The Annals of Human Genetics has an archive of material originally published in print format

by the Annals of Eugenics (1925-1954). This material is available in specialised libraries and

archives. We believe there is a clear academic interest in making this historical material more

widely available to a scholarly audience online.

These articles have been made available online, by the Annals of Human Genetics, UCL and

Blackwell Publishing Ltd strictly for historical and academic reasons. The work of

eugenicists was often pervaded by prejudice against racial, ethnic and disabled groups.

Publication of this material online is for scholarly research purposes is not an endorsement or

promotion of the views expressed in any of these articles or eugenics in general. All articles

are published in full, except where necessary to protect individual privacy.

We welcome your comments about this archive and its online publication.

O N T H E I N H E R I T A N C E O F M I G R A I N E : A P R E L I M I N A R Y N O T E

BY JULIA BELL. ( Under the Medical Research Council.)

SYNONYMS : HEMICRANIA, HETEROCRANIA, MEGRIM, ETC.

“It is not a softe shooe that healeth the Gowte.. .nor a crown of Pearle that cureth the meigrim.” Gosso~, 1679.

INTRODUCTORY. THERE appear to be a surprising number of people amongst the lay population who have either never heard of migraine, or only know it by name, or who are frankly sceptical as to whether the disease is not simply a fiction of the imagination on the part of the “nervous” sufferer, who has perhaps over-eaten himself. I am reminded of the late Leonard Guthrie who tells of his small brother screaming from a night terror, and of an unsympathetic nurse who looked in and said

gormandising ! ” Yet migraine has been recognised and distinguished from other forms of head- ache from very early days. Thus Aretaeus the Cappadocian” writing of headaches, says that in certain cases the affection is confined to “the parts on the right side or those on the left solely. . . and the pain does not pass this limit but remains in the half of the head. This is called Hetero- crania, an illness by no means mild, even though it intermits, and although it appears to be slight. For if a t any time it sets in acutely, it occasions unseemly and dreadful symptoms; spasm and distortion of the countenance take place; the eyes either fixed intently like horns, or they are rolled inwardly to this side or to that; vertigo; deep-seated pain of the eyes as far as the meninges; irrestrainable sweat; sudden pain of the tendons, as of one striking with a club (?); nausea; vomiting of bilious matters; collapse of the patient. . . there is much torpor, heaviness of the head, anxiety and ennui. For they flee the light; the darkness soothes their disease; nor can they bear readily to look upon or hear anything agreeable; their sense of smell is vitiated. . .the patients moreover are weary of life and wish to diet.”

Many other interesting references from the early centuries might be given-the condition is usually referred to as hemicrania and it is clear that the chief diagnostic features of the disease have been repeatedly set forth from the second century A.D. till the present day. The earliest reference, known to me, to a headache of hereditary source, is due to the Englishman, Thomas Willis (1621-1675) who writes of certain cases of headache in which a vicious or weak constitution of the affected part is the chief predisposing cause of the malady, and this, he tells us, is sometimes innate and hereditary as appears from the fact that the disease is often handed down from parents to children $. Willis also describes the case of a young woman suffering from hereditary headache.

I take it from Dr Hurst’s extremely interesting S a d 1 Lecture of 1924s that ‘‘ Caelius Aurelianus (A.D. 400) described some of the visual symptoms of the disease and Alexander Trallianus (A.D. 600) the associated disturbances in gastric function; but it was not until 1725 that Vater drew attention to the characteristic hemianopia, and fifty years later that Mirabeau, whilst in prison at Vincennes,

* Believed to have been a contemporary of Galen, born perhaps a little earlier-Galen also refers to Hemicrania. t Ref. No. 1. 1 “EX his priorem quandoque innatam et haereditariam esse inde constat quia morbus a parentibus saepe ad liberos

9 Ref. No. 14.

< L

traducitur.” Ref. No. 3.

39-2

312 ON T H E I N H E R I T A N C E O F M I G R A I N E

wrote the first of the long series of graphic descriptions of the visual phenomena for which the medical profession is indebted to lay victims of migraine.”

Many men of distinction in arts and science are known to have suffered from the disease, of whom I would mention Dr John Fordyce*, Dr Wollaston, Dr Parry of Bath, Du Bois-Reymond, Mr Benjamin Travers the ophthalmologist, Charles Dickens, de Balzac (“ Remember your promise, I pray you, and send me something to rid me of the megreme I have taken in reading the sotteries of these times”)?; Sir George Airy and his son also suffered from migraine, and Sir John Herschel on two occasions experienced the ocular spectra characteristic of the disease, which were in his case unaccompanied by headache. Many of these authors have left descriptions of their cases and have perhaps contributed to the tradition that migraine may justly be regarded as “ the disease of the alert mind.” Dr Hurst says, “in its crippling influence on the work of men and women of the highest intelligence during their years of greatest mental activity, migraine stands alone.” This may be true, but undoubtedly the disease may be associated with all grades of intelligence. Perhaps the poorer and less educated section of the community tend to bear with their migraine, which they find to be a transient if recurrent malady, and thus lead to a selection in the cases which are seen and reported upon.

The following very true and vivid picture of migraine in young children is given by the late Dr Guthrie 1 : “ Migraine is distinguished from other forms of headache by the disorders of vision and sensory disturbance which precede it, macropsia or micropsia, hemianopsia, amblyopia are common; surrounding objects may look steamy or misty, and in movement; dark clouds, flickering lights, fortification spectra may be seen. There may be hallucinations of hearing, taste and smell. Numbness and tingling of the fingers, usually on one side, may occur. There may be difficulty in articulation. . . . The headache in migraine is characterised by its excruciating severity and by the physical prostration which accompanies it. , . . The pain is not invariably unilateral. . . .The prodromata last from a few moments to half an hour and subside as the pain comes on; sometimes they may occur without subsequent headache. The headache increases in intensity for several hours until a t its height, the child lies groaning and whimpering, protesting against the slightest sound, hiding his face from the light. He will not speak above a whisper and sometimes not at all, so that he may be supposed to be unconscious. But he never is unconscious, nor does he ever shriek with pain and grate his teeth as when suffering from meningitis. The extremities are often cold and the patient may shiver.. . .Nausea and refusal of food are common but vomiting is infrequent.. . .The acute symptoms gradually subside, the patient usually falls asleep and wakes hungry, bright and well. He remains so until recurrence which may be a t weekly, monthly or longer intervals. Sufferers from migraine are often physically and mentally active. It is certainly a family affection.” I wonder if Dr Guthrie’s sympathetic account was based on personal experience. Writing on the content of dreams, he says: “In many instances the prominent feature is an elaborate visual hallucination. It is of some gigantic object dimly seen in constant intricate move- ment; a colossal wave, a seething maelstrom, a whirling mazy web and so forth. The phenomena are purely subjective, they do not represent any objects which could have been actually seen in waking hours.. . .They frequently occur in those who suffer from migraine and I would suggest that the hallucination is induced by the visual aura which so commonly precedes an attack of migraines.’, The suggestion is of interest; I have often known cases to be awakened from a heavy sleep by the severity of the characteristic one-sided headache but have never heard of the pro- dromal symptoms impressing the individual through dreams.

* Ref. No. 4. p Ref. No. 2. $ Ref. No. 8. 6 Ref. No. 6.

JULIA BELL 31 3

I do not propose to describe here in any detail the diagnostic signs and symptoms of migraine, but would recommend the interested reader to study Dr Liveing’s book* on the subject, or the more recent paper by Dr Hurst, already referred to, and the extremely interesting papers published by Colonel Elliot in 1932t. Colonel Elliot has been specialising in the treatment of migraine for ten years or more, and has collected information systematically with a view to its subsequent analysis ; I know of no material comparable with this from the point of view of the general description of the disease with all’its varied manifestations based entirely on personal observations. Colonel Elliot says: “There is one thing that strikes one with great force in looking at these data: the migraine attack varies enormously in different people. It may be so severe as to be taken for epilepsy, or it may present itself merely as a sick headache, not always one-sided; or rarely some one or more of the other symptoms may alone be present without any headache. A doubt may be suggested as to whether these are genuine migraine cases. The answer is simple, but conclusive. In quite a number of them an unmistakable migraine attack occurs from time to time in the course of atypical attacks, or again, in early years there may have been true migraine replaced afterwards by abortive attacks or vice versa. The ordinary general conception of migraine is that it is confined to one side of the head; that it is accompanied by nausea and vomiting, by hemianopia, and by zigzags or fortification signs; that it is definitely periodic in recurrence; that it runs a fixed course in each individual case; and that it begins in early life. This is very far from the conception of the disease that these notes give us, as may be gathered from an outline of some of the leading points derived from a consideration of the figures within the series.” Among Colonel Elliot’s 300 patients, 161 had definite one-sided headache; 224 had associated nausea and vomiting; only 55 had hemianopia; 70 patients described zigzags and fortification signs in the fields of vision; other alarming visual troubles were met with in 132 cases. Sir James Mackenzie points out that “the associated symptoms in migraine are mainly those of depressed activity of the nerves affected; when affecting the skin there is anaesthesia; when affecting the muscles there is paresis and loss of power of co-ordination; when affecting the stomach there is a delay in the digestive process, the food taken being rejected long afterwards, undigested; when affecting the brain there is mental lethargy, confusion of ideas and sometimes loss of consciousness; when affecting the sight there is partial blindness. . .we have abundant evidence that the sympathetic nerves are unduly excited during an attack. . . waves of goose-skin, due to stimulation of pilo-motor nerves ; extreme coldness of limited areas due to local contraction of arteries. . . 1.” This very observant physician does not discuss the source of the unconsciousness; may it be due to the severity of the pain, in some cases, or are we to conclude that it is always epileptic in character? Colonel Elliot writes of a history of definite unconsciousness, always described as “a fainting fit ” in eight of his 300 cases. Mackenzie’s note of the delay in the digestive process was beautifully demonstrated in one of Dr Hurst’s patients; she was given an opaque meal for X-ray examination, though on waking she had found a slight attack of migraine beginning; the X-rays revealed a complete absence of peristalsis in the stomach, and at the end of six hours of voluntary starvation, none of the opaque meal had passed through the pylorus into the duodenum.

There are some apparent inconsistencies in the varieties of migraine cases which I find it difficult to explain. One patient will have periodic attacks and will feel a measure of confidence in an interval of immunity following a headache, suggesting that an accumulation of some provocative substance occurs which is eliminated during an attack ; another patient has no definite periodicity, but one attack appears to predispose to another and he feels a sense of insecurity following a

-t Ref. Nos. 18, 19. * Ref. No. 5. $ Ref. No. 7.

314 ON THE I N H E R I T A N C E O F M I G R A I N E

headache. Again, one patient reports that any special effort or excitement or nervous tension will precipitate an attack, but that he has never yet experienced an attack when on holiday or resting after a strenuous period; another patient never fears an attack a t a critical moment, but knows well his liability during a period of relaxation after pressure; the week-ends and holidays are his dangerous times. There seems to me to be some very fundamental difference a t the roots of these varieties, but Colonel Elliot assures me that his patients do sometimes change over from the one type to the other.

ON THE INHERITANCE OF MIGRAINE. Some months ago Colonel Elliot invited my collaboration with him on an investigation into

the inheritance of migraine and its allied conditions; during the accumulation of his material relating to the malady, he had not set out primarily to consider in any detail the family histories of his patients, but it became apparent to him, without any probing for the fact, that the hereditary factor outweighed all other considerations in the etiology of the disease. It is only rarely that the busy practising physician seeks collaboration in this way and is willing to bring together an investigator and his patients with a view to the elucidation of a problem; so great an opportunity could only be grasped with enthusiasm.

This preliminary paper, based on a few cases only, can prove nothing, but it is hoped that the presentation of it will demonstrate the great interest and importance of the problem, and the difficulties which beset the investigator. Information for the main thesis can only accumulate slowly. I have not in my preliminary survey found any large mass of material in the literature bearing on the hereditary aspect of the malady, though the importance of this factor is commonly recognised; the recent stimulus to work on asthma and the allergies is bound to contribute much to our subject, but some parallel investigation starting with the migraine case should be of value.

At the outset we need to consider whether there is any selection in the cases which come to me-they are all Colonel Elliot’s private patients; there is thus some selection of class which may be of importance in respect of individual histories but should have little bearing on the manifesta- tion of the hereditary process. A more important selection arises from the fact that a physician can only invite his patients to come to me and give information about their families; he may tentatively suggest the co-operation of all patients, but all do not respond to the appeal. The more grateful and the more enlightened may respond, the more sensitive may avoid the unpleasant- ness of discussing family ailments; the greatest sufferers may find it extremely painful to talk of the condition a t all, so fearful are they lest the description of their symptoms may induce an attack-and their fears are not altogether unfounded; again, people do not readily reveal the occurrence of epileptoid attacks in themselves or their relatives unless they are seeking aid, yet undoubtedly there is some common determining factor a t the back of migraine and epileptoid states which may lead to the occurrence of the two maladies in the same individual or in the same families; patients with such associations may tend to avoid coming to talk about them. All these possibilities of selection must be borne in mind. I can only add a testimony to the generous disinterestedness, sparing neither trouble nor time, with which those patients who have volunteered to give information have carried out their undertaking; does this statement also involve some temperamental selection on the part of the subjects of my material?

In taking the histories I have sought information concerning the liability to any recurrent malady on the part of members of families, for it is generally recognised that asthma, hay fever, urticaria, eczema, the periodic vomiting of children, also a state resembling epilepsy, all bear some

JULIA B E L L 315

relationship to each other and to migraine; these conditions may be found closely associated in the same individual, or in different members of the same family; the inherited liability has a t the basis of it some factor which may be manifested by any of these conditions, and the cure of one of them not infrequently results in the manifestation of one of the allied symptoms. Ample demonstration of these facts can be seen in the pedigrees given below, to which I shall refer in more detail later. A further allied disease seems to be gout; I had overlooked this, as gout so rarely comes under observation in England to-day, but two of Colonel Elliot’s patients told me that gout had been a very troublesome family complaint with them, and Dr Hurst says, “it is quite clear, from the writings of John Fordyce, Sir Henry Holland and Parry of Bath, that gout and migraine, like gout and asthma, were often associated together”; Fig. 16 below shows the association of gout and hay fever in a history provided by Study*. Why has gout almost entirely disappeared from this country?

Now, having spoken of the diseases known to be allied to migraine I would call attention to an observation which seems to me to be of great interest. I wrote to a medical man working a t a hospital for functional nerve disease, asking whether he came across much migraine amongst his patients; he, and one of his colleagues, replied that they never found it in their cases, and that the personal histories taken were so detailed that they could not fail to have heard of migraine if it had ever occurred. This reply was a surprise to me. It would be of interest to investigate the family histories of these patients and discover whether the apparent immunity belongs to the neurotic individual only, or is also a characteristic, to some extent, of the family from which he comes.

The family histories of migraine and the allied diseases so far obtained include the following, illustrated on the accompanying Plate I.

Fig. 1. 111. 6, aged 36, suffers from migraine, urticaria and gout; she has been liable to migraine as long as she can remember; her attacks appear to come a t irregular intervals and tend to follow a period of strenuous work; they often occur during week-ends and may last as long as three days. At an earlier age vomiting was a prominent feature of the attack, which was of shorter duration than now; headache is now her chief complaint, usually on the right side only; nausea occurs towards the end of the attack; ocular symptoms are not a prominent feature of her case. On her father’s side, 111. 6, has a family history of gout in her father, grandfather and great- grandfather, also of urticaria in her paternal aunt, 11. 4. On her mother’s side multiple cases of migraine, asthma and hay fever have occurred. Thus her mother, 11. 7, has suffered from migraine all her life, but her attacks are less frequent than are those of 111. 6 and occur only about three or four times a year. 11. 7 also has a family history of migraine in her mother, with asthma and hay fever in her father’s side of the family, though her father himself, I. 4, suffered from none of these maladies. I. 5 and I. 7 suffered from asthma; both the children of I. 5 have very bad hay fever every summer; of the children of I. 7 , one is free from complaint, the other, 11. 17, suffers from asthma and a chronic rhinitis. I. 9 is free from complaint but her only son suffers from hay fever. Further cases of hay fever are described in 11. 13, the sister of 11. 7, and in her two sons, 111. 11 and 12.

The main interest of this pedigree lies in the fact that it provides two sibships, 11. 7-14, and 111. 5-7, both parents of which belong to families carrying migraine or its allied disorders.

Fig. 2. Two cases of migraine in a sibship of five. 111. 1, aged 48, has suffered from migraine since the age of 12 years; she cannot remember any long periods when she was free from acute

* Given to Lenz by Dr Study. See Ref. No. 16, p. 361.

316 ON THE I N H E R I T A N C E O F M I G R A I N E

Fg. 2. 1

PLATE I.

-I- -

I I

F 3 4. I

I I I I

Fii 7 I

Fi.3. I

r m 1 6 3

1p

F;g. 10

lW I

JULIA BELL 317

pain and sickness, but her attacks come on irregularly; she may be free for 3 4 months and then, for a time, attacks will be so frequent as to be almost continuous. During the attack 111. 1 sees no zigzags or fortification signs in the field of vision, but describes “ripples, like a heat mist rising”; this is followed by headache, usually confined to the left side; after a time nausea and vomiting occur, with no relief to the headache, which may last for two days; certain foods such as pastry, cream and pork tend to precipitate an attack. 111. 1 has two children aged 23 and 21 years; neither of them suffers from migraine, but the son, IV. 1, has been liable for 3-4 years to attacks, a t irregular intervals, of severe hay fever, accompanied by headaches which have no resemblance to migraine.

Of the siblings of 111. 1, one brother died, aged 28, from “chest trouble,” following a period of overwork and late hours during the war. 111. 4, aged 41, has been liable to migraine during recent years; his attacks differ from those of 111. 1 in their relatively late onset; he moreover complains of flashes of light and “blind attacks”; he appears to have more sickness and less severe pain than his sister, his pain is also of shorter duration. 111. 4 has two children who are now strong and healthy, though one of them suffered from digestive troubles at an early age. 111. 6 and 7 are free from migraine and allied troubles.

11. 4, father of 111. 1, was never known to complain of headache, hay fever, asthma or other recurrent ailment; one of his brothers, 11. 3, was said to have “fits,” and died when the children of 11. 4 were young. 11. 1 was believed to be robust and free from ailments. 11. 5, the mother of 111. 1, has always been liable to what the family describe as “brain storms,” but has no head- aches or symptoms suggestive of migraine. 11. 6 died young from chest trouble. 11. 7 is strong and healthy.

I. 2, the father of 11. 5-7, is believed to have been free from recurrent ailments; by his second wife he had two children of whom 11. 8 was liable to frequent and severe attacks of eczema. 11. 9 is reported to have had a cerebral tumour. Thus the migraine in the family appears to be confined to one sibship, and there is little evidence of the source of the trouble unless the eczema in 11. 8 may be regarded as an indicator.

Fig. 3. Migraine, asthma, recurrent vomiting and eczema in three generations of a family. 111. 19, aged 31, never had headaches until three years ago when she had a severe illness, lasting about 12 weeks, said to be due to gastritis; she had very bad headaches during this illness, and these recurred, following her recovery, a t first as frequently as three times in a week, later once a week. The pain in this case starts on the right side of the head and tends to spread to the right shoulder ; the accompanying eye symptoms and general cerebral disturbance are very disturbing, and anomalous in that the ocular spectra in the two eyes differ markedly; the patient describes a definite hemianopia in the left eye only, though she can sometimes see little with either eye; she sees something suggestive of a “revolving windmill with bright sails” in the left eye and black spots in the right; slight nausea occurs but no vomiting; the pain is evidently very severe and the attacks are a source of much misery. 111. 19 had two brothers of whom one, with “a difficult temperament,” died rather young, the other was killed in the war.

11. 15, father of 111. 19, had a nervous breakdown at the age of 50, lasting for about six years; he later suffered from melancholia and was liable to violent fits of temper, so that he had to be in an asylum for three years before his death at the age of 78. 11. 11 also was liable to fits of temper, but he was never certified or under restraint. 11. 12 was deaf, following scarlet fever. 11. 13, aged 81, was healthy and had two children, of whom 111. 21 died young; 111. 20, aged 50, had been liable to recurrent attacks of vomiting from childhood, but these had ceased for some years. Thus

EUGENICS V, I11 & IV 40

318 ON THE INHERITANCE O F MIGRAINE

we have no clear evidence that the source of the migraine in 111. 19 lies in her father’s side of the family.

11. 8, mother of 111. 19, was liable to recurrent “bilious attacks” when younger; these ceased at about the age of 55; she has never had migraine. 11. 4 died aged 58; he had troublesome eczema until the age of about 30, when it was cured; at this time the asthma first occurred which worried him during the remainder of his life; he had four children who have shown no signs of recurrent ailments. 111. 7 died, aged 43, from “a stroke.” 11. 6 died, aged 69, from a stroke; he is not known to have suffered from any recurrent ailment, though one of his six children, 111. 15, had periodic vomiting in childhood and now has characteristic migraine with visual spectra and hemianopia. 111. 14 was killed in the war. 11. 7 died, aged 64, having suffered from asthma since early child- hood. 11. 10 died, aged 61; she had rheumatoid arthritis from the age of 19, also asthma from about the age of 45 till her death. 11. 7, 9 and 10 were unmarried.

I. 5, the grandmother of 111. 19, suffered from asthma and was liable to epileptoid attacks; there seems to be some doubt as to whether she had true epilepsy or not. I. 6, a cousin of I. 5, used to have very severe headaches almost constantly; she was often quite prostrate and unable to see anybody; she died aged 52.

I. 2 and 4 are believed to have exhibited no sign of migraine or any allied malady, but the daughter of I. 2 was liable to recurrent headaches which used to prostrate her for several days; she, 11. 2, moreover had six children, of whom 111. 1 was crippled from some injury and died young. 111. 4 died young from meningitis. 111. 2 had recurrent very severe headaches; 111. 6 had a history of recurrent very bad headaches with ocular symptoms; she lost one eye from an accident and her headaches ceased after the excision of this eye. It cannot be definitely stated that I. 4 and 5 are both members of stocks carrying migraine, but 111. 19 has little doubt that the headaches in 11. 2,111. 2 and 111. 6 are of the same character as those from which she suffers.

Fig. 4. Migraine or allied condition, in a mother and in two of her seven children. 11. 2, aged 43, has been liable to migraine since the age of about 25; attacks occur about once in three to six weeks, or more frequently under pressure of work; this patient has no ocular spectra or dimming of vision; the pain is confined to the right side and is associated with giddiness, nausea and vomiting; the attack lasts for about 12 hours and is followed by malaise for another 12 hours. 11. 2 has an allergic idiosyncrasy for eggs. 11. 1 has, not very severe, attacks of hay fever and asthma each year, in the spring and autumn. 11. 3, 4 and 6 represent five siblings who are entirely free from migraine or other recurrent ailments. I. 1 suffered from severe headaches which 11. 2, a medical woman, believed to be of the migraine type. 11. 2 has never heard that her grandparents, aunts or uncles suffered from migraine or other recurrent maladies. I. 2 was liable to no recurrent malady. The seven children of 11. 4 have shown no sign of migraine.

Fig. 5. 111. 2, aged 59, has had migraine at rather irregular and infrequent periods during the last five years; the headache usually starts on the left side and spreads later to the right; this patient sees zigzags and rippling movements in the fields of vision of both eyes; nausea and vomiting may occur; there is also a tendency to giddiness and loss of balance; the attacks usually last about 48 hours. 111. 2 also suffers from nasal catarrh and from slight deafness in one ear; she had rheumatic fever a t the age of 22; she has been married for 23 years but has no children. 111. 1, aged 62, had an abscess in his ear a t the age of 18 and lost his hearing; he is now liable to giddy attacks associated with headache, but not with nausea or dimming of vision; he suffers also from nasal catarrh and from rheumatism; 111. 1 is married but childless. 111. 3, aged 56, has had migraine from time to time during the last ten years; her attacks are associated with giddiness

JULIA BELL 319

and vomiting but are less severe than those of her sister, 111. 2; she has severe nasal catarrh and slight deafness in one ear. 111. 3 has had bilateral cataract since childhood, and now has only the use of one eye. 111. 4 died in middle age from influenza; he had good health and was liable to no recurrent ailments; of his two children, a son, aged 30, is healthy; a daughter, IV. 2, aged 27, has suffered from persistent seborrhoea of the scalp since the age of 12 years, which all treatments have failed to cure.

The mother of 111. 1-4 died, aged 76, from diabetes; during a period of years starting in middle life she was liable to migraine associated with sudden attacks of giddiness and vomiting; she also suffered from rheumatism ; latterly she had bilateral cataract, probably diabetic in origin, and was very deaf. 11. 2 had three brothers who all died from kidney disease; two of them had children believed to show no sign of migraine. 11.4 died young. 11.5 lived to the age of 76 having shown no sign of migraine. I. 1 was healthy and strong and lived to the age of 84. 11. 1 died, aged 72, from angina pectoris. .

Fig. 6. Five rather severe cases of migraine, and one case of asthma in three generations. 111. 3, aged 49, has been liable to migraine since childhood; attacks were very rare between the ages of 24 and 38 years, and are very irregular now, never occurring on holidays and tending to follow from worries or overwork; ocular spectra in the form of zigzags and fortification signs are the first symptoms to occur; these are followed by an interval of complete blindness when the patient has to be led to bed; after about half an hour the vision clears and a severe generalised headache develops, associated with nausea, though vomiting is rare. 111. 3 is a very able man of academic distinction; he holds a responsible post and is always fearful lest an attack shall prevent his carrying out some important function; he could hardly bear to discuss the subject of migraine lest he should begin to see the signs he described. 111. 3 has five children, aged respectively 19, 17, 15, 13 and 10 years, of whom only one shows signs of migraine or allied disorders. IV. 6, aged 13, has very severe attacks of headache and vomiting every fortnight; this child has had periodic vomiting from earliest infancy, associated with much shivering ; his headaches start in the left frontal region, but become generalised; they last for about 24 hours, during which time he is prostrated. Unlike his father, IV. 6 has no ocular spectra or disturbance of vision during his attacks; he is a very clever boy with musical talents, and has recently won a foundation scholar- ship to one of the public schools, even though he was unable to sit for one of the examination papers owing to a migraine, and only carried on with the greatest difficulty. All treatment up to now has failed to help this patient or modify his attacks. It is of interest that all the four siblings of IV. 6 should be, up to now, entirely free from migraine and from the allied disorders.

111. 3 has one sister, aged 51, who is also liable to attacks of migraine which come on at irregular intervals, and tend to be precipitated by excitement or nervous strain; as a small child when specially excited about some entertainment which had been planned, she would almost surely have an attack and be prevented from going; her headaches are preceded by rotating wheels and a sense of upheaval in the field of vision, but she does not suffer the complete transient blindness of her brother, nor the persistent vomiting of her nephew.

111. 2 has two daughters, aged 15 and 13 respectively, who have not yet shown any signs of the trouble. 111. 2 and 3 have a half brother, 111. 5, by the same mother, 11. 11 ; he is liable to no recurrent ailments.

11. 1, father of 111. 2 and 3, died from typhoid fever before the birth of his son; he had not a t this time exhibited any signs of a liability to migraine, and since the condition was well recognised in the family, it is improbable that he had attacks without realising their nature.

40-2

320 ON T H E INHERITANCE O F MIGRAINE 11. 2, still living, has had very severe migraine all his life; he is quite incapacitated for 12-14

hours during an attack; he is very short-sighted; he is married but has no children. 11. 3 is not subject to headaches but had asthma as a child, and had to be sent to live away from home at about 6 years of age, because of this malady. 11. 4 was liable to migraine; her attacks always tended to come on in the early morning at about 3 o’clock, and lasted for about 17 hours. The attacks in 11. 2 and 11. 4 were associated with vomiting. Of other members of this sibship, 11. 5 died, aged 21, of yellow fever; he, 11. 6, 11. 7 and 11. 9, were all very short-sighted. It is of some interest that no fewer than six members of this sibship were married and childless.

11. 11, the mother of 111. 2 and 3, is a very healthy mentally alert woman; she knows of no migraine or allied disorders in her family. 111. 10, wife of 111. 3, is an active and mentally vigorous member of a family in which no recurrent maladies have given trouble.

Fig. 7. 111. 1, aged 34, the eldest of a sibship of fifteen, has suffered from recurrent migrainous headaches since early childhood; her attacks are associated with zigzags in the fields of vision and blurring of vision before the onset of the unilateral headache, which later becomes generalised ; the attlacks last for three or four days; certain foods such as lemon drinks and savouries tend to precipitate an attack; 111. 1 also complains of attacks of tachycardia. This patient left home a t an early age, and is not in close touch with many members of her family, but her mother reports that 111. 2, 111.4 and 111. 10 all suffer from recurrent very severe sick headaches; two brothers, 111. 6 and 7, died in infancy; three sisters died from tuberculosis, one died from congestion of the lungs; 111. 3 had tuberculosis as a child and now suffers from rheumatism; 111. 10 has been under treatment a t Swanley for a tuberculous affection of the eyes. The mother of this sibship, 11. 4, aged 58, has been liable to recurrent sick headaches since childhood; she recognises the same type of headache in her daughter, 111. 1. In the sibship of 11. 4 only the youngest sister, aged 50, has definitely migrainous attacks; they are evidently frequent and very severe in her case. 11.2 has headaches, “ which might be due to anything ” ; she is said to have had some sort of paralytic seizure as a child, and has always been rather “ a poor invalid,” with marked facial asymmetry; moreover she had one eye removed following an accident. 11. 5 died from a stroke at the age of 54. I. 1, the father of 11. 2-8, died, aged 42, from heart trouble and asthma; the nature of this asthma is uncertain but may well have been of cardiac origin.

11. 1 gives a vague history of headaches in himself and his four sisters and says his father died from asthma at the age of 71, but the conditions are probably not comparable with those of our series.

Fig. 8. IV. 3, aged 14 years, suffers from asthma and slight hay fever; he is also liable to wake in the morning with severe headaches associated with nausea, rarely with vomiting; he had eczema very badly up to 5 years of age. IV. 1 and 2 also had troublesome eczema up to about the age of 5 ; they are now aged 18 and 17 respectively and show no symptoms of migraine or allied dis- orders. III. 4, aged 43, the mother of IV. 1-3, is liable to no recurrent malady, though her parents both corne from stocks carrying migraine or asthma. 111. 5, the only sibling of 111. 4, aged 42, unmarried, has always had asthma, and had eczema as a child. 111. 8, the father of IV. 1-3, aged 60, had hay fever every year up to the age of 32, when it ceased to trouble him; he belongs to a family of nine siblings of whom three-111. 6, 7 and 17-have always been liable togastro- intestinal troubles of an uncertain nature; 111. 11 has a daughter, aged 17, who is liable to eczema, but it is rather doubtful whether any members of this family carry an inherent liability to the conditions associated with migraine.

11. 6, the mother of 111. 4, has had recurrent headaches with sickness all her life; she reports

JULIA BELL 32 1

that her mother, I. 2, suffered from migraine until the age of 50 years. There is no knowledge of further cases of migraine in the family of 11. 6, though one of her sisters, 11. 3, has a daughter with troublesome eczema. 11. 6 is married to 11. 7 who suffers from chronic catarrh; he, 11. 7, has two brothers and a sister who exhibit no liability to recurrent ailments. I. 6, the mother of 11. 7-10, suffered from acute asthma. None of the nine siblings of I. 6 was known to suffer from any recurrent ailment, but one brother, I. 8, had thirteen children of whom the fourth child, a boy, and the eleventh child, a girl, suffered severely from asthma all their lives; the fifth child, a boy, had asthma less badly, up to the age of 30 years only.

Fig. 9. 111. 2, a medical man, had constantly recurring migrainous headaches as a boy at school; he thinks they often came on Friday nights after the strain of a week’s school life. I. 1 and 11. 2, the grandfather and father respectively of 111. 2, were Scotchmen of outstanding ability who both suffered from gout. 111. 2 was the second youngest of thirteen children; he went abroad early and lost touch with the elder members of his family, and has no knowledge of their illness, but he knows that his sister, 111. 4, also suffered from migraine. This sister married and had two children who are believed not to suffer from migraine.

111. 2 has two children of whom the son, IV. 1, suffered in early days from periodic vomiting, to a very marked degree; an attack was looked for after any railway journey, after the first day of each term at school or whenever there was the slightest strain on his system; he was examined repeatedly by specialists, who were unable to help him; at the age of 12 years he had an appendix operation, and the exciting cause was evidently removed, for the child never had another attack. 111. 2 himself has suffered a good deal from intestinal trouble said to be associated with his migraine.

IV. 2, aged 26, also suffered as a child from periodic vomiting, and now is liable to migraine; the pain is on the right side; she sees no zigzags in the field of vision prior to the attack, but describes the phenomena known as “ wheels ” ; she has an associated nausea but no vomiting; in her case convulsive epileptoid attacks may follow the eye symptoms; she has two children; a third pregnancy caused regular epileptoid attacks which were stopped by abortion. 111. 2 knows of no case of asthma or hay fever in his family.

Fig. 10. 111. 2, aged 58, has suffered from very severe migraine as long as she can remember; her attacks are very frequent, now occurring every week, formerly every fortnight; the headache usually starts on the right side and later becomes generalised; nausea is a marked feature of the attack and vomiting occurs; she sees no zigzags or fortification spectra but complains that her sight becomes very dim, and describes circular waves in the field of vision. 111. 2 is married and has two children and a grandchild who have shown no signs of migraine or any allied condition. 111. 3 was liable to very severe headaches which recurred constantly, and incapacitated him during their progress, from the age of about 12 years until the age of 40; he has never had one since. 111. 4 died aged 3 years. The mother of 111. 2-4 died, aged 30, from phthisis; neither she nor her husband was known to have suffered from migraine or any allied disorder. 11. 2, how- ever, had a half-brother, 11. 3, who had migraine as severely as 111. 2; his attacks recurred about every 10 days and lasted for 24 hours; he had no migraine after the age of 65, though he lived to be 76. 111. 2 knows of no case of asthma or hay fever in her family.

What now can we deduce from this little group of pedigrees? They certainly are too few to form a basis for any general conclusions, but I think they do suggest that, from the genetic stand- point, the inheritable factor may become manifest in a variety of ways; the question is, how often is this factor present without demonstration, from the reason that the particular excitant required

3 22 ON THE INHERITANCE OF MIGRAINE to produce the symptoms has not been forthcoming? We know, for example, that in many cases of migraine a meticulous correction of errors of refraction will prevent the onset of an attack; are there possibly members of these pedigrees who have never had migraine, but who would have presented the characteristic train of symptoms if they had refractive errors needing correction? Or may we take it that the determining factor invariably finds an outlet, and if visual conditions protect the patient from one type of reaction, some other form of release will be found, as for example in asthma. It is repeatedly demonstrated that prevention of attacks of migraine result in a substitution malady, but it is also true that migraine may in certain cases be prevented without any replacement. I think it is clear that the number of affected members in the pedigree charts must be regarded as minimal values, for these ailments which recur throughout long periods or the whole life of an individual, and which are not a menace to life, are accepted with a minimum of complaint by the sufferer, and even near relations may be ignorant of their occurrence. The migraine patient is so glad to forget the dread complaint when it is not present, and is ever rather unready to talk about it unless he is seeking alleviation. Moreover, as Colonel Elliot has shown, symptoms of migraine may occur, for the first time, late in life; the onset was rather late in each member of Pig. 5; so that members of pedigrees noted as unaffected may still develop symptoms of the condition; we cannot be sure for example that the brothers of 111. 19 or of 111. 15 in Fig. 3, who were killed in the war, were definitely free of the trouble, when 111. 19, herself a most severe case, had her first attack of migraine at the age of 28 years.

Another question of primary importance in any discussion of this matter is related to the incidence of the condition in the population. If a disease is rare, and multiple cases occur in the same family, the probabilities are all in favour of a genetic determination, but if the disease be as common as say cancer or twinning the problem of estimating the genetic influence becomes very difficult. What then do we know of the incidence of migraine?

Colonel Elliot has told us that he found 300 cases of migraine amongst about 5000 new patients who sought his aid; thus about 6 yo of his patients had migraine. Colonel Elliot is well known as a specialist in the treatment of migraine, moreover all his patients are eye cases; for both these reasons, his figures should so greatly emphasize the incidence of migraine as to bear little relation- ship to the incidence in the general population. Attempts on my part to arrive at some apprecia- tion of the order of frequency of the malady have been conflicting and it is evident that only some carefully organised scheme on a large scale will reveal the facts.

Attempts in America to determine the incidence of migraine have also been very conflicting. Buchanan, in 1919*, found 1300 persons with migraine amongst patients at the Mayo Clinic; this constituted about 2-1 yo of the total registration for the year. Allant, on the other hand, reports a grotesque figure of over 50 yo for the incidence of migraine amongst a small group of medical men who were members of the Mecklenburg County Medical Society, and of an even higher figure for the general adult population. I point out these difficulties, and make only very tentative suggestions regarding the pedigrees given, not because I have any doubt of the etio- logical importance of heredity in migraine, but because the full genetic significance of all the allied conditions is by no means clear, and much more material is needed from which to draw general conclusions.

A few pedigrees, selected from the literature, are given on Plate 11, to illustrate some special points ; several of these demonstrate an exceptional potency of the hereditary factor in certain families. Pig. 11, published by Schmidt-Kehl$, shows a widespread liability to hay fever and

-f Ref. Nos. 15, 17. * Ref. No. 12. $ Ref. No. 21.

JULIA BELL 323

?a

324 ON T H E INHERITANCE O F MIGRAINE

eczema in a very fully worked-out family history, with only an occasional associated case of asthma and a single case of migraine. I think there is probably a very definite tendency, in most pedigrees of migraine and allied conditions, determining on the whole the predominant manifesta- tion of one of these conditions in a family; my material is not adequate to demonstrate this view but does not conflict with it.

Fig. 12 shows an extremely interesting history of recurrent attacks of motor paralysis with migraine in eleven members of three generations; Clarke" describes how the paralysis in these cases came on suddenly so that the patient would fall or have to be carried to bed; power of speech was lost; the paralysis was usually, but not always, confined to one side; after 1 or 2 hours the paralysis began to improve and intense migrainous headache followed. This is of interest in view of the fairly common complaint amongst Colonel Elliot's patients of numbness and tingling sensations during attacks of migraine, and occasionally of an associated localised weakness or twitching; all the cases in this pedigree give a similar type of history, and there is no record of an associated asthma; the condition was so severe and disabling in the affected members that perhaps if hay fever or eczema had occurred the family would have thought such symptoms too trivial to recount.

Fig. 13 shows the intimate association of migraine and asthma in a pedigree due to Dr Cockayne 1- ; ichthyosis is also present in one case of migraine and in four cases of asthma; eczema is noted in two of these cases. Dr Cockayne writes that the association between ichthyosis and the allergic conditions is now well established, but suggests that the relationship is one of genetic linkage, rather tlhan that ichthyosis is itself an allergy to some extent interchangeable with other allergies in its manifestation.

Fig. 14 shows thirteen cases of migraine in a small pedigree due to Dr UngerT; eleven of the cases result from the marriage of two people who both suffered from migraine. No clinical details of these cases are given, and no reference is made to the allied conditions; it would be of value to know that 11. 3 and 11. 6 were definitely free from asthma and the other allergies. Other examples of the intermarriage of subjects both of whom suffered from migraine are provided by Burnett5 in Figs. 15 and 18; this author suggests that the inbreeding of migraine changes the clinical picture of the simple non-inbred type ; he puts forward the proposition that the migraine becomes intensified, affects most, if not all, of the children, and tends to mental deterioration. The two histories illustrating Burnett's suggestions are of great interest, but it is doubtful whether all his deductions from them are of general application. Thus, in Fig. 15, I. 1 and 11. 2 showed a wandering delirium during the intense pain of their migraine attacks, with complete loss of all memory of that period afterwards; this fact, with its indications, possibly has more connection with the manifestation of dual personality in 111. 1, than has the marriage of his grandparents I. 1 and 2 who both suffered from migraine. Again, we are not justified, without a more detailed family history, in attributing the dual personality of 111. 2, Fig. 18, or the insanity in his sister, to the intermarriage of their migrainous parents. We have no reason to believe that migraine ever leads to mental deterioration, and a good deal of evidence to the contrary; if, however, severe migraine occurs in an already unstable individual, very serious developments might be expected to follow.

Fig. 17, due to Gansslenl, is of particular interest on account of the variety of manifestations of the hereditary factor, which are exhibited in different members of the family, in the form of migraine, asthma, hay fever, gout, urticaria and the more severe Quincke's oedema; gall stones

* Ref. No. 9. t Ref. No. 20. 1 Ref. No. 16. 3 Ref. No. 11. T[ Ref. Nos. 13 and 16.

J U L I A B E L L 325

also were found in a member of this family, possibly as a result of an irritated gall bladder due to abnormal secretion of mucous. This pedigree forms a striking contrast to the one above described by Schmidt-Kehl and to Figs. 14 and 19.

Fig. 19 is taken from Boenheim* who describes the occurrence of migraine in four generations, and in all the seven members of one sibship; the cases were remarkably uniform in this family and were generally associated with severe giddiness. I have been surprised to find relatively little reference to giddiness in the recent literature of migraine; this symptom was perhaps given more prominence by the earlier writers. Colonel Elliot finds it “a not very infrequent symptom of migraine, and considering the severity of the headache and the vomiting, this is not surprising.”

My very hearty thanks are due to Colonel Elliot for providing me with the means of access to such valuable material, and for his interest and readiness to discuss any point which may arise in connection with it. I hope, with his aid, to continue the systematic collection of family histories of migraine.

REFERENCES.

1. ARETAEUS, THE CAPPADOCIAN. The Extant Works of. Translated by F. Adams (Sydenham Society). London, 1856. A description of

2. DE BALZAC, J. L. G. Letters of. Translated by W. Tirwhyt, London, 1634. On p. 228, a reference to “megreme” occurs, in a letter

3. WILLIS, T. Opera Omniu. Amstelaedami, 1682. References to migraine and hereditary headache occur under the heading of De

4. FORDYOE, J. Historia Febris Miliaris et de Hemicrania. London, 1758. 5. LIVEING, E. On Megrim, Sick-headache and some Allied Disorkrs: a Contribution to the Pathology of Nerve Storms. London, 1873. 6. GUTHRIE, L. “ On Night Terrors, Symptomatic and Idiopathic, with Associated Disorders in Children.” Allbutt’s System of Medicine,

7. M~CKENZIE, Sir J. “Migraine.” Allbutt’s System of Medicine, Vol. vm, pp. 82-87. London, 1899. 8. GUTHRIE, L. Functional Nervous Disorders in Childhood. London, 1907. Reference quoted from pp, 150-151. 9. CLARKE, J. M. “On recurrent Motor Paralysis in Migraine.” British Medical Journal, Vol. i, for 1910, pp. 1534-1538. London, 1910.

10. BOENHEIM, F. “ Uber familiiire Hemicrania Vestibularis.” Neurologisches Centralblatt, Bd. XXXVI, S . 226-229. Leipzig, 1917. 11. BURNETT, S. G. “TWO Cases of Dual Personality in Inbred Migraines.” Chicago Medical Recorder, Vol. XL, pp. 27-33. Chicago, 1918. 12. BUGBANAN, J. A. “The Mendelianism of Migraine.” Medical Record, Vol. XC-, pp. 807-808. New York, 1920. 13. GANSSLEN, M. “Die Eosinophilie bei der Migriine.” Medizinische Klinik, Bd. XVII, S . 1232. Berlin, 1921. 14. HURST, A. F. “On Migraine.” Lancet, Vol. 11 for 1924, pp. 1-6. London, 1924. 15. ALLAN, W. “The Inheritance of Migraine.” Archives of Internal Medicine, Vol. XLII, pp. 590-599. Chicago, 1928. 16. BAUR, E., WSCHER, E. and LENZ, F. Human Heredity. Translated by G. E. and C. Paul. London, 1931. 17. ALLAN, W. “The Sex-Ratio in Migraine.” Archives of Neurology and Psychiatry, Vol. XXVII, pp. 1436-1440. Chicago, 1932. 18. ELLIOT, R. H. “Migraine.” Post-Graduate Medical Journal, Vol. vm, pp. 328-337, 363-374. London, 1932. 19. ELLIOT, R. H. “Migraine and Mysticism.” Post-Oraduute Medical Journal, Vol. WI, pp. 449459. London, 1932. 20. COCKAYNE, E. A. Inherited Abnormalities of the Skin and its Appendages. London, 1933. Reference on p. 208. 21. SCHMIDT-KEHL, L. ‘‘ Uber den Vererbungsmodus bei den allergischen Krankheiten.” Archiv f. Rassen- u. Cfesellschafts-Biologie,

* Ref. No. 10.

migraine will be found a t pp. 294-295 in Chap. 11, On Cephalaea.

to de Bois Robert, dated 1623.

Cephalalgia.

Vol. vm, pp. 218-233. London, 1899.

Bd. XXM, S. 175-179. Miinchen, 1933.

EUGENICS V, III”&! IV