulation, and this will be discussed later. Surprisingly, vessels of the optic fundus have shown either no significant16 " or only minor variations during migraine attacks (of the order of 14%). Conjunctival vessels, however, do show calibre changes
attacks. Wolff19 noted constriction of vessels during the aura, followed by arteriolar and venular dilatation on the ipsilateral side of the headache. Piovella2O, observed arteriolar and venular dilatation during the aura and further dilatation during the headache phase, although he does not refer to unilaterality. Blau and Davis21 found bilateral constriction in 6 out of 11 subjects and vasodilatation in the remaining 5, all visible vessels-arterioles, capillaries, and venules-being affected. None of our subjects had a classical aura, but like Wolff we noted conjunctival oedema in 3 (2 constrictors and 1 dilator). Further observations22 in subsequent attacks in these subjects and in other patients and volunteers has revealed a consistent conjunctival vascular reaction-i.e., the individual migraineur is either a constrictor or a dilator.
during migraine the conjunctival
These
observations, if confirmed, could explain why
temporal artery dilated and Du Bois Reymond2found his constricted. This suggests a testable hypothesis that dilators would respond to ergot and that constrictors would not respond and might even be made worse by this drug. However, in future experiments arterial Pco2 needs to be monitored to allow for its effect Wilks found his
on
blood-vessels.
6. Evidence for a generalised vasomotor response.Some indications of a generalised vascular reaction during a migraine have been mentioned-namely, facial pallor, lax neck and facial tissues, and cold extremities. Further, in some patients a brisk diuresis can herald the end of an attack or urinary output may be altered during a migraine. Even between attacks, in 8 out of 10 migrainous subjects the hand vessels failed to dilate when a hot stimulus was applied to the chest, whereas ice-cold water applied to the feet provoked normal handvessel constriction.23 (This experiment raises the question of a neural mechanism or component in migraine pathogenesis that is discussed below.) If the microcirculation in hands, feet, face, and kidneys is involved, it seems reasonable that the conjunctival vessels may not be the only ones from an intracranial source that are affected and that meningeal vessels are also reactive in the migraine syndrome. PATHOGENESIS OF MIGRAINE AURA
Does the aura arise from small or large intracranial vessels? There can be little doubt that a hemianopic or dysphasic aura arises from cortical inhibition and that teichopsiae arise from cortical excitation. This view is supported by electroencephalographic changes recorded in 3 patients during visual auras.24 Are these symptoms secondary to calibre changes in major vessels (posterior and middle cerebral arteries have been implicated) or to alteration in size of smaller branches that penetrate the cortex from the pial surface? In 1909 Beevor 2-1 showed that in man these vessels are end-arteries, and more recent electron-microscope studies in the rat demonstrated that they descend to come in direct contact with the neuropil .26 Lashley27 and Airy28 charted the migration of their scotomata and scintillating figures. Lashley27 calculated that 3 mm of cortex/min was involved in the progression of his own visual disturbance. Visual phenomena may travel right across the visual field, and objects may appear coloured, small, large, or distorted.29 These are
1138
features of transient ischsemic attacks that herald a stroke in cerebrovascular disease, where territories of supply by major blood-vessels are affected. 30 I therefore postulate that the cortical disturbances that manifest the aura arise from calibre variation in small vessels of the meninges that penetrate the cortex from without, and that the migration of teichopsiae or
not
arise from slowly migrating vascular changes such as observed on the exposed cortex by Penfield,311 which he likened to "a cloud shadow [that] may be seen to cross the landscape on a sunny day". Why a classical aura lasts only 20-30 minutes, remains unexplained. scotomata
DISCUSSION
therefore, that the migraine symptom-comarises from calibre variation in the leptomeningeal plex circulation, beginning with pial vessels that excite or inhibit the cortex locally to produce teichopsise, scotomata, or other sensory symptoms. This phase is succeeded by a more diffuse alteration in meningeal bloodflow-in arteries, capillaries, veins, and dural venous sinuses. The presence of nociceptive nerve-endings in the walls of these venous channels has been established by direct observation in man and would account for the steady ache that is as common as the throbbing pain. It may even explain the unilaterality of some migraines, because flow in cranial venous sinuses is often lateralised. Further, venous-sinus involvement is in keeping with pain accentuation during coughing, sneezing, and bending as well as sudden head movement. I suggest,
Are Conjunctival and
Meningeal Vessels Equivalent? suggested that the conjunctival and meningeal
I have circulations behave in the same way. This may not be correct: regional blood-flow can vary independently although both circulations have a dual source from the internal and external carotid arteries. It could be significant that so often the migraine pain is felt deeply behind one or both eyes, because Wolff32 clearly demonstrated that electrical stimulation of the floor of the anterior and middle fossae induced pain in and around the ipsilateral eye or temple.
Other DualBiologicalResponses Our observations on conjunctival vessels21 suggest that some patients are "dilators" and some "constrictors". At first sight it seems spurious to invoke divergent vascular reactions in the same condition. However, this is not a new concept-red and white "migraine" feature in the old literature. It is common experience that in anger some people go red and others pale. Another divergent biological reaction is seen in patients with chronic obstructive lung disease where some are "pink and puffing" and others are "blue and bloated". 33 More relevant to migraine is the catecholamine excretion during the anxiety of parachute jumping, when some subjects show an excess of adrenaline and others secrete more noradrenaline: von Euler related this difference to
personality types.34 In the aura phase of migraine some patients show cortical inhibition as with a hemianopia, whereas others manifest cortical excitation with teichopsiae. Another
opposite reaction may be seen before attacks, when some are tired and of the world".
patients
lethargic
and others feel "on top
’
If further observations were to confirm that some migraineurs have constriction and others dilatation of their vessels then we may have a rational explanation why only 50-60% of patients respond to a drug in a trial of a vasoconstrictor, for example. ’
Is Migraine Primarily Vascular, Neural,
or
Biochemical?
A neural basis for migraine is seldom mentioned now, although 90 years ago after discussing vascular and neural theories, Gowers35 agreed with Liveing36 on a neurological explanation. Those clinicians who supported a vasomotor disturbance-which was even then divided into dilator and constrictor changes-were orientated towards a neurogenic theory, as implied by the terms "sympathetico-paralytic" and "sympathetico-
tonic" . 35 Such a controversy is not unique to migraine. Pavlov favoured a neurogenic mechanism and Bayliss a humoral one for gastric secretion: and the two mechanisms have proved to be complementary.3’ And in pancreatic secretion, gastroenterologists nowadays talk about cephalic, gastric, and intestinal phases.38 In migraine a hormonal element must play a part in addition to a vascular and/or neural mechanism, because many women lose their migraine during pregnancy, and women taking the contraceptive pill may have increased attacks. This indicates that a variety of factors influence the threshold of vasomotor reactivity and that other precipitating factors determine whether or not an attack ensues. A primary biochemical mechanism cannot be neglected. Thus, evidence is accumulating that glutamate causes a slow spread of neuronal inhibition across the cerebral. cortex (3 mm/min) after strong stimulation at one point.39 Tyramine ingestion can initiate migraine attacks40 and affect the electroencephalogram.41 A series of pharmacological experiments from Sweden bring together neural and chemical hypotheses.42 Human pial arteries obtained at lobectomy contained adrenergic receptors which included contractile (a) and dilatory (j3) elements. Low doses of acetylcholine dilated and higher concentrations constricted the arteries, both reactions being inhibited by atropine. Furthermore, selective inhibition revealed specific histamine (H2) receptors, and methysergide blocked the constriction induced by 5-hydroxytryptamine. CONCLUSION
The marker
major problem in migraine is our lack of a or a diagnostic test. Hence we are dealing with a symptom-complex without objective support for the diagnosis. The second obstacle is that no observation has been pursued in depth to determine whether the variations are constant or, if they are associated, the extent of the association. The third difficulty is central to all scientific investigations-causality or concomitance. The clinical and experimental observations on patients during a migraine cast doubt on the current belief that the symptoms arise from extracranial vasodilatation. A contrary view has been presented herenamely, that the headache arises from meningeal vessels, particularly the venous sinuses, and that there are two types of migraineur, the vasodilator and the vasoconstrictor. It is argued that earlier observers have taken
1139 or vascular (whether dilator or constrictor) insufficient evidence. I believe that more observations on patients during attacks are required. In studying conjunctival vasculature we noted changes in all our patients during attacks, and in those observed during subsequent attacks these vessel changes were consistent. How do these calibre variations come about? Are they a response to a circulating agent or are they due to neural stimulation? What are the pharmacological reactions of these vessels during and between attacks? Are the vascular changes localised to the conjunctiva a reflection of the meningeal circulation?Can we counteract the vessel reaction; and if so, does this stop the migraine attack or not? If the attacks ceased we could have more effective treatment; if attacks continued then we would be forced to turn our attention to a central neural mechanism. It has been suggested that some migraine auras are so discrete that it is difficult to accept a vascular explanation even if the smallest blood-vessels were implicated.43 Support for a purely neurogenic aetiology derives from the observation that occasionally migraines begin immediately after exposure to a flash of bright light or an unpleasant smell. More than 100 years ago Airy2g concluded his communication to the Royal Society with these words: "Meanwhile our duty is to collect and record facts, in confidence that they will arrange themselves into a theory sooner or later". A century later we still need facts, but now that we have powerful drugs to control vasomotor and autonomic neural reactions, a solution may be within our reach. a
neural
Community Medicine
stance on
I am grateful to Sir George Pickering, F.R.s., for helpful discussion and to Dr R. A. Henson and Prof. J. Marshall for detailed criticism of the manuscript. REFERENCES 1
Wilks, S. Lectures
on
the Diseases of the Nervous
System; p. 553. London,
1883. 2. Du Bois Reymond, E. Arch. Anat. Physiol. 1860, 27, 461. 3. Wolff, H. G. Headache and Other Head Pain; p. 269. Oxford, 1963. 4. Friedman, A. P. in Modern Topics in Migraine (edited by J. Pearce);
p. 162.
London, 1975.
Heyck, H. Neue Beiträge zur Klinik und Pathogenese der Migräne; p. 29. Stuttgart, 1956. 6. Wolff, H. G Headache and Other Head Pain; p. 228. Oxford, 1963. 7. Wolff, H. G. ibid. p. 310. 8. Kunkle, S C. Archs Neurol. Psychiat., Chicago, 1959, 81, 135. 9. Tunis, M M., Wolff, H.G. ibid. 1953, 70, 551. 10. Northfield, D.W. C. Brain, 1938, 61, 133. 11. Wolff, H. G. Headache and Other Head Pain; p. 74. Oxford, 1963. 12. Pickering, G. W. Brain, 1945, 71, 274. 13. Pickering, G. W., Hess, W. Clin. Sci. 1933, 1, 77. 14. Von Storch, J. T. C. Archs Neurol. Psychiat., Chicago, 1940, 44, 316. 15. Best, C. H., McHenry, E. W. Physiol. Rev. 1931, 11, 371. 16. Wolff, H. G. Headache and Other Head Pain, p. 251, Oxford, 1963. 17. Blau, J. N. Unpublished. 18. Hitchings, R., Ide, G., Levy, I. Unpublished. 19. Wolff, H. G. Headache and Other Head Pain; p. 243. Oxford, 1963. 5.
20. Piovella, C. Res. clin Stud. Headache, 1972, 3, 277. 21. Blau, J. N , Davis, E. Lancet, 1970, ii, 740. 22. Davis, E , Green, M. Unpublished. 23. Appenzeller, O, Davison, K., Marshall. J. J. Neurol.
RE-EXAMINATION OF SOME OF THE FRAMINGHAM BLOOD-PRESSURE DATA TERENCE W. ANDERSON
Department of Preventive Medicine and Biostatistics,
University of Toronto, Toronto, Ontario, Canada, M5S 1A8 Mathematical smoothing of data for the Framingham study leads to the conclusion that there is no threshold of normality for blood-pressure. A reasonable therapeutic goal might be "the lower the
Summary
better". However, examination of the unsmoothed Framingham data indicates that while systolic pressures fit this no-threshold model reasonably well, changes in diastolic pressure below about 90 mm Hg have little or no prognostic significance. The poor fit of the diastolic points to the no-threshold model may also help to explain why at Framingham raised systolic pressure seemed to have a greater impact than raised diastolic pressure.
has provided much valuable the effects of hypertension, particularly concerning two questions of considerable practical as well as theoretical importance. First, is there a "normal" level of blood-pressure below which there is no improvement in prognosis? Second, is there any basis for the traditional clinical belief that elevated diastolic pressure is more dangerous than elevated systolic pressure? An investigation by the U.S. Society of Actuariesl indicated a smooth and continuous rise in mortality associated with increasing levels of either systolic or diastolic pressure, and thus no level of blood-pressure that could be used to delineate a boundary between "normotension" and "hypertension". Initially, the data from the Framingham study appeared to be consistent with this belief, and logistic smoothing of the morbidity and mortality curves was chosen as the most appropriate way of summarising the Framingham blood-pressure data 2. By the 18th year of follow-up enough cardiovascular events had occurred at Framingham to provide reasonably narrow 95% confidence limits of the event-rate at THE
Framingham study
information
on
32. Wolff, H. G. Headache and Other Head Pain; p. 60. Oxford, 1963. 33. Dornhorst, A. C. Personal communication. 34. Bloom, G. von Euler, U. S. Frankenhaeuser, M. Acta physiol. scand. 1963,
58, 77.
Neurosurg. Psychiat.
1963, 26, 447 24. Engel, G L., Ferris, E. B., Romano, J. Am. J. med. Sci. 1945, 209, 650. 25. Beevor, C. E. Phil. Trans. R. Soc. B, 1909, 200, 1. 26. Samarasinghe, D.D.J. Anat. 1965, 99, 815. 27. Lashley, K. S. Archs Neurol. Psychiat., Chicago, 1941, 46, 331. 28. Airy, H. Phil. Trans. R. Soc Lond. 1870, 160, 247. 29. Klee, A. in Modern Topics in Migraine (edited by J. Pearce); p. 45. London, 1975. 30. Marshall, J. The Management of Cerebrovascular Disease, p. 123. Oxford, 1976 31. Penfield. W. Ann. intern. med. 1933/34, 7, 303.
35. Gowers, W. R. A Manual of Diseases of the Nervous System; p. 789. London, 1888. 36. Liveing, E. On Megrim, Sick-headaches and Some Allied Disorders: A Contribution to the Pathology of Nerve-storms; p. 335. London, 1837. 37. Gregory, R. A. in The Pursuit of Nature; p. 109. Cambridge, 1977. 38. Wormsley, K.G. Br. J. hosp. Med. 1977, 18, 518. 39. Bradford, H. F. in Biochemistry and Neurology (edited by H. F. Bradford and C. D. Marsden); p. 208. London, 1976. 40 Hanington, E., Harper, A. M. Headache, 1968, 8, 84. 41. Scott, D. F., Moffet, A. M., Swash, A. M. J. Neurol. Neurosurg. Psychiat. 42.
1977, 40, 179. Edvinsson, L., Owman, C. in The Cerebral Vessel Wall (edited by J. CervósNavarro, E. Betz, F. Matakas, and R. Wüllenweber); p. 197. New York,
1976. 43. Wall, P. D. Personal communication.
Dogma Disputed
too was aware
of pallor, lax
"His face is occasionally red, but usually pale, sallow... The tone of the skin is usually poor, with evident wrinkles and folds, but there may be ’puffiness’ or edema of the face, as well as elsewhere. His extremities are usually cold, he complains of
MIGRAINE: A VASOMOTOR INSTABILITY OF THE MENINGEAL CIRCULATION*
feeling chilly..."
Wolff? dismissed Kunkle’s observationthat the Valsalva manoeuvre can accentuate migraine headache and the implication that migraine headache must arise intracranially. Wolff3 maintained that the migraine pain arises solely from extracranial arteries:
J. N. BLAU National Hospitals for Nervous Diseases, Queen Square, London WC1, and Maida Vale, London W9
The current view that the migraine aura arises from spasm of the major cerebral arteries and the ensuing headache from extracranial arterial vasodilatation is examined and refuted. It is proposed that the headache is due to stimulation of nociceptive nerve-endings in the walls of meningeal vessels (arterioles, venules, and particularly the dural venous sinuses); and that the aura arises from calibre changes in meningeal vessels that penetrate the outer cortex, resulting in localised inhibition or excitation. It is suggested that there are two types of migraine patients— vasodilators and vasoconstrictors.
Summary
INTRODUCTION
MIGRAINE pathogenesis is bedevilled by contradictions : thus Wilks’ observed that digital compression of his own carotid artery temporarily relieved his migraine pain, whereas Du Bois Reymond2 noted facial pallor and a constricted superficial temporal artery during his attacks. The current view on migraine pathogenesis is that of, Wolff,3 who summarised 30 years’ experimental evidence in support of the hypothesis that the aura is due to constriction of one of the major cerebral arteries and that the headache is caused by excessive pulsations of the extracranial arteries, specifically the supraorbital, superficial temporal, or occipital vessels. A succinct rebuttal of this hypothesis is given by Friedman.44 .
"Vasodilatation alone, however, cannot explain the painful phase of migraine. Most patients during an attack of migraine turn pale and feel cold, phenomena associated with vasoconstriction rather than vasodilatation. Further, headache is usually aggravated by coughing, straining, or applying the Valsalva test; from this we can infer that a venous component is involved."
"Thus the amplitude of the pulsations of the superficial branches of the external carotid artery closely parallels the intensity of the headache, and reduction in the intensity of the headache is intimately associated with decrease in amplitude of the pulsations. In fact, headache ends when the amplitude of these arteries in sufficiently decreased, whether by means of
ergotamine, epinephrine, or pressure." The crucial piece of evidence on which Wolff’s hypothesis stands or falls is, I suggest, his own tambour recordings of the superficial temporal artery9 (see accompanying figure). It is clear from the tracing that 36-72 h before the onset of migraine-i.e., when the patient is symptom-free-the arterial pulsations are of the same magnitude as when the headache is graded "7+" on a 0-10 scale. The conclusion is inescapable that on this evidence there is no relationship between the temporal-artery pulsation and the presence or absence of headache. Furthermore, as mentioned earlier, attempts to reproduce these tracings have not been successful.5 At the time when carotid angiograms were carried out after the neurosurgeon had dissected the carotid bifurcation under local anaesthesia, Northfieldlo injected histamine into the internal carotid artery of 5 patients, inducing ipsilateral headache. In the same 5 subjects histamine injected into the external carotid artery produced "no headache at all". In summary, the points against extracranial arterial dilatation as a cause of migraine headache are: 1. Clinical features of facial pallor, lax subcutaneous tissues, and patient feeling cold. 2. Wolff’s own tambour recordings during a pain-free period, 36-72 h before an attack.
-
Heyck5 emphasised that tissues of the face and scalp. become lax during attacks, and he was unable to repeat Wolff’s tracings of the superficial-temporal-artery pulsations. These contradictions should at least lead us to question the extracranial hypothesis. There is -a further, intellectual, difficulty in accepting that spasm of one group of vessels followed by vascular dilatation in another territory can account for one and the same attack. ’
Tunis and Wolff’s temporal-artery and during a migraine.
PATHOGENESIS OF HEADACHE IN MIGRAINE
Examination
andRefutation of Wolff’s Extracranial
Hypothesis From Wolff’s6
description
of the
migraineur
in
pulse-wave tracing before
-
an
*Based on a paper presented at a migraine workshop held in November, 1977, at the Wellcome Trust, London.
Note the amplitude of pulse-waves at 36-72 h before and during a "7+" headache: they are the same height. Hence extracranial vasodilatation is unrelated to the headache. (Reproduced, with permission, from M. M. Tunis and H. G. Wolff, Archs Neurol. Psychiat., Chicago, 1953,70, 551. Copyright 1953, American Medical Association.)
1137
Heyck’s failure to reproduce Wolff’s tracings. 4. Histamine injected into the internal carotid artery produced ipsilateral headache, but no headache was experienced when histamine was injected into the external carotid artery in the same patients. 3.
Points in Favour of an Intracranial Origin of Migraine 1. The
symptom-complex of headache, vomiting, and photophobia.-In temporal arteritis when the superficial arteries are inflamed, headache is prominent but gastrointestinal symptoms and photophobia are absent. In meningitis, however, headache, vomiting, and photophobia are cardinal symptoms and signs. By analogy, the headache phase of migraine mimics meningitis’ rather than giant-cell arteritis. 2. Variation
in
intracranial venous pressure.Coughing, sneezing, and bending down, each of which raises the intracranial venous pressure, potentiate the pain in the majority of migraineurs. This observation is derived from case-histories taken between attacks and has not been confirmed in patients during attacks. Furthermore, the Valsalva manoeuvre, which similarly affects the intracranial venous pressure, increases the headache briefly when the subject stops breath-holding.48 The pain mechanism here could be sudden pressure changes in the intracranial venous sinuses or the . effect of increased systemic blood-pressure on intracranial blood-flow. It is noteworthy that the dural venous sinuses have a liberal supply of nociceptive nerve-endings along their whole intracranial course, thus differing from the intracranial arteries, in which pain nerve-endings are restricted to the first few centimetres of origin at the base of the brain. 11 accentuation.-Most patients lie still during attacks because sudden head movement inthe head pain. Jolt accentuation arises intra-
3. Jolt migraine creases
cranially, being a feature of lumbar-puncture headache12 (which is caused by a disturbance of intracranial hydrodynamics) and histamine-induced headache. 13 That histamine headache arises intracranially was proved ingeniously by Pickering,13 who raised the pressure in a pneumatic cuff wound round the top of the head enough to occlude the superficial circulation; the headache was unaffected. 4. Histamine headache simulating migraine.-Von Storch 14 found that histamine headache simulated migraine pain in 33 out of 37 migraineurs. Injections of 0.015-2 mg of histamine induced intense headaches that could persist for hours or days-and with higher doses white and silver light flashes were experienced in the central field of vision.I5 It is not suggested that histamine causes migraine, but this evidence supports the view that migraine is primarily a vascular headache arising inside the skull. 5. Evidence from ocular and conjunctival vessels.Vessels to the optic fundus derive solely from the internal carotid artery through the ophthalmic artery, whereas the conjunctival circulation is an anastomosis of branches from the internal and external carotid arteries. I suggest that the conjunctival vasculature reflects the mcningeal circulation, and this will be discussed later. Surprisingly, vessels of the optic fundus have shown either no significant16 " or only minor variations during migraine attacks (of the order of 14%). Conjunctival vessels, however, do show calibre changes
attacks. Wolff19 noted constriction of vessels during the aura, followed by arteriolar and venular dilatation on the ipsilateral side of the headache. Piovella2O, observed arteriolar and venular dilatation during the aura and further dilatation during the headache phase, although he does not refer to unilaterality. Blau and Davis21 found bilateral constriction in 6 out of 11 subjects and vasodilatation in the remaining 5, all visible vessels-arterioles, capillaries, and venules-being affected. None of our subjects had a classical aura, but like Wolff we noted conjunctival oedema in 3 (2 constrictors and 1 dilator). Further observations22 in subsequent attacks in these subjects and in other patients and volunteers has revealed a consistent conjunctival vascular reaction-i.e., the individual migraineur is either a constrictor or a dilator.
during migraine the conjunctival
These
observations, if confirmed, could explain why
temporal artery dilated and Du Bois Reymond2found his constricted. This suggests a testable hypothesis that dilators would respond to ergot and that constrictors would not respond and might even be made worse by this drug. However, in future experiments arterial Pco2 needs to be monitored to allow for its effect Wilks found his
on
blood-vessels.
6. Evidence for a generalised vasomotor response.Some indications of a generalised vascular reaction during a migraine have been mentioned-namely, facial pallor, lax neck and facial tissues, and cold extremities. Further, in some patients a brisk diuresis can herald the end of an attack or urinary output may be altered during a migraine. Even between attacks, in 8 out of 10 migrainous subjects the hand vessels failed to dilate when a hot stimulus was applied to the chest, whereas ice-cold water applied to the feet provoked normal handvessel constriction.23 (This experiment raises the question of a neural mechanism or component in migraine pathogenesis that is discussed below.) If the microcirculation in hands, feet, face, and kidneys is involved, it seems reasonable that the conjunctival vessels may not be the only ones from an intracranial source that are affected and that meningeal vessels are also reactive in the migraine syndrome. PATHOGENESIS OF MIGRAINE AURA
Does the aura arise from small or large intracranial vessels? There can be little doubt that a hemianopic or dysphasic aura arises from cortical inhibition and that teichopsiae arise from cortical excitation. This view is supported by electroencephalographic changes recorded in 3 patients during visual auras.24 Are these symptoms secondary to calibre changes in major vessels (posterior and middle cerebral arteries have been implicated) or to alteration in size of smaller branches that penetrate the cortex from the pial surface? In 1909 Beevor 2-1 showed that in man these vessels are end-arteries, and more recent electron-microscope studies in the rat demonstrated that they descend to come in direct contact with the neuropil .26 Lashley27 and Airy28 charted the migration of their scotomata and scintillating figures. Lashley27 calculated that 3 mm of cortex/min was involved in the progression of his own visual disturbance. Visual phenomena may travel right across the visual field, and objects may appear coloured, small, large, or distorted.29 These are
1138
features of transient ischsemic attacks that herald a stroke in cerebrovascular disease, where territories of supply by major blood-vessels are affected. 30 I therefore postulate that the cortical disturbances that manifest the aura arise from calibre variation in small vessels of the meninges that penetrate the cortex from without, and that the migration of teichopsiae or
not
arise from slowly migrating vascular changes such as observed on the exposed cortex by Penfield,311 which he likened to "a cloud shadow [that] may be seen to cross the landscape on a sunny day". Why a classical aura lasts only 20-30 minutes, remains unexplained. scotomata
DISCUSSION
therefore, that the migraine symptom-comarises from calibre variation in the leptomeningeal plex circulation, beginning with pial vessels that excite or inhibit the cortex locally to produce teichopsise, scotomata, or other sensory symptoms. This phase is succeeded by a more diffuse alteration in meningeal bloodflow-in arteries, capillaries, veins, and dural venous sinuses. The presence of nociceptive nerve-endings in the walls of these venous channels has been established by direct observation in man and would account for the steady ache that is as common as the throbbing pain. It may even explain the unilaterality of some migraines, because flow in cranial venous sinuses is often lateralised. Further, venous-sinus involvement is in keeping with pain accentuation during coughing, sneezing, and bending as well as sudden head movement. I suggest,
Are Conjunctival and
Meningeal Vessels Equivalent? suggested that the conjunctival and meningeal
I have circulations behave in the same way. This may not be correct: regional blood-flow can vary independently although both circulations have a dual source from the internal and external carotid arteries. It could be significant that so often the migraine pain is felt deeply behind one or both eyes, because Wolff32 clearly demonstrated that electrical stimulation of the floor of the anterior and middle fossae induced pain in and around the ipsilateral eye or temple.
Other DualBiologicalResponses Our observations on conjunctival vessels21 suggest that some patients are "dilators" and some "constrictors". At first sight it seems spurious to invoke divergent vascular reactions in the same condition. However, this is not a new concept-red and white "migraine" feature in the old literature. It is common experience that in anger some people go red and others pale. Another divergent biological reaction is seen in patients with chronic obstructive lung disease where some are "pink and puffing" and others are "blue and bloated". 33 More relevant to migraine is the catecholamine excretion during the anxiety of parachute jumping, when some subjects show an excess of adrenaline and others secrete more noradrenaline: von Euler related this difference to
personality types.34 In the aura phase of migraine some patients show cortical inhibition as with a hemianopia, whereas others manifest cortical excitation with teichopsiae. Another
opposite reaction may be seen before attacks, when some are tired and of the world".
patients
lethargic
and others feel "on top
’
If further observations were to confirm that some migraineurs have constriction and others dilatation of their vessels then we may have a rational explanation why only 50-60% of patients respond to a drug in a trial of a vasoconstrictor, for example. ’
Is Migraine Primarily Vascular, Neural,
or
Biochemical?
A neural basis for migraine is seldom mentioned now, although 90 years ago after discussing vascular and neural theories, Gowers35 agreed with Liveing36 on a neurological explanation. Those clinicians who supported a vasomotor disturbance-which was even then divided into dilator and constrictor changes-were orientated towards a neurogenic theory, as implied by the terms "sympathetico-paralytic" and "sympathetico-
tonic" . 35 Such a controversy is not unique to migraine. Pavlov favoured a neurogenic mechanism and Bayliss a humoral one for gastric secretion: and the two mechanisms have proved to be complementary.3’ And in pancreatic secretion, gastroenterologists nowadays talk about cephalic, gastric, and intestinal phases.38 In migraine a hormonal element must play a part in addition to a vascular and/or neural mechanism, because many women lose their migraine during pregnancy, and women taking the contraceptive pill may have increased attacks. This indicates that a variety of factors influence the threshold of vasomotor reactivity and that other precipitating factors determine whether or not an attack ensues. A primary biochemical mechanism cannot be neglected. Thus, evidence is accumulating that glutamate causes a slow spread of neuronal inhibition across the cerebral. cortex (3 mm/min) after strong stimulation at one point.39 Tyramine ingestion can initiate migraine attacks40 and affect the electroencephalogram.41 A series of pharmacological experiments from Sweden bring together neural and chemical hypotheses.42 Human pial arteries obtained at lobectomy contained adrenergic receptors which included contractile (a) and dilatory (j3) elements. Low doses of acetylcholine dilated and higher concentrations constricted the arteries, both reactions being inhibited by atropine. Furthermore, selective inhibition revealed specific histamine (H2) receptors, and methysergide blocked the constriction induced by 5-hydroxytryptamine. CONCLUSION
The marker
major problem in migraine is our lack of a or a diagnostic test. Hence we are dealing with a symptom-complex without objective support for the diagnosis. The second obstacle is that no observation has been pursued in depth to determine whether the variations are constant or, if they are associated, the extent of the association. The third difficulty is central to all scientific investigations-causality or concomitance. The clinical and experimental observations on patients during a migraine cast doubt on the current belief that the symptoms arise from extracranial vasodilatation. A contrary view has been presented herenamely, that the headache arises from meningeal vessels, particularly the venous sinuses, and that there are two types of migraineur, the vasodilator and the vasoconstrictor. It is argued that earlier observers have taken
1139 or vascular (whether dilator or constrictor) insufficient evidence. I believe that more observations on patients during attacks are required. In studying conjunctival vasculature we noted changes in all our patients during attacks, and in those observed during subsequent attacks these vessel changes were consistent. How do these calibre variations come about? Are they a response to a circulating agent or are they due to neural stimulation? What are the pharmacological reactions of these vessels during and between attacks? Are the vascular changes localised to the conjunctiva a reflection of the meningeal circulation?Can we counteract the vessel reaction; and if so, does this stop the migraine attack or not? If the attacks ceased we could have more effective treatment; if attacks continued then we would be forced to turn our attention to a central neural mechanism. It has been suggested that some migraine auras are so discrete that it is difficult to accept a vascular explanation even if the smallest blood-vessels were implicated.43 Support for a purely neurogenic aetiology derives from the observation that occasionally migraines begin immediately after exposure to a flash of bright light or an unpleasant smell. More than 100 years ago Airy2g concluded his communication to the Royal Society with these words: "Meanwhile our duty is to collect and record facts, in confidence that they will arrange themselves into a theory sooner or later". A century later we still need facts, but now that we have powerful drugs to control vasomotor and autonomic neural reactions, a solution may be within our reach. a
neural
Community Medicine
stance on
I am grateful to Sir George Pickering, F.R.s., for helpful discussion and to Dr R. A. Henson and Prof. J. Marshall for detailed criticism of the manuscript. REFERENCES 1
Wilks, S. Lectures
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Heyck, H. Neue Beiträge zur Klinik und Pathogenese der Migräne; p. 29. Stuttgart, 1956. 6. Wolff, H. G Headache and Other Head Pain; p. 228. Oxford, 1963. 7. Wolff, H. G. ibid. p. 310. 8. Kunkle, S C. Archs Neurol. Psychiat., Chicago, 1959, 81, 135. 9. Tunis, M M., Wolff, H.G. ibid. 1953, 70, 551. 10. Northfield, D.W. C. Brain, 1938, 61, 133. 11. Wolff, H. G. Headache and Other Head Pain; p. 74. Oxford, 1963. 12. Pickering, G. W. Brain, 1945, 71, 274. 13. Pickering, G. W., Hess, W. Clin. Sci. 1933, 1, 77. 14. Von Storch, J. T. C. Archs Neurol. Psychiat., Chicago, 1940, 44, 316. 15. Best, C. H., McHenry, E. W. Physiol. Rev. 1931, 11, 371. 16. Wolff, H. G. Headache and Other Head Pain, p. 251, Oxford, 1963. 17. Blau, J. N. Unpublished. 18. Hitchings, R., Ide, G., Levy, I. Unpublished. 19. Wolff, H. G. Headache and Other Head Pain; p. 243. Oxford, 1963. 5.
20. Piovella, C. Res. clin Stud. Headache, 1972, 3, 277. 21. Blau, J. N , Davis, E. Lancet, 1970, ii, 740. 22. Davis, E , Green, M. Unpublished. 23. Appenzeller, O, Davison, K., Marshall. J. J. Neurol.
RE-EXAMINATION OF SOME OF THE FRAMINGHAM BLOOD-PRESSURE DATA TERENCE W. ANDERSON
Department of Preventive Medicine and Biostatistics,
University of Toronto, Toronto, Ontario, Canada, M5S 1A8 Mathematical smoothing of data for the Framingham study leads to the conclusion that there is no threshold of normality for blood-pressure. A reasonable therapeutic goal might be "the lower the
Summary
better". However, examination of the unsmoothed Framingham data indicates that while systolic pressures fit this no-threshold model reasonably well, changes in diastolic pressure below about 90 mm Hg have little or no prognostic significance. The poor fit of the diastolic points to the no-threshold model may also help to explain why at Framingham raised systolic pressure seemed to have a greater impact than raised diastolic pressure.
has provided much valuable the effects of hypertension, particularly concerning two questions of considerable practical as well as theoretical importance. First, is there a "normal" level of blood-pressure below which there is no improvement in prognosis? Second, is there any basis for the traditional clinical belief that elevated diastolic pressure is more dangerous than elevated systolic pressure? An investigation by the U.S. Society of Actuariesl indicated a smooth and continuous rise in mortality associated with increasing levels of either systolic or diastolic pressure, and thus no level of blood-pressure that could be used to delineate a boundary between "normotension" and "hypertension". Initially, the data from the Framingham study appeared to be consistent with this belief, and logistic smoothing of the morbidity and mortality curves was chosen as the most appropriate way of summarising the Framingham blood-pressure data 2. By the 18th year of follow-up enough cardiovascular events had occurred at Framingham to provide reasonably narrow 95% confidence limits of the event-rate at THE
Framingham study
information
on
32. Wolff, H. G. Headache and Other Head Pain; p. 60. Oxford, 1963. 33. Dornhorst, A. C. Personal communication. 34. Bloom, G. von Euler, U. S. Frankenhaeuser, M. Acta physiol. scand. 1963,
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35. Gowers, W. R. A Manual of Diseases of the Nervous System; p. 789. London, 1888. 36. Liveing, E. On Megrim, Sick-headaches and Some Allied Disorders: A Contribution to the Pathology of Nerve-storms; p. 335. London, 1837. 37. Gregory, R. A. in The Pursuit of Nature; p. 109. Cambridge, 1977. 38. Wormsley, K.G. Br. J. hosp. Med. 1977, 18, 518. 39. Bradford, H. F. in Biochemistry and Neurology (edited by H. F. Bradford and C. D. Marsden); p. 208. London, 1976. 40 Hanington, E., Harper, A. M. Headache, 1968, 8, 84. 41. Scott, D. F., Moffet, A. M., Swash, A. M. J. Neurol. Neurosurg. Psychiat. 42.
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