Migraine, Large Pupils, Mitral Valve Prolapse and Emotional Disturbances: An AutonomicDisorder

Peter Herman, M.D.

Department of Neurology, Mount Sinai Medical Center, New York, N.Y.

Reprint requests to: Peter Herman, M.D., Pupillography Lab, Annenberg Bldg. Rm. 213, Mount Sinai Medical Center, OneGustave L. Levy Place, New York, N.Y. 10029.

Accepted for Publication: May 12, 1987.

SYNOPSIS

Thirteen young women with vascular headaches and unusually large pupils seen at the Mount Sinai Headache Clinic, wereinvestigated for the presence of autonomic dysfunction. Two had had a significant cerebral event: one, a frontal infarct andone, a transient hemisphere deficit.

Measurement of the pupil size by pupillography showed only a small increase in size after Paredrine drops, indicating apartial saturation of iris adrenergic receptors.

Hypertension was present in three, and low blood pressure in five. Red blotching of the face, neck, and thorax waspresent in seven. Emotional disturbances ranging from neurosis to manic depressive episodes and schizoid features werepresent in all. Echocardiography performed in nine patients demonstrated a mitral valve prolapse in eight.

The severe headaches, as well as the mood swings and occasional cardiac complaints, responded well to propranolol(Inderal). This syndrome of autonomic dysfunction is thought to be a variant of "hyperdynamic ß adrenergic circulatory state"(1-2) affecting the vessels of the scalp, skin, heart, and iris.

The presence of M.V.P. places these migraine patients in a certain cardiac and neurologic risk category. Young patients with adiagnosis of ophthalmoplegic and hemiplegic migraine, should have a thorough cardiac evaluation in addition to CT Scan.

(Headache 27:340-344, 1987)

INTRODUCTION

The abundance of pain-sensitive cephalic vessels was demonstrated experimentally in 1940.3 Variation in the diameter of thesevessels and the subsequent changes in blood flow are caused partly by biogenic amines.4,5 Some evidence for variations in biogenicamines, and particularly in noradrenaline levels, in certain headache syndromes has been obtained by showing supersensitivity of thepupil to phenylephrine.6,7,8 Hyperdynamic beta-adrenergic circulatory state and its effects on the heart vessels and mood was describedin the early 1960's,1,2 although headaches were not specifically mentioned. More recently, a symptom complex, possibly caused byvariations in noradrenaline levels and receptors in many target organs, has been studied at the Mount Sinai Headache Clinic in youngwomen with severe headaches and large pupils. The purpose of this communication is to describe the clinical presentation of thesepatients, and the results of their pupillary and cardiac investigation. Propranolol (Inderal) has brought about rapid, prolonged relief.

REPRESENTATIVE CASES

Case #1. A thirty-year old female has had headaches since age 12. At times, they woke the patient up at night and wereaccompanied by vomiting, scotoma and chills. There was a history of past and present anxiety neurosis. Previous response to treatmentwith analgesics and ergot derivatives was poor.

The neurological examination was normal save for absent stretch reflexes and very large but reactive pupils. The blood pressure was100/80; pulse was 80.

The pupillography showed large unequal near maximal size pupils with normal light response and constriction. Her right pupil dilatedto Paredrine but the left one became smaller (See Table 2).

Routine laboratory tests including T4, 5-hr. GTT, and EKG were normal. During a trial of biofeedback, her pulse became veryirregular. Upon referral to a cardiologist, the diagnosis of mitral valve prolapse was documented. On propranolol, she had fairimprovement of her headaches and mood changes.

Case #6. A twenty-seven year old female with a long history of menstrual headaches had a grand mal seizure in 1981, secondary toa frontal infarct.

There was a past history of tension and occasional depression.

Significant findings included large pupils, left hyperreflexia and a left palmomental reflex. M.V.P. was documented byecho-cardiography. The pupilIography showed large pupils and nearly full dilation with Paredrine eye drops. She was treated originallywith phenobarbital and Esgic. Propranolol was added later with good results. Her sister has blotching of the skin, headaches, and amood disorder but has refused treatment.

Case #13. A 35-year-old, white female has since 1976 experienced spells of bright lights in the right visual field followed byheadache, confusion, and

nausea. On two occasions, the patient's right hand became numb and weak for hours. Spells occur about twice a year usually following exercise (playing tennis).

Her past history includes recurrent depression. She has experienced with excitement or anger, red blotching of the neck. Occasional shortness of breath, anda fast heartbeat have been noted, not always event-related.

A CT done in 1976 showed a ring-like density in the right parietal area. LP, EEG, and angiography were normal. A second CT performed in 1983 because ofrecurrent complicated migraine was normal. Her neurological examination was normal, save for a loud bruit at the base of the neck, on the right side.

Her EKG was normal on several occasions but in 1982, an echocardiogram demonstrated M.V.P. Her pupils were always strikingly large and thepupillography showed maximal dilation on Paredrine (See Table 2). Placed on propranolol, 80 mg. per day, she reports "being 50% better."

RESULTS

All the patients were white females, mean age 27 (See Table I). The duration of the headache history

Table 1

Saturated Blotching EmotionalMigraine Pupils M.V.P. of Skin Illness

1. J.G. 26 yo + + + - +2. G.B. 22 yo + N.D. + +3. J.B. 28 yo + + + + +4. S.H. 33 yo + + + + +5. R.W. 22 yo + + N.D. + ?6. V.K. 27 yo + + + - +7. L.B. 24 yo + + + - +8. J.P. 32 yo + + + + +9. M.M. 22 yo + + N.D. + +10. M.F. 27 yo + + - - +11. A.S. 38 yo + N.D. N.D. - +12. N.R. 29 yo + + + - -13. A.B. 34 yo + + + + +

N.D. = Not Done- = Absent

was variable; at times, as short as one year, and at other times beginning with menarche and extending through many years. Most patients had recurrent severeunilateral headaches associated with scotomata, vomiting, chills, and photophobia.

In some ways, the headache syndrome of these patients was no different from migraine as defined by the Ad-Hoc Committee.9 Various other features such asthe large pupils, frequent personality disorders, skin blotching, and very frequent presence of M.V.P. set this headache syndrome apart.

PUPILLOGRAPHY

Pupillography with an electronic scanner was performed under standard conditions.8 It showed (Table 2) that the average pupil diameter was significantlylarger than in the normal population10 (p<.05). Para-sympathetic inhibition was not a factor as shown by a normal constriction of the pupil (Table 2).

Paredrine 1% eye drops, a sympathomimethic,11 increased the pupil size but less than in a normal control group. We called this finding a "saturated pupil". Intwo patients, the pupil size decreased after Paredrine.

BLOOD PRESSURE

Measurements were taken from the left arm, with the patients seated. A Tycos office blood pressure cuff of regular size was used. Three measurements weredone.

Five patients had systolic blood pressure of 90 or lower; three were hypertensive (Figure 1). That patients with autonomic dysfunction have fluctuation

Table 2

Size Dilation Percentage of(mm.) (mm.) Constriction

R L R L R L1. J.G. 7.5 8.3 8.6 8.2 24 282. G.B. 5.8 6.4 7.9 7.9 38 403. J.B. 6.6 7.1 N.D. 34 334. S.H. 6.5 6.5 7.9 7.9 32 355. R.W. 7.0 7.5 8.5 8.5 28 226. V.K. 7.0 7.0 8.9 8.4 32 297. L.B. 8.9 9.0 8.3 9.0 24 218. J.P. 7.3 7.7 8.9 8.8 31 309. M.M. 8.4 8.0 9.0 9.0 25 2510. M.F. 8.0 8.0 9.1 9.3 29 2711. A.S. 6.3 7.0 7.8 8.0 19 2112. N.R. 7.3 7.0 9.5 9.6 34 3713. A.B. 6.5 7.0 9.0 8.8 44 37

N.D. Not Done

in blood pressure is well known and is recognized in a number of syndromes such as dysautonomia12 and Shy-Drager13 syndromes.

SKIN BLOTCHING

At least seven patients out of thirteen were aware of blotching of the skin, only one of them with exertion (Table 3). In the other six patients, skin blotching wascorrelated with mood changes such as excitement or anxiety, and visible mostly on the face, neck, and the chest. The literature on this subject is scant and theoccurrence of this skin finding with autonomic headaches has not been reported.

METANEPHRINE

Metanephrine levels in urine were measured, courtesy of Dr. S. Gitlow, by the Pisano method.

Five patients were examined. The levels were within normal limits. The urine specimens were,

Table 3Skin Blotching Distribution in Patients With Migraine and M.V.P.

Neck Chest Face Hand1. J.G. no no no no2. G.B. + + no no3. J.B. + + no no4. S.H. + + no no5. R.W. + + + no6. V.K. no no no no7. L.B. no ? ? ?8. J.P. + no + +9. M.M. + + no no10. M.F. no no no no11. A.S. no no no no12. N.R. no no no no13. A.B. + + + no

however, not necessarily obtained during headache periods.

MOOD CHANGES

Most patients were tense and anxious, with a long history of neurosis as shown by their early departure from home, unstable marital and social relationships,multiple job changes, and dissatisfaction with their present social and financial condition (Table 4). Specific psychiatric diagnoses include manic depressivefeatures in six, with radical mood swings, bouts of depression, and crying. Most of these symptoms occurred with headaches and alternated with periods of greatexcitement and feelings of elation, at which time few headaches were reported. The occurrence of severe headache in manic depressives has been described.14

Four patients had schizoid features and three of them were under psychiatric care.

Within this study it was not possible to correlate the mood swings with pupillary size and therefore, indirectly, with noradrenaline discharge. The studies ofRubin15 have attempted, in the past, to correlate mood changes and mental disease to pupil size.

NEUROLOGIC DATA

CT was performed in thirteen and was abnormal in two patients. Non-specific EEG abnormalities were found in four out of ten patients.

CARDIAC DISTURBANCES

A history of chest pain was elicited in at least two patients (#1 and #7) and tachycardia or irregular heart rhythm were found in ten others (Table 5).

Echocardiography demonstrated the presence of mitral valve prolapse in eight out of the nine patients tested. The EKG was normal in five cases andabnormal in four.

DISCUSSION

A proposed role for neurotransmitters in migraine headaches is not new. Earlier in the century Wolff16 spoke of "headache stuff". Presently under investi-

Table 4Personality Disorders

Manic/ DepressiveNormal Depressed Neurosis Schizoid

1. J.G. +2. G.B. +3. J.B. + +4. S.H. +5. R.W. +6. V.K. +7. L.B. +8. J.P. + +9. M.M. +10. M.F. + +11. A.S. + +12. N.R. +13. A.B. +

Table 5Cardiac Disturbances

Tachycardia EKG ECHO/MVP1. J.G. + N.D. +2. G.B. + Normal N.D.3. J.B. + Normal (sinus arrhythmnia) +4. S.H. + Abnormal +5. R.W. - N.D. N.D.6. V.K. - Normal +7. L.B. + Abnormal +8. J.P. + Abnormal +9. M.M. + N.D. N.D.10. M.F. + Normal Normal11. A.S. + Normal N.D.12. N.R. + Normal +13. A.B. + Abnormal +

+ = PresentN.D. = Not Done

gation are prostaglandins, tyramine, and other headache-inducing substances such as serotonin and phyenyethylamine.

It is presently recognized that fluctuations in the level of biogenic amines occur in normals as well as in headache sufferers. Such fluctuationswere found in the diurnal cycle of steroids,17,18 and similar changes in endogenous opioids have recently been shown.19 The breakdown ofendogenous regulatory processes may be the reason for wide fluctuations of the diurnal cycle of biogenic amines. It is suggested that an excess ofadrenaline secreted at times of stress, or an increase in ß receptors induce vascular changes.

WHAT IS THE RELATION OF VASCULAR CHANGES AND MIGRAINE TO M.V.P.?

An association between M.V.P. and migraine was noted by Litman and Friedman in 1978.21 In a study of 230 females with M.V.P. they foundsixty-four (30%) with migraine.

Mitral valve prolapse is a fairly common condition, occurring in 5 to 12% of the young female population20 and often being a chance finding.

Barnett et al.22 have extensively studied the stroke syndrome associated with M.V.P. They found a young female sub-group with ischemic eventsmostly in the anterior circulation. They emphasized the risk of recurrent stroke and bacterial endocarditis in this population, mentioning cases ofsudden death and recommending the use of dipyridamole, and a.s.a. Interestingly, they did not comment on the association of migraine and M.V.P.which occurred in three of their cases. Others have pointed out23 that phenylepinephrine may induce chest pain in patients with M.V.P.

Frohlich, et al.1 and Gorlin2 have described a hyperadrenergic ß state associated with M.V.P. and briefly noted the mood changes of those patients.The autonomic dysfunction associated with M.V.P. was emphasized by Gaffney, et al in 1979;24 Whooley et al.25 have, in a brief abstract, describedevidence of "hyperadrenergic" state in M.V.P.

More recently, a link between M.V.P. and other psychiatric disorders such as psychoneurosis,26 the panic syndrome27 and anxiety neurosis,28 hasbecome recognized.

One must recognize that a stroke syndrome may occur in young females with these headaches (e.g.: our patient #6). When the syndromedescribed above is present, an echocardiogram is indicated as M.V.P. may be expected in a high percentage.

The suspicion of an adrenergic disturbance in these patients is at this time based on the tabulated clinical data (Table I), the indirect chemicalevidence for adrenaline variation in migraine,6,8 the hyperadrenergic ß state, and the large percentage of M.V.P. known to be associated withexcessive metanephrine.29 Up to 22% of M.V.P. cases may have false negative echocardiograms.30 Our only patient with negative echocardiogrammay belong to this group. The response of headaches, the leveling of mood changes and the disappearance of tachycardia with a beta blocker(propranolol) provides additonal evidence that adrenergic excess may be at fault. Only one of our patients did not report improvement with Inderal.Ergotamine had significant side effects in two of the patients.

A subgroup of patients with what may be a related disorder have combined M.V.P. aortic and tricuspid prolapse, and appear to be at a significantlyhigher risk for strokes.31

In a recent report, Spence et al.32 re-emphasize the platelet abnormalities in migraine and M.V.P. described by Barnett.33 They suspect thatstrokes may occur during migraine attacks in the above syndrome but stop short of recommending antiplatelet therapy with dipyridamole assuggested by others.34

Finally, a note of caution is sounded for making the diagnosis of ophthalmoplegic migraine and hemiplegic migraine without a thorough cardiacinvestigation. Especially in cases with familial occurrence35 echocardiography should be performed to rule out M.V.P. and other valvular diseases.

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