Correspondence
Correction
Unruptured Intracranial Aneurysms
N Engl J Med 1999; 340:1439-1442May 6, 1999
- Article
To the Editor:
The conclusions reached by Wiebers et al. (Dec. 10 issue)1 about the natural history of aneurysmal subarachnoid hemorrhage arouse concern because of the inhomogeneous grouping of patients and the differences in the rates of subarachnoid hemorrhage at different sites. Since they included intracavernous aneurysms in their determination of rupture rates, the rates for aneurysms truly within the subarachnoid space may be underestimated, since intracavernous aneurysms rarely cause subarachnoid hemorrhage.2 To a lesser extent, the same caveat may apply to proximal infraclinoid ophthalmic aneurysms and those arising from the clinoidal segment of the carotid artery, since they are often protected by dura and bone. The grouping of aneurysms in these locations with aneurysms that are free within the subarachnoid space combines categories of aneurysms that entail very different risks of hemorrhage. Of the 1937 aneurysms, 669 (34.5 percent) were in these proximal locations, a point that may have important implications for the overall findings (Table 1Table 1
Distribution of Aneurysms.).From the data provided, we cannot determine the effect of this distribution of aneurysms on the much higher (by a factor of 11) risk of subarachnoid hemorrhage among the patients in group 2. Certainly, the difference of 15 percentage points between the two groups in the proportion of aneurysms free in the subarachnoid space may account for some of the results. The data shown in Table 1 of the article by Wiebers et al. suggest that the incidence of single aneurysms was the same in the two groups. Since patients in group 2 had had a previous subarachnoid hemorrhage that had been treated, they represent a population with a higher rate of multiple aneurysms and are not comparable to the patients in group 1. This factor may also have contributed to the difference in the natural history of unruptured intracranial aneurysms between the groups and must be acknowledged in any discussion of the natural history.
Another concern of ours is the relation between subarachnoid hemorrhage and the size of the aneurysm. Although Wiebers et al.3 have written about the absence of subarachnoid hemorrhage in patients with aneurysms that are less than 10 mm in diameter, many large series have shown that the mean diameter of aneurysms in patients who present with subarachnoid hemorrhage is less than 10 mm, as noted by Dr. Caplan in his editorial.4 Therefore, we conclude that there is little assurance that an aneurysm that is less than 10 mm will not bleed.
We believe that the conclusions of this article should be modified to reflect a higher risk of subarachnoid hemorrhage at certain sites, since this will affect the manner in which treatment options are presented to patients.
4 ReferencesAlejandro Berenstein, M.D.
Eugene S. Flamm, M.D.
Mark J. Kupersmith, M.D.
Beth Israel Medical Center, New York, NY 101281
The International Study of Unruptured Intracranial Aneurysms Investigators
Full Text | Web of Science | Medline2
Kupersmith MJ ,Hurst R ,Berenstein A ,Choi IS ,Jafar J ,Ransohoff J . The benign course of cavernous carotid artery aneurysms. J Neurosurg 1992;77:690-693
CrossRef | Web of Science | Medline3
Wiebers DO ,Whisnant JP ,O'Fallon WM . The natural history of unruptured intracranial aneurysms. N Engl J Med 1981;304:696-698
Full Text | Web of Science | Medline4
Caplan LR . Should intracranial aneurysms be treated before they rupture? N Engl J Med 1998;339:1774-1775
Full Text | Web of Science | Medline
To the Editor:
Although we were encouraged to see a report on the important problem of unruptured intracranial aneurysms, we are concerned that selection bias, especially in the retrospective cohort, may have undermined the study's findings and recommendations.
We were approached to participate in this study and include any patients with unruptured intracranial aneurysms who were being followed. Although we had several such patients, we declined the invitation because of our concern that the cohort would not be representative of the overall population of patients with unruptured aneurysms. For instance, the vast majority of patients with unruptured aneurysms who are referred to our institution have already been surgically treated, leaving only a small minority with aneurysms with a low risk on the basis of the natural history, and these aneurysms were, for example, heavily calcified, partly intracavernous, tiny and laterally located, or in elderly patients with other medical problems. Unfortunately, aneurysms such as these also often pose a greater surgical risk, further complicating the issue of their inclusion in a study.
We think that the data reported confirm our concern about selection bias. The cohort consisted of 1449 patients at 53 centers who were given a diagnosis over a period of 21 years (1970 to 1991). All the centers are regional referral institutions that would be expected, on the basis of the volume at our institution, to see 60 to 80 patients with newly diagnosed unruptured aneurysms annually. Assuming this to be the case, outcome data would have been reported for only 1.3 patients per year (2 percent of all patients seen). Even if one assumes the volume in the referral centers to be only 10 percent of this value, the cohort would represent only 20 percent of the patients in these centers, which is still too small a percentage to be representative of the population at large.
Thus, although we applaud any plans for a true population-based assessment and some type of randomized trial addressing this problem and hope that this article will trigger enough controversy to see that goal accomplished, we recall the initial impressions that carotid artery disease was benign and not in need of treatment, which were reversed by definitive studies showing that intervention was appropriate for patients who were properly identified. The same could apply to unruptured aneurysms, which the study shows still have a case fatality rate of 66 percent when they are left to bleed.
For those of us treating this disease, the identification of appropriate surgical candidates, combined with more cost-effective screening, probably offers the greatest hope, since ongoing efforts to prevent early rebleeding, cure vasospasm, reverse severe brain damage, and refine microsurgical and endovascular techniques are having little effect on overall morbidity due to this disease.
E. Sander Connolly, Jr., M.D.
J.P. Mohr, M.D.
Robert A. Solomon, M.D.
Columbia University, New York, NY 10032To the Editor:
The annual rupture rate reported by Wiebers et al. is considerably lower than that reported in other respected studies.1,2 One study found that unruptured aneurysms smaller than 5 mm in diameter that subsequently ruptured were larger after rupture.3 The Aneurysmal Subarachnoid Hemorrhage Cooperative Study2 demonstrated that 24 percent of ruptured aneurysms are 5 mm or less. Rupture of aneurysms smaller than 10 mm is not uncommon in our practice. The low rate of rupture of small aneurysms reported by Wiebers et al. is most likely explained by the fact that growth and rupture are time-dependent. Follow-up was not long enough to allow the expansion and rupture of aneurysms.
The rates of surgical morbidity and mortality were higher in this study than in other series.4 There have been microneurosurgical advances since 1970, when the retrospective component began. It would not be accurate to use high complication rates when one is analyzing the risks and benefits of the obliteration of aneurysms. We are sure that the authors accept the seriousness of these lesions and the potential for poor outcomes (a mortality rate of up to 50 percent after rupture). In addition, in 42 of the 205 patients who died during the 7.5 years of follow-up, death was caused by intracranial hemorrhage. Was this due to the aneurysm? Were autopsy data available?
Patients in whom the aneurysm was manipulated within 30 days after diagnosis were excluded. This cohort most likely represents younger patients who have aneurysms with worrisome features that make the decision to operate straightforward. If these assumptions are true, the rate of surgical complications would be lower in this group. The number of such patients and the reasons for treatment are not reported.
The locations of the aneurysms in this study differ from those in previous studies and suggest that there may have been a location-specific bias.5 There were 256 cavernous aneurysms. The likelihood of rupture is low if the lesion is completely intracavernous. These lesions account for 18 percent of aneurysms in the retrospective study, but for only 6 percent of cases of subarachnoid hemorrhage.
To advise patients with unruptured aneurysms properly, three factors require consideration: the size and location of the aneurysm and the patient's age. The study does not provide information regarding the rates of surgical complications as a function of the location or the size of the aneurysm or the patient's age. Unfortunately, all patients are combined into one group that reflects various microneurosurgical techniques. This approach is very misleading. We hope that this report will prompt further investigation into this important clinical issue.
5 ReferencesPhilip E. Stieg, Ph.D., M.D.
Robert Friedlander, M.D.
Brigham and Women's Hospital, Boston, MA 021151
Juvela S ,Porras M ,Heiskanen O . Natural history of unruptured intracranial aneurysms: a long-term follow-up study. J Neurosurg 1993;79:174-182
CrossRef | Web of Science | Medline2
Sahs AL, Nibbelink DW, Torner JC. Aneurysmal subarachnoid hemorrhage: report of the Cooperative Study. Baltimore: Urban & Schwarzenberg, 1981.
3
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;39:1096-1100
CrossRef | Web of Science | Medline4
King JT Jr ,Berlin JA ,Flamm ES . Morbidity and mortality from elective surgery for asymptomatic, unruptured, intracranial aneurysms: a meta-analysis. J Neurosurg 1994;81:837-842
CrossRef | Web of Science | Medline5
McCormick WF. Vascular disorders of nervous tissue: anomalies, malformations, and aneurysms. In: Bourne GH, ed. The structure and function of nervous tissue. Vol. 3. Biochemistry and disease. New York: Academic Press, 1969:537-95.
To the Editor:
In his editorial, Dr. Caplan states that “patients with previously ruptured aneurysms had 11 times the rate of rupture of patients without prior hemorrhage.” As I interpret the data of Wiebers et al., this excess is applicable only to the subgroup of patients with aneurysms that were less than 10 mm in diameter. Among patients with aneurysms that were 10 mm or more, the rates of rupture are roughly similar in the group with prior hemorrhage and the group without it.
Allan Brett, M.D.
University of South Carolina School of Medicine, Columbia, SC 29203Author/Editor Response
The authors reply:
To the Editor: Approximately half the patients with cavernous aneurysms also had noncavernous unruptured aneurysms. Although intracavernous aneurysms can cause subarachnoid hemorrhage, most are protected from the subarachnoid space. Other internal carotid aneurysms are not protected. The annual rates of rupture are only slightly increased by the exclusion of patients with cavernous aneurysms (Table 1Table 1
Mean Annual Rates of Confirmed Subarachnoid Hemorrhage.); patients in group 2 who had small (<10 mm) unruptured aneurysms remain approximately 10 times as likely to have a subsequent rupture as patients with small aneurysms in group 1.Currently, the numbers of patients are too small (only a total of 32 aneurysmal ruptures) to determine meaningful rupture rates in group 1 and group 2 according to the six different locations and two size categories (24 subgroups). The presence of multiple unruptured intracranial aneurysms was not a predictor of future rupture independent of the size and location of the largest unruptured aneurysm. Unruptured aneurysms were more likely to rupture in patients in group 2, but this risk does not appear to be related to the presence of multiple unruptured intracranial aneurysms.
The concern about microneurosurgical advances that have occurred since 1970 and the exclusion of patients who underwent surgery in the first 30 days after diagnosis is not relevant, since operative morbidity and mortality were assessed only in the patients in the prospective group, beginning in late 1991. The base-line characteristics of the surgically treated patients and those who were not so treated were virtually identical, with minor differences in the mean age and aneurysmal size only among patients in group 1, underscoring the lack of consensus about the selection of patients with unruptured intracranial aneurysms as candidates for surgery.
Comparison of our retrospective results with those of a 30-year study (1965 to 1995) in Rochester, Minnesota, of a population-based sample of patients with intracranial aneurysms1 (and unpublished data) yielded strikingly similar demographic characteristics, aneurysmal characteristics, and associated medical conditions, suggesting that our group (representing approximately 40 percent of patients with unruptured aneurysms who were seen at participating centers) may be representative of the general population. A randomized trial would involve a much greater prospective selection bias than our study because many patients would refuse to participate.
Data on the natural history of unruptured intracranial aneurysms confirm the conclusion that judgments about the probability of the rupture of such aneurysms cannot be extrapolated from data on patients with ruptured aneurysms. It appears that most aneurysms that are going to rupture do so when they form or soon afterward and that the critical size in terms of rupture is smaller for aneurysms that rupture early.
In our cohort, the patient's age significantly predicted operative morbidity and mortality. The influences of the size and location of aneurysms in this study are not yet clear because of insufficient numbers of patients; this is one of the central reasons that the study has been extended to involve a total of 5500 patients.
1 ReferencesDavid O. Wiebers, M.D.
David G. Piepgras, M.D.
John Huston, III, M.D.
Mayo Clinic, Rochester, MN 55905for the International Study of Unruptured Intracranial Aneurysms Investigators
1
Menghini VV ,Brown RD Jr ,Sicks JD ,O'Fallon WM ,Wiebers DO . The incidence and prevalence of intracranial saccular aneurysms and hemorrhage in Olmsted County, Minnesota, 1965 to 1995. Neurology 1998;51:405-411
Web of Science | Medline
Author/Editor Response
Dr. Brett is correct. Aneurysms that were less than 10 mm in diameter were 11 times as likely to rupture in patients who had prior bleeding from other aneurysms as in patients without prior subarachnoid hemorrhage. Aneurysms that were at least 10 mm had a similar rate of rupture whether or not there had been prior subarachnoid hemorrhage.
Louis R. Caplan, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215- Citing Articles (15)
Citing Articles
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Wajd N. Al-Holou, Adam Khan, Thomas J. Wilson, William R. Stetler, Gaurang V. Shah, Cormac O. Maher. (2011) Incidental findings on cranial imaging in nonagenarians. Neurosurgical Focus 31:6, 1-6
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Nohra Chalouhi, Rohan Chitale, Pascal Jabbour, Stavropoula Tjoumakaris, Aaron S. Dumont, Robert Rosenwasser, L. Fernando Gonzalez. (2011) The case for family screening for intracranial aneurysms. Neurosurgical Focus 31:6, 1-8
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Nohra Chalouhi, Aaron S. Dumont, Ciro Randazzo, Stavropoula Tjoumakaris, L. Fernando Gonzalez, Robert Rosenwasser, Pascal Jabbour. (2011) Management of incidentally discovered intracranial vascular abnormalities. Neurosurgical Focus 31:6, 1-12
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Yuhei Yoshimoto. (2006) A mathematical model of the natural history of intracranial aneurysms: quantification of the benefit of prophylactic treatment. Journal of Neurosurgery 104:2, 195-200
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Thottala Jayaraman, Vanessa Berenstein, Xiaguai Li, Jillian Mayer, Michael Silane, Yang Sam Shin, Yasunari Niimi, T??rker Kl??, Murat Gunel, Alejandro Berenstein. (2005) Tumor Necrosis Factor ?? is a Key Modulator of Inflammation in Cerebral Aneurysms. Neurosurgery 57:3, 558-564
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Gregory J. Zipfel, Ralph G. Dacey. (2004) Update on the management of unruptured intracranial aneurysms. Neurosurgical FOCUS 17:5, 1-10
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G. Edward Vates, Joseph M. Zabramski, Robert F. Spetzler, Michael T. Lawton. 2004. Intracranial Aneurysms. , 1279-1335.
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Peter DV HUGHES, Gavin J BECKER. (2003) Screening for intracranial aneurysms in autosomal dominant polycystic kidney disease. Review Article. Nephrology 8:4, 163-170
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Aaron S. Dumont, Giuseppe Lanzino, Neal F. Kassell. (2002) Editorial. Journal of Neurosurgery 96:1, 52-56
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David O. Wiebers, David G. Piepgras, Robert D. Brown, Irene Meissner, James Torner, Neal F. Kassell, Jack P. Whisnant, John Huston, Douglas A. Nichols. (2002) Editorial. Journal of Neurosurgery 96:1, 50-51
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H. Richard Winn, John A. Jane, James Taylor, Donald Kaiser, Gavin W. Britz. (2002) Prevalence of asymptomatic incidental aneurysms: review of 4568 arteriograms. Journal of Neurosurgery 96:1, 43-49
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Thomas R. Forget, Ronald Benitez, Erol Veznedaroglu, Ashwini Sharan, William Mitchell, Marco Silva, Robert H. Rosenwasser. (2001) A Review of Size and Location of Ruptured Intracranial Aneurysms. Neurosurgery 49:6, 1322-1326
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Jeffrey W. Brennan, Michael L. Schwartz. (2000) Unruptured Intracranial Aneurysms: Appraisal of the Literature and Suggested Recommendations for Surgery, Using Evidence-based Medicine Criteria. Neurosurgery 47:6, 1359-1372
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Kazuo Tsutsumi, Keisuke Ueki, Akio Morita, Takaaki Kirino. (2000) Risk of rupture from incidental cerebral aneurysms. Journal of Neurosurgery 93:4, 550-553
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Joseph P. Broderick. (2000) Coiling, clipping, or medical management of unruptured intracranial aneurysms: Time to randomize?. Annals of Neurology 48:1, 5-6
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