CLUSTER HEADACHE AND BRADYCARDIA G.W. Bruyn, M.D. B.K. Bootsma, M.D. H.L. Klawans, M.D. From the Departments of Neurology and Cardiology, Central Military Hospital, Utrecht. The Netherlands and the Division of Neurology, Michael Reese Hospital and Medical Center, Chicago, Illinois Submitted for publication-6/23/75 Revision accepted-8/12/75 SYNOPSIS A case of classic cluster headaches associated with paroxysmal bradycardia and hypertension is presented. This case suggests that dysfunction in the medulla oblongata is the primary event in cluster headache. A preliminary hypothesis is discussed which attributes the pathogenesis of cluster headache to a burst of increased central a-adrenergic activity while migraine involves an analogous burst of b-adrenergic activity. A GREAT deal is now known about vascular mechanisms and humoral changes related to the pathogenesis of migraine,1,2 but the primary mechanisms remain unknown. No clues have been discovered about the initiating events leading to platelet release of serotonin and what enables migraineurs to know that they are about to have an attack. In cluster headache an equal ignorance about the causes of increase of histamine prevails. A unifying concept of the pathogenesis of migraine and cluster headache has not yet been formulated. Though some suggest a metabolic derangement in the pathogenesis of migraine and cluster headache, others hold that the decisive initiating event is a physiological alteration within the central nervous system.3 We felt that the following observations may contribute to the understanding of basic mechanisms involved in these syndromes. CASE REPORT The patient was a retired airplane telegrapher who developed cluster headaches at 47 (1965) shortly after his discharge from the airline. The attacks usually occurred between 1 and 7 AM with excruciating pain in the right eye and forehead, often driving him to run from the house, crying loudly, and to crash his head into the nearest tree. The attacks were associated with ipsilateral blockage of the nostril and watering of the eye. The episodes were often provoked by excessive alcohol intake and smoking. He was admitted to hospital because of the severity of the attacks. Clinical examination was unremarkable. A raised lumbar cerebrospinal fluid protein level (90 mg/100 ml) was found but no cause for this abnormality could be uncovered. The headaches improved after treatment with methysergide. The attacks recurred in a long-lasting cluster in 1969 and a second admission to hospital showed essentially normal values on examination of blood, urine, CSF, EEG, skull x-rays, and pneumoencephalograms. The patient had a myocardial infarction in 1971. He continued to smoke and drink heavily. On routine examination in 1973 the heart was normal; blood pressure was 130/80 mm Hg. His electrocardiogram showed sinus rhythm of 72 beats/minute with the pattern of an old inferior infarction. Atrio-ventricular conduction was normal. New bouts of headaches recurred in 1971, 1972, and 1973. We first saw the patient in 1973 when he stated that most of his attacks were associated with bradycardia. His electrocardiogram was monitored on four different occasions with a Holter-Avionics system during attacks. This showed an extreme sinus-bradycardia with occasional R-R intervals of 3 seconds (Figure 1). Each headache was associated with the onset of irregular heart activity developing into
bradycardia ranging from 20-44/min. The patient's normal heart rate average 66 to 70. At the beginning of the attack the blood pressure rose to between 180/150 and 240/130mm Hg at the height of the attack. A most intriguing symptom was coughing and the patient always felt the urge to cough as soon as his heart rhythm became irregular. DISCUSSION Alterations in heart rate are not usually described in either migraine or cluster headaches. Paroxysmal tachycardia has been considered by some observers to be a migraine equivalent.4,7 The association between migraine and bradycardia is exceptional.8,10 Gordon Holmes, in his discussion of the case presented by Fisher,10 pointed out that he had suffered from migraine for many years, but that in his case the pulse rate rose as soon as the headache began. Leon-Sotomayor11 recently reported a series of 12 patients with "cardiac migraine," in whom the prodromes of a migraine attack were associated with palpitation, giddiness, tremulousness, weakness, anxiety states, diaphoresis, and chest pain, occasionally radiating to the arm. Examination of these patients showed labile, orthostatically altered blood pressure, symptoms of functional hypoglycemia, and electrocardiographic signs of exaggerated sympathetic activity with segmental coronary spasm predominating on the left. Oral sugar, transiently, and nitroglycerin and propranolol effectively relieved the chest pain. Nitroglycerin relieved the headache prodrome when present but precipitated one when absent; ergotamine aborted the headache but induced or aggravated the chest pain; and betazole reproduced both headache and chest pain. The beneficial effect of prophylactically administered propranolol, a b-adrenoceptor blocker, in migraine has been reported.12 One would expect vasoconstriction induced by b-blockade to improve migraine. Propranolol however inhibits cerebral arterial spasm. Whether this differential effect is due to cardiac b1 and vasomuscular b2 receptor blockade by propranolol is not known. Ergotamine is an a-adrenergic blocker; however, it relieves the headache by causing arterial vasoconstriction due to a direct action on vascular smooth muscle. These paradoxic actions can be explained by assuming a fundamental difference between central and peripheral b- and a-adrenergic effects. It is tempting to interpret migraine as a central b-adrenergic paroxysm. A few instances of spontaneous bradycardia have been recorded during cluster headache. Whether the paucity of reports is a sign of the exquisite rarity of this occurrence, or the result of negligence in history taking, or to a lack of self-observation on the part of the patient remains an open question. Von Eulenburg13,14 deserves credit for the first description of cluster headache; he also noticed bradycardia in association with the headache (cited by Heyck, 1974). An inverse relationship between angina pectoris and cluster headache has been reported.15-17 Induced attacks of cluster headache in contrast to spontaneous attacks often are associated with bradycardia. Nitroglycerin, 1 mg sublingually, will provoke a typical attack within 1 hour in patients suffering from cluster headache, associated initially with sinus bradycardia, and increased blood pressure and at the end of the attack by tachycardia and reduced blood pressure. The electrocardiogram may show P wave changes indicating increased parasympathetic activity. Infusion of noradrenaline or exercise during the latent period between nitroglycerin administration and the onset of the attack relieves the pain.18,19 These observations suggest both sympathetic and parasympathetic stimulation. The patient reported here showed severe bradycardia and cardiac arrhythmia during his attacks only, suggesting a common underlying pathogenetic mechanism. Ptosis or Horner's syndrome occurs in cluster headache with a frequency of about 30 percent. This is usually interpreted as a sign of sympathetic paralysis. The other pathognomonic symptoms of cluster headache, ipsilateral tearing and rhinorrhea can be taken as manifestations of increased parasympathetic rather than decreased sympathetic activity although this has not been decided. Nausea and vomiting too, seem to result from an increase in vagus tone or
excitation of the tractus solitarius and dorsal vagal nuclei. The bradycardia in our patient could be the result of cardiac inhibition by excessive vagus tone. Moreover, the observation that cluster headaches often occur in periods of relaxation and within two hours after onset of sleep, ie, at a time of increased parasympathetic tone supports the notion that cluster headache is a parasympathetic paroxysm. The observation reported here constitutes additional evidence for a primary adnormality of autonomic centers in the lower brain stem in cluster headaches. The pathogenetic concept of imbalance between (nor) adrenergic excitatory and cholinergic (inhibitory) neuronal networks is probably too simple. Recent evidence shows the presence of central a-noradrenergic20,22 inhibitory interneurons in the lower brain stem. The activation of these interneurons reduces blood pressure contrary to expectation based on traditional concepts. Intracisternally administered noradrenaline, or its precursor levodopa, produced bradycardia and reduction of blood pressure. Amphetamine (with a peripheral hypertensive effect) when given centrally induced arterial hypotension because it liberates noradrenaline in the brain. This effect is abolished by haloperidol which blocks a-adrenoceptors. The hypotensive effect of a-methyldopa results from the stimulating effect of its metabolite, a-methylnoradrenaline, upon central a-adrenoceptors. Clonidine, an a-adrenoceptor stimulant, likewise has potent hypotensive activity. These compounds activate central a-adrenergic neurons which inhibit peripheral sympathetic outflow. Clonidine, probably due to the same central a-adrenoceptor stimulation shows also a significant effect on vagal activity.23 Experimentally, electrostimulation of a depressor area corresponding to the site of the nucleus tractus solitarii causes marked bradycardia, or hypotension.22 A lesion of the nucleus tractus solitarii at the level of the obex however results in arterial hypertension. Within this experimental area the first synapses occur of the afferent fibers of the carotid nerve from carotid sinus baroreceptors. The stereotaxic administration of noradrenaline within this region caused bradycardia and (systolic) hypotension which was blocked by local administration of phentolamine.22 On the basis of these findings the a-noradrenergic inhibitory cardiovascular control of the middle caudal part of the nucleus of the tractus solitarius was confirmed.22 The inhibitory control of this viscero-sensory nucleus is mediated via visceromotor efferent nuclei of the IXth and Xth nerve: the dorsal vagal and ambiguus nuclei. Local serotonergic activation results in hypotension, whereas parachlorophenylalanine-induced serotonin depletion causes systolic hypertension. Stimulation of the solitary vagal complex and of a well circumscribed area near the lateral reticular nucleus induced a pressor response of 30-100mm Hg, whereas stimulation of a midline band corresponding to the raphe nucleus caused a depressor response.24 Evoked responses were enhanced by noradrenaline and depressed by serotonin and its precursors 5-hydroxytryptophan and L-tryptophan. It was inferred that sympathetic preganglionic neurons are controlled by noradrenergic excitatory and serotonergic inhibitory systems, and that the effects of noradrenaline and serotonin are pH-dependent.24 The prototype of an a-adrenergic cardiovascular-inhibitory paroxysm of the Hering nerve-solitary tract-ambiguus nucleus system is the well-documented combination of glossopharyngeal neuralgia with cardiac arrhythmia, asystole and cardiac arrest, arterial hypotension, syncope, and convulsions.25,26 In this disorder both arterial hypotension and asystole, purely depressor effects, have repeatedly been noted. Our patient showed a more complex syndrome with a mixture of pressor effects (systolic hypertension and peripheral vasoconstriction in view of the raised diastotic pressure) and depressor effects (bradycardia), accompanied by an uncontrollable urge to cough (nuclei X and XII). The interpretation of cluster headache attacks as parasympathetic crises clearly is untenable in the light of the above findings.
There are other neurologic disease which may include similar cardiovascular phenomena. Patients with cerebrovascular accidents (subarachnoid hemorrhage), meningitis, and brain stem tumors27,30 often have ST, QTc, and T wave changes that may be normalized by isoproterenol, a sympathomimetic31 and by propranolol, a b-sympathicolytic.32 They may also have arrhythmias ranging from atrial tachycardia and nodal rhythms to A-V block and extrasystole.33,34 Wolf35 has shown experimentally that these arrhythmias result from nucleus ambiguus or nucleus tractus solitarii stimulation. Intracranial hypertension above systemic arterial pressure often produces symptoms similar to those shown by our patient and known by every neurologist as the Cushing Response. This response persists after adrenalectomy, after prepontine decerebration, and after transection of all cranial nerves, but disappears upon transection of the spinal cord at C1 level.36 The receptive site from which the Cushing response can be elicited by local tissue distortion (ie, stretch of dendrites and perikarya) either by direct pressure, local injection of fluid, or axial displacement of the brain stem has been shown to be the mesicaudal part of the floor of the IVth ventricle37,38 Figure 2). Although Brashear and Ross39 argued that ß-adrenergic agonists are implicated in the Cushing response, involvement of a-adrenergic structures appear much more likely. The cardiovascular symptoms in the Cushing response and in some cases of cluster headaches are identical and must be related to local changes in the same area of the brain stem in both instances. Both syndromes may best be interpreted as a-adrenergic cardiovascular inhibitory paroxysms. Levi,40 at the beginning of this century marshalled arguments to interpret migraine as "un syndrome du plancher du quatrième ventricule." The patient reported there supports the concept of dysfunction of the medulla oblongata in cluster headache. One interpretation of the present case may be the hypothesis that cluster headache is essentially a central a-adrenergic paroxysm (both excitatory and inhibitory) whereas migraine might well be a central ß-adrenergic paroxysm.
REFERENCES 1.
Wolff HG: Headache and other pain. (New York: Oxford University Press, 1963)
2.
Lance JW, Anthony M: Migrainous neuralgia or cluster headache. J Neurol Sci 13:401-414, 1971.
3.
Sjaastad O: Vascular and biochemical changes in migraine. Symposium on Migraine, May 1974, Rotterdam.
4.
Critchley M, Ferguson FR: Migraine. Lancet 1:123-126; 182-187; 205-206, 1933.
5.
Bassoe P: Migraine. J Am Med Assoc 101:599-605, 1933.
6.
Ask-Upmark E: Migraine as a deadly disease. Br Med J 11:823-825, 1960.
7.
Perera GA: Paroxysmal arrhythmias and migraine. J Am Med Assoc 215:488-451, 1971.
8.
Curschmann H: Migräne (Hemikranie), in Hanbuch der inneren Medizin, ed Mohr, L., and Stählin, Berlin, Springer, 1912, pp. 885-889.
9.
Sachs OW: Migraine. Evolution of a common disorder. London: Faber and Faber, 1970.
10.
Fisher JH: Migraine. Pro Roy Soc Med 12:49-55, 1919.
11.
Leon-Sotomayor L.A.: Cardiac migraine-report of twelve cases. Angiology 25:161-171, 1974.
12.
Ludvigsson J: Propranolol used in prophylaxis of migraine in children. Acta Neurol Scand 50:109-115, 1974.
13.
Eulenburg A: Hemicranie, in Handbuch der Spec. Patholog. und Ther., ed. von Ziemssen, H. Leipzig: F.C.W. Vogel, 1877.
14.
Eulenburg A: Lehrbuch der Nervenkrankheiten. Berlin: Hirschwald, 1878. p 264.
15.
Kunkle EL, Anderson WB: Significance of minor eye signs in headache of migraine type. Arch Ophthalmol 65:504-508, 1961.
16.
Ekbom K, Lindahl J: Headache 11:57-62, 1971.
17.
Graham JR: Cluster headache. Headache 11:175-185, 1972.
18.
Ekbom K: Heart rate, blood pressure, and ECG changes during provoked attacks of cluster headache. Acta Neurol Scand 46:215-224, 1970.
19.
Ekbom K: Clinical aspects of cluster headache. Headache 13:1974.
20.
von Zwieten PA: The central action of antihypertensive drugs, mediated via central a-receptors. J Pharm Pharmacol 25:89-95, 1973.
21.
De Jong W: Noradrenaline: Central inhibitory control of blood pressure and heart rate. Eur J Pharmacol 29:179-185, 1974.
22.
De Jong W, Zandberg P, Bohus B: Central inhibitory noradrenergic cardiovascular control. Pro Brain Res 42:285-294.
23.
Kobinger W, Walland A: Eur J Pharmacol 16:120-122, 1971.
24.
Neumayr J, Hare BD, Franz DN: Evidence for bulbospinal control of sympathetic preganglionic neurones by monoaminergic pathways. Life Sci 14:793-806, 1974.
25.
Garretson HD, Elvidge AR: Glossopharyngeal neuralgia with asystole and seizures. Arch Neurol 8:26-31, 1963.
26.
Al-Ubaidy SS, Bakeen G, Gossous M: Paroxysmal glossopharyngeal neuralgia associated with cardiac arrest. Br J Oral Surg 11:243-245, 1974.
27.
Korczyn HD, Spitzer S, Kott E, Bornstein B: ECG abnormalities in patients with brain stem tumor. Confin Neurol 33:304-308, 1971.
28.
Galloon S, Rees GAD, Briscoe CE: Prospective study of ECG changes associated with subarachnoid hemorrhage. Br J Anaesth 44:511-516, 1972.
29.
Smith M: Ventricular bigeminy and quadrigeminy occurring in a case of subarachnoid hemorrhage. J Electrocardiol 5:78-85, 1972.
30.
Anderson GJ, Woodburn R, Fisch C: Cerebrovascular accidents with unusual ECG changes. Am Heart J 86:395-398, 1973.
31.
Daoud FS, Surawicz B: The effect of isoproterenol on the ECG of patients with intracranial lesions. Am J Cardiol 26:629-630, 1970.
32.
Uchida M, Yamaoka H: Effect of ß-adrenergic blocking agents on the changes in the ST segment and T wave observed in patients with brain stem damage. Resp Circulat (Tokyo) 20:1073-1074, 1972.
33.
Hersch C: ECG changes in subarachnoid hemorrhage, meningitis, and intracranial space occupying lesions. Br Heart J 26:785-793, 1964.
34.
Surawicz B: ECG pattern of cerebrovascular accident. J Am Med Assoc 197:191-192, 1966.
35.
Wolf S: Central autonomic influences of cardiac rate and rhythm. Monograph Conc Cardiovasc Dis 38:29-34, 1969.
36.
Hoff JT, Reiss DJ: Localization of regions mediating the Cushing response in brain and spinal cord of cat. Arch Neurol 23:228-240, 1970.
37.
Doba N, Reis DJ: Localization within the lower brain stem of a receptive area mediating the pressor response to increased intracranial pressure (the Cushing response). Brain Res 47:487-491, 1972.
38.
Reis DJ, Doba N: The central nervous system and neurogenic hypertension. Prog Cardiovasc Dis 17:51-71, 1974.
39.
Brashear RE, Ross JC: Circulating beta-adrenergic stimulator during elevated CSF pressure. Arch Intern Med 127:748-753, 1971.
40.
Lévi L: La migraine commune; Syndrome bulboprotubérantiel. Rev Neurol 13:166-172, 1905. Reprint requests to: Prof. Dr. G.W. Bruyn Department of Neurology University Hospital Leyden, The Netherlands
bradycardia ranging from 20-44/min. The patient's normal heart rate average 66 to 70. At the beginning of the attack the blood pressure rose to between 180/150 and 240/130mm Hg at the height of the attack. A most intriguing symptom was coughing and the patient always felt the urge to cough as soon as his heart rhythm became irregular. DISCUSSION Alterations in heart rate are not usually described in either migraine or cluster headaches. Paroxysmal tachycardia has been considered by some observers to be a migraine equivalent.4,7 The association between migraine and bradycardia is exceptional.8,10 Gordon Holmes, in his discussion of the case presented by Fisher,10 pointed out that he had suffered from migraine for many years, but that in his case the pulse rate rose as soon as the headache began. Leon-Sotomayor11 recently reported a series of 12 patients with "cardiac migraine," in whom the prodromes of a migraine attack were associated with palpitation, giddiness, tremulousness, weakness, anxiety states, diaphoresis, and chest pain, occasionally radiating to the arm. Examination of these patients showed labile, orthostatically altered blood pressure, symptoms of functional hypoglycemia, and electrocardiographic signs of exaggerated sympathetic activity with segmental coronary spasm predominating on the left. Oral sugar, transiently, and nitroglycerin and propranolol effectively relieved the chest pain. Nitroglycerin relieved the headache prodrome when present but precipitated one when absent; ergotamine aborted the headache but induced or aggravated the chest pain; and betazole reproduced both headache and chest pain. The beneficial effect of prophylactically administered propranolol, a b-adrenoceptor blocker, in migraine has been reported.12 One would expect vasoconstriction induced by b-blockade to improve migraine. Propranolol however inhibits cerebral arterial spasm. Whether this differential effect is due to cardiac b1 and vasomuscular b2 receptor blockade by propranolol is not known. Ergotamine is an a-adrenergic blocker; however, it relieves the headache by causing arterial vasoconstriction due to a direct action on vascular smooth muscle. These paradoxic actions can be explained by assuming a fundamental difference between central and peripheral b- and a-adrenergic effects. It is tempting to interpret migraine as a central b-adrenergic paroxysm. A few instances of spontaneous bradycardia have been recorded during cluster headache. Whether the paucity of reports is a sign of the exquisite rarity of this occurrence, or the result of negligence in history taking, or to a lack of self-observation on the part of the patient remains an open question. Von Eulenburg13,14 deserves credit for the first description of cluster headache; he also noticed bradycardia in association with the headache (cited by Heyck, 1974). An inverse relationship between angina pectoris and cluster headache has been reported.15-17 Induced attacks of cluster headache in contrast to spontaneous attacks often are associated with bradycardia. Nitroglycerin, 1 mg sublingually, will provoke a typical attack within 1 hour in patients suffering from cluster headache, associated initially with sinus bradycardia, and increased blood pressure and at the end of the attack by tachycardia and reduced blood pressure. The electrocardiogram may show P wave changes indicating increased parasympathetic activity. Infusion of noradrenaline or exercise during the latent period between nitroglycerin administration and the onset of the attack relieves the pain.18,19 These observations suggest both sympathetic and parasympathetic stimulation. The patient reported here showed severe bradycardia and cardiac arrhythmia during his attacks only, suggesting a common underlying pathogenetic mechanism. Ptosis or Horner's syndrome occurs in cluster headache with a frequency of about 30 percent. This is usually interpreted as a sign of sympathetic paralysis. The other pathognomonic symptoms of cluster headache, ipsilateral tearing and rhinorrhea can be taken as manifestations of increased parasympathetic rather than decreased sympathetic activity although this has not been decided. Nausea and vomiting too, seem to result from an increase in vagus tone or
excitation of the tractus solitarius and dorsal vagal nuclei. The bradycardia in our patient could be the result of cardiac inhibition by excessive vagus tone. Moreover, the observation that cluster headaches often occur in periods of relaxation and within two hours after onset of sleep, ie, at a time of increased parasympathetic tone supports the notion that cluster headache is a parasympathetic paroxysm. The observation reported here constitutes additional evidence for a primary adnormality of autonomic centers in the lower brain stem in cluster headaches. The pathogenetic concept of imbalance between (nor) adrenergic excitatory and cholinergic (inhibitory) neuronal networks is probably too simple. Recent evidence shows the presence of central a-noradrenergic20,22 inhibitory interneurons in the lower brain stem. The activation of these interneurons reduces blood pressure contrary to expectation based on traditional concepts. Intracisternally administered noradrenaline, or its precursor levodopa, produced bradycardia and reduction of blood pressure. Amphetamine (with a peripheral hypertensive effect) when given centrally induced arterial hypotension because it liberates noradrenaline in the brain. This effect is abolished by haloperidol which blocks a-adrenoceptors. The hypotensive effect of a-methyldopa results from the stimulating effect of its metabolite, a-methylnoradrenaline, upon central a-adrenoceptors. Clonidine, an a-adrenoceptor stimulant, likewise has potent hypotensive activity. These compounds activate central a-adrenergic neurons which inhibit peripheral sympathetic outflow. Clonidine, probably due to the same central a-adrenoceptor stimulation shows also a significant effect on vagal activity.23 Experimentally, electrostimulation of a depressor area corresponding to the site of the nucleus tractus solitarii causes marked bradycardia, or hypotension.22 A lesion of the nucleus tractus solitarii at the level of the obex however results in arterial hypertension. Within this experimental area the first synapses occur of the afferent fibers of the carotid nerve from carotid sinus baroreceptors. The stereotaxic administration of noradrenaline within this region caused bradycardia and (systolic) hypotension which was blocked by local administration of phentolamine.22 On the basis of these findings the a-noradrenergic inhibitory cardiovascular control of the middle caudal part of the nucleus of the tractus solitarius was confirmed.22 The inhibitory control of this viscero-sensory nucleus is mediated via visceromotor efferent nuclei of the IXth and Xth nerve: the dorsal vagal and ambiguus nuclei. Local serotonergic activation results in hypotension, whereas parachlorophenylalanine-induced serotonin depletion causes systolic hypertension. Stimulation of the solitary vagal complex and of a well circumscribed area near the lateral reticular nucleus induced a pressor response of 30-100mm Hg, whereas stimulation of a midline band corresponding to the raphe nucleus caused a depressor response.24 Evoked responses were enhanced by noradrenaline and depressed by serotonin and its precursors 5-hydroxytryptophan and L-tryptophan. It was inferred that sympathetic preganglionic neurons are controlled by noradrenergic excitatory and serotonergic inhibitory systems, and that the effects of noradrenaline and serotonin are pH-dependent.24 The prototype of an a-adrenergic cardiovascular-inhibitory paroxysm of the Hering nerve-solitary tract-ambiguus nucleus system is the well-documented combination of glossopharyngeal neuralgia with cardiac arrhythmia, asystole and cardiac arrest, arterial hypotension, syncope, and convulsions.25,26 In this disorder both arterial hypotension and asystole, purely depressor effects, have repeatedly been noted. Our patient showed a more complex syndrome with a mixture of pressor effects (systolic hypertension and peripheral vasoconstriction in view of the raised diastotic pressure) and depressor effects (bradycardia), accompanied by an uncontrollable urge to cough (nuclei X and XII). The interpretation of cluster headache attacks as parasympathetic crises clearly is untenable in the light of the above findings.
There are other neurologic disease which may include similar cardiovascular phenomena. Patients with cerebrovascular accidents (subarachnoid hemorrhage), meningitis, and brain stem tumors27,30 often have ST, QTc, and T wave changes that may be normalized by isoproterenol, a sympathomimetic31 and by propranolol, a b-sympathicolytic.32 They may also have arrhythmias ranging from atrial tachycardia and nodal rhythms to A-V block and extrasystole.33,34 Wolf35 has shown experimentally that these arrhythmias result from nucleus ambiguus or nucleus tractus solitarii stimulation. Intracranial hypertension above systemic arterial pressure often produces symptoms similar to those shown by our patient and known by every neurologist as the Cushing Response. This response persists after adrenalectomy, after prepontine decerebration, and after transection of all cranial nerves, but disappears upon transection of the spinal cord at C1 level.36 The receptive site from which the Cushing response can be elicited by local tissue distortion (ie, stretch of dendrites and perikarya) either by direct pressure, local injection of fluid, or axial displacement of the brain stem has been shown to be the mesicaudal part of the floor of the IVth ventricle37,38 Figure 2). Although Brashear and Ross39 argued that ß-adrenergic agonists are implicated in the Cushing response, involvement of a-adrenergic structures appear much more likely. The cardiovascular symptoms in the Cushing response and in some cases of cluster headaches are identical and must be related to local changes in the same area of the brain stem in both instances. Both syndromes may best be interpreted as a-adrenergic cardiovascular inhibitory paroxysms. Levi,40 at the beginning of this century marshalled arguments to interpret migraine as "un syndrome du plancher du quatrième ventricule." The patient reported there supports the concept of dysfunction of the medulla oblongata in cluster headache. One interpretation of the present case may be the hypothesis that cluster headache is essentially a central a-adrenergic paroxysm (both excitatory and inhibitory) whereas migraine might well be a central ß-adrenergic paroxysm.
REFERENCES 1.
Wolff HG: Headache and other pain. (New York: Oxford University Press, 1963)
2.
Lance JW, Anthony M: Migrainous neuralgia or cluster headache. J Neurol Sci 13:401-414, 1971.
3.
Sjaastad O: Vascular and biochemical changes in migraine. Symposium on Migraine, May 1974, Rotterdam.
4.
Critchley M, Ferguson FR: Migraine. Lancet 1:123-126; 182-187; 205-206, 1933.
5.
Bassoe P: Migraine. J Am Med Assoc 101:599-605, 1933.
6.
Ask-Upmark E: Migraine as a deadly disease. Br Med J 11:823-825, 1960.
7.
Perera GA: Paroxysmal arrhythmias and migraine. J Am Med Assoc 215:488-451, 1971.
8.
Curschmann H: Migräne (Hemikranie), in Hanbuch der inneren Medizin, ed Mohr, L., and Stählin, Berlin, Springer, 1912, pp. 885-889.
9.
Sachs OW: Migraine. Evolution of a common disorder. London: Faber and Faber, 1970.
10.
Fisher JH: Migraine. Pro Roy Soc Med 12:49-55, 1919.
11.
Leon-Sotomayor L.A.: Cardiac migraine-report of twelve cases. Angiology 25:161-171, 1974.
12.
Ludvigsson J: Propranolol used in prophylaxis of migraine in children. Acta Neurol Scand 50:109-115, 1974.
13.
Eulenburg A: Hemicranie, in Handbuch der Spec. Patholog. und Ther., ed. von Ziemssen, H. Leipzig: F.C.W. Vogel, 1877.
14.
Eulenburg A: Lehrbuch der Nervenkrankheiten. Berlin: Hirschwald, 1878. p 264.
15.
Kunkle EL, Anderson WB: Significance of minor eye signs in headache of migraine type. Arch Ophthalmol 65:504-508, 1961.
16.
Ekbom K, Lindahl J: Headache 11:57-62, 1971.
17.
Graham JR: Cluster headache. Headache 11:175-185, 1972.
18.
Ekbom K: Heart rate, blood pressure, and ECG changes during provoked attacks of cluster headache. Acta Neurol Scand 46:215-224, 1970.
19.
Ekbom K: Clinical aspects of cluster headache. Headache 13:1974.
20.
von Zwieten PA: The central action of antihypertensive drugs, mediated via central a-receptors. J Pharm Pharmacol 25:89-95, 1973.
21.
De Jong W: Noradrenaline: Central inhibitory control of blood pressure and heart rate. Eur J Pharmacol 29:179-185, 1974.
22.
De Jong W, Zandberg P, Bohus B: Central inhibitory noradrenergic cardiovascular control. Pro Brain Res 42:285-294.
23.
Kobinger W, Walland A: Eur J Pharmacol 16:120-122, 1971.
24.
Neumayr J, Hare BD, Franz DN: Evidence for bulbospinal control of sympathetic preganglionic neurones by monoaminergic pathways. Life Sci 14:793-806, 1974.
25.
Garretson HD, Elvidge AR: Glossopharyngeal neuralgia with asystole and seizures. Arch Neurol 8:26-31, 1963.
26.
Al-Ubaidy SS, Bakeen G, Gossous M: Paroxysmal glossopharyngeal neuralgia associated with cardiac arrest. Br J Oral Surg 11:243-245, 1974.
27.
Korczyn HD, Spitzer S, Kott E, Bornstein B: ECG abnormalities in patients with brain stem tumor. Confin Neurol 33:304-308, 1971.
28.
Galloon S, Rees GAD, Briscoe CE: Prospective study of ECG changes associated with subarachnoid hemorrhage. Br J Anaesth 44:511-516, 1972.
29.
Smith M: Ventricular bigeminy and quadrigeminy occurring in a case of subarachnoid hemorrhage. J Electrocardiol 5:78-85, 1972.
30.
Anderson GJ, Woodburn R, Fisch C: Cerebrovascular accidents with unusual ECG changes. Am Heart J 86:395-398, 1973.
31.
Daoud FS, Surawicz B: The effect of isoproterenol on the ECG of patients with intracranial lesions. Am J Cardiol 26:629-630, 1970.
32.
Uchida M, Yamaoka H: Effect of ß-adrenergic blocking agents on the changes in the ST segment and T wave observed in patients with brain stem damage. Resp Circulat (Tokyo) 20:1073-1074, 1972.
33.
Hersch C: ECG changes in subarachnoid hemorrhage, meningitis, and intracranial space occupying lesions. Br Heart J 26:785-793, 1964.
34.
Surawicz B: ECG pattern of cerebrovascular accident. J Am Med Assoc 197:191-192, 1966.
35.
Wolf S: Central autonomic influences of cardiac rate and rhythm. Monograph Conc Cardiovasc Dis 38:29-34, 1969.
36.
Hoff JT, Reiss DJ: Localization of regions mediating the Cushing response in brain and spinal cord of cat. Arch Neurol 23:228-240, 1970.
37.
Doba N, Reis DJ: Localization within the lower brain stem of a receptive area mediating the pressor response to increased intracranial pressure (the Cushing response). Brain Res 47:487-491, 1972.
38.
Reis DJ, Doba N: The central nervous system and neurogenic hypertension. Prog Cardiovasc Dis 17:51-71, 1974.
39.
Brashear RE, Ross JC: Circulating beta-adrenergic stimulator during elevated CSF pressure. Arch Intern Med 127:748-753, 1971.
40.
Lévi L: La migraine commune; Syndrome bulboprotubérantiel. Rev Neurol 13:166-172, 1905. Reprint requests to: Prof. Dr. G.W. Bruyn Department of Neurology University Hospital Leyden, The Netherlands
