ORIGINAL ARTICLES

"COMPLICATED MIGRAINE" ITS ASSOCIATION WITH INCREASED PLATELET AGGREGABILITY AND ABNORMAL PLASMA COAGULATION FACTORS ZDENKA KALENDOVSKY, M.D. JAMES H. AUSTIN, M.D. H. G. Wolff, M.D. Lecture Award, 1974. INTRODUCTION EPISODES OF TRANSIENT focal cerebral dysfunction are disturbing events in almost one-third of patients who have classical migraine.1 Our concern in this paper is why some of these episodes should be prolonged. These episodes themselves have been thought to be the result of vasoconstriction, of cerebral edema or edema of vessel walls.1,2,3,4 The focal symptoms usually correspond to the vascular territory of one major or minor branch at a time, even though several recent studies of regional cerebral blood flow during migraine have shown the reduction of flow was a generalized phenomenon involving the entire hemisphere.5,6,7 It is of interest that focal symptoms sometimes occur during the headache phase, regarded as a time of vasodilatation, and also occur in migraine patients in the absence of headache.8,9 These focal symptoms, usually transient, may sometimes persist for many hours or days1,10,11,12 or may even progress and become a cause of death.13 More and more authors admit the possibility that thrombosis might occur in these cases and indeed, thrombi have been demonstrated.1,2,12,14 It is important to note that these data involve young patients whose vessel walls show no local atherosclerosis or other obvious local process precipitating the thrombosis. These considerations together with our recent experience with several young patients who had both recurrent cerebrovascular occlusions and a history of migraine11 led us to the present study. We wished to measure the two coagulation mechanisms in blood, abnormalities of which can lead to thrombosis: 1) platelet aggregability,15,16 2) plasma coagulation factors.17 The aim of this study was: 1) to find whether vasoneuractive substances such as serotonin and epinephrine, already implicated in vascular pain, also cause platelets of migraine patients to become hyperaggregable, 2) if so, to determine whether such hyperaggregability would be genetically-determined noting that migraine itself is regarded as a genetic disease,9,18-23 and 3) to see whether the incidence and character of focal symptoms in migraine correlated with any abnormality in the two major coagulation mechanisms in blood. CLINICAL MATERIAL AND METHODS General approach Nineteen patients were studied whose vascular headaches were of the migraine type.24 Their ages ranged from 19 to 64 years. Five had classical migraine, 5 common migraine, 1 typical cluster headaches, 1 both classical migraine and cluster headaches, and 7 "complicated migraine".3,8,10,14 For the purposes of this study, complicated migraine was defined as prolonged episodes of focal cerebral deficit associated with, or occurring independently of, headaches. Six women and one man had complicated migraine. All patients in this group were younger than 46 years, and the average age was 31 years. Three patients with complicated migraine were hospitalized during or close-

ly following one such episode marked by prominent focal neurological deficit. The remaining patients were studied and followed in our neurology out-patient clinic. In two patients who had complicated migraine, the other family members were also studied. Each patient had a detailed personal and family history, a thorough general physical and neurological examination. Routine blood tests and urine analysis were used to exclude diabetes, hyperlipidemia, kidney and liver diseases and obvious hematological abnormality. All patients also had an EKG, skull and chest x-rays. Patients with complicated migraine and those over 50 years also had an EEG and brain scan. Two patients with complicated migraine had 4 vessel angiography performed via femoral artery catheterization. The control group included 23 subjects, 16 men and 7 women, none of whom had a personal or family history of migraine or early hypertension. They were drawn from an outpatient population and from the medical school personnel. Their ages ranged from 20-80 years, and averaged 34 years. Four were over 50 years of age. Special coagulation studies 1. Platelet aggregability: In patients with uncomplicated migraine, the studies were performed in between headache episodes. In patients who had complicated migraine, the studies were deferred sufficiently long after a completed stroke or last episode of transient focal cerebral dysfunction (Table 4) so as to exclude direct effects of tissue destruction and/ or direct effect of estrogens on platelets.25,26 Patient 7 was studied within the first week after she stopped using oral contraceptives, and her results were not included in the final statistical evaluation. Procedure: Whole venous blood without anticoagulants was used immediately after withdrawal. Platelet aggregability was measured in the Screen filtration pressure apparatus as described by Swank.27-29 The technical details of our procedure are described elsewhere in detail.11 In essence, this method measures the pressure required to force a standard amount of blood at a constant rate through a screen with openings 20 micra square and 20 micra deep. When platelet aggregates form, they obstruct the screen and the pressure rises. Anticoagulants are avoided because they all to some extent compromise platelet function.27-30 The aggregating agents were obtained commercially (SIGMA) and included: adenosine 5'-diphosphate (ADP), L-epinephrine (EPI), 5-hydroxytryptamine (serotonin; 5-HT) as the creatine sulfate complex. 5-hydroxytryptamine was calculated as the free base. The concentrations used were: ADP 2 µg/cc blood (4.24 X 10-6,); epinephrine 2.5 µg/cc blood (1.36 X 10-5M) and serotonin 4.5 µg/cc blood (2.58 X 10-5M). 2. Coagulation panel: These tests were performed only in patients with complicated migraine. The patients were studied while. they were in the acute stage of focal cerebral dysfunction before angiography, and within one week after their last transient episode or completed stroke. The tests performed cover various parameters of the plasma coagulation system.17 The studies were performed in the special Coagulation laboratory of the University of Colorado Medical Center and in the laboratories of the Denver General Hospital. This panel gives valuable information in the following two areas: a. Factors promoting clotting: kinetics of thrombin generation (thrombin generation test), the kinetics of fibrin formation (thromboelastography). b. Factors inhibiting clotting: spontaneous fibrinolytic activity (euglobulin lysis test), antithrombin III. 3. Indication that intravascular clotting is taking place: the presence of circulating fibrin monomers; a substantial drop in platelet count (more than 100,000) and fibrinogen (to levels below 160 mg%); presence of spontaneous platelet aggregation in platelet-rich plasma.

TABLE 1

-

F, FR M F S

F, FR

-

Hypertension

-

-

M† F -

-

-

Stroke

-

-

M -

M

Thrombo-p hlebitis -

-

-

F, C

-

-

F, S

Allergies

-

-

-

-

-

-

-

-

Platelet Aggregability and Pertinent Personal and Family History in Patients with Uncomplicated Migraine screen filtration Family History** pressure (mm Hg)* Pertinent Personal History Patient Age and Basal ADP EPI 5-HT Migraine No. Sex 8 24 M 26 205 405 340 Cluster headache 9 32 F 29 345 440 297 Common migraine; on M, MR con-traceptives for 10 years in the past; food allergy 10 25 F 20 158 > 450 > 450 Classical migraine; while on M, S contraceptives intensity and frequency increased 11 23 F 22 235 397 430 Common migraine M, S 12 45 F 12 265 477 425 Classical migraine M 13 31 M 18 258 407 450 Common migraine M, S 14 52 F 36 281 561 525 Classical migraine; recent increase in frequency 15 52 M 26 127 178 295 Classical migraine, lately M, S also cluster headache; food allergy 16 64 F 26 300 345 285 Common migraine S, C 17 63 M 25 224 337 421 Classical migraine; at age M, S 63 mild CVA 18 52 M 12 200 350 320 Classical migraine; at age M 62 awakened with left hemiplegia 19 57 F 27 130 90 225 Common migraine FR, C *Underlined values exceeded the normal upper limit mother; F, father; S, sibling; C, child; MR, relatives of mother; FR, relatives of father; --, absent Several CVA in presence of documented blood hypercoagulability **M,



TABLE 2

Family

Mother and siblings of patient No. 1

Age and Sex 42 F yes

yes

Headache

33

28

24

Basal

363

265

302

ADP

520

470

407

EPI

515

405

305

5-HT

Common migraine, sometimes incapacitating

Common migraine

Common migraine

Pertinent Personal History

M yes

Platelet Aggregability in Relatives of Patients with Complicated Migraine Screen filtration pressure (mm Hg)* Remarks

20 M 245 555

Relatives

1A 17 245 460

Mother

1B 203 408

On contraceptives 2 months later.

23 44

372 200

no yes

385 357

M F

277 200

12 59

22 24

1C Mother

yes

365 No headache. During headache In between headaches

Premenstrual common migraine; increase in frequency and intensity while on contraceptives Leftsided classical migraine independent of menstrual periods Common migraine; last two months cluster headaches Common migraine; last year with increasing frequency -

Common migraine, lately increasing in frequency and intensity; 10 years bronchial asthma and mild hypertension

F

195

20

195

6A

24

16 F yes

yes

6B 15 M

F

6C 14

yes

6D

500 637 615 585 447

no

447 555 655 562 425

M

345 330 405 356 157

13

24 24 24 26 23

6E Underlined values exceeded the normal upper limit

Mother and children of patient No. 6

*

TABLE 3 Family History of Patients with Complicated Migraine Family History of* Group of patients Sub-Group I (without plasma hypercoagulability) Sub-Group II (with plasma hypercoagulability)

Patient No. Migraine Hypertension Stroke Thrombophlebitis 1 M, MR, S 2 M, MR, C 3 M, F†, S 4 M M, S M, S 5 F F 6 M, C M 7 MR, F MR MR *M, mother; F, father; S, sibling; C, child; MR, relatives of mother; FR, relatives of father; -, absent †Father had life-long history of classical migraine; at age 40 he started having also "migraine without headache".

Diabetes F -

Allergies -

Seizure disorder -

Clinical material Table 1 summarizes the clinical characteristics and pertinent family histories of 12 patients with uncomplicated migraine. Table 2 summarizes the clinical characteristics of ten relatives of two patients who had complicated migraine. The following are abstracts of case reports of patients who had complicated migraine. Their pertinent family histories are summarized in Table 3. SUB-GROUP I PATIENTS WITH PLATELET HYPERAGGREGABILITY ONLY Patient No. 1 -- Basilar artery migraine,3 recently hemiplegic migraine. This 19-year-old Spanish-American female had recurrent episodes characterized by sudden onset of dizziness, nausea, vomiting and confusion associated with severe occipito-cervical headaches lasting one to several days. These occurred at the age of five, six, eight, thirteen and seventeen years. The first episode occurred while she was swinging, and at this time she fell off the swing and briefly lost consciousness.31 No seizure activity was observed, but an EEG done at another institution was said to be "abnormal".32 During the last two years, the character of her headache changed, and she had them more frequently3/4every 2-3 months. Several hours before each headache, she experienced a swollen feeling in the face. She then suddenly developed blurred vision in her left visual fields, numbness and weakness of her left hand and usually some difficulty speaking. As these symptoms waned during the next 1-2 hours, she gradually developed a bitemporo-occipital throbbing headache lasting up to two days. During the headache she became nauseated, dizzy and vomited frequently. Sometimes she had such headaches without preceding focal symptomatology. She had never taken contraceptives. Patient No. 2 -- Multiple episodes of cerebral dysfunction in the territory of left internal carotid artery occurred independently of attacks of classical right-sided migraine. Pulmonary embolus recently complicated major surgery. Since age 17, this 35-year-old, white woman had yearly episodes introduced by sudden blurring of vision in her left eye, followed by numbness and occasional weakness of her right upper extremity and right side of her face. She also experienced garbled speech and inability to find the correct words for her thoughts. The symptoms reached their peak 20 minutes after onset.

None of these episodes was associated with headache. Each disappeared without residuum in two to four hours. During her four pregnancies she had no such episodes. In addition to this, since age 17, she also had severe always right-sided trrobbing frontotemporal headaches lasting 2-4 days, occurring every 2-3 months. They were introduced by scintillating scotoma in both eyes and accompanied by photophobia and nausea. During the past 6 months, she had six episodes of mild dull left-sided retrobulbar pain and nausea, each lasting several hours to two days. Several hours after the onset of such pain, she suddenly became very light-headed and gradually started losing the vision in her left eye. Within an hour, she became completely blind in the left eye. The blindness resolved over a 3-4 hour period. Past medical history revealed that she had received estrogen injections for dysmenorrhea for the past two years. Three months ago, she had an abdominal hysterectomy for a myomatous uterus and a right salpingectomy. As an incidental finding, a small carcinoid, limited to the appendix, was removed. Following the operation, the dosage of estrogens was doubled. A pulmonary embolus occurred one week postoperatively, and she received heparin until one month prior to our examination. Patient No. 3 -- During contraceptive therapy, classical migraine culminated in a single attack of hemiplegic migraine. This 19-year-old white woman had occasional dull frontal headaches related to tension and occasionally to menstruation. For the previous 14 mouths, she took birth control pills ("Norinyl 1 +80 21 days".) Her chief complaint was blurring of vision in the left visual fields lasting 15 minutes. As vision was returning she developed numbness in her left hand, then numbness of the left side of her face. These symptoms cleared in about 5 minutes. Thereafter she developed a severe right sided throbbing headache lasting about 5 hours. She did not feel nauseated, nor did she vomit.14 This episode occurred at work at 11 a.m., and when examined 4 hours later, her neurological examination was entirely normal, but she still complained of headache. Seven months before this, having then been on the "pill" for 6 months,18 she developed severe alternating hemicranial aches occurring twice a month. None of her previous headaches were accompanied by any visual or sensory symptoms. SUB-GROUP II PATIENTS WITH BOTH PLATELET HYPERAGGREGABILITY AND PLASMA HYPERCOAGULABILITY Patient No. 4 -- A completed stroke occurred three weeks post-partum, during a prolonged period of decompensated vascular headache and against a background of life-long common migraine. This 32-year-old white woman had common migraine infrequently since the age of 15. Three years ago, for 1 year, she was on contraceptives (Orthonovum 1/80 - 21). Her third and fifth pregnancy ended by miscarriage in the 6th and 4th month. Therefore, during her sixth and last pregnancy, she was on supportive hormonal therapy and progesterone 25 mg/day. Five months ago, she gave birth to her last child. This last pregnancy and labor were otherwise uneventful. During her first week post-partum, she received Diethylstilbesterol orally, 15 mg/ day, to suppress lactation.33 Three days later, she began to have dull generalized headaches that at times became throbbing. The first few days these headaches would last only part of the day, but they gradually became constant during the following two weeks. They also became more severe and more throbbing.14 At the end of this two-weeks period in the late afternoon, she arose to feed the child, collapsed on the floor, and awakened unable to speak about 30 minutes later with a profound weakness of the right side of her body. At the hospital 1 hour later, she was drowsy, had a marked right-sided hemiparesis, a total expressive aphasia and a right-sided homonymous hemianopsia. During the first few hours in the hospital, her hemiparesis rapidly improved. At this time, a left carotid angiogram through direct carotid puncture was performed. It showed marked narrowing extending for 40 mm of the extracranial and infraclinoid portion of her left internal carotid artery. There was only a delayed flush filling of several Sylvian branches on the left. During the procedure, and shortly after the injection of contrast material, the patient had a right-sided focal seizure involving her face and upper extremity. Over the next few hours, her focal deficit again increased, and thereafter her improvement was much more gradual. She was discharged 3 weeks later with a mild right hemiparesis and residual aphasia. On the fourth day, she had four-vessel angiography through a femoral catheter. This confirmed the narrowing of the left internal carotid artery and showed collateral filling of the left anterior and middle cerebral arteries via the right carotid and left posterior cerebral arteries. All other vessels were normal including the aortic arch.

On subsequent visits to the neurology clinic, she complained of only occasional mild headache identical to those she had all her life. Patient No. 5 -- Life-long history of migraine. Episodes of cerebral dysfunction in the territory of the right posterior cerebral artery occurred during a time of documented plasma hypercoagulability. This 46-year-old white woman had a life-long history of throbbing occipital headaches that sometimes became generalized. They usually began in the morning upon awakening and were often introduced by blurred vision in both eyes and nausea. They regularly preceded menstruation but also occurred once or twice a month at other times. Three years ago, when she was receiving "hormone shots" for climacteric symptoms, her headaches increased so much in frequency and intensity over the 12 months period that hormonal therapy had to be stopped.18 One year ago, she had a mild dull constant bitemporo-occipital headache for four days. The fourth day, while washing dishes, she suddenly developed weakness and numbness of the left extremities. At the same time, she became dizzy, very nauseated and vomited. She also noted diplopia briefly and then her vision became blurred in both eyes. All symptoms subsided in 15 minutes, but were then followed by a severe generalized throbbing headache that lasted one week. The following day, during the headache, she had two more episodes of identical neurological symptoms, each lasting several minutes. She was admitted several hours after the last one. At that time, she complained of generalized headache and left-sided numbness. Examination revealed only hyperesthesia to pin prick over the entire left side of the body. Four vesseel angiography revealed no occlusion or abnormality in the vessels. Brain scan was normal. Following discharge of Aspirin, 1 g/day, she had no further episodes of focal cerebral dysfunction. Frequent throbbing occipital headaches have continued, each lasting 3-4 days, and accompanied by dizziness, nausea and vomiting. Patient No. 6 -- Acute left ponto-medullary syndrome on a background of recurrent occipital headache. The patient was described in detail previously.11 He was a 38-year-old white male with a five year history of recurrent brief stiffness of the neck muscles. This was followed by a dull occipital headache that became throbbing on physical activity. His headache lasted 1 day to 1 week, and was accompanied by photophobia. One such headache was complicated 2 hours after onset by the sudden development of a left ponto-medullary syndrome. He was placed on Coumadin and has remained on it with good control since. Since then, his headaches have recurred rarely, but 1-2 times a week he has had the sudden onset of generalized tiredness and weakness in all four extremities, tingling in the left tide of his face and drooping of his left eyelid. During this 15 months follow-up period, his prothrombin time was kept between 20-40% of control, but spontaneous platelet aggregation was observed in platelet-rich plasma and his platelet survival time was shortened from a normal of 3.4 ± .21 days16 to only 2.0 days. Patient No. 7 -- Long history of common migraine. Onset of complicated migraine with focal symptomatology referable to vertebrobasilar circulation during estrogen therapy. This 25-year-old Negro woman had mild common migraine headaches once a month since age 19. Eight months ago, she underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy for acute and chronic pelvic inflammation. Subsequently, shee took 2.5 mg/ day of Premarin (conjugated equine estrogen). During the last 3 months of this therapy, her headaches became more severe, occurred almost daily and were associated with new symptoms. Her latest type of headache was introduced by sudden blurring of vision in both eyes and diplopia suggesting dysfunction of the left abducens nerve. She then experienced rotatory vertigo, a tendency to fall to the right side and bilateral tinnitus. At this point, she became nauseated, frequently vomited, and experienced numbness and weakness of her right extremity and tongue. These symptoms lasted from 10 minutes to 2 hours and were followed by a severe throbbing occipital headache. This spread first to one or the other hemicranium and finally became generalized lasting 4-10 hours. During the week before she was seen, on two occasions, her focal symptoms started during the headache. In recent weeks, she also had 4 episodes of the sudden onset of ringing in the right ear, followed by reduced hearing lasting 12 hours, but without associated headache. RESULTS A. Special Coagulation Studies 1. Survey of plasma coagulation tests. In association with acute episodes of focal cerebral dysfunction, the tests revealed hypercoagulability in four out of seven patients with complicated migraine (patients 4-7): a. Clot promoting factors. Each of the four patients showed enhanced formation and increased yield of thrombin on the thrombin generation test, and

enhanced formation of fibrin on thromboelastogram. b. Coagulation inhibiting factors. Antithrombin III was decreased in patients 5 and 6 and was in the low normal range in patients 5 and 7.37 Fibrinolytic activity was normal in all patients. 2. Evidence of intravascular clotting. The additional findings in patients 4 and 5 suggested that intravascular clotting had occurred. Thus, the fibrinogen level in patient 4 dropped to only 50 mg% (normal 160-420 mg%); her platelet count dropped to only 100,000. On subsequent visits to the neurology clinic, her average levels of fibrinogen ranged from 180 to 250 mg% and her usual platelet count ranged from 250,000 to 305,000. In patient 5, an increased level of fibrin monomers was found (

"Complicated migraine" its association with increased platelet aggregability and abnormal plasma coagulation factors.

ORIGINAL ARTICLES "COMPLICATED MIGRAINE" ITS ASSOCIATION WITH INCREASED PLATELET AGGREGABILITY AND ABNORMAL PLASMA COAGULATION FACTORS ZDENKA KALENDO...
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