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Saccular cerebral aneurysms in young adults
Saccular Cerebral Aneurysms in Young Adults Hiroshi Kamitani, M.D., Hideaki Masuzawa, M.D., Itaru Kanazawa, M.D., and Toshiro Kubo, M.D. Department of Neurosurgery, Kanto Teishin Hospital, Tokyo, Japan
Kamitani H, Masuzawa H, Kanazawa I, Kubo T. Saccular cerebral aneurysms in young adults. Surg Neurol 2000;54:59 – 67. BACKGROUND
The formation and rupture of cerebral aneurysms has been controversial. In order to clarify their nature, this study investigates the size and location of ruptured and unruptured aneurysms in young adults and the results of surgery. METHODS
The subjects of this study are 35 patients with ruptured and two with unruptured aneurysms. They range in age from 20 to 39 years. The size and location of their aneurysms were determined by angiographic measure of their maximal inner diameters. Direct surgery was performed on 34 patients with ruptured aneurysms and on one with an unruptured aneurysm. RESULTS
Ruptured aneurysms in young adults increase in number and size as they grow older. In young adults showing no atherosclerosis or hypertension, ruptured aneurysms occurred in locations and with a frequency found in patients with hypertension. In young adults, aneurysms in the internal carotid artery larger than 3.5 mm (Fisher’s exact test; p ⬍ 0.05) and the anterior communicating artery showed a tendency to rupture. The surgery produced excellent results in young adults with grade I to III by Hunt and Kosnik classification, but extremely poor results for those with grade IV resulting from vasospasm (Fisher’s exact test; p ⬍ 0.05). CONCLUSION
It is possible that aneurysms found in young adults might in fact have been present from childhood and adolescence, increasing sufficiently in size to rupture in the forties and fifties. Accordingly, while aneurysm formation may be related to fragile arterial walls, aneurysm rupture may be the result of aging factors such as hypertension and atherosclerosis. Even in young adults, vasospasm had an impact on the outcome of surgery. © 2000 by Elsevier Science Inc. KEY WORDS
Cerebral aneurysms, cerebral angiography, subarachnoid hemorrhage, young adult. Address reprint requests to: Dr. H. Kamitani, Department of Neurosurgery, Kanto Teishin Hospital, 5-9-22, Higashi-Gotanda, Shinagawa-ku, Tokyo, Japan 141. Received September 13, 1999; accepted May 24, 2000. © 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
erebral aneurysms, both ruptured and unruptured, most frequently occur in patients over age 40. This tendency has led some investigators [5,6,29,30] to believe that cerebral aneurysms are not congenital but acquired, and that hemodynamic stress may serve as a major factor in aneurysm formation and rupture. Previous authors [7,22,23, 24,25,26,31] have shown some differences between aneurysms occurring in children and adolescents versus those found in adults. In trying to understand aneurysm formation and rupture, it is worth investigating cerebral aneurysms in young adults in their twenties and thirties, who are located at the midpoint in age between adolescents and adults over age 40. In general, these young adults do not exhibit signs of hypertension or arteriosclerosis or atherosclerosis. Based on a comparison of these age groups, this study discusses aneurysm formation and rupture as well as the outcome of surgery for ruptured aneurysms in young adults.
C
Patients and Methods Our hospital has admitted 286 patients (109 male, 177 female) with ruptured saccular cerebral aneurysms in the last 30 years (Table 1). Of these, five patients were in their twenties; 30 in their thirties (9 between the ages of 30 and 34, 21 between the ages of 35 and 39); 79 in their forties (33 between the ages of 40 and 44, 46 between the ages of 45 and 49); 82 in their fifties; 59 in their sixties; 25 in their seventies; and six in their eighties. There were more female patients than male patients in each age group. Direct surgery on the aneurysms was undertaken in 273 of the 286 patients. Thirty-seven young adults ranging in age from 21 to 39 years were included in this study. Of these, 35 had ruptured aneurysms and two unruptured ones that were detected by chance during hospital stays 0090-3019/00/$–see front matter PII S0090-3019(00)00265-2
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Kamitani et al
Ruptured Saccular Aneurysms in Patients Under and Over Age 40
UNDER 40
ICA
Group A Twenties Group B Thirties 30–34 35–39 Total
A COMM A
MCA
3
Forties 40–44 45–49 Fifties Sixties Seventies Eighties Total
POSTERIOR
2
3 6 12
OVER 40
ACA
3 8 11
2 3 7
ICA
A COMM A
MCA
8, (1) 9 22 24 10, (4) 1, (1) 74, (6)
14 18 29 10, (2) 4 1 76, (2)
6 14 19, (2) 14 3, (1) 2 58, (3)
TOTAL 5
2 2
ACA 2 5 6 4 1 0 18
1 1, (1) 2, (1)
9 20, (1) 34, (1)
POSTERIOR
TOTAL
1, (1) 4 5 2 1 13, (1)
31, (2) 46, 80, (2) 57, (2) 20, (5) 5, (1) 239, (12)
( ): Not operated. ICA: internal carotid artery; A Comm A: anterior communicating artery; MCA: middle cerebral artery; ACA: anterior cerebral artery; Posterior: posterior circulation.
for conditions other than subarachnoid hemorrhage. The 35 young adults with ruptured aneurysms were divided into two age groups (Groups A and B, Table 1); Group A consisted of five young adults in their twenties while Group B consisted of 30 in their thirties. Serial cerebral angiography supplemented by multisection angiotomography [19] and magnified angiography, detected ruptured aneurysms in patients with subarachnoid hemorrhage. By contrast, in the case of the two young adults suffering from vague headaches and hypertensive cerebral bleeding, the aneurysms were incidentally detected through MR imaging and/or MR angiography after cerebral angiography. Recently, digital subtraction angiography has replaced serial angiography. Allowing for different magnification (routine angiography ⫻ 1.12, angiotomography ⫻ 1.2, magnified angiography ⫻ 1.7), the size of the aneurysms was determined by measuring their maximal inner diameter on each angiography. Such
2
measurements were taken in 262 of the 286 patients with ruptured aneurysms (91.6%) and the two young adults with unruptured aneurysms. Tables 2, 3, and 4 give the numbers of hypertensive patients in individual male and female age groups, and the size and location of the aneurysms in 35 patients under 40 and 227 patients over 40, respectively. Table 3 also includes the two young adults with unruptured aneurysms. Table 5, which includes the incidence of perioperative vasospasm and hydrocephalus in young adults with a single or multiple instances of subarachnoid hemorrhage, shows the relationship between surgical prognosis [9] and preoperative clinical grading by the Hunt and Kosnik classification [8]. Direct surgery involving neck clipping, trapping, and wrapping or coating of the aneurysms was undertaken in 35 of 35 young adults with ruptured aneurysms and in one young adult with an unruptured aneurysm. Two young adults, one with a rup-
Hypertension in Patients with Ruptured Cerebral Aneurysms
AGE (YEARS) SEX
30–39
40–49
50–59
60–69
70–79
80–
Male Female Total
2/13 (15.4) 2/17 (11.8) 4/30 (13.3)
12/37 (32.4) 14/42 (33.3) 26/79 (32.9)
14/35 (40.0) 19/47 (40.4) 33/82 (40.2)
11/17 (64.7) 20/42 (47.6) 31/59 (52.5)
1/3 (33.3) 13/22 (59.1) 14/25 (56.0)
0/1 (0) 4/5 (80.0) 4/6 (66.7)
( ) ⫽ %.
Saccular Aneurysms in Young Adults
3
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Size (mm) and Location of Aneurysms in Young Adults
ICA Twenties Size Average Thirties 30–34 Size Average 35–39 Size Average Total Size Average
A COMM A
3 3.8–4.3 4.0
[1] 4.3 4.3
3 2.7–5.3 3.8 6 3.9–7.1 5.1 9 2.7–7.1 4.7
[3] 2.9–4.0 3.5 [3] 2.7–3.1 2.9 [6] 2.7–4.0 3.2
MCA
POSTERIOR CIRCULATION
ACA
2 6.0–9.0 7.5 3 5.4–10.9 7.8 8 3.5–21.6 8.7 11 3.5–21.6 8.4
2 2.8–5.4 4.1 3 3.8–7.4 5.5 5 2.8–7.4 5.0
[1] 4.8 [5] 2.4–4.4 3.2 [5] 2.4–4.4 3.2
2 4.0–4.5 4.3 2 4.0–4.5 4.3
1 8.1 8.1 2 7.1–7.2 7.2 3 7.1–8.1 7.5
[1] 4.8 4.8
[ ] Unruptured. ICA: internal carotid artery; A comm A: anterior communicating artery; MCA: middle cerebral artery; ACA: anterior cerebral artery.
tured aneurysm and the other with an unruptured aneurysm, refused surgery. This study excludes those patients with subarachnoid hemorrhage whose ruptured aneurysms could not be defined by angiography and/or surgery, and those in whom ruptured aneurysms were associated with arteriovenous malformations and general connective tissue diseases. This study tentatively includes unruptured intracavernous aneurysms in patients with
4
ruptured aneurysms as multiple aneurysms. Nevertheless, Table 4 excludes these unruptured aneurysms because of their low rate of rupture.
Results Cerebral angiography in all 37 young adults showed few arteriosclerotic or atherosclerotic changes
Size (mm) and Location of Aneurysms in Patients over Age 40
ICA Forties 40–44 Size Average 45–49 Size Average Fifties Size Average Sixties Size Average Seventies Size Average Eighties Size Average Total Size Average
8 2.5–7.1 5.1 7 5.9–8.6 7.2 17 5.3–12.1 7.8 23 4.2–18.0 8.8 11 3.5–15.0 8.0 2 4.8–6.9 5.9 68 2.5–18.0 7.7
[13] 2.7–9.0 4.7 [3] 2.8–4.0 3.4 [7] 2.8–7.1 4.4 [6] 3.3–7.3 5.2 [5] 3.1–6.3 5.0
[34] 2.7–9.0 4.6
A COMM A 12 3.2–8.2 6.0 17 4.0–10.8 7.5 26 5.0–10.4 7.5 12 4.0–9.9 7.5 5 3.2–5.5 4.4 1 15.0 15.0 73 3.2–15.0 7.1
[1] 6.6 6.6 [1] 5.4 5.4 [1] 3.8 3.8 [1] 4.7 4.7
[4] 3.8–6.6 5.1
MCA 5 5.4–16.7 9.3 12 4.3–9.9 6.0 21 3.4–16.9 7.5 12 3.0–25.0 10.1 4 7.6–10.6 9.6 2 3.5–6.1 4.8 56 3.0–25.0 8.0
ACA
[2] 2.7–6.3 4.5 [2] 3.0–5.4 4.2 [1] 3.6 3.6 [6] 3.0–8.4 5.7 [2] 2.7–8.4 5.2
2 2.8–6.1 4.5 5 2.6–10.4 7.0 6 3.2–15.7 7.5 3 4.3–11.2 7.1 1 5.0 5.0
[1] 2.5 2.5 [2] 3.8–5.3 4.6 [2] 2.2–5.1 3.7
[13] 2.7–8.4 4.4
17 2.6–15.7 6.8
[5] 2.2–5.3 2.7
POSTERIOR CIRCULATION 1 5.9 5.9
4 4.8–8.6 5.9 5 3.2–7.5 6.0 2 6.9–9.2 8.1 1 3.8 3.8 13 3.2–9.2 6.1
[ ] Unruptured. ICA: internal carotid artery; A Comm A: anterior communicating artery; MCA: middle cerebral artery; ACA: anterior cerebral artery.
[2] 4.8–6.3 5.6 [1] 7.5 7.5 [1] 5.0 5.0
[4] 4.8–7.5 5.9
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Kamitani et al
Clinical Grading and Surgical Prognosis
GRADE (HUNT & KOSNIK) Twenties SAH 1st
I
II
2 (LV: 1)
1
III
2nd 3rd Thirties SAH 1st 2nd
V
1 (DV: 1) 1 6 2 (LV: 1)
11 (DV: 1, NPH: 1) 3 (DV: 1, NPH: 1)
3 (DV: 1) 3 (DV: 1, LV: 2, NPH: 2)
3rd Prognosis Good recovery Moderately disabled Severely disabled Vegetative Dead
IV
(Glasgow outcome scale [9]) 11 14 1
1 (DV: 1, NPH: 1) 1 (DV: 1, NPH: 1)
6 1 2
SAH: subarachnoid hemorrhage; DV: diffuse vasospasm; LV: localized vasospasm; DLV: diffuse or localized vasospasm; NPH: normal pressure hydrocephalus.
such as irregular arterial walls or tortuous arterial course. Multiple cerebral aneurysms were found in seven of 35 hemorrhaging patients under 40 (20.0%) and 50 of 251 hemorrhaging patients over 40 (19.9%). In this study, male and female patients with ruptured aneurysms exhibited WHO-classified hypertension (160/95 mm Hg) at incidence rates of 15.4 and 11.8% in their thirties, 32.4 and 33.3% in their forties, 40.0 and 40.4% in their fifties, 64.7 and 47.6% in their sixties, 33.3 and 59.1% in their seventies, and 0 and 80% in their eighties (Table 2). By contrast, Japanese male and female adults in the general population show hypertension at incidence rates of 7.5 and 3.4% in the thirties, 18.9 and 13.2% in the forties, 33.6 and 27.7% in the fifties, 43.1 and 42.5% in the sixties, and 52.8 and 57.6% over seventy. In this study, there was no statistically significant difference in incidence of hypertension between male and female patients in their thirties and those in the general Japanese adult population. Male and female patients in their forties and female patients in their fifties; however, exhibited hypertension at significantly higher incidence rates (Fisher’s exact test; p ⬍ 0.05). The incidence of hypertension sharply increased as patients advanced in age over 40 and 50. The sudden increase of ruptured aneurysms in patients in hypertensive age groups forced us to consider that hypertension
might serve as an important factor for aneurysm rupture in patients over 40. There were some differences in the size and location of the aneurysms between patients in their twenties and those in their thirties (Table 3). In the former, ruptured aneurysms were very small (3.8 – 4.0 mm) in the internal carotid artery and mediumsized (6.0 –9.0 mm) in the middle cerebral artery. As patients advanced in age, their ruptured aneurysms in the anterior circulation increased in number and size or only in number. It was not until patients reached age 30 that ruptured aneurysms appeared in the anterior communicating and anterior cerebral arteries, and in the posterior circulation. In patients in their forties, ruptured aneurysms in the anterior circulation suddenly increased in number but those in the posterior circulation remained few in number. Ruptured aneurysms in patients in their thirties were similarly located to those in patients over age 40. In patients in their thirties, the ruptured aneurysms were found in the internal carotid artery (nine cases, 30.0%), the anterior communicating artery (11 cases, 36.7%), the middle cerebral artery (five cases, 16.7%), the anterior cerebral artery (two cases, 6.7%), and the posterior circulation (three cases, 10.0%). These incidence rates at different sites were roughly similar to those of ruptured aneurysms in patients over the age of forty
Saccular Aneurysms in Young Adults
(Table 1). Ruptured aneurysms in patients in their thirties ranged in size from 2.7 to 7.1 mm (4.7 mm on average) in the internal carotid artery, from 3.5 to 21.6 mm (8.4 mm on average) in the anterior communicating artery, from 2.8 to 7.4 mm (5.0 mm on average) in the middle cerebral artery, from 4.0 to 4.5 mm (4.3 mm on average) in the anterior cerebral artery, and from 7.1 to 8.1 mm (7.5 mm on average) in the posterior circulation. Although the ruptured internal carotid artery aneurysms in patients in the age range from 30 to 34 remained small in size, those in patients in the age range from 35 to 39 appeared somewhat larger. Compared to those in patients over age 40, ruptured aneurysms in young adults ranging in age from 20 to 39 seemed much smaller in the internal carotid artery (4.5 and 7.7 mm on average in young adults and patients in age over 40, respectively), somewhat smaller in the anterior (4.3 and 6.3 mm) and middle cerebral arteries (5.7 and 8.0 mm), and roughly similar-sized in the anterior communicating artery (8.4 and 7.1 mm) and posterior circulation (7.5 and 6.1 mm). As patients advanced in age, ruptured aneurysms in the internal carotid, and anterior and middle cerebral arteries increased in size, whereas those in the anterior communicating artery and posterior circulation did not (Tables 3 and 4). In the internal carotid artery of young adults, aneurysms larger than 3.5 mm showed a high probability of rupturing (Fisher’s exact test; p ⬍ 0.05). That all anterior communicating artery aneurysms ranging in size from 3.5 to 21.6 mm (8.4 mm on average) in patients in their thirties ruptured points to the significance of this site. By contrast, in the case of aneurysms in the posterior circulation, there was no significant difference in incidence of rupture between young patients (under 40) and those over 40. Even as patients advanced in age over 40, their ruptured posterior circulation aneurysms remained few in number. Perioperative angiography showed localized vasospasm in four young adults ranging in condition from grade I to III by Hunt and Kosnik classification and diffuse vasospasm in seven with conditions ranging from grade II to IV. Seven of the eight young adults with conditions rated from grade II to III recovered well despite exhibiting diffuse or localized vasospasm and hydrocephalus after an initial or second or even third episode of aneurysmal bleeding. On the other hand, all three grade IV patients showed diffuse vasospasm after a second or third episode of aneurysmal bleeding and died (two) or became vegetative (one). A second or third episode of bleeding on the same day or several days after an initial or second episode in young patients
Surg Neurol 2000;54:59 –67
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led to downgrading of their conditions. Young patients whose second episode of bleeding occurred more than 1 week after the initial episode, however, remained in conditions ranging from grade I to III. The manifestation of vasospasm was closely related to poor grading or poor surgical results (Fisher’s exact test; p ⬍ 0.05, Table 5). One female patient who had undergone wrapping surgery for a ruptured anterior cerebral artery aneurysm died of re-bleeding 8 years later. In this study, surgery on 35 young patients with ruptured and unruptured aneurysms disclosed their aneurysms and parent arteries as neither discolored nor atherosclerotic; moreover, even if the aneurysms were large, they appeared sufficiently pliable to allow easy control of intraoperative bleeding.
Discussion Previous authors [7,22,23,24,25,26,31] have demonstrated the differences in size and location between ruptured aneurysms in children and adolescents, and those in adults. Meyer et al [22] showed that ruptured aneurysms in children and adolescents tended to be huge and to be located in the posterior circulation. Ostergaad [24], however, noted 26 juvenile aneurysms predominantly located in the anterior circulation, especially in the internal carotid bifurcation. The majority of aneurysms in our young adults were located at the bifurcations of Willis’s circle in the anterior circulation. This study found some differences in size and location of aneurysms between patients in their twenties and those in their thirties. In the former, ruptured cerebral aneurysms were few in number and exclusively situated in the anterior circulation, especially in the internal carotid and middle cerebral arteries. Nevertheless, with advancing years, patients in their thirties showed ruptured aneurysms increasing in size and number. In the case of patients over 40, this study showed ruptured aneurysms at sites similar to those previously reported [13, 18]. The demonstration of ruptured or unruptured aneurysms in young adults, and the sudden increase of ruptured aneurysms in patients in age over 40 leads us to hypothesize that the aneurysms might have emerged when patients were children and adolescents at the latest, and that once they advanced into their twenties or thirties, the unruptured aneurysms reached the critical size for rupture. Moreover, patients in their thirties and forties had ruptured aneurysms in similar locations and multiple aneurysms at similar rates of occurrence, suggest-
64
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ing that a similar mechanism had led to aneurysm formation and rupture in both age groups. In the case of the posterior circulation, we could not find a significant difference in incidence of ruptured aneurysms between patients under 40 and those over 40. In other words, as patients grew older, ruptured aneurysms in the anterior circulation increased in number while those in the posterior circulation remained constant in number, suggesting that advancing age has little effect on aneurysm formation and rupture in the posterior circulation. As shown in Table 3, ruptured aneurysms varied considerably in size according to location. In patients under 40, ruptured aneurysms in the internal carotid artery ranged from 2.7 to 7.1 mm in diameter, showing that aneurysms larger than 3.5 mm have a high probability of rupturing (Fisher’s exact test; p ⬍ 0.05). By contrast, the ruptured anterior communicating artery aneurysms and posterior circulation aneurysms were as large as those in patients over forty (3.5 to 21.6 mm, with 8.4 mm as the average and 7.1 to 8.2 mm, 7.5 mm average, respectively). Previous investigators studied the size and rupture rate of cerebral aneurysms [12,20,33]. Kassell [12] noted that cerebral aneurysms in adults that were larger than 7 mm had a high probability of rupture. On the other hand, Wiebers et al [33] showed a low probability of rupture in cerebral aneurysms smaller than 10 mm. They posited that cerebral aneurysms smaller than 5 mm had a low risk of subsequent rupture. Earlier, however, Young et al [36] and more recently, Shievink et al [27], Yasui et al [35], Lin et al [17], and Kamitani et al [11], had shown rupturing of unruptured cerebral aneurysms and aneurysmal rests smaller than 5 mm after incomplete surgery. Aneurysmal size does not seem to be a reliable factor in predicting subsequent rupture. In general, ruptured aneurysms in young adults appeared small in the internal carotid artery and medium to large in the anterior communicating and middle cerebral arteries and in the posterior circulation. Accordingly, it seems that even small aneurysms of the internal carotid artery have a tendency to rupture while those of the anterior communicating and middle cerebral arteries need to grow larger than 5 mm, and posterior circulation aneurysms, 8 mm, before they rupture. In our hospital, ruptured aneurysms in young adults in their twenties and thirties comprised only 1.8 and 10.5% of all ruptured aneurysms, respectively. Most cerebral aneurysms are detected at the time of rupture and usually in patients over age 40. Recently in Japan, the use of MR imaging and/or MR angiography or CT scan for examining the brain has become popular
Kamitani et al
and has enabled us to detect unruptured aneurysms much more often than before. Nevertheless, it is usually patients over age 40 who undergo such examinations. As shown in our two cases, if young adults had more opportunity to undergo such neurovascular imaging, more unruptured aneurysms might have been detected. The formation and rupture of cerebral aneurysms remain open to debate [4,25,28,29,30]. Pathologically, the aneurysmal wall in childhood and adolescence shows alterations similar to those in adults, such as medial defect and interrupted internal elastic lamina. Degeneration of the internal elastic lamina appears essential for aneurysm formation. Atherosclerosis has been regarded as a major factor in such degeneration [4]. By contrast, previous experimental investigations [5,6] showed that cerebral aneurysms were generated by hemodynamic stress augmented by hypertension. At present, hemodynamic stress is regarded as the most important factor for the formation and growth of aneurysms, especially in atherosclerotic arterial walls. Previous authors [7,23,24,25,26] have noted that a vast majority of ruptured aneurysms in children and adolescents occur in the anterior circulation, especially in the internal carotid artery. The internal carotid artery has a blood flow much greater than the anterior communicating and middle cerebral arteries, which may exert intense hemodynamic stress on the arterial walls and result in aneurysm formation and rupture. The vast majority of young adults in our study, however, exhibited neither hypertension nor atherosclerosis. Clinically and neuroradiologically, we could not find any factors in young adults that increased hemodynamic stress sufficient to contribute to aneurysm formation. We question whether hemodynamic stress is sufficient to explain juvenile and adolescent cerebral aneurysms, as suggested by previous animal experiments [5,6]. The formation and rupture of aneurysms seems to depend upon an imbalance between arterial durability and hemodynamic stress. Surgery on our 34 patients with ruptured aneurysms showed the aneurysmal walls to be remarkably fragile. Such arterial fragility may lessen durability and relate to the formation and rupture of aneurysms. Some authors have stressed such intrinsic factors as metabolic deficiency [14,15] and type III collagen mutation [2,25], which decrease arterial durability in aneurysm formation. Ostergaard [25] emphasizes intrinsic factors as being of the greatest importance in the formation and rupture of juvenile aneurysms. It remains open to debate whether hypertension plays an important role in aneurysm formation and rupture [1,3,10,21,32,33]. Asari and Ohmoto [1] and
Saccular Aneurysms in Young Adults
Taylor et al [32] have noted hypertension to be a risk factor for aneurysm formation and/or rupture. Cohen [3] has proposed that hypertension is related to aneurysm rupture but not formation. McCormick et al [21] and Juvela et al [10], on the other hand, have shown that hypertension exerts little effect on aneurysm formation, rupture, or growth. We have also noted recently that the rupturing of unruptured or residual aneurysms depends upon the annual growth rates, which are unrelated to hypertension [11]. This study, however, showed ruptured aneurysms at similar locations and multiple aneurysms occurring at similar rates in patients in their thirties and those in their forties, with a sudden increase in the rupture rate in patients in their forties and fifties, who also exhibited higher rates of hypertension. In the case of children and adolescents, it seems plausible to attribute aneurysm formation to decreased arterial durability unrelated to atherosclerosis or hypertension but rather, to intrinsic arterial fragility, while in patients over age 40, ruptures may be influenced by such factors as hypertension and atherosclerosis. It is well known that children and adolescents with ruptured aneurysms, even when they exhibit angiographical vasospasm, have an excellent prognosis [23,26]. In this study, all 23 young adults with initial bleeding were classified as grade I, II, or III according to the Hunt and Kosnik classification, whereas three of twelve young adults with two or three occurrences of bleeding presented as grade IV. Preoperative angiography disclosed vasospasm in eight of 32 young adults with grade I, II, or III and in all three grade IV young adults, associating vasospasm with patients in poorer condition (Fisher’s exact test; p ⬍ 0.05). Surgical prognosis [9] was good recovery or moderate disability for those young adults graded I to III, but vegetation or death for grade IV patients (Fisher’s exact test; p ⬍ 0.01). Surgery on young adults showed the ruptured aneurysms to be sufficiently soft and fragile to bleed prematurely, but also that such premature bleeding could be easily controlled. In normotensive young adults, such arterial softness and fragility may decrease the durability of arterial walls and result in aneurysm bleeding on the one hand, while it may result in decreased bleeding on the initial occasion of aneurysmal rupture, on the other. This may account for the small volume of the subarachnoid hematoma as shown by Pasqualin et al [26]. Previous authors [23,26] have noted that vasospasm is of minor prognostic significance in children. Our young adults with poor grading, however, exhibited significant vasospasm resulting from repeated subarachnoid hemorrhaging on the same day or sev-
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19. Masuzawa H, Kobayashi M, Inoya H, Kamitani H, Sato J. Multisection angiotomography of intracranial aneurysms. Acta Neurochir (Wien) (Suppl) 1979;28:550 –3. 20. McCormick WF, Acosta-Rua GJ. The size of intracranial saccular aneurysms. An autopsy study. J Neurosurg 1970;33:422–7. 21. McCormick WF, Schmalstieg EJ. The relationship of arterial hypertension to intracranial aneurysms. Arch Neurol 1977;34:285–7. 22. Meyer FB, Sundt TM Jr, Fode NC, Morgan MK, Forbes GS, Mellinger JF. Cerebral aneurysms in childhood and adolescence. J Neurosurg 1989;70:420 –5. 23. Ostergaad JR, Voldby B. Intracranial arterial aneurysms in children and adolescents. J Neurosurg 1983; 58:832–7. 24. Ostergaad JR. A long-term follow-up study of juvenile aneurysm patients. Acta Neurochir (Wien) 1985;77: 103–9. 25. Ostergaard JR. Aetiology of intracranial saccular aneurysms in childhood. Br J Neurosurg. 1991;5:575– 80. 26. Pasqualin A, Mazza C, Cavazzani P, Scienza R, DaPian R. Intracranial aneurysms and subarachnoid hemorrhage in children and adolescents. Child Nerv Syst 1986;2:185–90. 27. Schievink WI, Piepgras DG, Wirth FP. Rupture of previously documented small asymptomatic saccular intracranial aneurysms. J Neurosurg 1992;76:1019 –24. 28. Sekher LN, Heros RC. Origin, growth, and rupture of saccular aneurysms: a review. Neurosurgery 1983;8: 248 – 60. 29. Stehbens WE. Etiology of intracranial berry aneurysms. J Neurosurg 1989;70:823–31. 30. Stehbens WE. Pathology and pathogenesis of intracranial berry aneurysms. Neurol Res 1990;12:29 –34. 31. Swamy NK, Pope FM, Coakham HB. Giant aneurysm of internal carotid artery in a four-year-old child: a case report. Surg Neurol 1993;40:138 – 41. 32. Taylor CL, Yuan Z, Selman WR, Ratcheson RA, Rimm AA. Cerebral arterial aneurysm formation and rupture in 20,767 elderly patients: hypertension and other risk factors. J Neurosurg 1995;83:812–9. 33. Wiebers DO, Whisnant JP, Sundt TM Jr, O’Fallon WM. The significance of unruptured intracranial saccular aneurysms. J Neurosurg 1987;66:23–9. 34. Winn HR, Almaani WS, Berga SL. The long-term outcome in patients with multiple aneurysms. Incidence of late hemorrhage and implications for treatment of incidental aneurysms. J Neurosurg 1983;59:642–51. 35. Yasui N, Magarisawa S, Suzuki A, Nishimura H, Okudera T, Abe T. Subarachnoid hemorrhage caused by previously diagnosed, previously unruptured intracranial aneurysms: a retrospective analysis of 25 cases. Neurosurgery 1996;39:1096 –1101. 36. Young B, Meacham WF, Allen JH. Documented enlargement and rupture of a small arterial sacculation. J Neurosurg 1971;34:814 –7.
COMMENTARY
Kamitani et al present their experience with cerebral saccular aneurysms seen in young adult patients, who predominantly presented with subarachnoid hemorrhage. They divided these aneurysms into two groups, and provide an inter-
Kamitani et al
esting discussion of the pathogenesis of aneurysm formation and rupture. We described the characteristics of cerebral aneurysms in the first three decades of life in 1978 [1]; our results were very similar to these authors’ except that the incidence of MCA aneurysms was extremely low in our series. The distribution of aneurysms in young adults in this study is similar to that in all patients in our study. This may be attributed to the faster growth in younger patients and/or the change to an older population that has occurred in Japan within the last two decades. Takashi Yoshimoto, M.D., Ph.D. Department of Neurosurgery Tohoku University School of Medicine Sendai, Japan REFERENCE 1. Yoshimoto T, Uchida K, Suzuki J. Intracranial saccular aneurysms in the first three decades. Surg Neurol 1978; 9:287–91.
To date, the pathogenesis of aneurysms has been a matter of debate. There are different schools of thought regarding the etiology of aneurysm formation, growth, and rupture. This is another thoughtprovoking article on the topic. The authors note the existence of aneurysms in similar locations in subgroups of patients in their 20s, 30s, and 40s, with increased aneurysm size and the addition of new sites of occurrence as age increases. They correlate these findings in a linear fashion with the pathogenesis of the aneurysms, and propose that the aneurysms in these patients may have begun to develop in the first or second decades of life, and became symptomatic in the third or fourth decades. This view points to a congenital origin for these aneurysms. The absence of features such as atherosclerosis and hypertension in the group of patients under 40 and the presence of these features in the group over 40, with increasing aneurysm size and number and frequency of rupture, also supports the role of these acquired factors in the development of aneurysms. Our view in regard to the pathogenesis of aneurysms is that their etiology is multifactorial. We think, as do these authors, that degenerative, hemodynamic, metabolic, and environmental factors are superimposed on congenital factors to contribute to the development of cerebral aneurysms. The data in this article suffer from an inadequate number of patients to derive statistical significance and allow one to draw conclusions. Also, the authors have not provided any physical or his-
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topathological evidence of increased arterial fragility to support their hypothesis regarding the pathogenesis of aneurysm formation in young adults. However, the article presents, if not a totally new view, at least a different perspective on this question. It would be interesting to see how the
T
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authors’ perspective applies to a large group of patients. Shigeaki Kobayashi, M.D. Department of Neurosurgery Shinshu University School of Medicine Matsumoto, Japan
eaching hospitals are not-for-profit institutions and provide approximately 50% of care for the indigent in the country. —Herbert Pardes, M.D. “The Perilous State of Academic Medicine” JAMA 2000;283:2427–9
ndividual managed care companies, pressed by a competitive market, are unwilling to pay for social goods.
I
—Herbert Pardes, M.D. “The Perilous State of Academic Medicine” JAMA 2000;283:2427–9
here has been an 18% reduction in the number of medical school applicants from 1996 to 1999. What effect will the decreasing medical school applicant pool have on medicine? Are the future physician teachers, mentors, clinicians, researchers, and role models going to be the best and brightest?
T
—Herbert Pardes, M.D. “The Perilous State of Academic Medicine” JAMA 2000;283:2427–9
Kamitani H, Masuzawa H, Kanazawa I, Kubo T. Saccular cerebral aneurysms in young adults. Surg Neurol 2000;54:59 – 67. BACKGROUND
The formation and rupture of cerebral aneurysms has been controversial. In order to clarify their nature, this study investigates the size and location of ruptured and unruptured aneurysms in young adults and the results of surgery. METHODS
The subjects of this study are 35 patients with ruptured and two with unruptured aneurysms. They range in age from 20 to 39 years. The size and location of their aneurysms were determined by angiographic measure of their maximal inner diameters. Direct surgery was performed on 34 patients with ruptured aneurysms and on one with an unruptured aneurysm. RESULTS
Ruptured aneurysms in young adults increase in number and size as they grow older. In young adults showing no atherosclerosis or hypertension, ruptured aneurysms occurred in locations and with a frequency found in patients with hypertension. In young adults, aneurysms in the internal carotid artery larger than 3.5 mm (Fisher’s exact test; p ⬍ 0.05) and the anterior communicating artery showed a tendency to rupture. The surgery produced excellent results in young adults with grade I to III by Hunt and Kosnik classification, but extremely poor results for those with grade IV resulting from vasospasm (Fisher’s exact test; p ⬍ 0.05). CONCLUSION
It is possible that aneurysms found in young adults might in fact have been present from childhood and adolescence, increasing sufficiently in size to rupture in the forties and fifties. Accordingly, while aneurysm formation may be related to fragile arterial walls, aneurysm rupture may be the result of aging factors such as hypertension and atherosclerosis. Even in young adults, vasospasm had an impact on the outcome of surgery. © 2000 by Elsevier Science Inc. KEY WORDS
Cerebral aneurysms, cerebral angiography, subarachnoid hemorrhage, young adult. Address reprint requests to: Dr. H. Kamitani, Department of Neurosurgery, Kanto Teishin Hospital, 5-9-22, Higashi-Gotanda, Shinagawa-ku, Tokyo, Japan 141. Received September 13, 1999; accepted May 24, 2000. © 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
erebral aneurysms, both ruptured and unruptured, most frequently occur in patients over age 40. This tendency has led some investigators [5,6,29,30] to believe that cerebral aneurysms are not congenital but acquired, and that hemodynamic stress may serve as a major factor in aneurysm formation and rupture. Previous authors [7,22,23, 24,25,26,31] have shown some differences between aneurysms occurring in children and adolescents versus those found in adults. In trying to understand aneurysm formation and rupture, it is worth investigating cerebral aneurysms in young adults in their twenties and thirties, who are located at the midpoint in age between adolescents and adults over age 40. In general, these young adults do not exhibit signs of hypertension or arteriosclerosis or atherosclerosis. Based on a comparison of these age groups, this study discusses aneurysm formation and rupture as well as the outcome of surgery for ruptured aneurysms in young adults.
C
Patients and Methods Our hospital has admitted 286 patients (109 male, 177 female) with ruptured saccular cerebral aneurysms in the last 30 years (Table 1). Of these, five patients were in their twenties; 30 in their thirties (9 between the ages of 30 and 34, 21 between the ages of 35 and 39); 79 in their forties (33 between the ages of 40 and 44, 46 between the ages of 45 and 49); 82 in their fifties; 59 in their sixties; 25 in their seventies; and six in their eighties. There were more female patients than male patients in each age group. Direct surgery on the aneurysms was undertaken in 273 of the 286 patients. Thirty-seven young adults ranging in age from 21 to 39 years were included in this study. Of these, 35 had ruptured aneurysms and two unruptured ones that were detected by chance during hospital stays 0090-3019/00/$–see front matter PII S0090-3019(00)00265-2
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1
Kamitani et al
Ruptured Saccular Aneurysms in Patients Under and Over Age 40
UNDER 40
ICA
Group A Twenties Group B Thirties 30–34 35–39 Total
A COMM A
MCA
3
Forties 40–44 45–49 Fifties Sixties Seventies Eighties Total
POSTERIOR
2
3 6 12
OVER 40
ACA
3 8 11
2 3 7
ICA
A COMM A
MCA
8, (1) 9 22 24 10, (4) 1, (1) 74, (6)
14 18 29 10, (2) 4 1 76, (2)
6 14 19, (2) 14 3, (1) 2 58, (3)
TOTAL 5
2 2
ACA 2 5 6 4 1 0 18
1 1, (1) 2, (1)
9 20, (1) 34, (1)
POSTERIOR
TOTAL
1, (1) 4 5 2 1 13, (1)
31, (2) 46, 80, (2) 57, (2) 20, (5) 5, (1) 239, (12)
( ): Not operated. ICA: internal carotid artery; A Comm A: anterior communicating artery; MCA: middle cerebral artery; ACA: anterior cerebral artery; Posterior: posterior circulation.
for conditions other than subarachnoid hemorrhage. The 35 young adults with ruptured aneurysms were divided into two age groups (Groups A and B, Table 1); Group A consisted of five young adults in their twenties while Group B consisted of 30 in their thirties. Serial cerebral angiography supplemented by multisection angiotomography [19] and magnified angiography, detected ruptured aneurysms in patients with subarachnoid hemorrhage. By contrast, in the case of the two young adults suffering from vague headaches and hypertensive cerebral bleeding, the aneurysms were incidentally detected through MR imaging and/or MR angiography after cerebral angiography. Recently, digital subtraction angiography has replaced serial angiography. Allowing for different magnification (routine angiography ⫻ 1.12, angiotomography ⫻ 1.2, magnified angiography ⫻ 1.7), the size of the aneurysms was determined by measuring their maximal inner diameter on each angiography. Such
2
measurements were taken in 262 of the 286 patients with ruptured aneurysms (91.6%) and the two young adults with unruptured aneurysms. Tables 2, 3, and 4 give the numbers of hypertensive patients in individual male and female age groups, and the size and location of the aneurysms in 35 patients under 40 and 227 patients over 40, respectively. Table 3 also includes the two young adults with unruptured aneurysms. Table 5, which includes the incidence of perioperative vasospasm and hydrocephalus in young adults with a single or multiple instances of subarachnoid hemorrhage, shows the relationship between surgical prognosis [9] and preoperative clinical grading by the Hunt and Kosnik classification [8]. Direct surgery involving neck clipping, trapping, and wrapping or coating of the aneurysms was undertaken in 35 of 35 young adults with ruptured aneurysms and in one young adult with an unruptured aneurysm. Two young adults, one with a rup-
Hypertension in Patients with Ruptured Cerebral Aneurysms
AGE (YEARS) SEX
30–39
40–49
50–59
60–69
70–79
80–
Male Female Total
2/13 (15.4) 2/17 (11.8) 4/30 (13.3)
12/37 (32.4) 14/42 (33.3) 26/79 (32.9)
14/35 (40.0) 19/47 (40.4) 33/82 (40.2)
11/17 (64.7) 20/42 (47.6) 31/59 (52.5)
1/3 (33.3) 13/22 (59.1) 14/25 (56.0)
0/1 (0) 4/5 (80.0) 4/6 (66.7)
( ) ⫽ %.
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3
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61
Size (mm) and Location of Aneurysms in Young Adults
ICA Twenties Size Average Thirties 30–34 Size Average 35–39 Size Average Total Size Average
A COMM A
3 3.8–4.3 4.0
[1] 4.3 4.3
3 2.7–5.3 3.8 6 3.9–7.1 5.1 9 2.7–7.1 4.7
[3] 2.9–4.0 3.5 [3] 2.7–3.1 2.9 [6] 2.7–4.0 3.2
MCA
POSTERIOR CIRCULATION
ACA
2 6.0–9.0 7.5 3 5.4–10.9 7.8 8 3.5–21.6 8.7 11 3.5–21.6 8.4
2 2.8–5.4 4.1 3 3.8–7.4 5.5 5 2.8–7.4 5.0
[1] 4.8 [5] 2.4–4.4 3.2 [5] 2.4–4.4 3.2
2 4.0–4.5 4.3 2 4.0–4.5 4.3
1 8.1 8.1 2 7.1–7.2 7.2 3 7.1–8.1 7.5
[1] 4.8 4.8
[ ] Unruptured. ICA: internal carotid artery; A comm A: anterior communicating artery; MCA: middle cerebral artery; ACA: anterior cerebral artery.
tured aneurysm and the other with an unruptured aneurysm, refused surgery. This study excludes those patients with subarachnoid hemorrhage whose ruptured aneurysms could not be defined by angiography and/or surgery, and those in whom ruptured aneurysms were associated with arteriovenous malformations and general connective tissue diseases. This study tentatively includes unruptured intracavernous aneurysms in patients with
4
ruptured aneurysms as multiple aneurysms. Nevertheless, Table 4 excludes these unruptured aneurysms because of their low rate of rupture.
Results Cerebral angiography in all 37 young adults showed few arteriosclerotic or atherosclerotic changes
Size (mm) and Location of Aneurysms in Patients over Age 40
ICA Forties 40–44 Size Average 45–49 Size Average Fifties Size Average Sixties Size Average Seventies Size Average Eighties Size Average Total Size Average
8 2.5–7.1 5.1 7 5.9–8.6 7.2 17 5.3–12.1 7.8 23 4.2–18.0 8.8 11 3.5–15.0 8.0 2 4.8–6.9 5.9 68 2.5–18.0 7.7
[13] 2.7–9.0 4.7 [3] 2.8–4.0 3.4 [7] 2.8–7.1 4.4 [6] 3.3–7.3 5.2 [5] 3.1–6.3 5.0
[34] 2.7–9.0 4.6
A COMM A 12 3.2–8.2 6.0 17 4.0–10.8 7.5 26 5.0–10.4 7.5 12 4.0–9.9 7.5 5 3.2–5.5 4.4 1 15.0 15.0 73 3.2–15.0 7.1
[1] 6.6 6.6 [1] 5.4 5.4 [1] 3.8 3.8 [1] 4.7 4.7
[4] 3.8–6.6 5.1
MCA 5 5.4–16.7 9.3 12 4.3–9.9 6.0 21 3.4–16.9 7.5 12 3.0–25.0 10.1 4 7.6–10.6 9.6 2 3.5–6.1 4.8 56 3.0–25.0 8.0
ACA
[2] 2.7–6.3 4.5 [2] 3.0–5.4 4.2 [1] 3.6 3.6 [6] 3.0–8.4 5.7 [2] 2.7–8.4 5.2
2 2.8–6.1 4.5 5 2.6–10.4 7.0 6 3.2–15.7 7.5 3 4.3–11.2 7.1 1 5.0 5.0
[1] 2.5 2.5 [2] 3.8–5.3 4.6 [2] 2.2–5.1 3.7
[13] 2.7–8.4 4.4
17 2.6–15.7 6.8
[5] 2.2–5.3 2.7
POSTERIOR CIRCULATION 1 5.9 5.9
4 4.8–8.6 5.9 5 3.2–7.5 6.0 2 6.9–9.2 8.1 1 3.8 3.8 13 3.2–9.2 6.1
[ ] Unruptured. ICA: internal carotid artery; A Comm A: anterior communicating artery; MCA: middle cerebral artery; ACA: anterior cerebral artery.
[2] 4.8–6.3 5.6 [1] 7.5 7.5 [1] 5.0 5.0
[4] 4.8–7.5 5.9
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Clinical Grading and Surgical Prognosis
GRADE (HUNT & KOSNIK) Twenties SAH 1st
I
II
2 (LV: 1)
1
III
2nd 3rd Thirties SAH 1st 2nd
V
1 (DV: 1) 1 6 2 (LV: 1)
11 (DV: 1, NPH: 1) 3 (DV: 1, NPH: 1)
3 (DV: 1) 3 (DV: 1, LV: 2, NPH: 2)
3rd Prognosis Good recovery Moderately disabled Severely disabled Vegetative Dead
IV
(Glasgow outcome scale [9]) 11 14 1
1 (DV: 1, NPH: 1) 1 (DV: 1, NPH: 1)
6 1 2
SAH: subarachnoid hemorrhage; DV: diffuse vasospasm; LV: localized vasospasm; DLV: diffuse or localized vasospasm; NPH: normal pressure hydrocephalus.
such as irregular arterial walls or tortuous arterial course. Multiple cerebral aneurysms were found in seven of 35 hemorrhaging patients under 40 (20.0%) and 50 of 251 hemorrhaging patients over 40 (19.9%). In this study, male and female patients with ruptured aneurysms exhibited WHO-classified hypertension (160/95 mm Hg) at incidence rates of 15.4 and 11.8% in their thirties, 32.4 and 33.3% in their forties, 40.0 and 40.4% in their fifties, 64.7 and 47.6% in their sixties, 33.3 and 59.1% in their seventies, and 0 and 80% in their eighties (Table 2). By contrast, Japanese male and female adults in the general population show hypertension at incidence rates of 7.5 and 3.4% in the thirties, 18.9 and 13.2% in the forties, 33.6 and 27.7% in the fifties, 43.1 and 42.5% in the sixties, and 52.8 and 57.6% over seventy. In this study, there was no statistically significant difference in incidence of hypertension between male and female patients in their thirties and those in the general Japanese adult population. Male and female patients in their forties and female patients in their fifties; however, exhibited hypertension at significantly higher incidence rates (Fisher’s exact test; p ⬍ 0.05). The incidence of hypertension sharply increased as patients advanced in age over 40 and 50. The sudden increase of ruptured aneurysms in patients in hypertensive age groups forced us to consider that hypertension
might serve as an important factor for aneurysm rupture in patients over 40. There were some differences in the size and location of the aneurysms between patients in their twenties and those in their thirties (Table 3). In the former, ruptured aneurysms were very small (3.8 – 4.0 mm) in the internal carotid artery and mediumsized (6.0 –9.0 mm) in the middle cerebral artery. As patients advanced in age, their ruptured aneurysms in the anterior circulation increased in number and size or only in number. It was not until patients reached age 30 that ruptured aneurysms appeared in the anterior communicating and anterior cerebral arteries, and in the posterior circulation. In patients in their forties, ruptured aneurysms in the anterior circulation suddenly increased in number but those in the posterior circulation remained few in number. Ruptured aneurysms in patients in their thirties were similarly located to those in patients over age 40. In patients in their thirties, the ruptured aneurysms were found in the internal carotid artery (nine cases, 30.0%), the anterior communicating artery (11 cases, 36.7%), the middle cerebral artery (five cases, 16.7%), the anterior cerebral artery (two cases, 6.7%), and the posterior circulation (three cases, 10.0%). These incidence rates at different sites were roughly similar to those of ruptured aneurysms in patients over the age of forty
Saccular Aneurysms in Young Adults
(Table 1). Ruptured aneurysms in patients in their thirties ranged in size from 2.7 to 7.1 mm (4.7 mm on average) in the internal carotid artery, from 3.5 to 21.6 mm (8.4 mm on average) in the anterior communicating artery, from 2.8 to 7.4 mm (5.0 mm on average) in the middle cerebral artery, from 4.0 to 4.5 mm (4.3 mm on average) in the anterior cerebral artery, and from 7.1 to 8.1 mm (7.5 mm on average) in the posterior circulation. Although the ruptured internal carotid artery aneurysms in patients in the age range from 30 to 34 remained small in size, those in patients in the age range from 35 to 39 appeared somewhat larger. Compared to those in patients over age 40, ruptured aneurysms in young adults ranging in age from 20 to 39 seemed much smaller in the internal carotid artery (4.5 and 7.7 mm on average in young adults and patients in age over 40, respectively), somewhat smaller in the anterior (4.3 and 6.3 mm) and middle cerebral arteries (5.7 and 8.0 mm), and roughly similar-sized in the anterior communicating artery (8.4 and 7.1 mm) and posterior circulation (7.5 and 6.1 mm). As patients advanced in age, ruptured aneurysms in the internal carotid, and anterior and middle cerebral arteries increased in size, whereas those in the anterior communicating artery and posterior circulation did not (Tables 3 and 4). In the internal carotid artery of young adults, aneurysms larger than 3.5 mm showed a high probability of rupturing (Fisher’s exact test; p ⬍ 0.05). That all anterior communicating artery aneurysms ranging in size from 3.5 to 21.6 mm (8.4 mm on average) in patients in their thirties ruptured points to the significance of this site. By contrast, in the case of aneurysms in the posterior circulation, there was no significant difference in incidence of rupture between young patients (under 40) and those over 40. Even as patients advanced in age over 40, their ruptured posterior circulation aneurysms remained few in number. Perioperative angiography showed localized vasospasm in four young adults ranging in condition from grade I to III by Hunt and Kosnik classification and diffuse vasospasm in seven with conditions ranging from grade II to IV. Seven of the eight young adults with conditions rated from grade II to III recovered well despite exhibiting diffuse or localized vasospasm and hydrocephalus after an initial or second or even third episode of aneurysmal bleeding. On the other hand, all three grade IV patients showed diffuse vasospasm after a second or third episode of aneurysmal bleeding and died (two) or became vegetative (one). A second or third episode of bleeding on the same day or several days after an initial or second episode in young patients
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63
led to downgrading of their conditions. Young patients whose second episode of bleeding occurred more than 1 week after the initial episode, however, remained in conditions ranging from grade I to III. The manifestation of vasospasm was closely related to poor grading or poor surgical results (Fisher’s exact test; p ⬍ 0.05, Table 5). One female patient who had undergone wrapping surgery for a ruptured anterior cerebral artery aneurysm died of re-bleeding 8 years later. In this study, surgery on 35 young patients with ruptured and unruptured aneurysms disclosed their aneurysms and parent arteries as neither discolored nor atherosclerotic; moreover, even if the aneurysms were large, they appeared sufficiently pliable to allow easy control of intraoperative bleeding.
Discussion Previous authors [7,22,23,24,25,26,31] have demonstrated the differences in size and location between ruptured aneurysms in children and adolescents, and those in adults. Meyer et al [22] showed that ruptured aneurysms in children and adolescents tended to be huge and to be located in the posterior circulation. Ostergaad [24], however, noted 26 juvenile aneurysms predominantly located in the anterior circulation, especially in the internal carotid bifurcation. The majority of aneurysms in our young adults were located at the bifurcations of Willis’s circle in the anterior circulation. This study found some differences in size and location of aneurysms between patients in their twenties and those in their thirties. In the former, ruptured cerebral aneurysms were few in number and exclusively situated in the anterior circulation, especially in the internal carotid and middle cerebral arteries. Nevertheless, with advancing years, patients in their thirties showed ruptured aneurysms increasing in size and number. In the case of patients over 40, this study showed ruptured aneurysms at sites similar to those previously reported [13, 18]. The demonstration of ruptured or unruptured aneurysms in young adults, and the sudden increase of ruptured aneurysms in patients in age over 40 leads us to hypothesize that the aneurysms might have emerged when patients were children and adolescents at the latest, and that once they advanced into their twenties or thirties, the unruptured aneurysms reached the critical size for rupture. Moreover, patients in their thirties and forties had ruptured aneurysms in similar locations and multiple aneurysms at similar rates of occurrence, suggest-
64
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ing that a similar mechanism had led to aneurysm formation and rupture in both age groups. In the case of the posterior circulation, we could not find a significant difference in incidence of ruptured aneurysms between patients under 40 and those over 40. In other words, as patients grew older, ruptured aneurysms in the anterior circulation increased in number while those in the posterior circulation remained constant in number, suggesting that advancing age has little effect on aneurysm formation and rupture in the posterior circulation. As shown in Table 3, ruptured aneurysms varied considerably in size according to location. In patients under 40, ruptured aneurysms in the internal carotid artery ranged from 2.7 to 7.1 mm in diameter, showing that aneurysms larger than 3.5 mm have a high probability of rupturing (Fisher’s exact test; p ⬍ 0.05). By contrast, the ruptured anterior communicating artery aneurysms and posterior circulation aneurysms were as large as those in patients over forty (3.5 to 21.6 mm, with 8.4 mm as the average and 7.1 to 8.2 mm, 7.5 mm average, respectively). Previous investigators studied the size and rupture rate of cerebral aneurysms [12,20,33]. Kassell [12] noted that cerebral aneurysms in adults that were larger than 7 mm had a high probability of rupture. On the other hand, Wiebers et al [33] showed a low probability of rupture in cerebral aneurysms smaller than 10 mm. They posited that cerebral aneurysms smaller than 5 mm had a low risk of subsequent rupture. Earlier, however, Young et al [36] and more recently, Shievink et al [27], Yasui et al [35], Lin et al [17], and Kamitani et al [11], had shown rupturing of unruptured cerebral aneurysms and aneurysmal rests smaller than 5 mm after incomplete surgery. Aneurysmal size does not seem to be a reliable factor in predicting subsequent rupture. In general, ruptured aneurysms in young adults appeared small in the internal carotid artery and medium to large in the anterior communicating and middle cerebral arteries and in the posterior circulation. Accordingly, it seems that even small aneurysms of the internal carotid artery have a tendency to rupture while those of the anterior communicating and middle cerebral arteries need to grow larger than 5 mm, and posterior circulation aneurysms, 8 mm, before they rupture. In our hospital, ruptured aneurysms in young adults in their twenties and thirties comprised only 1.8 and 10.5% of all ruptured aneurysms, respectively. Most cerebral aneurysms are detected at the time of rupture and usually in patients over age 40. Recently in Japan, the use of MR imaging and/or MR angiography or CT scan for examining the brain has become popular
Kamitani et al
and has enabled us to detect unruptured aneurysms much more often than before. Nevertheless, it is usually patients over age 40 who undergo such examinations. As shown in our two cases, if young adults had more opportunity to undergo such neurovascular imaging, more unruptured aneurysms might have been detected. The formation and rupture of cerebral aneurysms remain open to debate [4,25,28,29,30]. Pathologically, the aneurysmal wall in childhood and adolescence shows alterations similar to those in adults, such as medial defect and interrupted internal elastic lamina. Degeneration of the internal elastic lamina appears essential for aneurysm formation. Atherosclerosis has been regarded as a major factor in such degeneration [4]. By contrast, previous experimental investigations [5,6] showed that cerebral aneurysms were generated by hemodynamic stress augmented by hypertension. At present, hemodynamic stress is regarded as the most important factor for the formation and growth of aneurysms, especially in atherosclerotic arterial walls. Previous authors [7,23,24,25,26] have noted that a vast majority of ruptured aneurysms in children and adolescents occur in the anterior circulation, especially in the internal carotid artery. The internal carotid artery has a blood flow much greater than the anterior communicating and middle cerebral arteries, which may exert intense hemodynamic stress on the arterial walls and result in aneurysm formation and rupture. The vast majority of young adults in our study, however, exhibited neither hypertension nor atherosclerosis. Clinically and neuroradiologically, we could not find any factors in young adults that increased hemodynamic stress sufficient to contribute to aneurysm formation. We question whether hemodynamic stress is sufficient to explain juvenile and adolescent cerebral aneurysms, as suggested by previous animal experiments [5,6]. The formation and rupture of aneurysms seems to depend upon an imbalance between arterial durability and hemodynamic stress. Surgery on our 34 patients with ruptured aneurysms showed the aneurysmal walls to be remarkably fragile. Such arterial fragility may lessen durability and relate to the formation and rupture of aneurysms. Some authors have stressed such intrinsic factors as metabolic deficiency [14,15] and type III collagen mutation [2,25], which decrease arterial durability in aneurysm formation. Ostergaard [25] emphasizes intrinsic factors as being of the greatest importance in the formation and rupture of juvenile aneurysms. It remains open to debate whether hypertension plays an important role in aneurysm formation and rupture [1,3,10,21,32,33]. Asari and Ohmoto [1] and
Saccular Aneurysms in Young Adults
Taylor et al [32] have noted hypertension to be a risk factor for aneurysm formation and/or rupture. Cohen [3] has proposed that hypertension is related to aneurysm rupture but not formation. McCormick et al [21] and Juvela et al [10], on the other hand, have shown that hypertension exerts little effect on aneurysm formation, rupture, or growth. We have also noted recently that the rupturing of unruptured or residual aneurysms depends upon the annual growth rates, which are unrelated to hypertension [11]. This study, however, showed ruptured aneurysms at similar locations and multiple aneurysms occurring at similar rates in patients in their thirties and those in their forties, with a sudden increase in the rupture rate in patients in their forties and fifties, who also exhibited higher rates of hypertension. In the case of children and adolescents, it seems plausible to attribute aneurysm formation to decreased arterial durability unrelated to atherosclerosis or hypertension but rather, to intrinsic arterial fragility, while in patients over age 40, ruptures may be influenced by such factors as hypertension and atherosclerosis. It is well known that children and adolescents with ruptured aneurysms, even when they exhibit angiographical vasospasm, have an excellent prognosis [23,26]. In this study, all 23 young adults with initial bleeding were classified as grade I, II, or III according to the Hunt and Kosnik classification, whereas three of twelve young adults with two or three occurrences of bleeding presented as grade IV. Preoperative angiography disclosed vasospasm in eight of 32 young adults with grade I, II, or III and in all three grade IV young adults, associating vasospasm with patients in poorer condition (Fisher’s exact test; p ⬍ 0.05). Surgical prognosis [9] was good recovery or moderate disability for those young adults graded I to III, but vegetation or death for grade IV patients (Fisher’s exact test; p ⬍ 0.01). Surgery on young adults showed the ruptured aneurysms to be sufficiently soft and fragile to bleed prematurely, but also that such premature bleeding could be easily controlled. In normotensive young adults, such arterial softness and fragility may decrease the durability of arterial walls and result in aneurysm bleeding on the one hand, while it may result in decreased bleeding on the initial occasion of aneurysmal rupture, on the other. This may account for the small volume of the subarachnoid hematoma as shown by Pasqualin et al [26]. Previous authors [23,26] have noted that vasospasm is of minor prognostic significance in children. Our young adults with poor grading, however, exhibited significant vasospasm resulting from repeated subarachnoid hemorrhaging on the same day or sev-
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eral days after the initial episode; as with middleaged and elderly patients with poor grading [16], their prognosis was poor. REFERENCES 1. Asari S, Ohmoto T. Natural history and risk factors of unruptured cerebral aneurysms. Clin Neurol Neurosurg 1993;95:205–14. 2. Chyatte D, Reilly J, Tilson MD. Morphometric analysis of reticular and elastin fibers in the cerebral arteries of patients with intracranial aneurysms. Neurosurgery 1990;26:939 – 43. 3. Cohen MM. Cerebrovascular accidents. A study of two hundred one cases. Arch Pathol 1955;60:296 –307. 4. Crompton MR. The pathogenesis of cerebral aneurysms. Brain 1966;89:797– 816. 5. Handa H, Hashimoto N, Nagata I, Hazama F. Saccular cerebral aneurysms in rats. A newly developed animal model of the disease. Stroke 1983;14:857– 66. 6. Hashimoto N, Kim C, Kikuchi H, Kojima M, Kang Y, Hazama F. Experimental induction of cerebral aneurysms in monkeys. J Neurosurg 1987;67:903–5. 7. Heiskanen O, Vilkki J. Intracranial arterial aneurysms in children and adolescents. Acta Neurochir (Wien) 1981;59:55– 63. 8. Hunt WE, Kosnik EJ. Timing and perioperative care in intracranial aneurysm surgery. Clin Neurosurg 1974; 21:79 – 89. 9. Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet 1975;1:480 – 4. 10. Juvela S, Porras M, Heiskanen O. Natural history of unruptured intracranial aneurysms: a long-term follow-up study. J Neurosurg 1993;79:174 – 82. 11. Kamitani H, Masuzawa H, Kanazawa I, Kubo T. Bleeding risk in unruptured and residual cerebral aneurysms. Angiographic annual growth rate in nineteen patients. Acta Neurochir (Wien) 1999;141:153–9. 12. Kassell NF, Torner JC. Size of intracranial aneurysms. Neurosurgery 1983;12:291–7. 13. Kassell NF, Torner JC, Haley EC Jr. The international cooperative study on the timing aneurysm surgery. Part 1. Overall management results. J Neurosurg 1990;73:18 –36. 14. Kaufmann AM, Reddy KK, West M, Halliday WJ. Alkaptonuric ochronosis and multiple intracranial aneurysms. Surg Neurol 1990;33:213– 6. 15. Kretzschmar HA, Wagner H, Hubner G, Danek A, Witt TN, Mehraein P. Aneurysms and vacuolar degeneration of cerebral arteries in late-onset acid maltase deficiency. J Neurol Sci 1990;98:169 – 83. 16. Lanzino G, Kassell NF, Germanson TP, Kongable GL, Truskowsky LL, Torner JC, Jane JA. Age and outcome after aneurysmal subarachnoid hemorrhage: why do older patients fare worse? J Neurosurg 1996;85: 410 – 8. 17. Lin T, Fox AJ, Drake CG. Regrowth of aneurysm sacs from residual neck following aneurysm clipping. J Neurosurg 1989;70:556 – 60. 18. Locksley HB. Natural history of subarachnoid hemorrhage, intracranial aneurysms, and arteriovenous malformations: Based on 6368 cases in the cooperative study: I. In Sahs AL, Perret GE, Locksley HB et al, eds. Intracranial aneurysms and subarachnoid hemorrhage. Philadelphia: Lippincott, 1969, 58 –108.
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19. Masuzawa H, Kobayashi M, Inoya H, Kamitani H, Sato J. Multisection angiotomography of intracranial aneurysms. Acta Neurochir (Wien) (Suppl) 1979;28:550 –3. 20. McCormick WF, Acosta-Rua GJ. The size of intracranial saccular aneurysms. An autopsy study. J Neurosurg 1970;33:422–7. 21. McCormick WF, Schmalstieg EJ. The relationship of arterial hypertension to intracranial aneurysms. Arch Neurol 1977;34:285–7. 22. Meyer FB, Sundt TM Jr, Fode NC, Morgan MK, Forbes GS, Mellinger JF. Cerebral aneurysms in childhood and adolescence. J Neurosurg 1989;70:420 –5. 23. Ostergaad JR, Voldby B. Intracranial arterial aneurysms in children and adolescents. J Neurosurg 1983; 58:832–7. 24. Ostergaad JR. A long-term follow-up study of juvenile aneurysm patients. Acta Neurochir (Wien) 1985;77: 103–9. 25. Ostergaard JR. Aetiology of intracranial saccular aneurysms in childhood. Br J Neurosurg. 1991;5:575– 80. 26. Pasqualin A, Mazza C, Cavazzani P, Scienza R, DaPian R. Intracranial aneurysms and subarachnoid hemorrhage in children and adolescents. Child Nerv Syst 1986;2:185–90. 27. Schievink WI, Piepgras DG, Wirth FP. Rupture of previously documented small asymptomatic saccular intracranial aneurysms. J Neurosurg 1992;76:1019 –24. 28. Sekher LN, Heros RC. Origin, growth, and rupture of saccular aneurysms: a review. Neurosurgery 1983;8: 248 – 60. 29. Stehbens WE. Etiology of intracranial berry aneurysms. J Neurosurg 1989;70:823–31. 30. Stehbens WE. Pathology and pathogenesis of intracranial berry aneurysms. Neurol Res 1990;12:29 –34. 31. Swamy NK, Pope FM, Coakham HB. Giant aneurysm of internal carotid artery in a four-year-old child: a case report. Surg Neurol 1993;40:138 – 41. 32. Taylor CL, Yuan Z, Selman WR, Ratcheson RA, Rimm AA. Cerebral arterial aneurysm formation and rupture in 20,767 elderly patients: hypertension and other risk factors. J Neurosurg 1995;83:812–9. 33. Wiebers DO, Whisnant JP, Sundt TM Jr, O’Fallon WM. The significance of unruptured intracranial saccular aneurysms. J Neurosurg 1987;66:23–9. 34. Winn HR, Almaani WS, Berga SL. The long-term outcome in patients with multiple aneurysms. Incidence of late hemorrhage and implications for treatment of incidental aneurysms. J Neurosurg 1983;59:642–51. 35. Yasui N, Magarisawa S, Suzuki A, Nishimura H, Okudera T, Abe T. Subarachnoid hemorrhage caused by previously diagnosed, previously unruptured intracranial aneurysms: a retrospective analysis of 25 cases. Neurosurgery 1996;39:1096 –1101. 36. Young B, Meacham WF, Allen JH. Documented enlargement and rupture of a small arterial sacculation. J Neurosurg 1971;34:814 –7.
COMMENTARY
Kamitani et al present their experience with cerebral saccular aneurysms seen in young adult patients, who predominantly presented with subarachnoid hemorrhage. They divided these aneurysms into two groups, and provide an inter-
Kamitani et al
esting discussion of the pathogenesis of aneurysm formation and rupture. We described the characteristics of cerebral aneurysms in the first three decades of life in 1978 [1]; our results were very similar to these authors’ except that the incidence of MCA aneurysms was extremely low in our series. The distribution of aneurysms in young adults in this study is similar to that in all patients in our study. This may be attributed to the faster growth in younger patients and/or the change to an older population that has occurred in Japan within the last two decades. Takashi Yoshimoto, M.D., Ph.D. Department of Neurosurgery Tohoku University School of Medicine Sendai, Japan REFERENCE 1. Yoshimoto T, Uchida K, Suzuki J. Intracranial saccular aneurysms in the first three decades. Surg Neurol 1978; 9:287–91.
To date, the pathogenesis of aneurysms has been a matter of debate. There are different schools of thought regarding the etiology of aneurysm formation, growth, and rupture. This is another thoughtprovoking article on the topic. The authors note the existence of aneurysms in similar locations in subgroups of patients in their 20s, 30s, and 40s, with increased aneurysm size and the addition of new sites of occurrence as age increases. They correlate these findings in a linear fashion with the pathogenesis of the aneurysms, and propose that the aneurysms in these patients may have begun to develop in the first or second decades of life, and became symptomatic in the third or fourth decades. This view points to a congenital origin for these aneurysms. The absence of features such as atherosclerosis and hypertension in the group of patients under 40 and the presence of these features in the group over 40, with increasing aneurysm size and number and frequency of rupture, also supports the role of these acquired factors in the development of aneurysms. Our view in regard to the pathogenesis of aneurysms is that their etiology is multifactorial. We think, as do these authors, that degenerative, hemodynamic, metabolic, and environmental factors are superimposed on congenital factors to contribute to the development of cerebral aneurysms. The data in this article suffer from an inadequate number of patients to derive statistical significance and allow one to draw conclusions. Also, the authors have not provided any physical or his-
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topathological evidence of increased arterial fragility to support their hypothesis regarding the pathogenesis of aneurysm formation in young adults. However, the article presents, if not a totally new view, at least a different perspective on this question. It would be interesting to see how the
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authors’ perspective applies to a large group of patients. Shigeaki Kobayashi, M.D. Department of Neurosurgery Shinshu University School of Medicine Matsumoto, Japan
eaching hospitals are not-for-profit institutions and provide approximately 50% of care for the indigent in the country. —Herbert Pardes, M.D. “The Perilous State of Academic Medicine” JAMA 2000;283:2427–9
ndividual managed care companies, pressed by a competitive market, are unwilling to pay for social goods.
I
—Herbert Pardes, M.D. “The Perilous State of Academic Medicine” JAMA 2000;283:2427–9
here has been an 18% reduction in the number of medical school applicants from 1996 to 1999. What effect will the decreasing medical school applicant pool have on medicine? Are the future physician teachers, mentors, clinicians, researchers, and role models going to be the best and brightest?
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—Herbert Pardes, M.D. “The Perilous State of Academic Medicine” JAMA 2000;283:2427–9