"MIGRAINOUS" NEUROLOGIC DYSFUNCTION IN PATIENTS WITH PROSTHETIC CARDIAC VALVES Louis R. Caplan Howard Weiner Ronald M. Weintraub W. Gerald Austen From the Departments of Neurology and Cardiac Surgery, Beth Israel Hospital and Harvard Medical School. Accepted for publication: 8/4/76 SYNOPSIS Two patients developed frequent, multifocal, transient episodes of central nervous system dysfunction, frequently accompanied by headache, 14 and 42 months after insertion of prosthetic cardiac valves. The disorder satisfied the criteria for the diagnosis of classic migraine; it was self-limited in one patient and remitted after diphenylhydantoin in the other. Three other patients with "migrainous accompaniments" after cardiac surgery have been seen. "Symptomatic migraine" may occur in patients with prosthetic cardiac valves. The mechanism and etiology of this disorder is obscure. (Headache 16: 218-221) REPEATED transient focal central nervous system dysfunction usually warns of an impending stroke. We have seen two patients who developed, after cardiac surgery, frequent, severe, multifocal, central nervous system dysfunction, sometimes accompanied by headache. In these patients, the disorder was self-limited and did not lead to permanent central nervous system deficits during three years of follow-up. In these patients many clinical criteria for classic migraine were present. It is, however, unusual for classic migraine to begin in a male in the fifth decade, in the absence of a family history. The relationship of these "migrainous episodes" to the thoracic surgery with implantation of prosthetic heart valves suggests "symptomatic migraine", or functional spasm of cerebral vessels produced, perhaps by tiny cerebrovascular emboli mimicking classic migraine. CASE 1 A 55 year old white man was hospitalized in August 1972, because of recurrent focal cerebral dysfunction. An aortic insufficiency murmur was noted at age 19. Two episodes of acute pulmonary edema and dyspnea on exertion led to elective heart surgery in February, 1969. A Starr-Edwards valve prosthesis was inserted through a median sternotomy incision during cardiopulmonary bypass, replacing a calcified deformed stenotic and insufficient aortic valve. The postoperative course was complicated by a temporary bleeding diathesis, ventricular irritability with congestive heart failure and a sternal wound infection. Because of continued chest pain and a draining wound, surgical debridement of sternal chondritis and osteomyelitis was performed in August 1969. Digitalis and Warfarin were given from 1969 to 1972, during which time the patient was asymptomatic. In August 1972, six episodes of neurological dysfunction occurred. First, his right hand suddenly became numb at work; the numbness spread slowly to the right arm and right face and was accompanied by dysarthria. The deficit lasted 30 minutes and was followed by a severe, throbbing headache with nausea. Later the same day the right arm was numb for 20 minutes. This was not accompanied by headache. Dipyridamole, 25 mg four times a day, was added to the Warfarin and digitalis therapy. Three days later, there was left hand numbness associated with dropping of objects and later headache. The fourth episode occurred while driving. This consisted of left hand numbness and weakness, lasting fifteen minutes. One day before hospital admission, he had difficulty breathing while walking. This was followed by tingling in the right fingertips which progressed slowly to the right hand and ann. Later he developed dysarthria with repetitive speech, and a left frontal headache. That night, he had a sixth episode consisting of pain ascending the left arm with concurrent inability to find words and slow speech. This episode lasted 10 minutes.
The patient was hospitalized for further evaluation. The blood pressure was 110/70. A soft basal systolic murmur and normal prosthetic valvular clicks were audible. Bibasilar pulmonary rales were present. There were no cervical bruits. Neurologic examination was entirely normal. Central retinal artery pressures were 50 bilaterally. Hematocrit, sedimentation rate, urinalysis, white blood count and Wasserman test gave normal results. A chest X-ray showed mild vascular redistribution. A phonocardiogram showed no ball variance indicated by a normal opening to closing click ratio of .8. Cardiac catheterization showed normal hemodynamics and cardiac output. Cine-fluoroscopy and angiocardiography gave normal results. The aortic valve prosthesis was normally located with normal movement. Three blood cultures were negative. An electroencephalogram showed intermittent theta slowing in the left temporal region. A brain scan was normal. Despite heparin therapy, he continued to have transient focal neurologic deficits with headache. One attack consisted of numbness in the right thigh and hand while walking down the hall. The numbness spread to the face, and he noticed difficulty speaking. Examination showed a fluent aphasia and slight weakness of the right hand. One hour later, he was neurologically normal, but complained of headache. The patient continued to have further episodes, one consisting of numbness in the left anterior thigh which slowly moved to the arm and shoulder and then to the face. This was followed by a slight dysarthria. After these episodes he sometimes had throbbing headache. At other times, headache occurred without neurologic dysfunction. Physical examination between episodes remained normal. Diphenylhydantoin, 100 mg three times a day, was begun and no further episodes occurred in the hospital. In the succeeding three years, he has remained on diphenylhydantoin therapy and has had no significant central nervous system dysfunction, no severe headaches, and no deterioration of cardiac function. The patient denied any personal or family history of severe headache or other episodic dysfunction that might suggest migraine. CASE 2 A 43 year old man, had acute rheumatic fever at age 13. Chest discomfort began five years later. Between 1950 and 1965, he developed anginal pain, and in 1971 was hospitalized because of congestive heart failure. He was found to have aortic insufficiency and premature ventricular contractions. Cardiac catheterization showed severe aortic and mitral regurgitation. Coronary angiography was normal. On September 30, 1971, under cardiopulmonary bypass, a large aortic valve with calcification and rolled cusps was replaced by a Starr-Edwards valve. Transient ventricular fibrillation was treated by hypothermia and 3 direct current counter shocks. The postoperative course was uneventful. In September 1972, a readmission for chest pain failed to reveal significant myocardial disease. He was maintained on digitalis, Quinidine, and Warfarin. In November 1972, he noticed his first severe headache. Subsequently, headaches occurred about three times a week and were located over the forehead or over either eye. At times, there was visual blurring when reading which was not specifically associated with headache. The headaches usually lasted two hours and were sometimes accompanied by nausea but not vomiting. Numbness of one hand, one shoulder, both hands, or a feeling of a fat lip sometimes occurred with headache, but he could not define at which stage of the headache the feeling appeared. These feelings lasted only 15 minutes and occasionally occurred without headache. Transient difficulty with speech accompanied by headache on two occasions had led to neurologic consultation. Neurologic examination was within normal limits. The carotid pulses were palpable without bruits. An electroencephalogram showed bilateral slowing more prominent over the left hemisphere. Prothrombin time was in good control. Blood cultures were negative. Hematocrit and sedimentation rate were normal. No malfunction of his valve was found. The patient was encouraged to keep a record of his headaches, samples of which follow: "10:40 p.m. while reading, numbness in the right wrist and forearm from knuckles to elbow, then moving to the right shoulder and then the rib cage. Some tingling then in the right jaw and right ear, lasted one half hour; no headache." "Later that same evening there was more tingling in the same area and then some in the lower lip and jaw. Severe headache in the forehead especially when coughing or sneezing". December 1. Mild headache mainly in the forehead, no numbness. December 5. Moderate headache left forehead, accompanied by numbness in the left arm for about an hour. December 6 and 8. Numbness in the left hand and the left rib cage lasting about an hour. December 11. Numbness began in the upper arm, moved into the cheek and tip of the nose, then the lip, then followed by a headache. The frequency and severity of headaches and neurologic symptoms began to decrease until they occurred only about one a month. The episodes ceased in the summer of 1973. None has occurred in the past two years. As a teenager the patient briefly experienced headache relieved by changing glasses, but there is no other family or personal history of headache and no family members with migraine. DISCUSSION In classic migraine, visual or other sensory symptoms precede headache. The central nervous system dysfunction usually lasts 15-30 minutes. Gowers1 and subsequently Fisher2 emphasized the gradual march of
sensory phenomena. Paresthesiae, for example, frequently "march" up an extremity, passing from one finger to another, subsequently involve the whole hand, then the arm, and then spread to another member. Frequently, the "march" is slow, with sensation returning to normal in one area by the time the next is affected. In addition, when multiple sensory phenomena-for example, visual, tactile, and speech dysfunction-are present, the visual dysfunction has often cleared by the time tactile dysfunction appears; and both may have cleared when the patient becomes dysphasic. The headaches frequently follow the prodromata and may be pounding and accompanied by nausea. The disorder usually lasts hours. In each of our patients, the length, nature, varied location and march of the prodromal symptoms were typical of migraine accompaniments. The throbbing headaches, associated with nausea, occurring in isolation, or after sensory symptoms, also seemed characteristic of migraine. Our patients fulfilled all the criteria for classic migraine. EEG abnormalities are frequently found in classic migraine3,4,5 and were present in each of our patients after an episode. Because of this, diphenylhydantoin was used in one of our patients. The presence of prosthetic heart valves in each patient led initially to the belief that they were suffering from recurrent cerebral emboli. Several observations were against the presence of large cerebral emboli, however. There was no dysfunction of the valves, demonstrated by negative blood cultures, normal fluoroscopy, normal cine angiography and the absence of cardiac complications. Warfarin, dipyridamole and heparin in one patient and Warfarin and dipyridamole failed in the second patient to stop or change the attacks. This would be unusual in patients with repeated embolization of blood products engrafted on cardiac valves.6 The absence of systemic emboli and the benign and self-limited nature of the disorder is inconsistent with significant embolization. Whether acquired disease of cerebral vessels can exactly mimic classic migraine has been much debated. In our patients, the late-life appearance of migraine without a family history argues against "idiopathic migraine". Also, the occurrence after cardiac surgery seems more than fortutitous. Three additonal patients have been seen by one of us (LRC) who have developed transient scotomata, recurrent paresthesiae, and zig-zag lines without headache 6-12 months after cardiac surgery without recognizable fixed neurologic deficit. Migraine is associated with functional alteration in vessel size and in cerebral blood flow7 without structural changes in blood vessels. The etiology of the functional vascular disorder in our patients has not been clarified. An adequate explanation must take into account: the presence of artificial heart valves; the delay in onset of at least 6 months postoperatively; the lack of response to heparin, Warfarin and dipyridamole; and the benign clinical course. Several possible causes of this migrainous syndrome require clarification. Dimmick8 et al have commonly observed anisotropic, intra-arterial fibers similar to cotton or cellulose in pathologic specimens of patients (after cardiac surgery or catheterization). These frequently affected the walls of small blood vessels. Perhaps foreign body release, even if minute, could incite spasm in cerebral vessels without leaving significant residue. "Bends" or air bubble release can mimic migrainous scotomata.9 Sudden changes in blood flow and volume may trigger migraine in susceptible individuals. Leviton10 and Leviton and Caplan11 have reported patients with headache and classic migraine after carotid endarterectomy. Anemia, fever, alcohol intake, reserpine or other causes of vasodilatation can cause headache. In our patients, however, the delay of more than 12 months after cardiac surgery before symptoms
appeared and the absence of obvious hemodynamic changes argue against this explanation. A drop in serotonin levels occurs in patients with migraine.12 A chemical factor related to the surgery might affect serotonin levels and trigger a migraine-like disorder. Postoperative serotonin metabolism has not been studied; but it would be unlikely that changes in serotonin levels would be limited to patients submitted to cardiac surgery only. A prospective study is now underway to determine the frequency of postoperative migraine. Patients with blood dyscrasias may suffer from migraine,9 and hyperprebetalipoproteinemia may produce migraine also.13 No hematologic or serologic changes were, however, identified in our patients. The etiology of migrainous dysfunction after cardiac surgery remains obscure, but it is important to recognize that it does occur, and in our experience this has been benign. Further studies are underway to elucidate the mechanism of this disorder. Dr. A. Stone Freedberg referred Case #1. REFERENCES 1.
Gowers, R: A Manual of Diseases of the Nervous System, 2nd edition; London: J & A Churchill 1892, 84-841.
2.
Fisher, C: Migrainous accompaniments versus arteriosclerotic ischemia. Transactions of the American Neurological Association 93:211-213, 1968.
3.
Engel, G, Hamburger, W, Reiser, M, and Plunkett, J: Electroencephalographic and psychological studies of a case of migraine with severe preheadache phenomena. Psychosomatic Med. 15: 337-348, 1953.
4.
Hockaday, JM, and Whitty, CWM: Factors determining the electroencephalogram in migraine. Brain 92: 769-788, 1969.
5.
Smyth, VOG, and Winter, AL: The EEG in migraine, EEG and Clinical Neurophysiology 16:194-292, 1964.
6.
Sullivan, J, Harken, D, and Gorlin, R: Pharmacological control of thromboembolic complications of cardiac-valve replacement. N. E. J. M. 279:576-580, 1968.
7.
Simard, D, and Paulson, OB: Cerebral vasomotor paralysis during migraine attack. Arch. Neurol. 29:207-209, 1973.
8.
Dimmick, JE, Bove, K, McAdams, AJ, and Benzing, G: Fiber embolization-a hazard of cardiac surgery and catheterization. N. E. J. M. 292: 685-686, 1975.
9.
Graham, J: Migraine: Clinical Aspects. In Vinken, PJ, and Bruyn, GW (Eds.): Headaches and Cranial Neuralgias, Volume 5, Handbook of Clinical Neurology, North Holland Publishing Company, Amsterdam, 1968, pp. 45-58.
10.
Leviton, A: Post carotid endarterectomy "Hemicrania," "Headache Rounds." Headache 15:13-17, 1975.
11.
Leviton, A, Caplan, LR, and Salzman, E: Severe headache following carotid endarterectomy. Headache 15:207-210, 1975.
12.
Anthony, M., Hinterberger, H, and Lance, JW: Plasma serotonin in migraine and stress. Arch. Neurol. 16:544-558, 1967.
13.
Leviton, A, and Camenga, D: Migraine associated with hyperprebetalipoproteinemia. Neurology 19:963-965, 1969. Reprint requests to: Dr. Louis R. Caplan Neurology Department Beth Israel Hospital Boston, MA 02215
The patient was hospitalized for further evaluation. The blood pressure was 110/70. A soft basal systolic murmur and normal prosthetic valvular clicks were audible. Bibasilar pulmonary rales were present. There were no cervical bruits. Neurologic examination was entirely normal. Central retinal artery pressures were 50 bilaterally. Hematocrit, sedimentation rate, urinalysis, white blood count and Wasserman test gave normal results. A chest X-ray showed mild vascular redistribution. A phonocardiogram showed no ball variance indicated by a normal opening to closing click ratio of .8. Cardiac catheterization showed normal hemodynamics and cardiac output. Cine-fluoroscopy and angiocardiography gave normal results. The aortic valve prosthesis was normally located with normal movement. Three blood cultures were negative. An electroencephalogram showed intermittent theta slowing in the left temporal region. A brain scan was normal. Despite heparin therapy, he continued to have transient focal neurologic deficits with headache. One attack consisted of numbness in the right thigh and hand while walking down the hall. The numbness spread to the face, and he noticed difficulty speaking. Examination showed a fluent aphasia and slight weakness of the right hand. One hour later, he was neurologically normal, but complained of headache. The patient continued to have further episodes, one consisting of numbness in the left anterior thigh which slowly moved to the arm and shoulder and then to the face. This was followed by a slight dysarthria. After these episodes he sometimes had throbbing headache. At other times, headache occurred without neurologic dysfunction. Physical examination between episodes remained normal. Diphenylhydantoin, 100 mg three times a day, was begun and no further episodes occurred in the hospital. In the succeeding three years, he has remained on diphenylhydantoin therapy and has had no significant central nervous system dysfunction, no severe headaches, and no deterioration of cardiac function. The patient denied any personal or family history of severe headache or other episodic dysfunction that might suggest migraine. CASE 2 A 43 year old man, had acute rheumatic fever at age 13. Chest discomfort began five years later. Between 1950 and 1965, he developed anginal pain, and in 1971 was hospitalized because of congestive heart failure. He was found to have aortic insufficiency and premature ventricular contractions. Cardiac catheterization showed severe aortic and mitral regurgitation. Coronary angiography was normal. On September 30, 1971, under cardiopulmonary bypass, a large aortic valve with calcification and rolled cusps was replaced by a Starr-Edwards valve. Transient ventricular fibrillation was treated by hypothermia and 3 direct current counter shocks. The postoperative course was uneventful. In September 1972, a readmission for chest pain failed to reveal significant myocardial disease. He was maintained on digitalis, Quinidine, and Warfarin. In November 1972, he noticed his first severe headache. Subsequently, headaches occurred about three times a week and were located over the forehead or over either eye. At times, there was visual blurring when reading which was not specifically associated with headache. The headaches usually lasted two hours and were sometimes accompanied by nausea but not vomiting. Numbness of one hand, one shoulder, both hands, or a feeling of a fat lip sometimes occurred with headache, but he could not define at which stage of the headache the feeling appeared. These feelings lasted only 15 minutes and occasionally occurred without headache. Transient difficulty with speech accompanied by headache on two occasions had led to neurologic consultation. Neurologic examination was within normal limits. The carotid pulses were palpable without bruits. An electroencephalogram showed bilateral slowing more prominent over the left hemisphere. Prothrombin time was in good control. Blood cultures were negative. Hematocrit and sedimentation rate were normal. No malfunction of his valve was found. The patient was encouraged to keep a record of his headaches, samples of which follow: "10:40 p.m. while reading, numbness in the right wrist and forearm from knuckles to elbow, then moving to the right shoulder and then the rib cage. Some tingling then in the right jaw and right ear, lasted one half hour; no headache." "Later that same evening there was more tingling in the same area and then some in the lower lip and jaw. Severe headache in the forehead especially when coughing or sneezing". December 1. Mild headache mainly in the forehead, no numbness. December 5. Moderate headache left forehead, accompanied by numbness in the left arm for about an hour. December 6 and 8. Numbness in the left hand and the left rib cage lasting about an hour. December 11. Numbness began in the upper arm, moved into the cheek and tip of the nose, then the lip, then followed by a headache. The frequency and severity of headaches and neurologic symptoms began to decrease until they occurred only about one a month. The episodes ceased in the summer of 1973. None has occurred in the past two years. As a teenager the patient briefly experienced headache relieved by changing glasses, but there is no other family or personal history of headache and no family members with migraine. DISCUSSION In classic migraine, visual or other sensory symptoms precede headache. The central nervous system dysfunction usually lasts 15-30 minutes. Gowers1 and subsequently Fisher2 emphasized the gradual march of
sensory phenomena. Paresthesiae, for example, frequently "march" up an extremity, passing from one finger to another, subsequently involve the whole hand, then the arm, and then spread to another member. Frequently, the "march" is slow, with sensation returning to normal in one area by the time the next is affected. In addition, when multiple sensory phenomena-for example, visual, tactile, and speech dysfunction-are present, the visual dysfunction has often cleared by the time tactile dysfunction appears; and both may have cleared when the patient becomes dysphasic. The headaches frequently follow the prodromata and may be pounding and accompanied by nausea. The disorder usually lasts hours. In each of our patients, the length, nature, varied location and march of the prodromal symptoms were typical of migraine accompaniments. The throbbing headaches, associated with nausea, occurring in isolation, or after sensory symptoms, also seemed characteristic of migraine. Our patients fulfilled all the criteria for classic migraine. EEG abnormalities are frequently found in classic migraine3,4,5 and were present in each of our patients after an episode. Because of this, diphenylhydantoin was used in one of our patients. The presence of prosthetic heart valves in each patient led initially to the belief that they were suffering from recurrent cerebral emboli. Several observations were against the presence of large cerebral emboli, however. There was no dysfunction of the valves, demonstrated by negative blood cultures, normal fluoroscopy, normal cine angiography and the absence of cardiac complications. Warfarin, dipyridamole and heparin in one patient and Warfarin and dipyridamole failed in the second patient to stop or change the attacks. This would be unusual in patients with repeated embolization of blood products engrafted on cardiac valves.6 The absence of systemic emboli and the benign and self-limited nature of the disorder is inconsistent with significant embolization. Whether acquired disease of cerebral vessels can exactly mimic classic migraine has been much debated. In our patients, the late-life appearance of migraine without a family history argues against "idiopathic migraine". Also, the occurrence after cardiac surgery seems more than fortutitous. Three additonal patients have been seen by one of us (LRC) who have developed transient scotomata, recurrent paresthesiae, and zig-zag lines without headache 6-12 months after cardiac surgery without recognizable fixed neurologic deficit. Migraine is associated with functional alteration in vessel size and in cerebral blood flow7 without structural changes in blood vessels. The etiology of the functional vascular disorder in our patients has not been clarified. An adequate explanation must take into account: the presence of artificial heart valves; the delay in onset of at least 6 months postoperatively; the lack of response to heparin, Warfarin and dipyridamole; and the benign clinical course. Several possible causes of this migrainous syndrome require clarification. Dimmick8 et al have commonly observed anisotropic, intra-arterial fibers similar to cotton or cellulose in pathologic specimens of patients (after cardiac surgery or catheterization). These frequently affected the walls of small blood vessels. Perhaps foreign body release, even if minute, could incite spasm in cerebral vessels without leaving significant residue. "Bends" or air bubble release can mimic migrainous scotomata.9 Sudden changes in blood flow and volume may trigger migraine in susceptible individuals. Leviton10 and Leviton and Caplan11 have reported patients with headache and classic migraine after carotid endarterectomy. Anemia, fever, alcohol intake, reserpine or other causes of vasodilatation can cause headache. In our patients, however, the delay of more than 12 months after cardiac surgery before symptoms
appeared and the absence of obvious hemodynamic changes argue against this explanation. A drop in serotonin levels occurs in patients with migraine.12 A chemical factor related to the surgery might affect serotonin levels and trigger a migraine-like disorder. Postoperative serotonin metabolism has not been studied; but it would be unlikely that changes in serotonin levels would be limited to patients submitted to cardiac surgery only. A prospective study is now underway to determine the frequency of postoperative migraine. Patients with blood dyscrasias may suffer from migraine,9 and hyperprebetalipoproteinemia may produce migraine also.13 No hematologic or serologic changes were, however, identified in our patients. The etiology of migrainous dysfunction after cardiac surgery remains obscure, but it is important to recognize that it does occur, and in our experience this has been benign. Further studies are underway to elucidate the mechanism of this disorder. Dr. A. Stone Freedberg referred Case #1. REFERENCES 1.
Gowers, R: A Manual of Diseases of the Nervous System, 2nd edition; London: J & A Churchill 1892, 84-841.
2.
Fisher, C: Migrainous accompaniments versus arteriosclerotic ischemia. Transactions of the American Neurological Association 93:211-213, 1968.
3.
Engel, G, Hamburger, W, Reiser, M, and Plunkett, J: Electroencephalographic and psychological studies of a case of migraine with severe preheadache phenomena. Psychosomatic Med. 15: 337-348, 1953.
4.
Hockaday, JM, and Whitty, CWM: Factors determining the electroencephalogram in migraine. Brain 92: 769-788, 1969.
5.
Smyth, VOG, and Winter, AL: The EEG in migraine, EEG and Clinical Neurophysiology 16:194-292, 1964.
6.
Sullivan, J, Harken, D, and Gorlin, R: Pharmacological control of thromboembolic complications of cardiac-valve replacement. N. E. J. M. 279:576-580, 1968.
7.
Simard, D, and Paulson, OB: Cerebral vasomotor paralysis during migraine attack. Arch. Neurol. 29:207-209, 1973.
8.
Dimmick, JE, Bove, K, McAdams, AJ, and Benzing, G: Fiber embolization-a hazard of cardiac surgery and catheterization. N. E. J. M. 292: 685-686, 1975.
9.
Graham, J: Migraine: Clinical Aspects. In Vinken, PJ, and Bruyn, GW (Eds.): Headaches and Cranial Neuralgias, Volume 5, Handbook of Clinical Neurology, North Holland Publishing Company, Amsterdam, 1968, pp. 45-58.
10.
Leviton, A: Post carotid endarterectomy "Hemicrania," "Headache Rounds." Headache 15:13-17, 1975.
11.
Leviton, A, Caplan, LR, and Salzman, E: Severe headache following carotid endarterectomy. Headache 15:207-210, 1975.
12.
Anthony, M., Hinterberger, H, and Lance, JW: Plasma serotonin in migraine and stress. Arch. Neurol. 16:544-558, 1967.
13.
Leviton, A, and Camenga, D: Migraine associated with hyperprebetalipoproteinemia. Neurology 19:963-965, 1969. Reprint requests to: Dr. Louis R. Caplan Neurology Department Beth Israel Hospital Boston, MA 02215
