Migraine Headache: Diagnosis and Management John R. Graham, M.D. Headache Research Foundation, The Faulkner Hospital, Jamaica Plain, Massachusetts. Reprint requests to: John R. Graham, M.D., The Faulkner Hospital, 1153 Center Street, Jamaica Plain, MA 02130. To start with, let us review several general concepts about migraines and those who have them. 1. Almost all authorities agree that migraine runs in families. A positive family history occurs in about 70% of migraineurs. A lack of a positive family history makes one think twice about the diagnosis. 2. In my opinion, the prodrome of migraine is probably the basic phenomenon of the disorder; the headache, which may or may not follow, probably represents an abnormal compensatory event. 3. The basic disturbance probably arises in centers of the brain which govern responses in the vegetative and neurovascular systems - not only in the brain, but also in the body - to stimuli from within and without the body. The migraineur seems to be genetically ill-equipped to handle these responses appropriately. The resulting abnormalities may be so severe that function of certain areas of the brain is temporarily impaired and early damage begins to take place. This dangerous state is repaired by a complicated set of biochemical and vascular responses which provide a temporary immunity, but also cause headache. 4. During the prodrome, as Dr. Edmeads has shown, blood supply to the brain is impaired - more in some areas than others. Blood is normally distributed to the brain in relation to local functional requirements. Areas of relative deficiency may develop when function is increased in the face of a local or general reduction in flow, or when blood is stolen even from a resting area by hyperactivity in another terrain. Such changes may explain the malfunction of the prodromal stage. Local compensatory vasodilatation (to bring relief), including involvement of the extracranial circulation as well as the intracranial vascular response, combined with biochemical changes, leads to the headache phase. A normal response to reduction of blood supply in the vicinity of the brain cell is followed by an appropriate reparative vasodilatation; hence, damage or malfunction does not occur. It's a symptom-free physiologic event. In migraine, reduced blood flow induces a hyper or inappropriate response (Fig. 1 ). The
initial reduction of blood supply causes the cell to "be sick" and malfunction results. Repair or counter-response is extreme and associated with a painful inflammatory exudate resulting in headache. The capacity for migraine to present a kaleidoscope of syndromes which present remarkable dissimilarities in their clinical manifestations may nevertheless be linked together by a common basic pathophysiology. The form assumed by these variable syndromes of migraine may very well be influenced also in their shapes by the anatomical, physiological and psychological makeup of the individuals who genetically come by the basic migraine trait. I'm sure you will recognize that these are just my concepts and, as Dr. Edmeads has pointed out, many of our concepts need a great deal more basic information from the experimental laboratory. 5. Migraine can follow the victim from the cradle to the grave. It can include, on its way: colic in the infant; motion sickness and cyclic vomiting attacks in the child; classic, common and occasionally cluster headaches in adults. A given individual may have any or all parts of this spectrum for short or long periods, starting and ending at various milestones in the patient's life. Migraine families may contain individuals with only one type or with all kinds of migraine. The disease is so protean that serious questions may be justifiably raised as to whether all members of the migraine family are legitimate. 6. Migraine severity and frequency are related to the balance between the patient's resistance and life stress and important milestones in life's responsibilities, such as going to school, puberty, senior year in
high school, first job, marriage, deaths and family problems. Individual episodes tend to come after the hard week at the office, after the dinner party or after Mother's illness is over. Periods of increased anti-stress-resource states, such as during pregnancy or in recovery from operations or illness, bring relief to migraine. Diminished stress-resource states, such as occur in withdrawal from steroids, are loaded with migraine. These features are characteristic of migraine but not of many other forms of headaches.
7. Migraine is a self-repairing periodic disorder related to stress and possibly involving repeated episodes of transient slight damage to the vascular system. Evidence is beginning to suggest its relationship to vascular disorders such as Raynaud's disease, lupus, rheumatoid arthritis and other disorders of collagens, hypertension, renal disease and possibly even coronary disease. As seen in Fig. 2, the atrophied "hide-bound" fingertips of this patient with scleroderma appeared years after she presented with migrainous headaches as a chief complaint. Let us now look at the spectrum of the migraines - and I'm sure there are some here who may not agree that all of these entities should be included under the same umbrella. First, recognize that one may have only the prodrome without headache. Illustrated in Fig. 3 is the classical fortification spectrum of scintillating lights expanding laterally in one or both visual fields, with homonymous hemianopsia and blindness temporarily following in its wake. This scintillating phenomenon is to be differentiated from the transient ischemic attack in which blindness is monocular and does not have a shining, positive lighted edge, or from the loss of vision from insulin reactions, which give bilateral blurring or absence of vision without lights. Such prodromes may consist of hemianesthesia, aphasia and confusion, and need to be differentiated from minor strokes. In classic migraine, the prodrome with or without headache is usually neurologically clear-cut and short in duration, usually 20 to 30 minutes. It may occasionally recur during the headache but usually immediately precedes the headache and disappears as headache supervenes. In common migraine, the prodrome is vague, prolonged, lasts hours before the headache supervenes and often is not even recognized, unless perhaps, as in about 40% of the time, the patient becomes aware some hours later of an abnormal mood or mental state which regularly presages the headache.
Some people do not consider cluster a member of the migraine family (and with considerable justice, although I think it remains a moot question). Prodromes are minimal if any. A short episode of burning sensation in the temple, or tearing, nasal blocking or rhinorrhea may precede the abrupt onset of severe headache, which usually is of short duration and may recur several times a day. Further along on this spectrum are the rare disorders known as hemiplegic and ophthalmoplegic migraine, in which distinct neurological deficits appear during the headache and outlast the headache. These are rare and whenever the usual classic sequence of neurologic deficit first, and headache second, is reversed, as it is in these rare types of migraine, a thorough neurological workup must be carried out to eliminate the possibility of confusing the disorder with a bleeding aneurysm or other space-occupying lesions. Finally, we come to the lower-half headache, or atypical facial neuralgia. It may start off as typical intermittent attacks of common migraine early in life, which gradually become closer together to form a continuum of pain in the lower half of the face that never goes away, or if it does, may leave overt psychosis in its wake. Now I would like to review the migraine profile relevant to, first, the attack itself, and second, the
profile of these attacks over the years in relation to life's milestones (Fig. 4). The attack profile should illuminate the following points: the nature and timing of the headache, as Dr. Kunkel has mentioned earlier, and the nature and timing of the prodrome, if any. The Time of Onset. Migraine frequently comes at night or on awakening, as opposed to other headaches which usually develop during the activities of the day. How long does it take for the headache to reach its peak? Subarachnoid hemorrhage is usually a hammer-blow. Cluster headache reaches its zenith in five minutes. Common migraine may take three or four hours. Total Duration of the Headache. Classic migraine commonly lasts one to six hours, with exceptions, of course. Common migraine may last all day or two to three days; cluster headache, 30 to 90 minutes, with some rare exceptions. Unilaterality. Although migraine can be limited to the same side, it switches occasionally, thus providing reassurance regarding a fixed organic lesion. Type of Pain. Migraine is steady or throbbing, not lancinating like tic douloureux. Throbbing confirms the vascular nature of the pain; it's synchronous with the pulse. Precipitants, such as food, drink, noise, smell, menses, fasting, position, sleep, naps, anger, fear and anxiety are usually related to the onset of attacks. A favorable response to ergotamine, properly given early in an attack, is highly suggestive of the presence of a migrainous mechanism. Accompanying symptoms of nausea, vomiting, polyuria, diarrhea, sweating or icy hands and feet suggest a migrainous type of headache. Behavior during attacks of classic or common migraine is usually hibernation. Patients will seek shelter from noise, light, smells, problems, TV and children. Cluster patients usually pace the floor, cry out, do bizarre things, and resent being touched. Hysterical patients may even smile as they describe their terrible pains. The life profile needs to record the following: family history of migraine is too often passed off by the patient as negative because no one in the family has headaches as bad as his; or a parent's history is really not known. A parent may have left home, or died. Cyclic vomiting and car sickness are migraine forerunners. Brain tumor, sinusitis and many other headaches do not relate to these factors of migraine headaches. During pregnancies, migraine patients show increased incidence of toxemia and hyperemesis gravidarum. But relief of headache is found 80% of the time in spite of the other symptoms during pregnancy. This observation is characteristic of migraine and not of other headache types. Check major dents in the patient's medical and family history especially with regard to hypertension, vascular disease, diabetes, renal disease, endocrine disorders, Raynaud's disease and disorders of collagen. Some of these disorders are related, directly or indirectly, I believe, to the occurrence of migraine and are often important in the use of therapeutic drugs. A history of family disruption by desertion, separation, illness, death and divorce, and the effects on the patient, are also important. The life setting in which the headaches began is important since they may give clues to similar settings which are now causing more attacks. There are a few special points in the physical examination of the headache patient seen during an attack. Some features pointing toward a diagnosis of migraine include pallor, rarely redness of the face, and ipsilaterally distended, tender, pulsating temporal arteries. Relief may be obtained by compressing these arteries or infiltrating novocaine around them. In temporal arteritis, the vessels are similarly distended, red and tender, but the pulse is usually absent and pressure increases the pain. Blockage of the nose without purulent drainage is common in common migraine and, especially, in cluster headaches. Varying degrees of Horner's syndrome and tearing may be noticed in migraine, but markedly in cluster headache. The presence of bruits or abnormal vascular anomalies should be ruled out in the examination of the patient. Look at the whole patient. This is often neglected. While zeroing in on the details of the history and physical examination, one may forget to look at this individual patient as a whole. Cushing's syndrome, scleroderma or other syndromes may be missed if one is not looking at the whole patient. This is exemplified by the man in Fig. 5, who was seen for 20 years with that birthmark on his face and had never had a skull x-ray or other studies. His angiogram is seen in Fig. 6. In one patient being studied for headache, the diagnosis really came with one look (which equalled a thousand words) (Fig. 7.) Tests verified that she had an early Cushing's syndrome, characterized by buffalo hump and other signs. Her headache was related to Cushing's syndrome and probably to an associated hypertension, and has been cured by treatment of her condition.
Another patient, whose atrophic fingertips are seen in Fig. 2, had first presented with telangiectasic spots on her face resulting from severe scleroderma. Migraine and "hide-bound" headaches may be associated features of her collagen disorder (Fig. 8).
TREATMENT The concept that the migraineur reacts abnormally to stimuli calling for change in the cranial neurovasculature may be compared to a loaded firecracker. Such stimuli, from external, physiological and psychological sources, may light the fuse. These are the stimuli to migraine. The body of the firecracker is the patient, loaded with genetically explosive powder. The explosion is a migraine attack. Although not very scientific, this concept is useful, since therapy involves these three areas; first, eliminating or reducing the number of stimuli, which I might add are additive in their effect; second, dampening the "firecracker" so that it won't go off so easily; and third, containing the explosion as best we can, if it happens. Often the external stimuli cannot be avoided, but combinations of two or more often can be discouraged. These include: shifts in the weather, especially hot, muggy days; oxygen deprivation, as in high altitudes or carbon monoxide poisoning; ingestion of certain foods containing nitrites (as "hot dogs"); tyramine, found in other foods; alcohol in any form; Chinese food that is heavily salted with monosodium glutamate content; bright light, loud noise, strong smells, excessive smoking and vasodilating medicines. The physiologic stimuli include the menstrual period, oversleeping in the morning, skipped or late meals, prolonged mental strain and probably some others. The psychological stimuli include fear, anxiety and rage, especially repressed rage.
It is the additive insults which are most important in migraine induction. While shopping on a hot summer day, little Johnny, who is beginning to get migraine, eats a chocolate bar and gets carsick on the way home. Meanwhile, Mother, a well-established migraineur, has a bad headache on arriving home, without the new suit for Johnny, without lunch and full of anger at the salesman. Situations can be controlled by patients. The dinner party doesn't have to be held on the hottest day of summer, nor at the crucial time of the menstrual cycle. All the work for the exam does not need to be left until the night before. Daddy can get up in time to have a bite of breakfast and not sleep until 9:00 a.m. on Saturday morning. The chronic frustration of sexual incompatibility must be recognized and treated, and the problems with in-laws straightened out. It is the physician's job to instruct patients on these matters and the patient's responsibility to carry out the changes. Then we come to strengthening the firecracker, which is mainly the doctor's job. Starting with general measures, the physician can aim therapy closer to the disturbed physiology of migraine. General methods include improving any medically abnormal condition, such as: anemia, endocrine disorders, hypertension, kidney disease, malabsorption syndromes, arthritis, cervical abnormalities and bleeding tendencies. Now we can turn to some medicines which are useful in prophylactic management. These include: the anti-inflammatory and antiplatelet drugs (indomethacin, aspirin, and possibly even papaverine, which has been used by some in preventing scotomatous headaches); anticonvulsants, such as Dilantin,(r) especially in children with abnormal EEGs; antidepressants (monamine oxidase inhibitors and tricyclic compounds especially seem to be useful in helping to prevent migraine in some patients). The antihistamine and antiserotonin drugs (cyproheptadine is particularly useful in children for whom stronger drugs are not indicated. Benadryl occasionally is useful taken at bedtime in helping to prevent the wake-up headache). Migraine patients in our experience tend to get hypertension more frequently than others. It is apt to be a mild form of hypertension and when it happens, the migraine that they had once a week turns out to be a daily "wake-up" headache in the morning, as hypertension supervenes. I believe that treating mild hypertension in these patients is very often helpful in relieving headaches. In my experience, small amounts of reserpine may be useful. Large amounts may precipitate headaches, but a tenth of a milligram of reserpine may be helpful. The Danes have also reported this to be the case. Propranolol has been particularly helpful, especially when there is vasomotor instability and mild hypertension is present; it treats both hypertension and the overactive sympathetic beta-adrenergic system. Spironolactone also may be useful. Combinations of these drugs, together with chlorothiazides, in the presence of mild hypertension seem to help prevent such migraine patients having more frequent attacks. Catapres may be another addition to this group of drugs. Ergot in short-term prophylaxis for special events seems justified; events like graduations, weddings, funerals and menstrual periods are always fraught with headache. Short-term use of daily ergot may be justified. Occasionally, cortisone in large amounts is effective in stopping persistent migraine but is ill-advised as a constant therapy. Short courses in certain situations may be useful (Fig. 9). The Pill is
contraindicated in classic migraine sufferers. It may be tried in common migraine sufferers, who should be carefully watched for headache or blood pressure increase and discontinued in such events. There are some patients with migraine who improve on the Pill, and there are those who have dangerous complications from its use. Methysergide is related to serotonin in its chemical structure and at some receptor sites acts like serotonin and at others, neutralizes the effects of serotonin (Fig. 10). It is a very effective migraine preventative, probably the best. But its side
effects limit its usefulness to those patients having severe migraine and who will report reliably for checkups, and agree to stop the drug for two weeks every four months. Its side effects include gastrointestinal disturbances; neurological disturbances; weight gain, which is very troublesome; edema and, as with ergots, marked vasoconstriction in major vessels (including coronaries); inflammatory fibrosis in the retroperitoneal space, aorta, heart and pleural space. Evidence of retroperitoneal fibrosis is noted in Fig. 11, showing distention of the left renal pelvis, and in the latter, beginning distention and medial deviation of the ureter on the opposite side; all of which went away after three or four months, although the patient continued to have mild hypertension. Usually, symptoms of fibrosis recede on stopping the drug. If they do not, one should consider surgery to insure that one is not missing a tumor, which can produce the same symptoms. In this same patient, even two years after clinical remission, renal vein studies revealed that the iliac vein was blocked by the fibrotic process. Large collaterals in the lumbar vein system were also exhibited (Fig. 12). Incidentally, an IVP in a patient
suspected of having fibrotic complications of methysergide should probably be performed via the femoral vein since the dye column may stop at the blockage caused by a fibrotic plaque. One patient, in whom a pulmonary tumor was suspected, turned out to have pleuropulmonary fibrosis at surgery. Note the pleural thickening and resultant obliteration of the costophrenic angles, and "ball" of fibrosis (Figs. 13 and 14). The fibrotic complications gradually cleared over a couple of years, but very slowly. Drs. Monroe and Kunkel described a case similar to ours, in which a heart valve was removed showing a collagenous deposit on top of a normal valve (Fig. 15). This is quite different from rheumatic fever, but resembles the type of disturbance one sees in the carcinoid syndrome, which involves serotonin. A deposit of collagen on a normal mitral valve in a carcinoid-syndrome patient of Dr. Roberts is shown in Fig. 16. Considering all these problems associated with pharmaceutical prophylaxis, it is small wonder that everyone is interested in nondrug treatments. These include biofeedback, yoga, meditation and relaxation training, and electrical counterstimulation. All such
treatment modalities, in various hands, have shown some degree of success - especially in association with psychotherapy (group or individual type). Its effectiveness may lie in the psychotherapeutic com-
ponents to which the patient is introduced in a nonthreatening manner. But others at this symposium can talk with more authority on this subject. Containing the explosion of the attack. In treating individual attacks of migraine, measures to abort the prodrome are few and rarely successful. They include physical exercise, breathing 100% oxygen, increasing CO2 by rebreathing in a bag, or ingesting tiny amounts of nitroglycerin. Papaverine sedatives may help but results are unpredictable and usually not particularly helpful. It is important to try to arrange a quiet, peaceful setting for the patient in an attack. An hour or two of rest and hibernation may greatly enhance the effect of medication. Sometimes
removal of the patient to a hospital may be necessary to achieve this form of hibernation, though occasionally hospitalization is not as hibernific as it might seem. Analgesics of the APC variety and some sedation or antinausea medication like Dramamine(r) or Compazine(r) may be helpful. One hesitates to use narcotics in a chronically recurrent illness but occasionally they may be indicated. These should usually not be administered by the spouse but should be individually prescribed at the time by a physician. Midrin(r), a mild vasoconstrictor plus analgesic, may be useful in some mild cases. But when these measures fail, ergot is usually necessary. Preferably, ergotamine should be given early in the headache phase but may still be effective even late in the attack. Its oral, sublingual or inhalational use has the important advantage of convenience but, dose for dose, is less effective than the rectal or parenteral preparations. The first dose to a patient should start with a small amount (especially with women) to test tolerance. Too much can make one sick. Parenteral ergotamine, 0.5 m., or half of a rectal suppository followed if necessary after an hour by a second dose, is a good start. One or two repeated doses may be used, but if not effective, further doses only sicken the patient without stopping the attack. There should be at least two days a week, or more, in which ergot is not taken so as to prevent ergot dependency. We have seen people abuse this drug in order to help them continue working and never stop to give themselves the rest they need to get over their attacks. When ergot is ineffective, a dose of 40 mg. of prednisone on one day, followed by 10-20 mg. the next morning, may bring relief in a very stubborn attack. Once an effective dose has been determined for ergot, it may be well to give the total dose at the onset, or two-thirds of it, and then later, another third. When using sublingual ergotamine, I suggest 1 or 2 mg., or one or two pills at the beginning, and maybe another one in an hour or two. I think ergot should always be given an hour to work. If you watch the decrease in amplitude of temporal artery pulsations after ergot, it goes hand and hand with a decrease in headache; the major effect of ergot is usually about 1 hour after it has been taken by mouth. If that doesn't do it, I wouldn't add more. One or two whiffs from an ergotamine medihaler followed in an hour by another one or two, and maybe a third dose, is also effective. You have to remember that the medihaler contains about 0.35 mg. of ergotamine, which equals about half of a suppository. Rectal ergotamine is more effective but less convenient. A housewife at home can use a rectal suppository; somebody working in an office might find this difficult. One has to suit the use of the ergot to the person's situation. I often use just half of a suppository at the beginning, repeat it with another half and possibly a third half, if necessary. If you find that it always requires that much, you may want to start with one at the beginning and one-half later.
The vasoconstrictive effect of ergot, demonstrated by our studies in Dr. Wolff's laboratory 40 years ago, is shown in Fig. 17. Although ergotamine constricts cranial vessels preferentially, we were able to show a significant blood pressure increase following I.V. administration. My own preference is never to use ergot I.V. It may well constrict the coronaries, aorta, femoral vessels, and axillary arteries, as well as the temporal vessels. If one wishes to explore its diagnostic usefulness, it is best to give it parenterally early in an attack. One has to remember that Cafergot(r) taken orally is effective only in about 40% to 50% of the patients, or 40% or 50% of the time. Non-success does not rule out the diagnosis of migraine. Its success rate, when used rectally, is 60%, and between 70% and 90% by parenteral administration. So before you give up on ergot, give it by the best route, early in the attack. With oral Gynergen(r) or Cafergot, I recommend one to three pills at the beginning, one or two 1 hour later; not more than six. Usually, if it doesn't work in two hours, I wouldn't use
more. The ergot in Cafergot seems to be better absorbed. Contraindications to all ergot derivatives (and this would include methysergide) include: hypertension; vascular disease; age 60 or over, when one is likely to have a few slightly narrowed vessels; severe renal or hepatic disease; pregnancy; people who are very sick, since vascular episodes may be precipitated in people who are cachectic and depleted; people with chronic pulmonary disease who may develop pulmonary complications; anybody with heart valve disease; and collagen disease. I should mention that if a patient with migraine has been taking methysergide effectively but begins to develop symptoms or signs of one of the fibrotic complications, the drug must be stopped. What is often forgotten is that when the patient's headache recurs in force and the patient is then permitted ergot drugs, continuation or recrudescence of their fibrotic complications may result. We now have six or more patients in whom we believe fibrotic complications have taken place in patients taking only ergotamine rather than methysergide. GENERAL REFERENCES Graham, JR: Cluster Headache. Headache 11:175, 1972. Graham, JR: Fibrosis associated with methysergide therapy. Drug-induced Diseases 3:249. Excerpta Medica, 1968. Graham, JR: Headache, Diagnosis, Mechanisms and Treatment. Parts I and II. A.C.P. Self-learning series. A tape slide course available through the American College of Physicians, 4200 Pine St., Philadelphia, Pennsylvania. Graham, JR: Treatment of Migraine. Boston, Little, Brown and Co, 1955. Lance, JL: Mechanism and Management of Headache (3rd ed). Philadelphia, J.B. Lippincott, 1978. Ostfeld, Adrian M: The Common Headache Syndromes. American Lecture Series. Springfield, Illinois, Charles C Thomas, 1962. Wolff, HG: Headache and Other Head Pain (3rd ed). Oxford Press (revised by Donald Dalessio, M.D.), 1972. DISCUSSION Question: Dr. Graham, do you feel that a single dose of Cafergot(r) in a pregnant woman is of more risk to the developing fetus or of immediate abortion? Dr. Graham: I don't know about the risk to the fetus. The use of ergotamine tartrate to induce abortion has not been particularly successful; however, I think you are obliged to avoid it during pregnancy because of its oxytocic effect. If you have to use any form of the ergotamines, dihydroergotamine, which is much less oxytocic, is alleged to be safe up to the eighth month. Personally, I think that when a patient becomes pregnant - the first sign of which may be relief of her headaches - one is well advised to stop the use of ergot derivatives, except possibly in very exceptional cases. Question: Does anyone know of any evidence of damage to a developing fetus? Richard V. Albery, M.D., Phoenix, Arizona: The data from animal studies show that Cafergot causes decreased placental blood supply and fetal reabsorption, but I don't know of any evidence that it has a teratogenic effect in humans. Gleb G. Bourianoff, M.D., Houston, Texas: Earlier this year, in a letter to Headache, Dr. Diamond reported several cases of fibrotic complications from propranolol. Have there been any further developments? Seymour Diamond, M.D., Chicago, Illinois: In my letter, I mentioned that there had been two isolated reports of fibrosis with the use of propranolol, and I asked that if any others are also observing this, they should mention it. But at this time I have not heard of any additional reports of this finding. Dr. Graham: There have been perhaps half a dozen or so reports - some from the Australian literature indicating the development of intraperitoneal fibrosis, in particular, in patients taking propranolol. It's very hard to decide that a drug is causing a complication of that sort without many more data. I have one patient to whom I had given propranolol for a cardiac condition. This patient had three recurrences of severe abdominal adhesions, requiring surgery to undo the obstruction which resulted. When we stopped giving propranolol, the patient's complications also stopped. I think we should bear in mind that there may be some relation between fibrosis and drugs that block the beta-adrenergic system.
initial reduction of blood supply causes the cell to "be sick" and malfunction results. Repair or counter-response is extreme and associated with a painful inflammatory exudate resulting in headache. The capacity for migraine to present a kaleidoscope of syndromes which present remarkable dissimilarities in their clinical manifestations may nevertheless be linked together by a common basic pathophysiology. The form assumed by these variable syndromes of migraine may very well be influenced also in their shapes by the anatomical, physiological and psychological makeup of the individuals who genetically come by the basic migraine trait. I'm sure you will recognize that these are just my concepts and, as Dr. Edmeads has pointed out, many of our concepts need a great deal more basic information from the experimental laboratory. 5. Migraine can follow the victim from the cradle to the grave. It can include, on its way: colic in the infant; motion sickness and cyclic vomiting attacks in the child; classic, common and occasionally cluster headaches in adults. A given individual may have any or all parts of this spectrum for short or long periods, starting and ending at various milestones in the patient's life. Migraine families may contain individuals with only one type or with all kinds of migraine. The disease is so protean that serious questions may be justifiably raised as to whether all members of the migraine family are legitimate. 6. Migraine severity and frequency are related to the balance between the patient's resistance and life stress and important milestones in life's responsibilities, such as going to school, puberty, senior year in
high school, first job, marriage, deaths and family problems. Individual episodes tend to come after the hard week at the office, after the dinner party or after Mother's illness is over. Periods of increased anti-stress-resource states, such as during pregnancy or in recovery from operations or illness, bring relief to migraine. Diminished stress-resource states, such as occur in withdrawal from steroids, are loaded with migraine. These features are characteristic of migraine but not of many other forms of headaches.
7. Migraine is a self-repairing periodic disorder related to stress and possibly involving repeated episodes of transient slight damage to the vascular system. Evidence is beginning to suggest its relationship to vascular disorders such as Raynaud's disease, lupus, rheumatoid arthritis and other disorders of collagens, hypertension, renal disease and possibly even coronary disease. As seen in Fig. 2, the atrophied "hide-bound" fingertips of this patient with scleroderma appeared years after she presented with migrainous headaches as a chief complaint. Let us now look at the spectrum of the migraines - and I'm sure there are some here who may not agree that all of these entities should be included under the same umbrella. First, recognize that one may have only the prodrome without headache. Illustrated in Fig. 3 is the classical fortification spectrum of scintillating lights expanding laterally in one or both visual fields, with homonymous hemianopsia and blindness temporarily following in its wake. This scintillating phenomenon is to be differentiated from the transient ischemic attack in which blindness is monocular and does not have a shining, positive lighted edge, or from the loss of vision from insulin reactions, which give bilateral blurring or absence of vision without lights. Such prodromes may consist of hemianesthesia, aphasia and confusion, and need to be differentiated from minor strokes. In classic migraine, the prodrome with or without headache is usually neurologically clear-cut and short in duration, usually 20 to 30 minutes. It may occasionally recur during the headache but usually immediately precedes the headache and disappears as headache supervenes. In common migraine, the prodrome is vague, prolonged, lasts hours before the headache supervenes and often is not even recognized, unless perhaps, as in about 40% of the time, the patient becomes aware some hours later of an abnormal mood or mental state which regularly presages the headache.
Some people do not consider cluster a member of the migraine family (and with considerable justice, although I think it remains a moot question). Prodromes are minimal if any. A short episode of burning sensation in the temple, or tearing, nasal blocking or rhinorrhea may precede the abrupt onset of severe headache, which usually is of short duration and may recur several times a day. Further along on this spectrum are the rare disorders known as hemiplegic and ophthalmoplegic migraine, in which distinct neurological deficits appear during the headache and outlast the headache. These are rare and whenever the usual classic sequence of neurologic deficit first, and headache second, is reversed, as it is in these rare types of migraine, a thorough neurological workup must be carried out to eliminate the possibility of confusing the disorder with a bleeding aneurysm or other space-occupying lesions. Finally, we come to the lower-half headache, or atypical facial neuralgia. It may start off as typical intermittent attacks of common migraine early in life, which gradually become closer together to form a continuum of pain in the lower half of the face that never goes away, or if it does, may leave overt psychosis in its wake. Now I would like to review the migraine profile relevant to, first, the attack itself, and second, the
profile of these attacks over the years in relation to life's milestones (Fig. 4). The attack profile should illuminate the following points: the nature and timing of the headache, as Dr. Kunkel has mentioned earlier, and the nature and timing of the prodrome, if any. The Time of Onset. Migraine frequently comes at night or on awakening, as opposed to other headaches which usually develop during the activities of the day. How long does it take for the headache to reach its peak? Subarachnoid hemorrhage is usually a hammer-blow. Cluster headache reaches its zenith in five minutes. Common migraine may take three or four hours. Total Duration of the Headache. Classic migraine commonly lasts one to six hours, with exceptions, of course. Common migraine may last all day or two to three days; cluster headache, 30 to 90 minutes, with some rare exceptions. Unilaterality. Although migraine can be limited to the same side, it switches occasionally, thus providing reassurance regarding a fixed organic lesion. Type of Pain. Migraine is steady or throbbing, not lancinating like tic douloureux. Throbbing confirms the vascular nature of the pain; it's synchronous with the pulse. Precipitants, such as food, drink, noise, smell, menses, fasting, position, sleep, naps, anger, fear and anxiety are usually related to the onset of attacks. A favorable response to ergotamine, properly given early in an attack, is highly suggestive of the presence of a migrainous mechanism. Accompanying symptoms of nausea, vomiting, polyuria, diarrhea, sweating or icy hands and feet suggest a migrainous type of headache. Behavior during attacks of classic or common migraine is usually hibernation. Patients will seek shelter from noise, light, smells, problems, TV and children. Cluster patients usually pace the floor, cry out, do bizarre things, and resent being touched. Hysterical patients may even smile as they describe their terrible pains. The life profile needs to record the following: family history of migraine is too often passed off by the patient as negative because no one in the family has headaches as bad as his; or a parent's history is really not known. A parent may have left home, or died. Cyclic vomiting and car sickness are migraine forerunners. Brain tumor, sinusitis and many other headaches do not relate to these factors of migraine headaches. During pregnancies, migraine patients show increased incidence of toxemia and hyperemesis gravidarum. But relief of headache is found 80% of the time in spite of the other symptoms during pregnancy. This observation is characteristic of migraine and not of other headache types. Check major dents in the patient's medical and family history especially with regard to hypertension, vascular disease, diabetes, renal disease, endocrine disorders, Raynaud's disease and disorders of collagen. Some of these disorders are related, directly or indirectly, I believe, to the occurrence of migraine and are often important in the use of therapeutic drugs. A history of family disruption by desertion, separation, illness, death and divorce, and the effects on the patient, are also important. The life setting in which the headaches began is important since they may give clues to similar settings which are now causing more attacks. There are a few special points in the physical examination of the headache patient seen during an attack. Some features pointing toward a diagnosis of migraine include pallor, rarely redness of the face, and ipsilaterally distended, tender, pulsating temporal arteries. Relief may be obtained by compressing these arteries or infiltrating novocaine around them. In temporal arteritis, the vessels are similarly distended, red and tender, but the pulse is usually absent and pressure increases the pain. Blockage of the nose without purulent drainage is common in common migraine and, especially, in cluster headaches. Varying degrees of Horner's syndrome and tearing may be noticed in migraine, but markedly in cluster headache. The presence of bruits or abnormal vascular anomalies should be ruled out in the examination of the patient. Look at the whole patient. This is often neglected. While zeroing in on the details of the history and physical examination, one may forget to look at this individual patient as a whole. Cushing's syndrome, scleroderma or other syndromes may be missed if one is not looking at the whole patient. This is exemplified by the man in Fig. 5, who was seen for 20 years with that birthmark on his face and had never had a skull x-ray or other studies. His angiogram is seen in Fig. 6. In one patient being studied for headache, the diagnosis really came with one look (which equalled a thousand words) (Fig. 7.) Tests verified that she had an early Cushing's syndrome, characterized by buffalo hump and other signs. Her headache was related to Cushing's syndrome and probably to an associated hypertension, and has been cured by treatment of her condition.
Another patient, whose atrophic fingertips are seen in Fig. 2, had first presented with telangiectasic spots on her face resulting from severe scleroderma. Migraine and "hide-bound" headaches may be associated features of her collagen disorder (Fig. 8).
TREATMENT The concept that the migraineur reacts abnormally to stimuli calling for change in the cranial neurovasculature may be compared to a loaded firecracker. Such stimuli, from external, physiological and psychological sources, may light the fuse. These are the stimuli to migraine. The body of the firecracker is the patient, loaded with genetically explosive powder. The explosion is a migraine attack. Although not very scientific, this concept is useful, since therapy involves these three areas; first, eliminating or reducing the number of stimuli, which I might add are additive in their effect; second, dampening the "firecracker" so that it won't go off so easily; and third, containing the explosion as best we can, if it happens. Often the external stimuli cannot be avoided, but combinations of two or more often can be discouraged. These include: shifts in the weather, especially hot, muggy days; oxygen deprivation, as in high altitudes or carbon monoxide poisoning; ingestion of certain foods containing nitrites (as "hot dogs"); tyramine, found in other foods; alcohol in any form; Chinese food that is heavily salted with monosodium glutamate content; bright light, loud noise, strong smells, excessive smoking and vasodilating medicines. The physiologic stimuli include the menstrual period, oversleeping in the morning, skipped or late meals, prolonged mental strain and probably some others. The psychological stimuli include fear, anxiety and rage, especially repressed rage.
It is the additive insults which are most important in migraine induction. While shopping on a hot summer day, little Johnny, who is beginning to get migraine, eats a chocolate bar and gets carsick on the way home. Meanwhile, Mother, a well-established migraineur, has a bad headache on arriving home, without the new suit for Johnny, without lunch and full of anger at the salesman. Situations can be controlled by patients. The dinner party doesn't have to be held on the hottest day of summer, nor at the crucial time of the menstrual cycle. All the work for the exam does not need to be left until the night before. Daddy can get up in time to have a bite of breakfast and not sleep until 9:00 a.m. on Saturday morning. The chronic frustration of sexual incompatibility must be recognized and treated, and the problems with in-laws straightened out. It is the physician's job to instruct patients on these matters and the patient's responsibility to carry out the changes. Then we come to strengthening the firecracker, which is mainly the doctor's job. Starting with general measures, the physician can aim therapy closer to the disturbed physiology of migraine. General methods include improving any medically abnormal condition, such as: anemia, endocrine disorders, hypertension, kidney disease, malabsorption syndromes, arthritis, cervical abnormalities and bleeding tendencies. Now we can turn to some medicines which are useful in prophylactic management. These include: the anti-inflammatory and antiplatelet drugs (indomethacin, aspirin, and possibly even papaverine, which has been used by some in preventing scotomatous headaches); anticonvulsants, such as Dilantin,(r) especially in children with abnormal EEGs; antidepressants (monamine oxidase inhibitors and tricyclic compounds especially seem to be useful in helping to prevent migraine in some patients). The antihistamine and antiserotonin drugs (cyproheptadine is particularly useful in children for whom stronger drugs are not indicated. Benadryl occasionally is useful taken at bedtime in helping to prevent the wake-up headache). Migraine patients in our experience tend to get hypertension more frequently than others. It is apt to be a mild form of hypertension and when it happens, the migraine that they had once a week turns out to be a daily "wake-up" headache in the morning, as hypertension supervenes. I believe that treating mild hypertension in these patients is very often helpful in relieving headaches. In my experience, small amounts of reserpine may be useful. Large amounts may precipitate headaches, but a tenth of a milligram of reserpine may be helpful. The Danes have also reported this to be the case. Propranolol has been particularly helpful, especially when there is vasomotor instability and mild hypertension is present; it treats both hypertension and the overactive sympathetic beta-adrenergic system. Spironolactone also may be useful. Combinations of these drugs, together with chlorothiazides, in the presence of mild hypertension seem to help prevent such migraine patients having more frequent attacks. Catapres may be another addition to this group of drugs. Ergot in short-term prophylaxis for special events seems justified; events like graduations, weddings, funerals and menstrual periods are always fraught with headache. Short-term use of daily ergot may be justified. Occasionally, cortisone in large amounts is effective in stopping persistent migraine but is ill-advised as a constant therapy. Short courses in certain situations may be useful (Fig. 9). The Pill is
contraindicated in classic migraine sufferers. It may be tried in common migraine sufferers, who should be carefully watched for headache or blood pressure increase and discontinued in such events. There are some patients with migraine who improve on the Pill, and there are those who have dangerous complications from its use. Methysergide is related to serotonin in its chemical structure and at some receptor sites acts like serotonin and at others, neutralizes the effects of serotonin (Fig. 10). It is a very effective migraine preventative, probably the best. But its side
effects limit its usefulness to those patients having severe migraine and who will report reliably for checkups, and agree to stop the drug for two weeks every four months. Its side effects include gastrointestinal disturbances; neurological disturbances; weight gain, which is very troublesome; edema and, as with ergots, marked vasoconstriction in major vessels (including coronaries); inflammatory fibrosis in the retroperitoneal space, aorta, heart and pleural space. Evidence of retroperitoneal fibrosis is noted in Fig. 11, showing distention of the left renal pelvis, and in the latter, beginning distention and medial deviation of the ureter on the opposite side; all of which went away after three or four months, although the patient continued to have mild hypertension. Usually, symptoms of fibrosis recede on stopping the drug. If they do not, one should consider surgery to insure that one is not missing a tumor, which can produce the same symptoms. In this same patient, even two years after clinical remission, renal vein studies revealed that the iliac vein was blocked by the fibrotic process. Large collaterals in the lumbar vein system were also exhibited (Fig. 12). Incidentally, an IVP in a patient
suspected of having fibrotic complications of methysergide should probably be performed via the femoral vein since the dye column may stop at the blockage caused by a fibrotic plaque. One patient, in whom a pulmonary tumor was suspected, turned out to have pleuropulmonary fibrosis at surgery. Note the pleural thickening and resultant obliteration of the costophrenic angles, and "ball" of fibrosis (Figs. 13 and 14). The fibrotic complications gradually cleared over a couple of years, but very slowly. Drs. Monroe and Kunkel described a case similar to ours, in which a heart valve was removed showing a collagenous deposit on top of a normal valve (Fig. 15). This is quite different from rheumatic fever, but resembles the type of disturbance one sees in the carcinoid syndrome, which involves serotonin. A deposit of collagen on a normal mitral valve in a carcinoid-syndrome patient of Dr. Roberts is shown in Fig. 16. Considering all these problems associated with pharmaceutical prophylaxis, it is small wonder that everyone is interested in nondrug treatments. These include biofeedback, yoga, meditation and relaxation training, and electrical counterstimulation. All such
treatment modalities, in various hands, have shown some degree of success - especially in association with psychotherapy (group or individual type). Its effectiveness may lie in the psychotherapeutic com-
ponents to which the patient is introduced in a nonthreatening manner. But others at this symposium can talk with more authority on this subject. Containing the explosion of the attack. In treating individual attacks of migraine, measures to abort the prodrome are few and rarely successful. They include physical exercise, breathing 100% oxygen, increasing CO2 by rebreathing in a bag, or ingesting tiny amounts of nitroglycerin. Papaverine sedatives may help but results are unpredictable and usually not particularly helpful. It is important to try to arrange a quiet, peaceful setting for the patient in an attack. An hour or two of rest and hibernation may greatly enhance the effect of medication. Sometimes
removal of the patient to a hospital may be necessary to achieve this form of hibernation, though occasionally hospitalization is not as hibernific as it might seem. Analgesics of the APC variety and some sedation or antinausea medication like Dramamine(r) or Compazine(r) may be helpful. One hesitates to use narcotics in a chronically recurrent illness but occasionally they may be indicated. These should usually not be administered by the spouse but should be individually prescribed at the time by a physician. Midrin(r), a mild vasoconstrictor plus analgesic, may be useful in some mild cases. But when these measures fail, ergot is usually necessary. Preferably, ergotamine should be given early in the headache phase but may still be effective even late in the attack. Its oral, sublingual or inhalational use has the important advantage of convenience but, dose for dose, is less effective than the rectal or parenteral preparations. The first dose to a patient should start with a small amount (especially with women) to test tolerance. Too much can make one sick. Parenteral ergotamine, 0.5 m., or half of a rectal suppository followed if necessary after an hour by a second dose, is a good start. One or two repeated doses may be used, but if not effective, further doses only sicken the patient without stopping the attack. There should be at least two days a week, or more, in which ergot is not taken so as to prevent ergot dependency. We have seen people abuse this drug in order to help them continue working and never stop to give themselves the rest they need to get over their attacks. When ergot is ineffective, a dose of 40 mg. of prednisone on one day, followed by 10-20 mg. the next morning, may bring relief in a very stubborn attack. Once an effective dose has been determined for ergot, it may be well to give the total dose at the onset, or two-thirds of it, and then later, another third. When using sublingual ergotamine, I suggest 1 or 2 mg., or one or two pills at the beginning, and maybe another one in an hour or two. I think ergot should always be given an hour to work. If you watch the decrease in amplitude of temporal artery pulsations after ergot, it goes hand and hand with a decrease in headache; the major effect of ergot is usually about 1 hour after it has been taken by mouth. If that doesn't do it, I wouldn't add more. One or two whiffs from an ergotamine medihaler followed in an hour by another one or two, and maybe a third dose, is also effective. You have to remember that the medihaler contains about 0.35 mg. of ergotamine, which equals about half of a suppository. Rectal ergotamine is more effective but less convenient. A housewife at home can use a rectal suppository; somebody working in an office might find this difficult. One has to suit the use of the ergot to the person's situation. I often use just half of a suppository at the beginning, repeat it with another half and possibly a third half, if necessary. If you find that it always requires that much, you may want to start with one at the beginning and one-half later.
The vasoconstrictive effect of ergot, demonstrated by our studies in Dr. Wolff's laboratory 40 years ago, is shown in Fig. 17. Although ergotamine constricts cranial vessels preferentially, we were able to show a significant blood pressure increase following I.V. administration. My own preference is never to use ergot I.V. It may well constrict the coronaries, aorta, femoral vessels, and axillary arteries, as well as the temporal vessels. If one wishes to explore its diagnostic usefulness, it is best to give it parenterally early in an attack. One has to remember that Cafergot(r) taken orally is effective only in about 40% to 50% of the patients, or 40% or 50% of the time. Non-success does not rule out the diagnosis of migraine. Its success rate, when used rectally, is 60%, and between 70% and 90% by parenteral administration. So before you give up on ergot, give it by the best route, early in the attack. With oral Gynergen(r) or Cafergot, I recommend one to three pills at the beginning, one or two 1 hour later; not more than six. Usually, if it doesn't work in two hours, I wouldn't use
more. The ergot in Cafergot seems to be better absorbed. Contraindications to all ergot derivatives (and this would include methysergide) include: hypertension; vascular disease; age 60 or over, when one is likely to have a few slightly narrowed vessels; severe renal or hepatic disease; pregnancy; people who are very sick, since vascular episodes may be precipitated in people who are cachectic and depleted; people with chronic pulmonary disease who may develop pulmonary complications; anybody with heart valve disease; and collagen disease. I should mention that if a patient with migraine has been taking methysergide effectively but begins to develop symptoms or signs of one of the fibrotic complications, the drug must be stopped. What is often forgotten is that when the patient's headache recurs in force and the patient is then permitted ergot drugs, continuation or recrudescence of their fibrotic complications may result. We now have six or more patients in whom we believe fibrotic complications have taken place in patients taking only ergotamine rather than methysergide. GENERAL REFERENCES Graham, JR: Cluster Headache. Headache 11:175, 1972. Graham, JR: Fibrosis associated with methysergide therapy. Drug-induced Diseases 3:249. Excerpta Medica, 1968. Graham, JR: Headache, Diagnosis, Mechanisms and Treatment. Parts I and II. A.C.P. Self-learning series. A tape slide course available through the American College of Physicians, 4200 Pine St., Philadelphia, Pennsylvania. Graham, JR: Treatment of Migraine. Boston, Little, Brown and Co, 1955. Lance, JL: Mechanism and Management of Headache (3rd ed). Philadelphia, J.B. Lippincott, 1978. Ostfeld, Adrian M: The Common Headache Syndromes. American Lecture Series. Springfield, Illinois, Charles C Thomas, 1962. Wolff, HG: Headache and Other Head Pain (3rd ed). Oxford Press (revised by Donald Dalessio, M.D.), 1972. DISCUSSION Question: Dr. Graham, do you feel that a single dose of Cafergot(r) in a pregnant woman is of more risk to the developing fetus or of immediate abortion? Dr. Graham: I don't know about the risk to the fetus. The use of ergotamine tartrate to induce abortion has not been particularly successful; however, I think you are obliged to avoid it during pregnancy because of its oxytocic effect. If you have to use any form of the ergotamines, dihydroergotamine, which is much less oxytocic, is alleged to be safe up to the eighth month. Personally, I think that when a patient becomes pregnant - the first sign of which may be relief of her headaches - one is well advised to stop the use of ergot derivatives, except possibly in very exceptional cases. Question: Does anyone know of any evidence of damage to a developing fetus? Richard V. Albery, M.D., Phoenix, Arizona: The data from animal studies show that Cafergot causes decreased placental blood supply and fetal reabsorption, but I don't know of any evidence that it has a teratogenic effect in humans. Gleb G. Bourianoff, M.D., Houston, Texas: Earlier this year, in a letter to Headache, Dr. Diamond reported several cases of fibrotic complications from propranolol. Have there been any further developments? Seymour Diamond, M.D., Chicago, Illinois: In my letter, I mentioned that there had been two isolated reports of fibrosis with the use of propranolol, and I asked that if any others are also observing this, they should mention it. But at this time I have not heard of any additional reports of this finding. Dr. Graham: There have been perhaps half a dozen or so reports - some from the Australian literature indicating the development of intraperitoneal fibrosis, in particular, in patients taking propranolol. It's very hard to decide that a drug is causing a complication of that sort without many more data. I have one patient to whom I had given propranolol for a cardiac condition. This patient had three recurrences of severe abdominal adhesions, requiring surgery to undo the obstruction which resulted. When we stopped giving propranolol, the patient's complications also stopped. I think we should bear in mind that there may be some relation between fibrosis and drugs that block the beta-adrenergic system.
