J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.47.5.437 on 1 May 1984. Downloaded from Journal ofNeurology, Neurosurgery, and Psychiatry 1984;47:437-442 Occasional review Migraine pathogenesis: the neural hypothesis reexamined JN BLAU From the National Hospitals for Nervous Diseases, Queen Square, and Maida Vale, Northwick Park Hospital, Harrow and City ofLondon Migraine Clinic, London, UK SUMMARY The hypothesis that migraine is a primary neurological disturbance with secondary vascular manifestations is tested by analysing the five phases of migraine attacks and the eight groups of recognised precipitating factors. Accessory evidence from cerebral blood flow and EEG recordings taken during attacks is also considered. The evidence supports the concept that the sensory cortex and hypothalamus could be initiating sites for migraine attacks, and indicates that a neurological mechanism, suggested by Liveing and Gowers 100 years ago, remains viable and needs to be considered in future research. Protected by copyright. A vascular cause for migraine has been accepted for aspect of the patient. The pallor of the surface must several decades, on the assumption that extracranial be due to contraction of the arteries, and the flush- vasodilatation produced the characteristic throbbing ing of the skin due to their dilatation, and it is headache.' The extracranial hypothesis was chal- assumed that a corresponding condition of the ves- lenged because facial pallor is common during mig- sels of the brain is the cause of the derangement of raine episodes and because patients with temporal functions.... According to the other and alternative arteritis do not vomit or have photophobia.2 Subse- explanation of the disease, the primary derangement quent observations revealed that in 49/50 patients is of nerve-cells of the brain. Their function from examined during migraine attacks, some pain arose time to time is disturbed in a peculiar manner, and from the meninges. This site would account for the the visible vaso-motor disturbance is secondary in cardinal symptoms of migraine, headache, vomiting origin". and photophobia, akin to the symptomatology of More recently clinicians supporting a neurological meningitis. cause include Appenzeller,' Bruyn,6 Johnson,7 No one questions that blood vessels are involved Pearce,8 Sjaastad,9 and Ziegler.'0 http://jnnp.bmj.com/ in the migraine process, but the hypothesis proposed here is that the vasomotor features are secondary to Hypothesis neural stimulation. That migraine is a neurogenic disorder is not novel, being favoured 100 years ago Migraine is a primary neurological disturbance with by Liveing and supported by Gowers4 who wrote: secondary vasomotor changes. "Two chief theories have been held regarding the origin of attacks. One is based upon the alteration in EXAMINATION OF HYPOTHESIS the state of the vessels that is so conspicuous in the The hypothesis is tested by analysing the five stages on September 29, 2021 by guest. of migraine attacks, the eight groups of recognised precipitants that induce attacks and evidence from and cerebral blood Address for reprint requests: Dr JN Blau, The National Hospital of electroencephalography (EEG) Nervous Diseases, Queen Sq, London WC1N 3B9, UK flow (CBF) studies carried out during the headache phase of migraine attacks. Received 18 November 1983. Accepted 8 December 1983 Based on a communication delivered to the American Association The five phases of migraine attacks for the Study of Headache held at Washington DC, USA, in June Prodromal symptoms The separation of prod- 1981. romes from the aura"I led me to favour a neurologi- 437 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.47.5.437 on 1 May 1984. Downloaded from 438 Blau cal basis for migraine having previously supported a toms would therefore require spasm sequentially of vasomotor theory.2 None of the prodromes is expl- successive branches on the posterior aspect of the icable on a vascular basis; they are all in the mind or middle cerebral artery without altering the blood arise from the brain. Prodromal symptoms occur supply anteriorly. "How the arrangement could sub- 1-24 hours before the advent of an aura or serve a slow gradual extremely orderly spread of an headache and consist of altered behaviour, mood ischaemic process staggers the imagination".'5 We changes, food craving, particularly for carbohydrate, are forced to agree with Miller Fisher that this yawning, altered bowel frequency, feeling unduly notion is untenable. tired or inappropriately cold. (3) Lashley'6 charted his own migrating teichopsiae A major differential between migraine and other more than 100 times, the slowly enlarging scintillat- headaches is the concomitant alimentary distur- ing arc that "drifts across the visual field" leaving bance; craving before, nausea and vomiting during, normal vision behind. He calculated that this pro- and restricted food tolerance after the headache. cess would transgress the calcarine cortex at a rate of Hence the conclusion in a recent review'2 that "the 3 mm per minute. However, vasospasm or integration of the impulses causing appetite regula- ischaemia could not explain this classic phenomenon tion takes place mainly in the hypothalamus" is according to Miller Fisher, who suggested that only relevant. Further, altered intestinal sympathetic and a "neuro-electric" disturbance comparable with parasympathetic activity results from experimental Leao's"7 spreading depression could provide a poss- destruction of the hypothalamus, whose nuclei have ible explanation. serotonergic, dopaminergic and glucose receptors (4) Finally, Miller Fisher found the arteriographic and even respond to iontophoretic application of evidence obtained during migraine attacks conflict- free fatty acids; each of these chemicals has been ing. implicated in migraine precipitation. The recent suc- Headache Phase Patients carefully questioned say cessful trial of a peripheral dopamine antagonist, their headache is throbbing for some ofthe time, but Protected by copyright. Motilium, in aborting migraine during the pro- it is a steady ache for the remainder of the headache dromal phase'3 is relevant, so is the efficacy of phase. But, even a throbbing pain need not be metoclopramide, a central dopamine antagonist, primarily vascular: a toothache, throbbing or aching, taken early during the headache phase.'4 is not a primary vascular disorder, but a vascular Feeling cold when hungry and warm after a meal response to local inflammation. is a common physiological experience. Impaired Neurological symptoms during the headache temperature control is also closely linked with appe- phase include photophobia, phonophobia, general tite in hypothalamic damaged animals.'2 It may irritability, hypersensitivity to vibration and smells, therefore be significant that many migraineurs com- lack of concentration, sleepiness, yawning, tempera- plain of feeling cold before and during a migraine: ture lability and occasionally patients mention they attempt to get warm and managing to do so increased libido in spite of pain. Clearly more than heralds or accompanies the end of an attack. extracranial vasodilatation is involved but there is The classic aura Most of us have accepted for no way of determining at present whether these many years that at least the aura of migraine must be neural disturbances during the headache phase are vascular in origin. Surprisingly Miller Fisher,'5 one primary or secondary to cerebro-vascular derange- http://jnnp.bmj.com/ of the world's authorities on cerebro-vascular dis- ments, hence further consideration of these symp- ease, has presented compelling arguments why the toms cannot help our analysis. Nevertheless, as dis- aura cannot be explained on a vascular basis: cussed later, experimentally, vascular changes fol- (1) The gradual spread of the visual or other sen- low within milliseconds of metabolic changes in the sory aura taking 10-30 minutes from beginning to cerebral cortex.'8 end does not occur, in his experience, in cerebrovas- Sleep Resolution The fact that sleep, a neurological cular disease-a most telling point bearing in mind event, is the most common way that migraine Miller Fisher's many original contributions and his attacks resolve'9 does not necessarily mean that the on September 29, 2021 by guest. 30 years' experience in this field. underlying migraine process is neurological. How- (2) Miller Fisher's own dissection showed that as ever, looking at the attack as a whole, tiredness and the middle cerebral artery ascends the Rolandic yawning begin as prodromes before the headache fissure it sends branches anteriorly to the motor cor- starts, continue during and persist after the tex and posteriorly to the sensory cortex. Unilateral headache phase, indicating a neurological sub- paraesthesiae without motor involvement beginning stratum to the whole attack. If we add that sleep in the fingers, spreading slowly up the arm and then could have a cerebral and mental restorative func- down the leg, are well recognised as a sensory aura tion,20 and that mental stress or insufficient sleep can in migraine. The slow progression of sensory symp- induce attacks (see next section) then sleep resolu- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.47.5.437 on 1 May 1984. Downloaded from Migraine pathogenesis: the neural hypothesis ree-xamined 439 Protected by copyright. Prodrome Aura Headache Sleep Recovery phase phase Fig Phases and symptoms during complete