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The EEG in migraine
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ELECTROENCEPHALOGRAPHY AND CLINICAL NEUROPFIYSIOLOGY
THE EEG IN MIGRAINE 1 V. O. G. SMYTHAND A. L. WINTER Burden Neurological Institute, Bristol (Great Britain)
INTRODUCTION
The difficulties in interpreting EEG observations in studies of migraine arise from four sources. 1. Headache, the principal component of the syndrome, is the commonest complaint in most neuro-psychiatric disorders - - and even in normal control populations. 2. The associated signs and symptoms whereby certain types of headache are distinguished as migraine are mostly transient, and subjective-objective corroboration (e.g. of scotoma by perimetry) is rarely possible. 3. Migraine is often associated with other disorders - - epilepsy, head injury, acute or chronic tension - - any of which may themselves be associated with EEG abnormalities. 4. There is no specific sign, amounting to a diagnostic pattern, in the resting interparoxysmal EEG. "Abnormalities" in this condition are matters of degree or extent rather than of kind. These factors make differential diagnosis, statistical analysis and EEG interpretation particularly difficult. In order to obtain unequivocal evidence of association between migraine and any EEG feature it is necessary to study clinical control groups without migraine but with the associated complaints, as well as entirely normal controls, and the patients in all groups should be matched at least for age. The EEG features must be assessed separately and in combination; small anomalies in delta, theta, fast activities and frontal extension of alpha rhythms have all been described as evidence of "abnormality" in relation to migraine, though all these occur frequently in many other conditions, as well as in some normals. For these reasons EEG records should be analysed quantitatively and objectively and the numerical results should be subjected to statistical tests of significance. Statements of percentage abnormality, without reference to control stud1 Report IV on: The EEG of non-epileptic paroxysmal disturbances.
ies, are almost meaningless and can be entirely misleading. For convenience, the evidence relating EEG observations to migraine may be considered under six headings: A1. statistical features characteristic of the interparoxysmal resting records; A2. the statistical analysis of effects of sensory or other activation on interparoxysmal records; B1. features during attacks; B2. the effects of activation during an attack; C. experimental information relating to the aetiology and mechanism of attacks; D. the effects of treatment. MATERIAL
The clinical population used for this survey consisted of 1198 patients aged 15-45 years referred to the out-patient department of the Burden Neurological Institute during 1959-60. The diagnoses of these patients were epilepsy 496, migraine 202, syncopal attacks 177, tension headache or psychoneurosis with headache 144, post-concussional syndrome 97, cerebral tumour 42, miscellaneous 40. Many of these patients were seen on several occasions and all received a complete neuropsychiatric examination as well as EEG studies. A few cases were admitted as in-patients for prolonged or repeated observation and treatment. The diagnosis of migraine was based on criteria similar to those suggested by Dow and Whitty (1947): paroxysmal recurrent headache, without demonstrable structural Jntracranial lesion, accompanied by three of the five following clinical features: 1. family history of similar headache; 2. relief of headache by ergotamine; 3. hemicranial distribution at some stage; 4. association with nausea or vomiting; 5. preceding symptoms of teichopsia, scotoma, hemianopia, paraesthesiae, monoplegic or hemiplegic weakness, or dysphasia. Several patients who satisfied these criteria had other significant clinical features or histories; Electroeneeph. clin. Neurophysiol., 1964, 16:194-202
EEG IN MIGRAINE
e.g., six h a d sustained severe h e a d injuries before the d e v e l o p m e n t o f migraine, one h a d a b l o o d pressure o f 220/130. S u c h cases were n o t included in the migraine g r o u p . A c o n t r o l p o p u l a t i o n o f 66 n o r m a l a d u l t volunteers was also studied, with p a r t i c u l a r reference to the responses e v o k e d by flicker. The g r a n d t o t a l o f the survey material was therefore 1264. METHOD T h e E E G r e c o r d s were o b t a i n e d with a n 8channel i n s t r u m e n t , fitted with an a u t o m a t i c frequency a n a l y s e r o f recent design. I n m a n y patients p o l y g r a p h i c r e c o r d s were also t a k e n to display E K G , G S R a n d respiration. M e a s u r e m e a t s o f the responses t o p h o t i c a c t i v a t i o n were m a d e with the a u t o m a t i c system described b y G o l l a a n d W i n t e r (1959). I n two cases there were o p p o r t u n i t i e s for o b s e r v a t i o n s o f i n t r a c e r e b r a l activity by m e a n s o f c h r o n i c i m p l a n t e d electrodes. I n f o r m a t i o n o b t a i n e d f r o m E E G analyses, t o g e t h e r with t h e clinical observations, were transferred to p u n c h e d c a r d s for statistical analysis, usually b y calculation o f chi-squared, for e s t i m a t i o n o f contingency. OBSERVATIONS
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TABLE I Distribution of abnormalities in resting EEG of patients with migraine EEG analysis Clinical features
Normal
Headache lasting > 6 h lasting < 6 h
Theta Delta Total
72 38
41 18
17 10
130 66
incapacitating not incapacitating
36 74
27* 32
12" 15
75 121
more often than 1 a month less often
83 27
40 19
19 8
142 54
73 40
37 22
23* 4
133 66
Family history: migraine 32 epilepsy 9 mental disease 7 migraine and epilepsy 4 migraine and mental disease 6 mental disease and epilepsy 0
23 4 0 2 1 1
9 3 2 5 0 1
64 16 9 11 7 2
Total No family history
58 52
31 28
20* 7
109 87
Males Females
36 74
21 38
5 22*
62 134
Vomiting None
85 25
48 11
19 8
152 44
Visualsigns None
76 34
28 31"*
16 11
120 76
Under 25 Over 25
28 82
10 49
8 19
46 150
Under 35 Over 35
69 41
39 20
15 12
123 73
Relieved by ergotamine Not relieved by ergotamine
66 50
37 22
0 27**
103 99
Relieved by anti-convulsants 12 Not relieved by anticonvulsants 104
0
27**
39
59
0
163
Length of history: 5 yrs. < 5 yrs.
A I . Statistical features of interparoxysmal rec-
ords Several a u t h o r s ( D o w a n d W h i t t y 1947; Ulett et al. 1952; H e y c h 1956; Selby and L a n c e 1960) have described a b n o r m a l i t i e s o f v a r i o u s types in the E E G o f patients c o m p l a i n i n g o f migraine, t a k e n between attacks. T h e incidence o f r e p o r t ed a b n o r m a l i t y varies f r o m 1 3 - 6 0 per cent, dep e n d i n g on the criteria o f i n t e r p r e t a t i o n as well as o n the d i a g n o s t i c s t a n d a r d s a n d the inclusion o f mixed conditions. F o c a l a b n o r m a l i t i e s are rarely r e p o r t e d ( 3 - 6 % ) . I n this survey a b o u t 43 per cent o f the 202 migraine records c o u l d be d e s c r i b e d as a b n o r m a l by criteria which w o u l d a d m i t E E G " a b n o r m a l i t y " in a b o u t 10 per cent o f a n o r m a l p o p u l a t i o n (Table I). Weil (1952) described as " d y s r h y t h m i c m i g r a i n e " a s y n d r o m e identified b y gross E E G a b n o r m a l i t i e s associated with m i g r a i n o u s headaches, syncope, a n d sometimes d y s p h a s i a in which the c o m p l a i n t d i d not r e s p o n d to a d m i n i s t r a t i o n o f e r g o t a m i n e , b u t did t o anti-convul-
* Anti-chance odds >20:1. ** Anti-chance odds > 100:1. sants. I n the present survey, o u t of 202 patients with migraine there were 39 (19%) w h o s e e m e d to c o n f o r m to this d e s c r i p t i o n clinically a n d p h a r m a c o l o g i c a l l y , b u t o f these only 27 h a d ab-
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V . O . G . SMYTH AND A. L. WINTER
normal resting EEGs. In some, ergotamine was not merely ineffective, but positively exacerbated the headaches. The resting EEG abnormality in these cases was distinctive within the migraine group, consisting of wide-spread and often rhythmic delta activity; this is not, however, diagnostic in any sense, since similar features occur in many other conditions. Of greater significance was the observation that 38 of these 39 "dysrhythmic" migraine cases showed the " H response" of Golla and Winter (1959) (see below: A2). Theta activity was a prominent abnormality in 59 migraine patients (29%). Statistical checks, however, showed no highly significant correlation between this feature and any other aspect of the population, although there was a marginal positive association with the severity of the headaches, and a just significant one with absence of visual disturbance. As in the case of the delta activity, theta rhythm was found equally often in other conditions besides migraine and cannot be regarded as characteristic of this complaint. The majority (60~}'0)of the patients in the normal and theta groups, unlike those in the delta category, responded to administration of ergotamine; this suggests the possibility of a sub-classification based on EEG features combined with responsiveness to drugs. Since this distinction is essentially statistical there are bound to be exceptions, as in the case descrilzed by Tarlau et al. (1961) in which a grossly abnormal EEG with pronounced delta activity was associated with relief by ergotamine. In such cases the possibility of organic disturbance with cerebral vascular mechanisms should always be considered, particularly when the onset of attacks is in later life. Since the incidence of theta rhythm showed no association with age, this feature cannot be considered as evidence of "immatulity", as has been suggested in other conditions. A2. The effects of activation As in other clinical EEG problems, attempts have been made to circumvent the difficulty of interpreting resting records by various methods of activation, particularly rhythmic photicstimulation. Ulett et al. (1953) and Shagass (1954) included some cases with headache in their material, though they were primarily concerned with anxiety states. Golla and Winter (1959) compared
the effects of photic stimulation in 113 cases of typical episodic headache with 50 normal and clinical subjects without this complaint, using an automatic frequency analyser to provide quantitative measures of response at various fixed stimulus frequencies. They discovered a highly significant association between the complaint of migrainous headache and extem/on of theflicker response to flash rates above 20/scc. Only eight of the control subjects showed this effect compared with 108 of the patients with mi~'raine. This type of frequency response (which c m be identified by plotting normalised amplitude-frequency curves, or more simply by deriving numerical ratios from three points on the lrequency histogram) was designated the " H response" to photic stimulation. On the evidence qtoted above the H response is nearly as "diagnostic" of migraine as wave and spike patterns are ol petit maL This procedure has been exteqded to the larger population described above using the same methods of analysis. The result~ are shown in Table II. Of the 202 patients w~lh migraine 191 (95%) gave an H response while only 194 of the other 996 patients (20%) and 9 ol the 66 normals (14%) did so. As in the previous survey, the antichance odds of the association between migraine and the H response are over one million to one. In this population particular attention was paid to the conditions other thin migraine in which an H response was signiticantly frequent (Table liD. The only large clinica' group with an incidence higher than others was the head injuries (64 out of 97, 66%). Six p;atients, all with an H response, had typical migraine, but had also sustained a severe head injt~ry and are inTABLE ii Distribution o f H response in patier~ts and normal controls Analysis o f I EG duringflicker Diagnostic category
Patients with migraine Patients with other complaints Total patients Normal subjects G r a n d total
H response 191
No H r,~sponse I1
Total 202
194 (385)
~t)2 ~S l 3)
996 (1198)
9 394
57 g70
66 1264
Eleetroenceph. clin. Neurophysiol., 1964, 16:194-202
EEG IN MIGRAINE TABLE HI A. Distribution of H response in various clinical conditions Total Migraine Head injury Syncopal attacks Cerebral tumour Tension headache Epilepsy Totals Controls
H response
202 97 177 42 144 496 1158
191 (94.5%) 64 (66%) 26 (14.5%) 6 (14%) 18 (12.5%) 50 00%) 355 (31%)
66
9 (13.5%)
B. Of the remaining 40 cases, 30 showed an H response, as follows
Cerebral angioma Thyrotoxicosis Atypical migraine Hypoglycaernia Acromegaly Coronary thrombosis Subarachnoid haemorrhage Hypertension Meni6re's disease Totals
Total
H response
6 3 3 6 2 2 2 6 10 40
5 3 3 4 2 2 2 6 3 30
cluded in the latter group. Patients with syncopal attacks, cerebral tumour, tension headaches and epilepsy all showed an incidence similar to that of the nolmal controls - - 14 per cent. In the groups containing numbers too small for statistical analysis, the H response was very c o m m o n in the small numbers of cases of cerebral angioma, thyrotoxicosis, acromegaly, coronary thrombosis, subarachnoid haemorrhage, hypertension and atypical migraine, but was less frequent in Meni6re's disease and hypoglycaemia. Together with the head injuries, these miscellaneous conditions account for 104 of the 194 non-migrainous patients with an H response. These results indicate that, as suggested originally, the H response is related to disturbances of vascular or basic metabolic control. The very high incidence of the H response in migrainous patients would thus be an illustration of the tendency for such disturbances to produce migrainous headaches rather than a reflection of the
197
pain syndrome itself. This is borne out by the previously reported persistence of the H response in patients whose headaches were entirely prevented or relieved by treatment. The relation of the H response to head injury is still being investigated in terms of clinical state, severity, fracture, haematoma and so forth. B1. Features during attacks Inevitably, there are few opportunities for taking satisfactory EEGs during a migraine attack. Engel et al. (1944, 1945) reported focal delta activity during the scotoma phase in a few subjects during attacks induced by decompression sickness, and in three subjects with clinical migraine in whom an aura of h o m o a y m o u s hemianopia was followed by contralateral hemicrania. The E E G focus corresponded roughly with the presumed cerebral disturbarlce but was apparent only during the phase of visual deficit. Dow and Whitty (1947) obtained records in thirteen cases during attacks but found no consistent abnormality; the resting features (delta or theta rhythm) tended to be exaggerated during the aura but not during the headache phase. In the present series, focal delta activity was found in two patients during an attack when focal symptoms were also present. Carotid angiograms in these patients were normal, and the resting records showed no delta activity. In one of these patients the delta activity recurred in a subsequent attack and on this occasion was immediately abolished by inhalation of COz (see below: B2 and C). B2. Activation during attacks As previously reported the results of photic activation, in particular the H response, are not measurably different during migraine attacks from the interparoxysmal features. ]'his suggests again that the H effect is associated with the underlying anomalies rather than with their symptomatic expression. As mentioned above and under C, activation by COz has a dramatic effect on the symptoms and local E E G signs in some patients, but this does not influence the H response. Because of their relatively small number and diversity other observations of patients during attacks are repotted in the next section.
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V . O . G . SMYTH AND A. L. WINTER
C. Experimental information On the general and widely accepted hypothesis of vascular and autonomic involvement in migraine, observations have been made of heart rate, respiration, galvanic skin response (GSR) and other variables at rest, during activation and during attacks in a number of patients and control subjects. Contrary to expectation these revealed no characteristic patterns of behaviour, and it must be concluded that the mechanisms underlying migraine are not reflected in peripheral autonomic activity to any major extent. More detailed and accurate measurements are now being made to discover whether any secondorder variables (such as rate of acceleration of pulse, differential latency of conditional GSR) can be detected. Two patients with a history of typical migraine and H response were referred fer psychiatric treatment because of intractable chronic psychoneurotic symptoms. In these cases the treatmeat decided on was multi-focal controlled prefrontal !eucotomy by implanted electrodes (Crow et al. 1961). The implantation consisted of 68 gold electrodes in various brain regions, and these were left in place for periods of up to 3 months. Opportunities were therefore available for extensive study of the intracerebral features of the H response and for measurements of local and general changes in oxygen availability (O2a) as indicated polarographically with reference to any gold electrode and a non-polarisable reference. Topographic analysis of the responses evoked by flicker within the brain showed that, as inferred from conventional scalp analyses, the extension of the response to higher stimulus rates involves a wider participation of different brain regions ralher than an extended characteristic in any particular region. Occipital brain zones only a few millimetres apart displayed highly individual response characteristics in relation to frequency; one zone wouldrespond steadily up to say 14f/'sec, when it became relatively inert while the adjacent zone, previously less responsive, took up the response and maintained a steady following rhythm up to 20 ~,sec. Comparison with intracerebral responses in other patients without migraine shows that, although this is a general feature of intracerebral responses to rhythmic stimulation,
the effect is grossly exaggerated in those with migraine. Observations of Oza within the brain show several types of fluctuation (Cooper et al. 1960, 196 I). In relation to migraine, three of these types of fluctuation appear to be important; those due to cardiac pulsation, the local ch~tnges due to activation, and the spontaneous changes, at about 6/rain, which are considered to i~dicate rhythmic fluctuations in the calibre of inm~cerebral vessels under the combined influence ol local CO2 tension and central vaso-constrict(,," control. Both types of fluctuation vary over a v.,ide range from one brain region to another and are often very local; as in the case of evoked potentials, adjacent regions only a few millime1 res apart often show quite distinctive local patterns. In one migraine patient the cardiac pulsations were extraordinarily large at one electrode i,t the right frontal region - - over twenty times larger than those in other parts of the same brain ,.~r in the brains of other patients. The migrainous laeadaches were localised to this part of the heat. Moreover, in this patient the cardiac pulsations showed two components, indicating two s o u m s of oxygen arriving by separate routes, with ,}~fferent delays; in other words, an anastomosis ~etween two intracerebral arterial supplies. The: relative amplitudes of these two pulses, and to a lesser extent their latencies, varied over a ,vide range in a slow rhythmic pattern, related o the fluctuations in basic Oza level at about ,:,:rain. The amplitude of these cardiac pulsati,?ns was greatly increased by inhalation of 100~I~ Oe, while the magnitude of the 6/rain fluctmtions was not much affected. On the other han,:L, inhalation of 7'~o CO2 abolished the 6/min rl', thins by completely relaxing the cerebral vessels, without affecting the cardiac pulsations. In view of the dramatic effects of CO~ inhalation on certain types of delta acti,, ity (Crow and Winter 1960) and on the headac}~es in some migraine patients, the possibility sh,mld be considered that the mechanism of migrainous headaches is related to the homeostatic processes re;ponsible for the regulation of ctrebral circula:ion. Intracerebral observations demonstrate the lability of vaso-motor tone, and the slow local rhythmic fluctuations suggest "hunting" in a servo-mechanism withconsiderable backlash and Electroenceph. clin. Neuroph),siol., 1964, 16:194-202
EEG IN MIGRAINE
variable loading. These fluctuations are diminished by increase in load (that is by activation, such as sensory stimulation) or by reduction in bias (administration of CO2). Schumacher and Wolff (1941) reported that COz inhalation could abort a headache in the prodromal phase of a migraine attack. In several patients included in this survey inhalation of COz terminated the attack, even when the headache was fully developed and did not respond to ergotamine. The original assumption was that the sensory aura of art attack was due to cerebral vaso-constriction, while the headache was associated with subsequent compensating vasodilatation. It is easy to see why CO2 inhalation might relieve the condition in the constrictive phase, as reported by Schumacher and Wolff, but not so obvious why relief should be obtained by this means in the dilatative phase as reported here. If, however, the remarkably local character of intracerebral vaso-motor control is considered, it seems possible that when local vaso-dilatation has succeeded vaso-constriction with accompanying headache, the inhalation of COz could produce relief by general vaso-dilatation, resulting in shunting of blood from the already fully dilated region, thus reducing the local congestion. The conditions might be particularly liable to disorder in regions relying on anastomosis between two vascular sources. The prime function of cerebral vascular control is the maintenance of neuro-metabolism (as evidenced by the constancy of E E G patterns during changes in blood gas concentration): to this end, coordination along the vascular tree must be of great importance. The local variations are so pronounced and idiosyncratic, and the basic metabolism is so high, that the regulating mechanisms can scarcely cope even with normal physiological emergencies. In most patients the cerebral factor of safety, provided by reserve vascular dilatation, is only about t w o . Although there are no local oxygen stores this is adequate for adaptation to normal changes in posture and cardio-respiratory variations. For example, a series of extrasystoles, producing in effect a reduction to one half in cardiac output for a few seconds, is accompanied by an abrupt fall in O2a in all regions for the first few beats, but the resulting accumulation of CO2 in the
t99
more sluggish circulation quickly dilates the intracerebral blood vessels, resulting in an overswing of O2a sufficient to compensate amply for the few seconds of relative hypoxia. But this is about the limit of the homeostatic reserve; any more prolonged or serious deficit cannot be compensated for intracranially. In considering the limitations of this system as they apply to the problem of migraine, reference may be made to the general theory of control by retroactive operation, the so-called "error-operated feedback servo", in which information from the output of a system is fed back to regulate the input so as to maintain constancy and stability in some essential parameter. This .seems to be precisely the case in the cerebro-vascular system, since the output or product of metabolism (CO2) controis the input (Oz and glucose) and this is performed by a vast multitude of local systems so that minor topical and transient variations are less likely to affect the functional coordination of the whole. The efficacy of such a system depends on a large and constant reserve of the factor to be controlled, and this is of course ensured in normal circumstances by the ample blood supply of the brain. A further consideration is that the overall stability of this system, when subjected to major stresses, must depend on the time and space relations of the local chemovascular feedback circuits. In the case of migraine the possibility arises that lhe differential vascular tone along a cerebral blood vessel may play a significant role. A slight lag or lead in the retroactive regulation could easily set up an instability in which local regions would be alternately congested and anaemic, l'his supposition would explain why either induced vasoconstriction o r dilatation might provide relief even in the same case, by alteration of the "bias" of the system. There is some evidence that, as well as local chemo-vascular controls, there exists a more general regulator, responsible for the bias-setting of large sections of the intracerebral circulation. The suppression of the spontaneous 6Pmin rhythms by sensory activation and by sleep, the action of neurotropic drugs, the regional differences in response to systemic variations, the loose but occasionally significant coupling between the 6/min vascular rhythms and respiraElectroenceph.
olin. Neurophysiol., 1964, 16:194-202
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V . O . G. SMYTH AND A. L. WINTER
tion, all point to intervention by the brain-stem reticular formations. These structures have been implicated conjecturally in nearly all physiological functions, but their participation in human brain activity is admittedly difficult to establish beyond doubt. Nevertheless, as in the analysis of voluntary control of movement, there seems a real possibility that these still rather poorly defined structures exercise a supervisory - - even perhaps an anticipatory - - function in ensuring readiness for adaptation in the cerebral circulation. The clinical association of migraine attacks with mental strain and fatigue could be explained more easily on this supposition, and the peculiar effects of COz inhalation may also be due to the excitatory influence of carbonic acid on the reticular structures (Dell 1958) as well as to its direct action on the cerebral blood vessels.
D. The effects of treatment In this survey all the patients were treated in some way and most (70%) responded as expected to the usual drugs or to anti-convnlsants. As already mentioned here and reported previously, whether effective or not, the administration of anti-migrainous compounds had no effect on the H response in those who showed it, nor did administration of histamine induce an H response in normal volunteers, even when accompanied by headache. Patients in the delta group showed some changes after prolonged administration of anti-convulsant drugs, but in the others there was no correlation with treatment, whether effective or not. Since the EEG is not affected by medication it cannot be used to establish dosage, but therapeutic trials can be considerably abbreviated in some cases by including EEG analysis in the clinical assessments leading to differential diagnosis within the migraine category. For example, patients with migraine whose E E G records show delta rhythm are more likely to be relieved by anti-convulsants than by anti-sympathomimetic compounds. SUMMARY
I. E E G records and clinical observations were obtained from a population of 1264 subjects (age 15-45) comprising 1198 patients and 66 normal adult volunteers. In the clinical group 202 pa-
tients were diagnosed as suffering from migraine, using the criteria of Dow and Whitty (1947). The EEG records were analysed while resting and during ccntrolled activation by flicker, as described by GoUa and Winter (1959). The results of analysis and the clinical observations were correlated by computation of contingency. 2. Of the 202 migraine records 87 (43%)could be described as abnormal while resting. In 27 cases the abnormality consisted in delta rhythm and in 59 in theta rhythm. One patient showed spike and wave patterns. 3. The incidence of delta rhythm was significantly related to the severity of headache, length of history and the family history of migraine. The proportion of women among the patients with delta rhythm was significantly higher than in the whole migraine population. 4. The only significant relation between theta rhythm and clinical features was with absence of visual disturbance, and possibly with severity of headache. 5. There was no association bet~ een age and the resting abnormalities, suggesting that these were not indications of "immaturity". 6. Administration of ergotamirm afforded relief in 66 (57%) of the 116 patients with normal records and in 37 (63%) of those with theta rhythm. On the other hand none of the 27 patients with delta rhythm responded to this drug, but all of these were relieved by anti-convulsant medication, as were another twelve ~ith normal resting records. This group of 39 patients may correspond with the description of "dysrhythmic migraine" (Weil 1952). 7. There was no significant relation between theta rhythm and arty clinical feature except absence of visual disturbance, and possibly severity of headache. 8. The H response to flicker was found in 191 (95%) of the patients with migraine, in 194 (20%) of those with other complaints and in 9 (14%) of the normal controls. There was no stazistical relation between the resting record and incidence of the H response, nor was this affected by medication, whether effective or not. 9. The only large clinical group apart from migraine showing a significantly high incidence of the H response was that of head injuries (66% of 97 cases). Electroeneeph. elin. Neurophysiol., 1964, 16:194-202
201
EEG IN MIGRAINE
10. Polygraphic electrophysiological studies indicate that the mechanisms underlying migraine are not reflected in peripheral autonomic activity to any major extent. I1. Administration of CO2 has a dramatic effect on the symptoms and the LEG signs in some patients but it does not influence the H response. In several patients inhalation of 7% CO2 in O~ terminated the migraine attack even when the headache was fully developed and did not respond to ergotamine. 12. Spatial analysis of the H response with chronic intracerebral electrodes in two patients showed that the typical extension of the evoked responses to higher stimulus rates involves participation of several adjacent brain regions at different frequencies. This corroborates the interpretation of two-channel frequency analysis of scalp records. 13. Observations of oxygen availability (O2a) within the brain in two cases, by means of chronically implanted gold electrodes, suggest that three types of fluctuation appear to be important in relation to migraine: those due to cardiac pulsation, local changes due to activation and the "spontaneous" rhythmic variations at about 6/min. 14. It is suggested that the differential vascular tone along cerebral blood vessels in regions of anastomosis may play a significant role in the manifestation of the migraine attack. 15. The above observations, together with the high incidence and diversity of abncrmalities in resting records and the persistence of the H responses throughout various clinical states and treatments, suggest that migraine may be due to instability of the control system relating vascular tone to cortical activity. Stabilisation may be achieved in about 50 per cent of cases by medication directed toward the central vascular regulation, and in about 20 per cent by modification of cerebral excitability. 16. The EEG features, taken with the high proportion of family histories of migraine, particularly in patients with delta rhythm, suggest that the postulated instabilities are associated with an inborn susceptibility to strain of the cerebrovascular regulatory system. The precise nature of the mechanisms involved and the genetic factors associated with them deserve further investigation.
The LEG and polygraphic records for this survey were made with an electroencephalograph loaned to us by the Mental Health Research Fund, to whom we are deeply grateful. The intracerebral observations were made with a transistorised instrument loaned by Dr. Franklin Offner, to whom also we are much indebted. We also wish to express our great appreciation to Dr. Grey Walter for his constant encouragement, stimulating guidance and enthusiastic support. REFERENCES COOPER, R., CROW, H. J., WALTER, W. G. and WINTER, A. L. Studies of the level of "available oxygen" in human brain. Electroenceph. clin. NeurophysioL, 1960, 12: 760. COOPER, R., CROW, H. J., WALTER, W. G. and WINTER, A. L. Electrical excitability and responses of human cortex in relation to metabolic activity. Electroenceph. clin. Neurophysiol., 1961, 13: 143. CROW, H. J., COOPER, R. and PHILLIPS, D. G. Controlled multifocal frontal leucotomy for psychiatric illness. J. Neurol. Neurosarg. Psychiat., 1961, 24: 353-360. CROW, H. J. and WINTER,A. L. Effects of alerting and CO2 on delta activity. Electroenceph. c//n. NeurophysioL, 1960, 12: 544. DELL, P. C. Humoral effects on the brain stem reticular formation. In H. H. JASPER, L. D. PROCTOR, R. S. KNIGHTON, W. C. NOSHAY and R. T. COSTELLO (Editors), Reticular formation of the brain. Little, Brown and Co., Boston, 1958: 365-379. Dow, D. J. and WHITTY, C. W. M. LEG changes in migraine. Lancet, 1947, 2: 52-54. ENGEL, G. L., FERRIS, E. B. and ROMANC J. Focal electroencephalographic changes during the scotomas of migraine. Amer. J. reed. Sci., 1945, 209: 650-657. ENGEL, G. L., WEBB, J. P., FERRIS, E. B . ROMANO, J., RYDER, H. and BLANKENHORN, M. A. ~ migraine-like syndrome complicating decompress on sickness: scintillating scotomas, focal neurologic signs and headache: clinical and electroencephalographic observations. War Med. (Chicago), 1944, 5: 304. GOLLA, F. L. and WINTER,A. L. Analysis of cerebral responses to flicker in patients complaining of episodic headache. Electroenceph. clin. Neurophvs'iol., 1959, 11: 539-549. HEYCt-I, H. Neue Beitriige zur Klinik und Pathogenese der Migriine. Thieme, Stuttgart, 1956. SCHUMACHER, G. A. and WOLFF, H. G. Experimental studies of headache. Arch. Neurol. Ps~ chiat. (Chic.), 1941, 45: 199-214. SELBY, G. and LANCE, J. W. Observations on 500 cases of migraine and allied vascular headache. J. NeuroL Neurosurg. Psychiat., 1960, 23: 23-32. SHAGASS, C. Clinical significance of the photomyoclonic response in psychiatric patients. Elecrroenceph. clin. Neurophysiol., 1954, 6: 445-453. TARLAU, M., ALLAN, D. F. and POMINA, A. Dysrhythmic migraine with unusual clinical and electroencephalographic features. Electroenceph. clin. Neurophysiol., 1961, 13: 114-116.
Electroenceph. clin. Neurophysiol.,
1964, 16:194-202
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ULETT, G. A., EVANS,D. and O'LEARY, J. L. Survey of EEG findings in 1,000 patients with chief complaint of headache. Electroenceph. c/in. Neurophysiol., 1952, 4: 463-470, ULETT, G. A., GLESOR,G., WINOKUR,G. and LAWLER,A. The EEG and reaction to photic stimulation as an
index of anxiety-proneness. Electroenceph. clin. Neuro-
physioL, 1953, 5: 23-32. WE~L, A. A. EEG findings in a certain type of psychosom a t i c headache: dysrhythmic migraine. Electroenceph. clin. NeurophysioL, 1952, 4: 181-186.
Reference: S~VTH, V. O. G. and ~V[N~FR, A. [. The EEG in migraine. Electroenceph. clin. Neurophysiol., 1964, 16: 194-202.
ELECTROENCEPHALOGRAPHY AND CLINICAL NEUROPFIYSIOLOGY
THE EEG IN MIGRAINE 1 V. O. G. SMYTHAND A. L. WINTER Burden Neurological Institute, Bristol (Great Britain)
INTRODUCTION
The difficulties in interpreting EEG observations in studies of migraine arise from four sources. 1. Headache, the principal component of the syndrome, is the commonest complaint in most neuro-psychiatric disorders - - and even in normal control populations. 2. The associated signs and symptoms whereby certain types of headache are distinguished as migraine are mostly transient, and subjective-objective corroboration (e.g. of scotoma by perimetry) is rarely possible. 3. Migraine is often associated with other disorders - - epilepsy, head injury, acute or chronic tension - - any of which may themselves be associated with EEG abnormalities. 4. There is no specific sign, amounting to a diagnostic pattern, in the resting interparoxysmal EEG. "Abnormalities" in this condition are matters of degree or extent rather than of kind. These factors make differential diagnosis, statistical analysis and EEG interpretation particularly difficult. In order to obtain unequivocal evidence of association between migraine and any EEG feature it is necessary to study clinical control groups without migraine but with the associated complaints, as well as entirely normal controls, and the patients in all groups should be matched at least for age. The EEG features must be assessed separately and in combination; small anomalies in delta, theta, fast activities and frontal extension of alpha rhythms have all been described as evidence of "abnormality" in relation to migraine, though all these occur frequently in many other conditions, as well as in some normals. For these reasons EEG records should be analysed quantitatively and objectively and the numerical results should be subjected to statistical tests of significance. Statements of percentage abnormality, without reference to control stud1 Report IV on: The EEG of non-epileptic paroxysmal disturbances.
ies, are almost meaningless and can be entirely misleading. For convenience, the evidence relating EEG observations to migraine may be considered under six headings: A1. statistical features characteristic of the interparoxysmal resting records; A2. the statistical analysis of effects of sensory or other activation on interparoxysmal records; B1. features during attacks; B2. the effects of activation during an attack; C. experimental information relating to the aetiology and mechanism of attacks; D. the effects of treatment. MATERIAL
The clinical population used for this survey consisted of 1198 patients aged 15-45 years referred to the out-patient department of the Burden Neurological Institute during 1959-60. The diagnoses of these patients were epilepsy 496, migraine 202, syncopal attacks 177, tension headache or psychoneurosis with headache 144, post-concussional syndrome 97, cerebral tumour 42, miscellaneous 40. Many of these patients were seen on several occasions and all received a complete neuropsychiatric examination as well as EEG studies. A few cases were admitted as in-patients for prolonged or repeated observation and treatment. The diagnosis of migraine was based on criteria similar to those suggested by Dow and Whitty (1947): paroxysmal recurrent headache, without demonstrable structural Jntracranial lesion, accompanied by three of the five following clinical features: 1. family history of similar headache; 2. relief of headache by ergotamine; 3. hemicranial distribution at some stage; 4. association with nausea or vomiting; 5. preceding symptoms of teichopsia, scotoma, hemianopia, paraesthesiae, monoplegic or hemiplegic weakness, or dysphasia. Several patients who satisfied these criteria had other significant clinical features or histories; Electroeneeph. clin. Neurophysiol., 1964, 16:194-202
EEG IN MIGRAINE
e.g., six h a d sustained severe h e a d injuries before the d e v e l o p m e n t o f migraine, one h a d a b l o o d pressure o f 220/130. S u c h cases were n o t included in the migraine g r o u p . A c o n t r o l p o p u l a t i o n o f 66 n o r m a l a d u l t volunteers was also studied, with p a r t i c u l a r reference to the responses e v o k e d by flicker. The g r a n d t o t a l o f the survey material was therefore 1264. METHOD T h e E E G r e c o r d s were o b t a i n e d with a n 8channel i n s t r u m e n t , fitted with an a u t o m a t i c frequency a n a l y s e r o f recent design. I n m a n y patients p o l y g r a p h i c r e c o r d s were also t a k e n to display E K G , G S R a n d respiration. M e a s u r e m e a t s o f the responses t o p h o t i c a c t i v a t i o n were m a d e with the a u t o m a t i c system described b y G o l l a a n d W i n t e r (1959). I n two cases there were o p p o r t u n i t i e s for o b s e r v a t i o n s o f i n t r a c e r e b r a l activity by m e a n s o f c h r o n i c i m p l a n t e d electrodes. I n f o r m a t i o n o b t a i n e d f r o m E E G analyses, t o g e t h e r with t h e clinical observations, were transferred to p u n c h e d c a r d s for statistical analysis, usually b y calculation o f chi-squared, for e s t i m a t i o n o f contingency. OBSERVATIONS
195
TABLE I Distribution of abnormalities in resting EEG of patients with migraine EEG analysis Clinical features
Normal
Headache lasting > 6 h lasting < 6 h
Theta Delta Total
72 38
41 18
17 10
130 66
incapacitating not incapacitating
36 74
27* 32
12" 15
75 121
more often than 1 a month less often
83 27
40 19
19 8
142 54
73 40
37 22
23* 4
133 66
Family history: migraine 32 epilepsy 9 mental disease 7 migraine and epilepsy 4 migraine and mental disease 6 mental disease and epilepsy 0
23 4 0 2 1 1
9 3 2 5 0 1
64 16 9 11 7 2
Total No family history
58 52
31 28
20* 7
109 87
Males Females
36 74
21 38
5 22*
62 134
Vomiting None
85 25
48 11
19 8
152 44
Visualsigns None
76 34
28 31"*
16 11
120 76
Under 25 Over 25
28 82
10 49
8 19
46 150
Under 35 Over 35
69 41
39 20
15 12
123 73
Relieved by ergotamine Not relieved by ergotamine
66 50
37 22
0 27**
103 99
Relieved by anti-convulsants 12 Not relieved by anticonvulsants 104
0
27**
39
59
0
163
Length of history: 5 yrs. < 5 yrs.
A I . Statistical features of interparoxysmal rec-
ords Several a u t h o r s ( D o w a n d W h i t t y 1947; Ulett et al. 1952; H e y c h 1956; Selby and L a n c e 1960) have described a b n o r m a l i t i e s o f v a r i o u s types in the E E G o f patients c o m p l a i n i n g o f migraine, t a k e n between attacks. T h e incidence o f r e p o r t ed a b n o r m a l i t y varies f r o m 1 3 - 6 0 per cent, dep e n d i n g on the criteria o f i n t e r p r e t a t i o n as well as o n the d i a g n o s t i c s t a n d a r d s a n d the inclusion o f mixed conditions. F o c a l a b n o r m a l i t i e s are rarely r e p o r t e d ( 3 - 6 % ) . I n this survey a b o u t 43 per cent o f the 202 migraine records c o u l d be d e s c r i b e d as a b n o r m a l by criteria which w o u l d a d m i t E E G " a b n o r m a l i t y " in a b o u t 10 per cent o f a n o r m a l p o p u l a t i o n (Table I). Weil (1952) described as " d y s r h y t h m i c m i g r a i n e " a s y n d r o m e identified b y gross E E G a b n o r m a l i t i e s associated with m i g r a i n o u s headaches, syncope, a n d sometimes d y s p h a s i a in which the c o m p l a i n t d i d not r e s p o n d to a d m i n i s t r a t i o n o f e r g o t a m i n e , b u t did t o anti-convul-
* Anti-chance odds >20:1. ** Anti-chance odds > 100:1. sants. I n the present survey, o u t of 202 patients with migraine there were 39 (19%) w h o s e e m e d to c o n f o r m to this d e s c r i p t i o n clinically a n d p h a r m a c o l o g i c a l l y , b u t o f these only 27 h a d ab-
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V . O . G . SMYTH AND A. L. WINTER
normal resting EEGs. In some, ergotamine was not merely ineffective, but positively exacerbated the headaches. The resting EEG abnormality in these cases was distinctive within the migraine group, consisting of wide-spread and often rhythmic delta activity; this is not, however, diagnostic in any sense, since similar features occur in many other conditions. Of greater significance was the observation that 38 of these 39 "dysrhythmic" migraine cases showed the " H response" of Golla and Winter (1959) (see below: A2). Theta activity was a prominent abnormality in 59 migraine patients (29%). Statistical checks, however, showed no highly significant correlation between this feature and any other aspect of the population, although there was a marginal positive association with the severity of the headaches, and a just significant one with absence of visual disturbance. As in the case of the delta activity, theta rhythm was found equally often in other conditions besides migraine and cannot be regarded as characteristic of this complaint. The majority (60~}'0)of the patients in the normal and theta groups, unlike those in the delta category, responded to administration of ergotamine; this suggests the possibility of a sub-classification based on EEG features combined with responsiveness to drugs. Since this distinction is essentially statistical there are bound to be exceptions, as in the case descrilzed by Tarlau et al. (1961) in which a grossly abnormal EEG with pronounced delta activity was associated with relief by ergotamine. In such cases the possibility of organic disturbance with cerebral vascular mechanisms should always be considered, particularly when the onset of attacks is in later life. Since the incidence of theta rhythm showed no association with age, this feature cannot be considered as evidence of "immatulity", as has been suggested in other conditions. A2. The effects of activation As in other clinical EEG problems, attempts have been made to circumvent the difficulty of interpreting resting records by various methods of activation, particularly rhythmic photicstimulation. Ulett et al. (1953) and Shagass (1954) included some cases with headache in their material, though they were primarily concerned with anxiety states. Golla and Winter (1959) compared
the effects of photic stimulation in 113 cases of typical episodic headache with 50 normal and clinical subjects without this complaint, using an automatic frequency analyser to provide quantitative measures of response at various fixed stimulus frequencies. They discovered a highly significant association between the complaint of migrainous headache and extem/on of theflicker response to flash rates above 20/scc. Only eight of the control subjects showed this effect compared with 108 of the patients with mi~'raine. This type of frequency response (which c m be identified by plotting normalised amplitude-frequency curves, or more simply by deriving numerical ratios from three points on the lrequency histogram) was designated the " H response" to photic stimulation. On the evidence qtoted above the H response is nearly as "diagnostic" of migraine as wave and spike patterns are ol petit maL This procedure has been exteqded to the larger population described above using the same methods of analysis. The result~ are shown in Table II. Of the 202 patients w~lh migraine 191 (95%) gave an H response while only 194 of the other 996 patients (20%) and 9 ol the 66 normals (14%) did so. As in the previous survey, the antichance odds of the association between migraine and the H response are over one million to one. In this population particular attention was paid to the conditions other thin migraine in which an H response was signiticantly frequent (Table liD. The only large clinica' group with an incidence higher than others was the head injuries (64 out of 97, 66%). Six p;atients, all with an H response, had typical migraine, but had also sustained a severe head injt~ry and are inTABLE ii Distribution o f H response in patier~ts and normal controls Analysis o f I EG duringflicker Diagnostic category
Patients with migraine Patients with other complaints Total patients Normal subjects G r a n d total
H response 191
No H r,~sponse I1
Total 202
194 (385)
~t)2 ~S l 3)
996 (1198)
9 394
57 g70
66 1264
Eleetroenceph. clin. Neurophysiol., 1964, 16:194-202
EEG IN MIGRAINE TABLE HI A. Distribution of H response in various clinical conditions Total Migraine Head injury Syncopal attacks Cerebral tumour Tension headache Epilepsy Totals Controls
H response
202 97 177 42 144 496 1158
191 (94.5%) 64 (66%) 26 (14.5%) 6 (14%) 18 (12.5%) 50 00%) 355 (31%)
66
9 (13.5%)
B. Of the remaining 40 cases, 30 showed an H response, as follows
Cerebral angioma Thyrotoxicosis Atypical migraine Hypoglycaernia Acromegaly Coronary thrombosis Subarachnoid haemorrhage Hypertension Meni6re's disease Totals
Total
H response
6 3 3 6 2 2 2 6 10 40
5 3 3 4 2 2 2 6 3 30
cluded in the latter group. Patients with syncopal attacks, cerebral tumour, tension headaches and epilepsy all showed an incidence similar to that of the nolmal controls - - 14 per cent. In the groups containing numbers too small for statistical analysis, the H response was very c o m m o n in the small numbers of cases of cerebral angioma, thyrotoxicosis, acromegaly, coronary thrombosis, subarachnoid haemorrhage, hypertension and atypical migraine, but was less frequent in Meni6re's disease and hypoglycaemia. Together with the head injuries, these miscellaneous conditions account for 104 of the 194 non-migrainous patients with an H response. These results indicate that, as suggested originally, the H response is related to disturbances of vascular or basic metabolic control. The very high incidence of the H response in migrainous patients would thus be an illustration of the tendency for such disturbances to produce migrainous headaches rather than a reflection of the
197
pain syndrome itself. This is borne out by the previously reported persistence of the H response in patients whose headaches were entirely prevented or relieved by treatment. The relation of the H response to head injury is still being investigated in terms of clinical state, severity, fracture, haematoma and so forth. B1. Features during attacks Inevitably, there are few opportunities for taking satisfactory EEGs during a migraine attack. Engel et al. (1944, 1945) reported focal delta activity during the scotoma phase in a few subjects during attacks induced by decompression sickness, and in three subjects with clinical migraine in whom an aura of h o m o a y m o u s hemianopia was followed by contralateral hemicrania. The E E G focus corresponded roughly with the presumed cerebral disturbarlce but was apparent only during the phase of visual deficit. Dow and Whitty (1947) obtained records in thirteen cases during attacks but found no consistent abnormality; the resting features (delta or theta rhythm) tended to be exaggerated during the aura but not during the headache phase. In the present series, focal delta activity was found in two patients during an attack when focal symptoms were also present. Carotid angiograms in these patients were normal, and the resting records showed no delta activity. In one of these patients the delta activity recurred in a subsequent attack and on this occasion was immediately abolished by inhalation of COz (see below: B2 and C). B2. Activation during attacks As previously reported the results of photic activation, in particular the H response, are not measurably different during migraine attacks from the interparoxysmal features. ]'his suggests again that the H effect is associated with the underlying anomalies rather than with their symptomatic expression. As mentioned above and under C, activation by COz has a dramatic effect on the symptoms and local E E G signs in some patients, but this does not influence the H response. Because of their relatively small number and diversity other observations of patients during attacks are repotted in the next section.
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V . O . G . SMYTH AND A. L. WINTER
C. Experimental information On the general and widely accepted hypothesis of vascular and autonomic involvement in migraine, observations have been made of heart rate, respiration, galvanic skin response (GSR) and other variables at rest, during activation and during attacks in a number of patients and control subjects. Contrary to expectation these revealed no characteristic patterns of behaviour, and it must be concluded that the mechanisms underlying migraine are not reflected in peripheral autonomic activity to any major extent. More detailed and accurate measurements are now being made to discover whether any secondorder variables (such as rate of acceleration of pulse, differential latency of conditional GSR) can be detected. Two patients with a history of typical migraine and H response were referred fer psychiatric treatment because of intractable chronic psychoneurotic symptoms. In these cases the treatmeat decided on was multi-focal controlled prefrontal !eucotomy by implanted electrodes (Crow et al. 1961). The implantation consisted of 68 gold electrodes in various brain regions, and these were left in place for periods of up to 3 months. Opportunities were therefore available for extensive study of the intracerebral features of the H response and for measurements of local and general changes in oxygen availability (O2a) as indicated polarographically with reference to any gold electrode and a non-polarisable reference. Topographic analysis of the responses evoked by flicker within the brain showed that, as inferred from conventional scalp analyses, the extension of the response to higher stimulus rates involves a wider participation of different brain regions ralher than an extended characteristic in any particular region. Occipital brain zones only a few millimetres apart displayed highly individual response characteristics in relation to frequency; one zone wouldrespond steadily up to say 14f/'sec, when it became relatively inert while the adjacent zone, previously less responsive, took up the response and maintained a steady following rhythm up to 20 ~,sec. Comparison with intracerebral responses in other patients without migraine shows that, although this is a general feature of intracerebral responses to rhythmic stimulation,
the effect is grossly exaggerated in those with migraine. Observations of Oza within the brain show several types of fluctuation (Cooper et al. 1960, 196 I). In relation to migraine, three of these types of fluctuation appear to be important; those due to cardiac pulsation, the local ch~tnges due to activation, and the spontaneous changes, at about 6/rain, which are considered to i~dicate rhythmic fluctuations in the calibre of inm~cerebral vessels under the combined influence ol local CO2 tension and central vaso-constrict(,," control. Both types of fluctuation vary over a v.,ide range from one brain region to another and are often very local; as in the case of evoked potentials, adjacent regions only a few millime1 res apart often show quite distinctive local patterns. In one migraine patient the cardiac pulsations were extraordinarily large at one electrode i,t the right frontal region - - over twenty times larger than those in other parts of the same brain ,.~r in the brains of other patients. The migrainous laeadaches were localised to this part of the heat. Moreover, in this patient the cardiac pulsations showed two components, indicating two s o u m s of oxygen arriving by separate routes, with ,}~fferent delays; in other words, an anastomosis ~etween two intracerebral arterial supplies. The: relative amplitudes of these two pulses, and to a lesser extent their latencies, varied over a ,vide range in a slow rhythmic pattern, related o the fluctuations in basic Oza level at about ,:,:rain. The amplitude of these cardiac pulsati,?ns was greatly increased by inhalation of 100~I~ Oe, while the magnitude of the 6/rain fluctmtions was not much affected. On the other han,:L, inhalation of 7'~o CO2 abolished the 6/min rl', thins by completely relaxing the cerebral vessels, without affecting the cardiac pulsations. In view of the dramatic effects of CO~ inhalation on certain types of delta acti,, ity (Crow and Winter 1960) and on the headac}~es in some migraine patients, the possibility sh,mld be considered that the mechanism of migrainous headaches is related to the homeostatic processes re;ponsible for the regulation of ctrebral circula:ion. Intracerebral observations demonstrate the lability of vaso-motor tone, and the slow local rhythmic fluctuations suggest "hunting" in a servo-mechanism withconsiderable backlash and Electroenceph. clin. Neuroph),siol., 1964, 16:194-202
EEG IN MIGRAINE
variable loading. These fluctuations are diminished by increase in load (that is by activation, such as sensory stimulation) or by reduction in bias (administration of CO2). Schumacher and Wolff (1941) reported that COz inhalation could abort a headache in the prodromal phase of a migraine attack. In several patients included in this survey inhalation of COz terminated the attack, even when the headache was fully developed and did not respond to ergotamine. The original assumption was that the sensory aura of art attack was due to cerebral vaso-constriction, while the headache was associated with subsequent compensating vasodilatation. It is easy to see why CO2 inhalation might relieve the condition in the constrictive phase, as reported by Schumacher and Wolff, but not so obvious why relief should be obtained by this means in the dilatative phase as reported here. If, however, the remarkably local character of intracerebral vaso-motor control is considered, it seems possible that when local vaso-dilatation has succeeded vaso-constriction with accompanying headache, the inhalation of COz could produce relief by general vaso-dilatation, resulting in shunting of blood from the already fully dilated region, thus reducing the local congestion. The conditions might be particularly liable to disorder in regions relying on anastomosis between two vascular sources. The prime function of cerebral vascular control is the maintenance of neuro-metabolism (as evidenced by the constancy of E E G patterns during changes in blood gas concentration): to this end, coordination along the vascular tree must be of great importance. The local variations are so pronounced and idiosyncratic, and the basic metabolism is so high, that the regulating mechanisms can scarcely cope even with normal physiological emergencies. In most patients the cerebral factor of safety, provided by reserve vascular dilatation, is only about t w o . Although there are no local oxygen stores this is adequate for adaptation to normal changes in posture and cardio-respiratory variations. For example, a series of extrasystoles, producing in effect a reduction to one half in cardiac output for a few seconds, is accompanied by an abrupt fall in O2a in all regions for the first few beats, but the resulting accumulation of CO2 in the
t99
more sluggish circulation quickly dilates the intracerebral blood vessels, resulting in an overswing of O2a sufficient to compensate amply for the few seconds of relative hypoxia. But this is about the limit of the homeostatic reserve; any more prolonged or serious deficit cannot be compensated for intracranially. In considering the limitations of this system as they apply to the problem of migraine, reference may be made to the general theory of control by retroactive operation, the so-called "error-operated feedback servo", in which information from the output of a system is fed back to regulate the input so as to maintain constancy and stability in some essential parameter. This .seems to be precisely the case in the cerebro-vascular system, since the output or product of metabolism (CO2) controis the input (Oz and glucose) and this is performed by a vast multitude of local systems so that minor topical and transient variations are less likely to affect the functional coordination of the whole. The efficacy of such a system depends on a large and constant reserve of the factor to be controlled, and this is of course ensured in normal circumstances by the ample blood supply of the brain. A further consideration is that the overall stability of this system, when subjected to major stresses, must depend on the time and space relations of the local chemovascular feedback circuits. In the case of migraine the possibility arises that lhe differential vascular tone along a cerebral blood vessel may play a significant role. A slight lag or lead in the retroactive regulation could easily set up an instability in which local regions would be alternately congested and anaemic, l'his supposition would explain why either induced vasoconstriction o r dilatation might provide relief even in the same case, by alteration of the "bias" of the system. There is some evidence that, as well as local chemo-vascular controls, there exists a more general regulator, responsible for the bias-setting of large sections of the intracerebral circulation. The suppression of the spontaneous 6Pmin rhythms by sensory activation and by sleep, the action of neurotropic drugs, the regional differences in response to systemic variations, the loose but occasionally significant coupling between the 6/min vascular rhythms and respiraElectroenceph.
olin. Neurophysiol., 1964, 16:194-202
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V . O . G. SMYTH AND A. L. WINTER
tion, all point to intervention by the brain-stem reticular formations. These structures have been implicated conjecturally in nearly all physiological functions, but their participation in human brain activity is admittedly difficult to establish beyond doubt. Nevertheless, as in the analysis of voluntary control of movement, there seems a real possibility that these still rather poorly defined structures exercise a supervisory - - even perhaps an anticipatory - - function in ensuring readiness for adaptation in the cerebral circulation. The clinical association of migraine attacks with mental strain and fatigue could be explained more easily on this supposition, and the peculiar effects of COz inhalation may also be due to the excitatory influence of carbonic acid on the reticular structures (Dell 1958) as well as to its direct action on the cerebral blood vessels.
D. The effects of treatment In this survey all the patients were treated in some way and most (70%) responded as expected to the usual drugs or to anti-convnlsants. As already mentioned here and reported previously, whether effective or not, the administration of anti-migrainous compounds had no effect on the H response in those who showed it, nor did administration of histamine induce an H response in normal volunteers, even when accompanied by headache. Patients in the delta group showed some changes after prolonged administration of anti-convulsant drugs, but in the others there was no correlation with treatment, whether effective or not. Since the EEG is not affected by medication it cannot be used to establish dosage, but therapeutic trials can be considerably abbreviated in some cases by including EEG analysis in the clinical assessments leading to differential diagnosis within the migraine category. For example, patients with migraine whose E E G records show delta rhythm are more likely to be relieved by anti-convulsants than by anti-sympathomimetic compounds. SUMMARY
I. E E G records and clinical observations were obtained from a population of 1264 subjects (age 15-45) comprising 1198 patients and 66 normal adult volunteers. In the clinical group 202 pa-
tients were diagnosed as suffering from migraine, using the criteria of Dow and Whitty (1947). The EEG records were analysed while resting and during ccntrolled activation by flicker, as described by GoUa and Winter (1959). The results of analysis and the clinical observations were correlated by computation of contingency. 2. Of the 202 migraine records 87 (43%)could be described as abnormal while resting. In 27 cases the abnormality consisted in delta rhythm and in 59 in theta rhythm. One patient showed spike and wave patterns. 3. The incidence of delta rhythm was significantly related to the severity of headache, length of history and the family history of migraine. The proportion of women among the patients with delta rhythm was significantly higher than in the whole migraine population. 4. The only significant relation between theta rhythm and clinical features was with absence of visual disturbance, and possibly with severity of headache. 5. There was no association bet~ een age and the resting abnormalities, suggesting that these were not indications of "immaturity". 6. Administration of ergotamirm afforded relief in 66 (57%) of the 116 patients with normal records and in 37 (63%) of those with theta rhythm. On the other hand none of the 27 patients with delta rhythm responded to this drug, but all of these were relieved by anti-convulsant medication, as were another twelve ~ith normal resting records. This group of 39 patients may correspond with the description of "dysrhythmic migraine" (Weil 1952). 7. There was no significant relation between theta rhythm and arty clinical feature except absence of visual disturbance, and possibly severity of headache. 8. The H response to flicker was found in 191 (95%) of the patients with migraine, in 194 (20%) of those with other complaints and in 9 (14%) of the normal controls. There was no stazistical relation between the resting record and incidence of the H response, nor was this affected by medication, whether effective or not. 9. The only large clinical group apart from migraine showing a significantly high incidence of the H response was that of head injuries (66% of 97 cases). Electroeneeph. elin. Neurophysiol., 1964, 16:194-202
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10. Polygraphic electrophysiological studies indicate that the mechanisms underlying migraine are not reflected in peripheral autonomic activity to any major extent. I1. Administration of CO2 has a dramatic effect on the symptoms and the LEG signs in some patients but it does not influence the H response. In several patients inhalation of 7% CO2 in O~ terminated the migraine attack even when the headache was fully developed and did not respond to ergotamine. 12. Spatial analysis of the H response with chronic intracerebral electrodes in two patients showed that the typical extension of the evoked responses to higher stimulus rates involves participation of several adjacent brain regions at different frequencies. This corroborates the interpretation of two-channel frequency analysis of scalp records. 13. Observations of oxygen availability (O2a) within the brain in two cases, by means of chronically implanted gold electrodes, suggest that three types of fluctuation appear to be important in relation to migraine: those due to cardiac pulsation, local changes due to activation and the "spontaneous" rhythmic variations at about 6/min. 14. It is suggested that the differential vascular tone along cerebral blood vessels in regions of anastomosis may play a significant role in the manifestation of the migraine attack. 15. The above observations, together with the high incidence and diversity of abncrmalities in resting records and the persistence of the H responses throughout various clinical states and treatments, suggest that migraine may be due to instability of the control system relating vascular tone to cortical activity. Stabilisation may be achieved in about 50 per cent of cases by medication directed toward the central vascular regulation, and in about 20 per cent by modification of cerebral excitability. 16. The EEG features, taken with the high proportion of family histories of migraine, particularly in patients with delta rhythm, suggest that the postulated instabilities are associated with an inborn susceptibility to strain of the cerebrovascular regulatory system. The precise nature of the mechanisms involved and the genetic factors associated with them deserve further investigation.
The LEG and polygraphic records for this survey were made with an electroencephalograph loaned to us by the Mental Health Research Fund, to whom we are deeply grateful. The intracerebral observations were made with a transistorised instrument loaned by Dr. Franklin Offner, to whom also we are much indebted. We also wish to express our great appreciation to Dr. Grey Walter for his constant encouragement, stimulating guidance and enthusiastic support. REFERENCES COOPER, R., CROW, H. J., WALTER, W. G. and WINTER, A. L. Studies of the level of "available oxygen" in human brain. Electroenceph. clin. NeurophysioL, 1960, 12: 760. COOPER, R., CROW, H. J., WALTER, W. G. and WINTER, A. L. Electrical excitability and responses of human cortex in relation to metabolic activity. Electroenceph. clin. Neurophysiol., 1961, 13: 143. CROW, H. J., COOPER, R. and PHILLIPS, D. G. Controlled multifocal frontal leucotomy for psychiatric illness. J. Neurol. Neurosarg. Psychiat., 1961, 24: 353-360. CROW, H. J. and WINTER,A. L. Effects of alerting and CO2 on delta activity. Electroenceph. c//n. NeurophysioL, 1960, 12: 544. DELL, P. C. Humoral effects on the brain stem reticular formation. In H. H. JASPER, L. D. PROCTOR, R. S. KNIGHTON, W. C. NOSHAY and R. T. COSTELLO (Editors), Reticular formation of the brain. Little, Brown and Co., Boston, 1958: 365-379. Dow, D. J. and WHITTY, C. W. M. LEG changes in migraine. Lancet, 1947, 2: 52-54. ENGEL, G. L., FERRIS, E. B. and ROMANC J. Focal electroencephalographic changes during the scotomas of migraine. Amer. J. reed. Sci., 1945, 209: 650-657. ENGEL, G. L., WEBB, J. P., FERRIS, E. B . ROMANO, J., RYDER, H. and BLANKENHORN, M. A. ~ migraine-like syndrome complicating decompress on sickness: scintillating scotomas, focal neurologic signs and headache: clinical and electroencephalographic observations. War Med. (Chicago), 1944, 5: 304. GOLLA, F. L. and WINTER,A. L. Analysis of cerebral responses to flicker in patients complaining of episodic headache. Electroenceph. clin. Neurophvs'iol., 1959, 11: 539-549. HEYCt-I, H. Neue Beitriige zur Klinik und Pathogenese der Migriine. Thieme, Stuttgart, 1956. SCHUMACHER, G. A. and WOLFF, H. G. Experimental studies of headache. Arch. Neurol. Ps~ chiat. (Chic.), 1941, 45: 199-214. SELBY, G. and LANCE, J. W. Observations on 500 cases of migraine and allied vascular headache. J. NeuroL Neurosurg. Psychiat., 1960, 23: 23-32. SHAGASS, C. Clinical significance of the photomyoclonic response in psychiatric patients. Elecrroenceph. clin. Neurophysiol., 1954, 6: 445-453. TARLAU, M., ALLAN, D. F. and POMINA, A. Dysrhythmic migraine with unusual clinical and electroencephalographic features. Electroenceph. clin. Neurophysiol., 1961, 13: 114-116.
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Reference: S~VTH, V. O. G. and ~V[N~FR, A. [. The EEG in migraine. Electroenceph. clin. Neurophysiol., 1964, 16: 194-202.