Warning signs prior to rupture of an intracranial aneurysm

Warning signs prior to rupture of an intracranial aneurysm SHIGE-HIsA OKAWARA, M.D. Division o] Neurosurgery, University of Iowa, College of Medicine, Iowa City, Iowa Warning signs prior to major hemorrhage were analyzed in 112 cases of single intracranial aneurysm. Fifty-four of 112 patients (48.2%) showed such signs, and the incidence for women was slightly higher (49.2%) than that for men (46.6%). Incidence decreased as patient age advanced, more steeply for men than women. Incidence and characteristics of warning signs varied according to location of aneurysm. Nineteen different signs occurred in 97 instances for 54 patients (average 1.76), and were placed into three groups according to possible etiologies: Group 1, vascular origin due to expansion of aneurysm and adjacent artery; Group 2, minor bleeding; and Group 3, ischemic lesion, arterial spasm, or occlusion. The average time interval from onset of warning sign to major hemorrhage was 20.7 days: 110.5 days for Group 1, 10.4 days for Group 2, and 21.0 days for Group 3. Therefore, signs in Group 2 suggest the necessity of most urgent medical attention. Results of treatment clearly suggested the group with warning signs fared better than the others. Possible reasons for this are discussed. KEY WORDS warning signs ruptured intraeranial aneurysm expansion of aneurysm minor bleeding arterial spasm I T is well known that some intracranial aneurysms produce neurological signs without major hemorrhage. Yet the significance of these signs has not been emphasized. Unruptured aneurysms, for example, may produce visual deficits ranging from total blindness in one eye to varying visual field defects. 13 They may cause endocrine disturbances by interfering with pituitary and hypothalamic function, 14 or poorly differentiated headache frequently characterized as migraine. 1,4,5 Most neurosurgeons agree that the treatment of an aneurysm before massive hemorrhage provides a more favorable outcome. 1~ If it were possible to recognize warning signs of an impending aneurysmal hemorrhage, the surgeon would have a distinct advantage. It is my impression that such warning signs do exist, erroneously suggesting influenza, sinusitis, "stiff neck," migraine, or other diseases, 1,4,~ but that their true nature is only appreciated after catastrophic major hemorrhage. The purpose of this paper is to investigate the significance of warning signs that herald a major hemorrhage, thus leading to an early diagnosis and better results from treatment of intracranial aneurysms. Materials and Methods An analysis of warning signs in 112 patients with ruptured single aneurysms J. Neurosurg. / Volume 38 / May, 1973 575

Shige-Hisa Okawara forms the basis of this report. The factors analyzed include: 1) the incidence of warning signs relative to the patient's sex, age, and location of aneurysm; 2) characteristics of the warning signs; 3) interval between warning signs and major hemorrhage; and 4)warning signs related to patient survival. The histories of 112 patients with subarachnoid hemorrhage from a single ruptured aneurysm were reviewed. Hemorrhage was documented by lumbar puncture, and the presence of the aneurysm by fourvessel angiography. Forty-three of the patients were men; 69 were women. Ages ranged from 16 to 68 years. There was one case in the second decade, seven in the third, 12 in the fourth, 29 in the fifth, 40 in the sixth, and 23 in the seventh decade. The locations of the aneurysms are given in Table 1. Analysis of Cases Incidence of Warning Signs Fifty-four (48.2%) of the 112 patients showed warning signs. Sex and Age Distribution. Of 43 men, 20 (46.6%) showed warning signs, whereas the incidence among women was 49.2% (34 of 69). There was a significantly higher incidence of warning signs in younger patients, especially men, decreasing gradually as age advanced (Fig. 1 ). The incidence for men decreased steeply from 100% in the third decade to 33.3% in the seventh decade. With women the age range was wider, but generally as age advanced the incidence of warning signs declined gradual- q~ I00 80 60 40 20 ~,~ Men... Women I I I l I I i 0 I0 20 30 40 50 60 70 Age (Yeors) FIG. 1. Age and sex distribution of warning signs. ly from 66.7% in the third decade to 47.6% in the seventh decade. Location of Aneurysm. Aneurysms at certain locations tended to show warning signs more frequently than at others (Table 1 ). For example, aneurysms at the internal carotid-posterior communicating junction had a higher incidence (69.2%) than the average (48.2%) of all aneurysms. Next in frequency were aneurysms at the carotid bifurcation (60%) and the middle cerebral artery (59.1%). Of the anterior communicating artery aneurysms, 41% were associated with signs interpreted as warning of subarachnoid hemorrhage, whereas the incidence was 28.6% for aneurysms of the peripheral anterior cerebral artery and 16.7% for those of the carotid-ophthalmic artery junction. Aneurysms in the posterior Location TABLE 1 Location of aneurysms in 112 patients anterior communicating artery internal carotid and posterior communicating artery junction middle cerebral artery peripheral anterior cerebral artery internal carotid and ophthalmic artery junction internal carotid artery bifurcation vertebral artery and its branches basilar artery total Total No. of Cases 70 with Warning Signs 41 41.57o 26 69.2 70 22 59.1 70 7 28.670 6 16.770 5 60.070 3 070 2 070 112 48.270 (average) 576 J. Neurosurg. / Volume 38 / May, 1973

Warning signs prior to rupture of intracranial aneurysm TABLE 2 Warning signs: characteristics and interval before hemorrhage in 54 patients >~.- _~ ~ ~.= No. of patients 6 26 5 41 7 22 5 Group 1 visual field defect 2 2 3.7 2.1 22.5 EOM impairment 6 1 7 13.0 7.4 29.6 eye pain 1 2 1 4 8.9 4.2 53.2 facial pain 2 2 4.4 2. l 53.2 localized head pain 6 1 7 1 2 17 31.5 17.9 165.3 total 1 18 1 7 1 4 0 32 71.2 33.7 110.5 Group 2 general headache 1 6 2 7 l 7 24 44.5 25.2 10.2 nausea 2 1 1 1 5 9.3 5.3 10.6 neck, back pain 2 1 2 1 6 11.1 6.3 5.0 lethargy 2 1 5 8 14.8 8.4 11.4 photophobia 1 1 1.9 1.1 35.0 total 1 13 4 15 2 9 0 44 97.8 46.3 10.4 Group 3 balance lost 1 3 4 7.4 4.2 35.7 dizziness 1 2 1 4 7.4 4.2 13.0 diarrhea 2 1 3 5.6 3.2 5.3 insomnia 2 2 3.7 2.1 7.0 feverish feeling 2 2 3.7 2.1 33.5 motor impairment 1 1 1.9 1.1 45.5 sensory impairment 1 1 1.9 1.1 45.5 visual hallucination 1 1 1.9 1.1 5.0 depression 1 1 1.9 1.1 20.0 total 0 2 0 7 1 9 0 19 42.2 20.0 21.0 Overall total 2 33 5 29 3 22 0 95 211.1 20.9 fossa were not associated with warning signs. Characteristics of Warning Sign~ Fifty-four of the 112 patients demonstrated 19 distinct warning signs before major rupture of their aneurysms (Table 2). Each of the 19 signs was allocated to one of three categories based on its presumed etiology: 1 ) expansion of the aneurysm and adjacent artery, 2) minor bleeding, or 3) local ischemic lesion due to vasospasm or occlusion. These 19 signs occurred a total of 95 times in the 54 patients; many demonstrated more than one sign for an average of 1.76 warning signs per patient. The most frequent warning sign was generalized headache (25.2%), followed by localized head pain (17.9%), lethargy (8.4%), impairment of extraocular movement (7.4%), face and eye pain (6.3%), and neck and back pain (6.3%). Certain signs appeared related to aneurysms at specific locations. Aneurysms of the internal-carotid posterior-communicating junction were associated with impairment of extraocular movement (6/26), visual field defect (2/26), eye pain (2/26), and face pain (2/26). For middle cerebral artery aneurysms, loss of balance, insomnia, motor and sensory impairment, and visual hallucinations were common symptoms. For anterior communicating artery aneurysms, lethar- J Neurosurg. / Volume 38 / May, 1973 577

Shige-Hisa Okawara gy, diarrhea, and fever were frequent symptoms. Interval Between Warning Signs and Major Hemorrhage The average interval between the onset of warning signs and major hemorrhage in the 54 patients was 20.9 days (Table 2). In 26 patients (48.1% ), this interval was less than 1 week, in 40 (74.1%) less than 3 weeks, and in 49 (90.8%) less than 6 weeks. The average interval in Group 1 (warning signs due to expansion of the aneurysm and adjacent artery) was the longest at 110.5 days, in Group 3 (local ischemic lesion) 21 days, and in Group 2 (minor bleed) 10.4 days. Warning Signs Correlated with Survival Survival of the patients with warning signs was better than that for the patients without such signs. Morbidity and mortality rates after operative treatment were 28.9% for the group with and 43.2% for the group without warning signs. For nonoperative cases, the mortality and morbidity rates were 22.2% for the group with and 71.4% for the group without warning signs. Incidence Discussion With advancing age, the incidence of warning signs prior to catastrophic hemorrhage from a ruptured aneurysm fell quickly for men and more slowly for women. In other words, aneurysmal rupture in older patients tended to be associated with fewer warning signs than in younger patients. This lower incidence with advancing age may be due to arteriosclerosis and hypertension with attendant loss of supportive elasticity of the arteries. 9 In this study, the incidence of warning signs varied according to the location of the aneurysm. An incidence higher than the average (48.2%) was seen with aneurysms involving the internal carotid posterior communicating artery junction, the carotid bifurcation, and the middle cerebral artery. Contrary to these observations, some authors '~ indicate that aneurysms of vessels in the posterior fossa have the highest incidence of warning signs. The incidence of particular signs varied with the location of the aneurysm. The anatomical relationships of the posterior communicating artery aneurysm readily explain the disturbance of the third, fourth, fifth, and sixth cranial nerves. On the other hand, the position of the carotid artery bifurcation aneurysm, receiving the direct jet stream from the parent carotid artery, is more often associated only with insidious subarachnoid hemorrhage of varying degree. ~ The relationship of a middle cerebral artery aneurysm to its arterial distribution in the local cerebral cortex probably accounts for the high incidence of warning signs of widest variety. Characteristics of Warning Signs Of the 19 warning signs of major aneurysmal hemorrhage in 54 of 112 patients studied, the important mechanisms in their production are as follows: 1) vascular disturbances, 2) minor leakage of blood, and 3 ) ischemic lesions. Vascular Origin. Localized headache or pain in the patient with an aneurysm is probably referred pain, according to the concepts of Ray and Wolff 11 and Feindel, et al? These workers reproduced headache and head pain by stimulation of arteries in the circle of Willis which derive their innervation from the fifth, ninth, and tenth cranial nerves and C-1 to C-3 spinal nerves. Histological study of aneurysms in patients with warning signs before major rupture often shows minor hemorrhages in the aneurysmal wall and adherence of the aneurysm to the contiguous brain via reactive changes2. 7 NystrSm 8 thought that vasa vasorum extravasating blood into the aneurysmal and adiacent arterial walls passed in the marginal direction through enlarged fenestrations of the elastic layer. These small hemorrhages, by stimulating sensory nerve endings both mechanically and chemically, caused referred pain. Thirtytwo of 95 instances of warning signs (33.7 %) were considered due to this mechanism. Localized head pain was present in 15.3% of the patients (17/112) while EOM impairment was present in 6.25% (7/112). Minor Leakage of Blood. Microscopic 578 J. Neurosurg. / Volume 38 / May, 1973

Warning signs prior to rupture of intracranial aneurysm examination of the cerebrospinal fluid at the onset of these warning signs may reveal red blood cells in small numbers. Generalized headache, lethargy, nausea, neck and back pain may be the manifestations of meningeal irritation due to blood in the subarachnoid space, even if bleeding is minor. Nearly half (44/95) of all instances of warning signs belonged to this group and also nearly onefourth of the patients (24/112) in this study had generalized headache as a warning sign. lschemic Lesions. It is my opinion that parenchymal (usually cortical) ischemic lesions due to arterial spasm or small local hematomas may produce warning signs. These were characterized most commonly by nine signs as shown in Group 3 in Table 2. These signs were most often seen with middle cerebral aneurysms. Although symptoms such as diarrhea, insomnia, fever, and depression seem to be nonspecific, their appearance coincident to definite neurological symptoms justifies their inclusion among the warning signs related to aneurysmal rupture. Interval Between Warning Signs and Major Hemorrhage The observations suggest that patients with the warning signs noted in Group 2 require the most urgent attention in order to prevent catastrophic hemorrhage averaging 10.4 days after the onset of warning signs. In Group 3 this interval was 21 days, while in Group 1 an average period of 110 days preceded a major hemorrhage. Analysis of these intervals indicated that the most significant were neck and back pains occurring only 7 days prior to major hemorrhage. The varying intervals among the warning signs may suggest varying etiologies. Also it was noted that most signs appearing in Group 3 were followed by those of Group 2. It is suggested that if such changes in signs develop, precise diagnosis and necessary treatment to prevent major hemorrhage is urgently needed. Survival Survival for the patients with warning signs was better than that for the group without warning signs. Several factors may be pertinent: 1. Younger patients tended to show warning signs more frequently than older patients, and because they are younger, might have a better chance of survival. The average age for patients with warning signs was 46.5 years and for those without such signs was 51.7 years. 2. The patient with warning signs definitely has a better chance to seek medical aid earlier, and this earlier medical consultation may allow for urgent diagnostic measures. 3. Nearly half of warning signs were due to repeated minor leakage of blood. This minor leakage is probably of an intermittent and recurrent character. Extravasated blood may create some fibrotic adhesive reactions around the aneurysm which in turn functions as resistance against further extravasation and hemorrhage. 4. As seen on angiographic studies of the patient showing warning signs, arterial spasm may be present in the parent artery of an aneurysm. This existing arterial spasm may function as a protective mechanism when major hemorrhage starts, although it may not always be sufficient to arrest hemorrhage completely. Summary For optimal patient recovery, diagnosis of an intracranial aneurysm before or during a period of warning signs is essential. The recognition of warning signs, their natural history, relationship to clinical course is extremely important for this purpose. In this study, warning signs in 112 patients with ruptured single aneurysms were analyzed. Fifty-four of 112 patients (48.2%) showed such signs prior to major hemorrhage. The incidence of warning signs decreased with advancing age. This pattern was more marked in men. The incidence of warning signs varied with the location of the aneurysm, being highest with internal carotidposterior communicating artery aneurysms (69.2%), and lowest with posterior fossa aneurysms (0%). 1. Neurosurg. / Volume 38 / May, 1973 579

Shige-Hisa Okawara Nineteen different warning signs were analyzed in reference to three etiological mechanisms, and the time interval prior to major hemorrhage. In 48.2% of patients with warning signs, intervals were within 1 week, in 74% within 3 weeks, and in 90.8% within 6 weeks. The overall average interval was 20.7 days. Warning signs caused by minor leakage of blood into CSF, as in Group 2, need the most urgent attention as the average time interval to major hemorrhage was 10.4 days, whereas, this interval in Group 3 was 21 days, and in Group 1, 110.5 days. The morbidity and mortality rate for the group with warning signs was much less than for the group without such signs. This difference was greater in the unoperated cases compared to the operated cases. Acknowledgments The author gratefully acknowledges the guidance of Professors J. F. Gillingham, G. Perret, and C. J. Graf. References 1. Adie WJ: Permanent hemianopia in migraine and subarachnoid haemorrhage. Lancet 2:237-238, 1930 2. Dott NM: Brain: movement and time. Brit Med J 2:12-16, 1960 3. Feindel W, Penfield W, McNaughton F: The tentorial nerves and localization of intracranial pain in man. Neurology (Minneap) 10:555-563, 1960 4. Frankel K: Relation of migraine to cerebral aneurysm. Arch Neurol Psychiat 63:195-204, 1950 5. Friedman AP, Harter DH, Merritt HH: Ophthalmoloplegic migraine. Arch Neurol 7:320-327, 1962 6. Gillingham FJ: The management of ruptured intracranial aneurysm. Ann Roy Coll Surg Eng 23:89-117, 1958 7. Hyland HH, Barnett HJM: The pathogenesis of cranial nerve palsies associated with intracranial aneurysms. Proc Roy Soe ivied 47:141-146, 1954 8. NystrSm SHM: Development of intracranial aneurysms as revealed by electron microscopy. J Neurosurg 20:329-337, 1963 9. Nystr6m SHM: On factors related to growth and rupture of intracranial aneurysms. Aeta Nenropath 16:64-72, 1970 10. Pool JL, Potts DG: Aneurysms and Arteriovenous Anomalies of the Brain: Diagnosis and Treatment. New York, Harper & Row, 1965 11. Ray BS, Wolff HG: Experimental studies on headache: pain-sensitive structures of the head and their significances in headache. Arch Surg 41:813-856, 1940 12. Shenkin HA, Polakoff P, Finneson BE: Intracranial internal carotid artery aneurysms: results of treatment by cervical carotid artery ligation. J Neurosurg 15:183-191, 1958 13. Walsh FB: Visual field defects due to aneurysms at the circle of Willis. Arch Ophth 71:15-27, 1964 14. White JC, Ballantine HT Jr: Intrasellar aneurysms simulating hypophyseal tumours. J Neurosurg 18:34-50, 1961 15. Young B, Meacham WF, Allen JH: Documented enlargement and rupture of a small arterial sacculation: case report. J Neurosurg 34:814-817, 1971 Address reprint requests to: Shige Okawara, M.D., Division of Neurosurgery, University of Iowa, College of Medicine, Iowa City, Iowa. 580 J. Neurosurg. / Volume 38 / May, 1973