ANNOTATIONS m 00 W r\l W W - m m- 2 M 1 u 682 Migraine, Epilepsy, Post-traumat ic Syndromes, and Spreading Depression MIGRAINE was initially considered to be a vascular disorder, but later it was realised that changes in the circulation were secondary to a disturbance of cerebral function. There has been much discussion on the possible links between migraine and epilepsy, and since the cerebral mani- festations of these and certain post- traumatic phenomena have common clinical features, there may be an explanation in a similar underlying disturbance affecting the brain. Migraine In classical migraine, up to a day before the onset of aura or headache, there is often a prodromal phase during which there is tiredness, yawning, feelings of coldness, changes of mood, craving for food and fluid retention. Surely this is not be be explained on a vascular basis, any more than similar symptoms in the recovery period, such as limited food tolerance, tiredness, yawning, mood changes and diuresis. The aura may affect a variety of sensory modalities and take up to 30 minutes to spread, as Gowers suggested, ‘like ripples in a pond into which a stone is thrown’. The phenomenon of sensations spreading up and down the legs is not compatible with the vascular supply to the cortex, and arteriographic evidence is conflicting, with no definite proof of arterial spasm. OLESON’ found that during attacks of migraine provoked by carotid arteriography, injection of xenon133 showed that hypoperfusion was not confined to one major cerebral artery, but spread across the cortex, indicating a process within the cortex. The throbbing which is so characteristic of the headache does not have to be primarily of vascular origin; the pain of toothache, for example, is a vascular response to local inflammation. Evidence is much more in favour of a primary neural disturbance; this is supported by EEG abnormalities found in migraine sufferers, which outlast the headaches by several days and sometimes occur between attacks. Metabolic disorder can also cause vascular changes. BLAU’ suggests that there may be a disturbance in the oxidative pathway of neuronal metabolism involving a number of neurotransmitters, insofar as migraine can be precipitated by anoxia, hypo- glycaemia and alcohol, as well as similar symptom-complexes with headache, nausea, hunger and behavioural changes occurring in non-migrainous subjects. He
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ANNOTATIONS
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Migraine, Epilepsy, Post-traumat ic Syndromes, and Spreading Depress ion MIGRAINE was initially considered to be a vascular disorder, but later it was realised that changes in the circulation were secondary to a disturbance of cerebral function. There has been much discussion on the possible links between migraine and epilepsy, and since the cerebral mani- festations of these and certain post- traumatic phenomena have common clinical features, there may be an explanation in a similar underlying disturbance affecting the brain.
Migraine In classical migraine, up to a day before the onset of aura or headache, there is often a prodromal phase during which there is tiredness, yawning, feelings of coldness, changes of mood, craving for food and fluid retention. Surely this is not be be explained on a vascular basis, any more than similar symptoms in the recovery period, such as limited food tolerance, tiredness, yawning, mood changes and diuresis. The aura may affect
a variety of sensory modalities and take up to 30 minutes to spread, as Gowers suggested, ‘like ripples in a pond into which a stone is thrown’. The phenomenon of sensations spreading up and down the legs is not compatible with the vascular supply to the cortex, and arteriographic evidence is conflicting, with no definite proof of arterial spasm. OLESON’ found that during attacks of migraine provoked by carotid arteriography, injection of xenon133 showed that hypoperfusion was not confined to one major cerebral artery, but spread across the cortex, indicating a process within the cortex. The throbbing which is so characteristic of the headache does not have to be primarily of vascular origin; the pain of toothache, for example, is a vascular response to local inflammation.
Evidence is much more in favour of a primary neural disturbance; this is supported by EEG abnormalities found in migraine sufferers, which outlast the headaches by several days and sometimes occur between attacks. Metabolic disorder can also cause vascular changes. BLAU’ suggests that there may be a disturbance in the oxidative pathway of neuronal metabolism involving a number of neurotransmitters, insofar as migraine can be precipitated by anoxia, hypo- glycaemia and alcohol, as well as similar symptom-complexes with headache, nausea, hunger and behavioural changes occurring in non-migrainous subjects. He
proposes that specific sensory areas of the cortex and hypothalamus can be sites in which attacks of migraine may be initiated. It may well be that the many potentiators of migraine can act through modulation of sympathetic activity by their effect on the noradrenergic system3.
The clustering and periodicity of migraine supports a cerebral mechanism with a varying threshold, such as a recurrent disturbance of hypothalamic activity related to emotional stress via the limbic system. A varying threshold of such a limbic-hypothalamic axis is physiologically comparable to a varying cortical threshold in idiopathic epilepsy, and could explain the clusters of attacks, exacerbations and remissions common to both migraine and epilepsy. If migraine is a reaction to neural mechanisms of varying threshold, then many factors such as stress, hormone levels, contraceptives, dietary amines, food allergies, photic stimulation and noise could lower the threshold and trigger an attack4, as happens in epilepsy.
Epilepsy A possible relationship between migraine and epilepsy has been argued since the days of Jackson and Gowers. There are obvious similarities, such as the aura of migraine and partial epilepsy. BASSER’ found that the incidence of epilepsy and of loss or impairment of consciousness is greater among those with migraine than those with tension headaches, while the incidence of syncope was no different in the two groups. It is certainly possible that migraine, with the associated metabolic changes, and particularly basilar migraine, with its effect on brain- stem function, can be precipitating factors for epileptic seizures. It has been claimed that epilepsy associated with paroxysmal activity in the occipital areas may trigger migrainous phenomena in children6, and frequently there is a family history of migraine among those with benign rolandic epilepsy. Obviously only some forms of epilepsy are likely to be linked to migraine and there is no evidence of an over-all genetic relation- ship, although there is a high incidence of both migraine and true petit ma1 in certain families. Although the relationship may
be coincidental in some people, the incidence of EEG abnormalities among patients with migraine should be noted and the possibility of a common under- lying constitutional liability considered.
Of 100 patients studied by SCHON and BLAU’, 50 per cent suffered from post- ictal headache; 9 per cent also had migraine, and in all but one of these, mild attacks of migraine were precipitated by fits. Post-ictal headaches are similar to migraine headaches in many ways: they are accentuated by coughing, bending and sudden head-movements, and are relieved by sleeping. These headaches may well be related to the vasodilation known to follow seizures. It has been observed that if fits occur during operations under local anaesthesia, pulsations in the pial arteries will disappear over the cerebral hemi- spheres, returning towards the end of the seizure to a greater degree than before. This post-ictal hyperaemia may last in the region of the discharging focus for up to 30 minutes.
Post-traumatic syndromes There also seem to be links between migraine and symptoms precipitated by trauma. Migraine and its neurological manifestations can be triggered by mild trauma: HAAS and SOVNER’ suggest that cerebral arterial spasm is the initial event, induced by sudden traction on arteries at the base of the brain displaced at the time of injury. Then platelet aggregation may occur, with release of serotonin, which with other factors causes increased capillary permeability and oedema.
Transient cortical blindness after minor head-injury is well documented’. Patients are dazed or stunned after the accident, but not unconscious. After 15 to 45 minutes they may say they cannot see and may be restless, disoriented and unsteady for several hours; the pupil reactions to light are normal, which can cause diag- nostic confusion. There may be a family history of migraine, which can be a suggestive finding. The visual phenomenon could be due to interruption of the blood supply to the optic nerves and chiasm, to the effect on the occipital cortex of com- pression of the posterior cerebral arteries against the tentorium, or to local cerebral oedema as a result of focal trauma.
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OKA et al l0 stress that loss of consciousness, amnesia and epilepsy appear to correlate with the severity of the injury to the brain, but that convulsions, nearly always preceded by other symptoms, can occur among infants and young children after trivial head-injuries, without loss of consciousness. Usually these children are under three years of age. The symptoms may raise a suspicion of expanding intracranial haematoma, with a lucid interval after the injury. The symptoms and signs include headache, nausea and vomiting, pallor, somnolence, irritability, restless confusion, stupor and coma, hemiplegia and motor aphasia. These patients make a rapid recovery and are left without any permanent neuro- logical deficit; and tests, including cerebral arteriography, are negative, except for EEGs, which show slow wave activity.
GREENBLATT" found that four of five patients aged nine to 15 years with the benign syndrome of post-traumatic transient cerebral blindness had a migraine or seizure diathesis. HAAS et a/.'' recorded attacks of hemiparesis, somnolence, irritability and vomiting, blindness and brainstem signs after mild head-injuries, which were considered to resemble classical migraine and to be due to similar mechanisms. They mostly occurred in patients under the age of 14 years. Footballer's migraine is another example of migraine occurring after mild trauma to the head as a result of heading the ball.
Spreading depression of Ledo If it is now thought that vascular mechanisms cannot explain some of the clinical manifestations of migraine, epilepsy and head trauma, is there another mechanism which may unite them? Although unproven, it seems that the spreading depression of Lea0 may do so, as suggested by OKA et a/. lo.
BASER' thought that spreading de- pression could be a common link between migraine and epilepsy. The slow and regular progression of the migrainous march, except for its timing, has some similarities with partial epilepsy, and apart from the clinical findings there is an overlap of encephalographic and genetic
features. Studies have led to the idea of a common underlying constitutional liability, leading in some individuals to migraine, in others to epilepsy and occasionally to both conditions in one individual.
Spreading depression was first described by LEAo'~. During studies to explain the electrocorticogram in experimental epilepsy, he found that weak faradic or mechanical stimulation of the exposed cortex of rabbits caused a marked and enduring reduction of spontaneous electrical activity of the cortex, which spreads smoothly over the surface, due to biochemical changes which will be considered later. A discharge, typical of experimental epilepsy, may occur in a region of the cortex when it is reached by a wave of depression, and the depression of cortical activity and the epileptic discharges appeared to be closely related and probably involve the same cortical structures. The progress of the depression was not controlled by the region of origin, as rapid excision of the stimulated area did not stop the response or its spread.
The evidence is that the spread is a cortico-cortical process, and not from the basal ganglia, and recovery takes at least five to 10 minutes. It may spread to the opposite hemisphere if the stimulus is very marked, and it will first affect the region symmetrical to the original stimulus. The depression affects not only spontaneous electrical activity, but also responses to touch, stimulation of afferent nerves and illumination of the retinal4.
A wave of marked vasodilation of the pial vessels and increased blood-flow has been found to travel over the cortex simultaneously with the wave of depression elicited in rabbits by weak electrical or mechanical s t im~la t ion '~ . However, this may be because the experiments were carried out on barbiturate-anaesthetised animals, with cortical blood-flow being reduced because of decreased energy metabolism. Vasodilation did not occur in halothane-anaesthetised animals, and no evidence of elevated perfusion was found during spreading depression. Decreased cortical blood-flow was found for one hour or more after spreading depression had occurred16.
It seems that the spreading depression
of activity in the cerebral cortex is a change of the same nature as that resulting from prolonged interruption of the cir~ulation’~. The capacity to respond with spreading depression or spreading convulsions develops in rabbits between 24 and 30 days after birth; before that the superficial dendritic plexuses, which seem essential to the phenomenon of spreading depression, are not fully developed.
Spreading depression can be trans- formed into spreading convulsions under certain conditions, such as the adminis- tration of coz in inspired air, or treatment of the cortex with acetylcholine or pilocarpine’*. GRAFSTEIN” confirmed in cats that a brief phase of neuronal excitation preceded the spreading depression and the decrease in cortical excitability, with a slow change in the cortical D.C. potential. As the amplitude of the slow negative depression potential is decreased in a region subjected to strong repetitive stimulation, it is suggested that the propagation of spreading depression depends on a substance liberated from neurons during intense activity. It may well that potassium ions ( K + ) play a specific r81e, with the movement of positively charged particles into the interstitial spaces as a result of the initial intense activity, possibly induced by focal brain hypoxia”.
Glial cells may play an important r81e in potassium dynamics2’. They may contribute to buffering the extracellular K + concentration of brain tissue through such means as the ‘spatial buffer mechanism’. This can act to speed the dispersal of local accumulations of potassium and help to prevent spreading depression. A K + efflux from neurons induced when the extracellular K + concentration rises above a critical level is probably crucial in causing this condition. Neuroglia may account for the observed extracellular potential changes, raise the threshold for any stimuli that initiate spreading depression, hasten the rate of progagation, and in some situations exert sufficient stabilising influence on the K + dynamics of the tissue to make it not susceptible to the depression of activity at all. L A S H L E Y ~ ~ , while analysing his own migraine, plotted the march of the flickering sensations followed by profound
scotoma. The propagation is at a rate of about 3mm per minute-the same rate of development and recovery as the spreading depression of LeBo-and is compatible with a spreading excitation and depression of activity at a cortical
Possible links If there are links, the initiator of spread- ing depression could be reduced blood- flow, related to a disturbance of the autonomic nervous system or of platelet function. This may be one explanation for the relief of early symptoms of classical migraine by vasodilators. If spreading depression does occur in migraine, it may release active substances in a chain of events that leads fo vasodilatation and headache, and one r6le of neuroglia in the vertebrate nervous system may be to prevent or minimise migraine. FISHER24 suggests that only a ‘neuro-electric’ disturbance, such as spreading depression, can explain the phenomenon of migraine, and not vasospasm and ischaemia. Spreading depression is not limited to the cortex in animals, but can also affect the hypothalamus and brainstem, so providing an explanation for the start of migraine attacks and certain aspects of the prodromal symptoms and aura4.
The spreading oligaemia shown by LAURITZEN and HANSEN25 to occur in classical migraine (but not in common migraine) does not seem to be the cause of the symptoms, as it occurs both before and after them. They are more likely to be due to a disturbance of tissue function underlying the perfusion changes. The oligaemia in migraine and spreading depression starts in the posterior aspects of the hemisphere and spreads at a velocity of about 2 to 3mm per minute. The hyperfusion is propagated according to the architecture of the cortex, and not the blood supply. There are close similarities, therefore, between classical migraine and spreading depression, and although LAURITZEN’~ admits that there is much still to be learnt, he suggests that classical migraine may be an indication of how spreading depression manifests itself in man. The spread of depression of cortical activity and oligaemia to the motor strip and other areas may also be
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responsible for the clinical epileptic seizures which can be triggered by the classical migraine aura.
It seems likely, therefore, that migraine is a central dysautonomia with related vascular changesz6, probably initiated by a metabolic eventz7. The possible links between migraine and epilepsy cannot be ignored, and there are also a number of common factors between migraine, epilepsy and symptoms occurring after head injury. The only hypothesis so far suggested is the phenomenon of spreading depression, most likely due to the effects of potassium ions on cortical function; and it is of interest that people suffering from disorders of potassium metabolism, such as hypokalaemic periodic paralysis, have a high incidence of migraine2’. However, it must be emphasised that the experimental work has been on animals and is more acceptable to the underlying mechanisms of migraine than to the other conditions. Spreading depression could account for many of the symptoms of migraine, including the pain; this could be due to depolarisation of sensory nerve fibres of the trigeminovascular system and release of substance P, which activates pain mechanisms and increases vascular permeability3. The mechanisms of spreading depression support links between migraine, epilepsy and post traumatic syndromes.
NEIL GORDON Booth Hall Children’s Hospital, Charlesto wn Road, Blackley, Manchester A49 2AA.
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