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There are approximately 7000 deathsattributed to aneurysmal subarachnoidhemorrhage (aSAH) in the United States

annually (18). In 1966, the Cooperative Studyon Intracranial Aneurysms and SubarachnoidHemorrhage (65) reported a 50% mortality ratewithin 1 month of hospitalization for patientswith aSAH. Since that time, there have beensignificant advances, including the use of themicroscope for aneurysm clip application,improved imaging modalities, endovascular

methods for aneurysm treatment, dedicatedneurointensive care units, and more aggressivetherapy for cerebral vasospasm. Althoughthese advancements have revolutionized themanagement of this condition, the in-hospitalmortality rate after aSAH continues to exceed33%. In short, there continues to be much roomfor improvement in outcome after aSAH (18).

This work highlights controversial adjuvanttechniques, maneuvers, and therapies sur-rounding the surgical treatment of rupturedcerebral aneurysms. Rather than review the

basic management of aSAH that has beenthoroughly defined, we discuss aspects withinthe therapeutic paradigm of aSAH that lack aconsensus opinion. These include centralizedcare in high-volume centers, as well as theuse of antifibrinolytic therapy, routine cere-

brospinal fluid (CSF) diversion, intraoperative

hypothermia, temporary clip application, neu-roprotective drugs, intraoperative angiogra-phy, and decompressive hemicraniectomy.Although definitive answers will only be pos-sible through future multicenter collaboration,we review the controversy surrounding theseadjuncts and report the consensus opinionfrom a highly experienced audience.

396 | VOLUME 62 | NUMBER 2 | FEBRUARY 2008 www.neurosurgery-online.com

J. LAWRENCE POOL SYMPOSIUM

Ricardo J. Komotar, M.D.

Department of Neurological Surgery,Columbia University,

New York, New York

Brad E. Zacharia, B.S.

Department of Neurological Surgery,

Columbia University,New York, New York

J Mocco, M.D.

Department of Neurological Surgery,Columbia University,New York, New York

E. Sander Connolly, Jr., M.D.

Department of Neurological Surgery,Columbia University,New York, New York

Reprint requests:Ricardo J. Komotar, M.D.,

Department of Neurological Surgery,Neurological Institute of New York,Columbia University Medical Center,710 West 168th Street, Box 199,

New York, NY 10032.Email: [email protected]

Received, April 4, 2007.

Accepted,June 18, 2007.

CONTROVERSIES IN THE SURGICAL TREATMENT OFRUPTURED INTRACRANIAL ANEURYSMS: THE FIRSTANNUAL J. LAWRENCE POOL MEMORIAL RESEARCHSYMPOSIUMCONTROVERSIES IN THE MANAGEMENTOF CEREBRAL ANEURYSMS

THE MANAGEMENT OF aneurysmal subarachnoid hemorrhage has evolved over time,including the use of the microscope for aneurysm clip application, improved imagingmodalities, endovascular methods for aneurysm treatment, dedicated neurointensivecare units, and more aggressive therapy for cerebral vasospasm. Although these advance-ments have reduced the morbidity and mortality associated with aneurysmal subarach-noid hemorrhage, outcomes for this patient population continue to leave much room

for improvement. This work highlights controversial adjuvant techniques, maneuvers,and therapies surrounding the surgical treatment of ruptured cerebral aneurysms thatcurrently lack a consensus opinion. These treatments include centralized care in high-volume centers, as well as the use of antifibrinolytic therapy, routine cerebrospinal fluiddiversion, intraoperative hypothermia, temporary clip application, neuroprotectivedrugs, intraoperative angiography, and decompressive hemicraniectomy. Althoughdefinitive answers will only be possible through future multicenter collaboration, we reviewthe controversy surrounding these adjuncts and report the consensus opinion from ahighly experienced audience.

KEY WORDS: Aneurysmal subarachnoid hemorrhage, Antifibrinolytic therapy, Centralized care, Cerebralaneurysm, Hemicraniectomy, Hypothermia, Neuroprotection, Temporary clip

Neurosurgery 62:396407, 2008 DOI: 10.1227/01.NEU.0000297043.82035.99 www.neurosurgery-online.com

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Despite evidence correlating greater case volume with im-proved outcomes, it remains uncertain whether or not the ben-efits of receiving care at such tertiary care medical centers out-weighs the costs and risks of transfer (61). Bardach et al. (6)recently performed a cost-utility analysis to quantify the costsand benefits of transferring a patient with SAH who arrives at

a hospital with a low volume of SAH admissions to a regionalcenter with a high volume of SAH admissions. In this study, ifthe patient was transferred to a high-volume center, there wasa net gain of 1.60 quality-adjusted-life-years (QALYs) perpatient at a cost of $10,548/QALY. This analysis suggests thattransferring patients with SAH who arrive at low-volume hos-pitals to high-volume hospitals is likely cost-effective.Regionalization of treatment for patients with SAH nonethelessinvolves a tradeoff between an initial period of greater instabil-ity and increased risk of aneurysmal rebleeding during patienttransfer and a potential reduction in the risk of morbidity ormortality from SAH. (7) Taken together, the current literaturestrongly suggests that further regionalization of SAH treatmentin high-volume centers will be instrumental in decreasing the

high incidence of mortality associated with this condition.Despite the Class III data, the audience (see appendix for par-ticipants) strongly supported this conclusion.

ANTIFIBRINOLYTIC THERAPY

Approximately 3000 patients die annually from rebleeding ofa ruptured cerebral aneurysm (41). As a result, recent empha-sis has been placed on early surgical intervention to eliminatethe risk of recurrent SAH and improve outcomes. Despite earlyoperative intervention, rebleeding is, nevertheless, a major con-cern as the highest rate of this complication occurs in the first24 hours after the initial ictus. This fact was borne out by theInternational Cooperative Study on Timing of Aneurysm

Surgery (43), which reported a 5.7% rebleeding rate with highmortality even in patients assigned to the early treatmentgroup. Clearly, such individuals are beyond the reach of eventhe most ambitious protocol for diagnosis and referral.

In an effort to prevent rebleeding, in 1968, Mullan andDawley (66) proposed the use of the antifibrinolytic agentepsilon-aminocaproic acid (Amicar; Wyeth-Ayerst, Collegeville,PA) to prolong the duration of the naturally occurring hemosta-tic clot within and around the wall of the recently rupturedaneurysm. Previous studies have demonstrated that fibrinolytictherapy dramatically reduced the risk of rebleeding from cere-

bral aneurysms (2, 25, 57, 67, 86, 89), but this advantage wasoffset by an increase in morbidity caused by ischemic eventsand hydrocephalus (1, 42, 86, 89). It is important to note that

many of these studies evaluating the overall effectiveness ofantifibrinolytic therapy were hampered by methodologicalproblems, a lack of dose standardization, and administration ofthe drug during the period of vasospasm which was, in turn,associated with an increased rate of delayed cerebral ischemia(DCI) (20, 28, 41, 79).

As early surgical intervention gained popularity, the use ofantifibrinolytics in the management of aSAH was largely aban-

CENTRALIZATION OF CARE

Greater case volume has been shown to be related toimproved outcome in a variety of procedures ranging fromaneurysm clip placement to coronary artery bypass graftingand angioplasty (11, 12, 59, 78, 81). Studies evaluating the rela-

tionship between hospital case volume of subarachnoid hemor-rhage (SAH) and mortality rates have consistently found animprovement in outcome related to an increased case volume(7, 39, 81, 84). Cross et al. (18) tested the hypothesis of a hospi-tal SAH volumemortality rate relationship in a large data setrepresenting all admissions for SAH in 18 states while attempt-ing to control for case severity and treatment prognosis. In thelowest SAH case volume quartile, the mortality rate was 1.4times that of the highest quartile. This variance in outcomemay be attributed to a number of variables including, but notlimited to, the training, skill, and experience of physicians andstaff, as well as hospital equipment.

Case volume has been shown to improve outcomes after sur-gery for unruptured cerebral aneurysms in several studies.

Considering the similar surgical skill set used, these findingsmay be applicable to patients with aSAH. In 1996, Solomonet al. (81) reviewed 47,408 patients reported in the New YorkState database during an 8-year period and found an inverserelationship between the number of craniotomies for aneurysmclipping performed and in-hospital mortality rate. More specif-ically, the data demonstrated a 43% decrease in mortality ratein hospitals performing at least 30 craniotomies for aneurysmclipping per year versus lower volume hospitals (4.6 versus8.1% mortality, respectively). In 1997, Taylor et al. (84) demon-strated teaching hospitals to have significantly lower surgery-related mortality (16.3%) than nonteaching ones (23.1%) withequal operative volume. In 2001, Johnston et al. (40) analyzedthe outcomes of 1321 patients in California after unruptured

cerebral aneurysm surgery and demonstrated that adverseevents, including death or discharge to a nursing home or reha- bilitation hospital, occurred significantly more often at low-volume hospitals. More specifically, in-hospital death was 2.5times more likely at nontertiary care medical centers. The sameyear, Chyatte and Porterfield (16) showed that the number ofaneurysms treated by a specific surgeon is a strong predictor of

better functional outcome (r 0.99, P 0.05) by reviewing theclinical course of 449 aneurysms treated by 10 different sur-geons. Along the same lines, Barker et al. (8) also investigatedthe in-hospital complication rate of 3498 patients with unrup-tured intracranial aneurysms treated at 463 hospitals by 585surgeons. Compared with high-volume hospitals (20 cases/yr),the authors found that low-volume hospitals (4 cases/yr) dis-

charged fewer patients home, 76.2 versus 84.4%, and hadgreater rates of mortality, 2.2 versus 1.6%. In 2003, Berman et al.(10) reviewed the treatment of 2200 unruptured cerebralaneurysms with an overall mortality and morbidity rate of 2.5and 21.3%, respectively, and found hospital volume to be asso-ciated with less operative risk (morbidity odds ratio, 0.89; P0.0001 and mortality odds ratio, 0.94, P 0.002 for each 10additional cases/yr).

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with antifibrinolytic therapy, and there were no indications ofincreased ischemic clinical manifestations or vasospasm in thetreatment group.

Considering the current aSAH management paradigm withprogressive centralization, patients are more frequentlyexposed to treatment delay. Unfortunately, it is during this

period of transportation, assessment, and diagnostic testingwhen the patient is at greatest risk of recurrent SAH (38, 42, 79).Thus, interventions aimed at lowering the incidence of rebleed-ing without undue risk during this period will be critical inimproving outcomes. It appears that adopting a protocol ofearly aneurysm treatment together with antifibrinolytic drugadministration is in order, as this combination reduces the riskof rebleeding. Despite the data supporting this conclusion, theaudience participants expressed the need for considerablymore studies before instituting such a protocol.

CSF DIVERSION

External Ventricular Drainage for Hunt and HessGrade III Patients

The value of prompt ventricular drainage in Hunt and HessGrades IV and V patients with acute hydrocephalus after aSAHis well established (29, 53, 72, 82). Placement of extraventricu-lar drains (EVDs) in Hunt and Hess Grade III patients, how-ever, is controversial because it is believed that cessation ofaneurysmal hemorrhage occurs when the intracranial pressure(ICP) approaches the mean arterial pressure after rupture.Thus, lowering ICP during the period after aneurysmal rupturehas been proposed to increase transmural pressure across theaneurysm and result in a greater risk of rebleeding (68). Thestudies of the risk of rebleeding after EVD in patients withaSAH have yielded conflicting results (29, 53, 62, 68, 72, 82). In

2004, Heuer et al. (31) retrospectively reviewed the variablesassociated with ICP after aSAH and their impact on outcome in433 patients who had undergone surgical occlusion of theiraneurysm as well as ICP monitoring. The authors foundincreased ICP to occur in nearly 50% of good grade patients(Hunt and Hess Grades IIII) and more than 60% of poor-gradepatients (Hunt and Hess Grades IV and V). Increased ICP wasassociated with several admission variables, including worseHunt and Hess clinical grade (P 0.0001), lower GlasgowComa Scale motor score (P 0.0001), worse Fisher grade (P0.0001), the presence of ICH (P 0.024), and intraventricularhemorrhage (P 0.0001), and the occurrence of early rebleed-ing (P 0.0048). As expected, increased ICP adversely affectedoutcome, as 71.9% of patients with normal ICP demonstrated

favorable 6-month outcomes, compared with 63.5% of patientswith ICP elevated between 20 and 50 mmHg and 33.3% ofpatients with ICP greater than 50 mmHg. In addition, allpatients whose increased ICP did not respond to mannitol ther-apy experienced poor outcomes, and 95.2% died. These find-ings confirm that increased ICP is common after SAH and leadsto worse patient outcomes, particularly if it is nonresponsive tomedical therapy. Thus, timely ventricular drainage in patients

doned (57). Considering the incidence of rebleeding during thefirst 24 hours after hemorrhage, however, Amicar may still playan important role in the management of these patients. If sur-gery to clip a ruptured aneurysm was routinely performedimmediately upon a patients arrival to the intensive care unit,the risk for recurrent SAH would be eliminated. However, this

is not practical given the frequent delay in securing the diagno-sis with either a high-quality computed tomographic angiogra-phy or digital subtraction angiography and transfer of thepatient to an appropriate neurosurgical facility. This issue takeson even greater importance with the recent push toward cen-tralization of aSAH treatment because antifibrinolytic agentsmay be given immediately after the diagnosis of SAH has beenestablished at the local hospital level and contribute to the min-imization of early rebleeding.

To evaluate the potential benefit of antifibrinolytic therapy,Leipzig et al. (57) studied the effects of high-dose Amicar inreducing the rebleeding rate in aSAH patients awaiting earlysurgical intervention. In this series of 307 patients, the rebleed-ing rate was only 1.3%, which, although difficult to compare

directly, is substantially lower than the early rebleeding rate of5.7% reported in the International Cooperative Study onTiming of Aneurysm Surgery and translates into an 80% re-duction. This study also indicated that complications previ-ously related to prolonged use of Amicar may be reduced oreliminated when the agent is administered shortly beforeearly surgical intervention and discontinued immediately fol-lowing lesion obliteration. When dosed appropriately, therates of ischemic stroke and hydrocephalus in these patientscompare favorably with those in patients not receiving antifib-rinolytic therapy (30, 43).

In 2002, Hillman et al. (32) conducted a prospective, ran-domized, multicenter trial to assess the efficacy of short-termantifibrinolytic treatment with tranexamic acid in preventing

rebleeding. Enrolled patients received a 1-g intravenous doseof tranexamic acid immediately after the diagnosis of SAH,followed by sequential doses every 6 hours until aneurysmobliteration, not to exceed 72 hours. Overall, the investigationincluded 254 study patients and 251 control patients, withcomparable age, sex, Hunt and Hess scores, Fisher grades, andaneurysm locations between groups. The authors found thatearly treatment protocols were well executed because morethan 90% of patients reached major neurosurgical centerswithin 12 hours of their first hospital admission and 70% of allaneurysms were clipped or coiled within 24 hours of the firsthospital admission. As a result, only one rebleed occurred laterthan 24 hours after the first hospital admission. Despite thisfocused effort on early intervention, however, 27 ultra-early

rebleeds occurred in the control group within hours of ran-domization, with nearly 50% mortality. By contrast, in thetreatment group receiving antifibrinolytic therapy only, sixpatients experienced ultra-early rebleeds, with 33% mortality.This translates into a reduction in the rebleeding rate from10.8 to 2.4% and an 80% reduction in the mortality rate fromearly rebleeding with tranexamic acid administration.Moreover, favorable outcome increased from 70.5 to 74.8%


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has the potential to considerably improve the level of morbid-ity associated with aSAH.

In a recent prospective study, Andaluz and Zuccarello (4)reported the effects of fenestrating the lamina terminalis onhydrocephalus, vasospasm, and frontobasal injury in 106patients with anterior communicating artery aneurysms and

Fisher Grade III aSAH. Patients were divided into fenestrationor nonfenestration groups based on surgeon preference, with53 patients in each group. In concordance with the previousstudy from authors at Johns Hopkins (51), the authors found70% less shunt-dependent hydrocephalus in patients undergo-ing fenestration compared with those who did not (4.25 versus13.9%, P 0.001). Interestingly, the incidence of vasospasmwas also reduced after fenestration of the lamina terminalis, or29.6 and 54.7% (45% reduction) in the treatment and controlgroups, respectively (P 0.001). Outcome was noted toimprove in those patients undergoing fenestration of the lam-ina terminalis, with 69.81% experiencing good outcomes com-pared with only 33.96% of patients who did not (P 0.001).Most importantly, no complications were linked to fenestra-

tion of the lamina terminalis in either study.The mechanism by which creating an anterior third ventricu-lostomy reduces the incidence of shunt-dependent hydro-cephalus is not completely understood. This maneuver mayfacilitate CSF fluid dynamics in the ventricles and over thecerebral convexities with increased blood clearance, decreasedleptomeningeal fibrosis, and maintenance of proper balance

between CSF production and reabsorption in the setting ofcommunicating hydrocephalus. However, it has been proposedthat chronic hydrocephalus after aSAH may commonly be ofthe noncommunicating type, with obstruction at the outflow ofthe fourth ventricle outside the foramina of Luschka andMagendie. This hypothesis is supported by dilation of all fourventricles in patients with post-aSAH hydrocephalus, the

greater incidence of hydrocephalus found after the rupture ofposterior circulation aneurysms, and the effectiveness of fenes-tration of the lamina terminalis in reducing shunt-dependenthydrocephalus. The proposed mechanism by which fenestra-tion of the lamina terminalis may alter the incidence ofvasospasm is a decrease in the concentration of blood-derivedspasmogenic agents in the CSF (4, 60, 90).

The current literature suggests that fenestration of the laminaterminalis leads to more favorable outcomes by significantlydecreasing the shunting rate and incidence of vasospasm. Weadvocate incorporating fenestration of the lamina terminalis,when possible, into the current standard of care for rupturedcerebral aneurysms, as this straightforward technique has thepotential to considerably improve the level of morbidity asso-

ciated with aSAH by preventing what are presently commonand debilitating long-term complications.

It is important to recognize that fenestration of the laminaterminalis, together with concomitant spinal drainage, maypotentially cause an iatrogenic herniation syndrome secondaryto critical postcraniotomy CSF hypovolemia (50). This condi-tion, also termed brain sag or sinking brain syndrome, isdefined by three diagnostic criteria: clinical signs of transtento-

with potentially elevated ICP, even when in good clinicalgrade, might be expected to decrease the morbidity and mortal-ity associated with this condition. The audience participants,however, favored noninvasive management in this setting.

Spinal Drainage

Research has shown that the presence of blood in the sub-arachnoid space is directly related to the pathophysiology ofvasospasm. A number of strategies have attempted to exploitthis mechanism, ranging from cisternal administration of fib-rinolytic agents to head-shaking and cisternal irrigation.Secondary to mixed results, potential for morbidity, and fearof hemorrhage, these therapies have failed to gain wide-spread acceptance. It continues to be proposed, however, thatlumbar cisternal drainage, by promoting CSF circulationfrom the ventricles through the subarachnoid spaces andevacuating the large reservoir of bloody CSF, may representa simple and effective means to reduce the incidence in CV.In a recent, nonrandomized, controlled-cohort study, Klimoet al. (47) compared the incidence of vasospasm, hydro-

cephalus, and outcome in 266 SAH patients receiving lumbarCSF drainage versus those who did not have a lumbar drainplaced. The lumbar drain, typically placed at the time of sur-gery, is beneficial intraoperatively to facilitate brain relax-ation and can be helpful even with an EVD in place, as itallows more CSF to be drained off. Interestingly, in this study,the lumbar drains were continued throughout the vasospasmrisk period and conferred a statistically significant protec-tive effect over EVD alone, reducing clinical vasospasm from51 to 17% and the risk of cerebral infarction from 27 to 7%. Inaddition, twice as many patients in the lumbar drain grouphad a 1- to 3-month Glasgow Outcome Scale (GOS) score of5 compared with the control group. This is a controversialarticle, with an historical control group and a seemingly

excessive incidence of vasospasm and delayed cerebralinfarction in the control group. Nonetheless, this issue war-rants a randomized prospective trial, as the audience partic-ipants were equivocal regarding the utility of this technique.

Fenestration of the Lamina Terminalis

Dandy (21) first described the creation of an alternate pathfor the redirection of CSF from the ventricular system into thesubarachnoid space in 1922. Dandys technique was subse-quently modified during the following 60 years, and referencewas made to fenestration of the lamina terminalis as an adjunc-tive maneuver in prevention of post-SAH hydrocephalus andvasospasm (34, 36, 37, 44, 46, 51, 69, 75). Komotar et al. (51)were the first group to report on the relationship between fen-

estration of the lamina terminalis and the incidence of shunt-dependent hydrocephalus after aSAH. In this retrospectivestudy, the rate of shunt dependent hydrocephalus in the fenes-tration cohort was 2.3% versus a shunt rate of 12.6% for allother patients (P 0.011; odds ratio, 0.15), translating intogreater than 80% reduction of this common complication. Inlieu of these data, the authors concluded that this straightfor-ward technique should be performed whenever possible, as it



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ictus). Second, GOS, although widely used and universallyaccepted, is a relatively crude measurement of clinical outcomethat may not detect subtle cognitive changes. Finally, this studyonly applies to good-grade patients and may not be extrapo-lated to the general aSAH population. Most importantly, evenafter enrolling more than 1000 patients, the study appears

underpowered. Closer inspection reveals that intraoperativehypothermia led to absolute and relative improvements in GOS1 of 3.2 and 5.0%, respectively. The trial, however, was onlypowered to identify absolute and relative improvements inGOS 1 of 10.0 and 15.0%, respectively. To address this issue,future trials would ideally examine the effects of intraoperativehypothermia exclusively in patients at increased risk forischemic events.

It is difficult to advocate another expanded randomizedtrial, given the minimal bleeding and cardiovascular risksincurred by mild hypothermia. In the future, neurosurgeonsshould selectively use this adjuvant technique in cases withexpected prolonged ischemia, use of temporary clips, andthose involving larger aneurysms with intraluminal thrombus

or calcification. Without definitive data supporting the wide-spread use of hypothermia during craniotomy for aneurysmclipping, the audience participants believed its use should bedetermined by clinical judgment, individual case circum-stances, and surgeon preference.

TEMPORARY OCCLUSION/CEREBRAL PROTECTION

Advances in surgical technique, instrumentation, and tech-nology have decreased the morbidity associated with surgicaltreatment of aSAH. Despite these improvements, intraopera-tive rupture (IOR) remains a well-appreciated risk that can sub-stantially affect a patients chance for successful recovery. Rates

of IOR in the literature have ranged between 5 and 50%, mainlybecause of differing opinions as to what constitutes an IOR (9,26, 33, 55, 74, 77). Considering their incidence and related mor-

bidity, minimizing the occurrence of IOR and associated intra-operative complications is critical in improving outcome afteraSAH.

In 1986, Ausman and Diaz (5) commented on the use of tem-porary occlusion in the surgical management of intracranialaneurysms as a means to reduce IOR. Multiple short periods oftemporary occlusion serve to soften the aneurysm while it is

being manipulated. In a large, modern, retrospective series,Leipzig et al. (56) studied the factors associated with IOR. Inthis series of 1269 patients with 1694 aneurysms, the IOR ratewas 6.7% per aneurysm, 7.9% per surgery, and 8.9% per

patient. Minor leaks were included in the IOR category, and, ifthese cases are excluded, the incidence decreases to 3.2% peraneurysm, 3.8% per surgery, and 4.3% per patient. Of note,these IOR rates compare favorably with the risk of perforationreported for endovascular procedures, which hovers close to3% (27, 87). The authors found posteroinferior cerebellar arteryand anterior and posterior communicating artery aneurysms to

be more liable to IOR. As expected, the IOR rate was greater in

rial herniation, head computed tomographic (CT) scan reveal-ing effacement of the basal cisterns with an oblong brainstem,and improvement of symptoms upon placing the patient in theTrendelenberg position. Brain sag most commonly develops

between 2 and 4 days postoperatively, with pupillary asymme-try being the initial sign in a majority of patients. Of note, these

patients also commonly have a significant amount of pneumo-cephalus on CT scans. Upon Trendelenberg positioning, theacute and substantial change in brainstem morphologyobserved on CT scans during the event resolves concurrentlywith symptomatic improvement. At our institution, critical CSFhypovolemia was found to occur in approximately 8% of thepatients and is included in the differential diagnosis for acutepostoperative clinical deterioration after craniotomy. Fortu-nately, prompt recognition of this syndrome and placement ofthe patient in the Trendelenburg position leads to rapid symp-tomatic improvement and prevents any long-term sequelae(50). Despite the lack of Class I evidence supporting fenestra-tion of the lamina terminalis, the audience believed this maneu-ver should be performed whenever possible during ruptured

aneurysm surgery.Intraoperative Hypothermia

New neurological deficits may occur after intracranial vascu-lar surgery, even in the absence of overt complications.Consequently, several efforts have emerged in an attempt toprotect the brain intraoperatively. The use of systemic hypo-thermia as a protective adjunct to neurosurgery was firstreported in 1955 (58) but fell out of favor during the 1970s and1980s. Interest was revived after demonstration in the labora-tory of a beneficial effect of mild hypothermia (3335C) onischemic and traumatic brain injury (17, 24, 63, 64). Althoughhypothermia has since been implemented in the treatment ofhead trauma, stroke, and cardiac arrest, its benefit during neu-

rovascular surgery remains controversial.In a well-matched, modern, prospective, international mul-

ticentered, randomized study, the Intraoperative Hypothermiafor Aneurysm Surgery Trial investigators studied the effects ofmild hypothermia (target temperature of 33C, using surfacecooling techniques) in 1001 good-grade patients (WorldFederation of Neurological Surgeons score of I, II, or III) withaSAH (85). Outcome was assessed at 90 days postoperativelyusing the GOS. There were no significant differences foundamong the groups, leading the authors to conclude that use ofmild hypothermia during the intraoperative period does notimprove outcome in a good-grade aSAH population. Further-more, there was a trend toward more frequent bacteremia inthe hypothermic group, although there was no difference in

pneumonia, urinary tract infection, meningitis, or woundinfection rate.

These results appear robust, considering the study design,sample size, cohort similarities, adjudicated outcomes, protocolcompliance, and near-perfect follow-up. There are, however, anumber of limitations to this trial. First, subgroup analysis ofthe data suggests a beneficial effect of intraoperative hypother-mia when used in males undergoing late surgery (814 d post-


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favored use of temporary clip placement and pharmacologicalneuroprotection during aneurysm microdissection.

Intraoperative Angiography

Traditional convention has been that intraoperative angiog-raphy is used on a selective basis solely for complex an-

eurysms. Recently, however, a number of studies have demon-strated a benefit to routine intraoperative angiography forcerebral aneurysm surgery (3, 14, 22, 70, 83). In the two largeststudies, the authors found that the use of intraoperativeangiography resulted in alteration of surgical treatment inapproximately 11% of cases and was associated with neurolog-ical morbidity in less than 0.5% of cases (14, 83). Klopfensteinet al. (48) recently addressed the accuracy of surgeons in pre-dicting the need for intraoperative angiography as a means todetermine whether or not routine intraoperative angiographyis necessary. Remarkably, in cases in which the surgeons haddeemed intraoperative angiography unnecessary, there was a4.4% rate of clip alteration. This indicates that, postoperatively,4.4% of patients who do not undergo intraoperative angiogra-

phy would harbor residual, treatable lesions. In fact, this repo-sition rate of 4.4% is rather minimal in comparison to datafrom the literature indicating a 7 to 15% reposition rate.

In 1995, Derdeyn et al. (23) examined angiographic technicalsuccess, safety, and accuracy in 112 consecutive procedures.The authors found that intraoperative angiography altered sur-gery in 13 out of 112 procedures on 104 patients, all of whichwere either arteriovenous malformation resections or aneurysmclippings. In 1996, Alexander et al. (3) determined the fre-quency of unexpected arterial occlusion and incompleteaneurysm clipping by reviewing data collected prospectivelyon 100 consecutive craniotomies. Unexpected angiographicfindings necessitating at least one clip adjustment occurred in12 cases (11%). These clip readjustments restored flow through

six major arterial occlusions (6%) and completely obliterated 10persistently filling aneurysms (10%). In 1997, Derdeyn et al.(22) correlated aneurysm size and location with the need forclips repositioning in 199 consecutive patients with 234intracranial aneurysms. Findings from intraoperative angio-grams resulted in clip repositioning in 46 out of 273 (16.8%)studies. Clip repositioning was statistically significantly lessfrequent with aneurysms of the posterior communicating andanterior choroidal arteries, whereas high rates of clip reposi-tioning were found in aneurysms of the superior hypophysealartery, superior cerebellar artery, and bifurcation of the internalcarotid artery. The authors concluded that routine intraopera-tive angiography might not be necessary for posterior commu-nicating or anterior choroidal artery aneurysms.

In 1998, Payner et al. (71) evaluated the efficacy of selectiveintraoperative angiography in 151 consecutive patients. Inthese selective cases, angiography led to immediate reposition-ing of the aneurysm clip in 27% of the patients, with anteriorcerebral artery aneurysms requiring clip repositioning lessoften and superior hypophyseal artery aneurysms requiredrepositioning more often than aneurysms in other locations.Furthermore, large and giant aneurysms required clip reposi-

ruptured than unruptured aneurysms (10.7 versus 1.2%, P 0.0001). Most importantly, there was a lower rate of IOR in pro-cedures in which surgeons used temporary arterial occlusion(3.1 versus 8.6%, P 0.0001), suggesting that the use of tempo-rary clips may be a useful adjunctive technique that minimizesthe rate of significant IOR.

Lavine et al. (54) evaluated the effectiveness of neuroprotec-tive anesthetics in reducing the risk of focal infarction second-ary to temporary occlusion during 49 middle cerebral arteryaneurysm cases. In this study, a group of patients treated withthe intravenous agents propofol, etomidate, and pentobarbital,administered individually or in combination, was comparedwith a group treated with the inhalational agent isoflurane.Postoperative radiographic evidence of new infarction wasused as the threshold for failure of occlusion tolerance. Theauthors found an overall infarction rate of 22.4%, including15.8% in the intravenous neuroprotective group versus 45.5%in the group that did not receive intravenous neuroprotection.For patients without infarction, the mean duration of tempo-rary occlusion was 13.6 and 3.9 minutes with and without neu-

roprotection, respectively. For patients with infarction, themean duration of temporary occlusion was 18.5 and 12.2 min-utes with and without neuroprotection, respectively. Theauthors concluded that the use of neuroprotective agents, suchas pentobarbital, confers a significant advantage in patientsexposed to focal iatrogenic ischemia during middle cerebralartery aneurysm clip ligation, particularly if more than 10 min-utes of occlusion time is required.

Samson et al. (76) reviewed their series of 100 patients whounderwent elective temporary arterial occlusion during an-eurysm surgery under a standard neuroanesthetic regimen,including etomidate-induced burst suppression, normoten-sion, normovolemia, and normothermia. Failure of occlusiontolerance was defined as postoperative radiographic evidence

of ischemic brain injury in the distribution of the arteriesoccluded. The authors found that patients older than 61 yearsof age and those in poor neurological condition (Hunt andHess Grades III or worse) did not tolerate temporary occlu-sion as well as patients who were younger and in good con-dition. Patients routinely tolerated 14 minutes or less of tem-porary occlusion, whereas all patients occluded for more than31 minutes had both clinical and radiographic evidence ofcerebral infarction.

Our institution has adopted a protocol involving multipleshort periods of temporary occlusion in order to soften theaneurysm during microdissection. We use alternating tempo-rary occlusion, with 3 minutes of occlusion followed by 5 min-utes of reperfusion, at the surgeons discretion. Furthermore,

thiopental induced burst suppression is used for any casesnecessitating temporary occlusion for greater than 5 minutes.Although multiple clip manipulations may, in theory, increasethe risk of vasospasm through vessel irritation, preliminarydata from our institution indicate no greater incidence ofvasospasm with the use of temporary clipping nor with greaternumbers of short temporary occlusion episodes. Interpretingthe available literature, the audience participants strongly



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tioning more often than small aneurysms. These results sup-port the selective use of intraoperative angiography in the treat-ment of complex aneurysms, particularly large and giantaneurysms, as well as superior hypophyseal artery aneurysms.In 1999, Origitano et al. (70) found that intraoperative angiog-raphy led to clip adjustment in 18 out of 52 (34%) aneurysms,

with four out of 18 (22%) for parent artery stenosis, eight out of18 (44%) for residual aneurysm, and six out of 18 (33%) for both. Only two complications occurred during 220 angio-graphic runs. Recently, Katz et al. (45) at Cornell UniversityMedical Center determined the frequency and predictors ofunanticipated angiographic findings necessitating clip adjust-ment in a consecutive series of 147 aneurysms. Postoperativeangiography demonstrated two (1.4%) unexpected residuals,four anticipated residuals (2.7%), and four (2.7%) vessel com-promises. Of the six unanticipated outcomes, two out of two(100%) unexpected residuals and three out of four (75%) vesselcompromises were from large aneurysms (P 0.0001). Thus,the authors recommend intraoperative angiography only dur-ing the treatment of complex or large aneurysms, as its high

cost-benefit ratio, false-negative rate, and moderate risk maypreclude routine use.An important issue when considering whether or not intra-

operative angiography should be used on a routine basis is theassociated rate of complications. Both Chiang et al. (14) andTang et al. (83) found that routine use of intraoperative angiog-raphy was associated with major morbidity in only 0.4 and1.3% of cases, respectively. Thus, procedural morbidity appearsto be outweighed by improved lesion obliteration. These com-plication rates may be greater, however, than if angiographywas being performed in the endovascular suite. The questionthen becomes: can the operating room be transformed into anendovascular suite better equipped to accommodate the rou-tine use of intraoperative angiography? A second issue per-

tains to the accuracy and efficiency of routine intraoperativeangiography. False-negative rates have ranged from 0 to 8.7%(14, 48, 83), whereas the false-positive rates are inconsequential.Overall, the current literature demonstrates that the accuracy ofintraoperative angiography is excellent. Moreover, the authorsof these studies have indicated that an experienced teamrequires only 20 to 30 minutes to perform intraoperativeangiography, quickly integrating into the standard of care forintracranial aneurysm surgery. Finally, there is no additionalcost associated with intraoperative angiography, as it substi-tutes for the traditional postoperative angiogram (14, 48, 83).Despite the conflicting data in the current literature, the audi-ence participants strongly favored routine use of intraoperativeangiography during aneurysm surgery.

Decompressive Hemicraniectomy

Decompressive hemicraniectomy has been shown toimprove outcomes in patients experiencing massive ischemicinfarction and head trauma (13, 15, 52, 73). Its role in aSAH,however, is less well defined. In a series of eight patients, Smithet al. (80) studied the efficacy of decompressive hemicraniec-


KOMOTAR ET AL.

tomy in patients with poor-grade aSAH and demonstratedgood or excellent 12-month GOS scores in 63% of them. Thisdata lends support to the hypothesis that decompressive hem-icraniectomy may be an appropriate adjunct in carefullyselected aSAH patients.

Although this intervention may decrease mortality, it leads toa poor long-term quality of life in those who survive (35, 49,88). DAmbrosio et al. (19) reported their experience usingdecompressive hemicraniectomy in a select group of poor-grade aSAH patients presenting with focal intracerebral hem-orrhage and found hemicraniectomy patients to have a loweroverall mortality rate compared with the control group. Theauthors also aimed to assess whether or not there was a bene-fit in terms of QALYs for survivors. A comparison of meanQALYs after hospitalization failed to demonstrate a difference

between the study cohort and the controls, suggesting thatearly decompressive hemicraniectomy offers no quality of life

benefit over standard craniotomy with clot evacuation andaneurysm clipping. Moving forward, the audience participants

believe hemicraniectomy should only be performed in care-fully selected patients, as logistics and costs deter completion ofa prospective, multicenter trial.

CONCLUSION

Although the management of aSAH has evolved over time,resulting in reduced morbidity and mortality, outcomes for thispatient population continue to leave much room for improve-

ment. To this end, further refinement in adjuvant techniques,maneuvers, and therapies surrounding the surgical treatmentof ruptured cerebral aneurysms is critical. This work serves tohighlight some of the controversial issues surrounding aSAHtherapy in an attempt to obtain consensus opinions from cere-

brovascular experts attending the J. Lawrence Pool ResearchSymposium (Table 1). For now, the use of these techniques willremain based on surgeon preference on a case-by-case basis, as

a aSAH, aneurysmal subarachnoid hemhorrhage; Tx, therapy; EVD, external ventricular

drain.

TABLE 1. Consensus opinions from the J. Lawrence Pool ResearchSymposiuma

Strongly Moderately MinimallyTechnique

agree agree agree

Centralization of aSAH Tx X

Early antifibrinolytic Tx (Amicar) XEVD for Hunt and Hess X

Grade III patients

Intraoperative spinal drainage X

Fenestration of lamina terminalis X

Intraoperative hypothermia X

Temporary clip placement X

Pharmacologic neuroprotection X

Intraoperative angiography X

Hemicraniectomy X

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their widespread acceptance into or rejection from the stan-dard of care for aSAH is only possible through future multicen-ter collaboration and funded trials.

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APPENDIX

Faculty Participants at the 2005 J. Lawrence PoolResearch Symposium

Beverly Aagaard Kienitz, M.D., The University of WisconsinAlejandro Berenstein, M.D., Beth Israel & St. Lukes

Suzanne Brennfleck, M.H.A., M.B.A., North Shore Long Island JewishHealth SystemRobert Brown, M.D., Ph.D., Mayo Clinic

Jeffrey Bruce, M.D., Columbia UniversityDavid Chalif, M.D., North Shore Long Island Jewish Health SystemE. Sander Connolly, Jr., M.D., Columbia UniversityMitchell Elkind, M.D., Columbia University

Jeffrey Farkas, M.D., Maimonides Medical CenterMatthew Fink, M.D., Weill Cornell Medical CenterRobert Friedlander, M.D., Brigham & Womens HospitalRobert Goodman, M.D., Ph.D., Columbia UniversityAmrit Grewal, M.D., Neurology Group of Bergen CountyMurat Gunel, M.D., Yale University

Jafar Jafar, M.D., New York University Medical CenterAlexander Khandji, M.D., Columbia UniversityNeil Kitchen, M.D., Queens SquareEzriel Kornel, M.D., Neurosurgeons of New YorkDavid Langer, M.D., St. Lukes-RooseveltSean Lavine, M.D., Columbia University

Jonathan Lustgarten, M.D., Columbia UniversityStephan Mayer, M.D., Columbia UniversityGuy McKhann II, M.D., Columbia UniversityPhilip Meyers, M.D., Columbia University

JP Mohr, M.D., Columbia UniversityPeter Nelson, M.D., New York University Medical CenterMika Niemel, M.D., Ph.D., Helsinki University Central HospitalChristopher Ogilvy, M.D., Massachusetts General HospitalTom Origitano, M.D., Ph.D., Loyola University Medical CenterAugusto Parra, M.D., Columbia UniversityAman Patel, M.D., Mount Sinai Medical CenterReed Perron, M.D., Neurology Group of Bergen County

Charlie Prestagiacomo, M.D., University of Medicine and Dentistry ofNew Jersey

Donald Quest, M.D., Columbia UniversityHoward Riina, M.D., Weill Cornell Medical CollegeAvi Setton, M.D., North Shore University HospitalAllen Sills, M.D., Semmes-Murphy ClinicMichael Sisti, M.D., Columbia UniversityRobert Solomon, M.D., Columbia UniversityRobert Spetzler, M.D., Barrow Neurological InstituteBennett Stein, M.D., Columbia UniversityByron Gregory Thompson, M.D., University of Michigan Health

SystemFernando Vinuela, M.D., University of California, Los AngelesChristopher Winfree, M.D., Columbia UniversityH. Richard Winn, M.D., Mount Sinai Medical Center

Bruce Zablow, M.D., St. Vincents Medical Center

COMMENTS

In this excellent review, Komotar et al. highlight eight controversiessurrounding the treatment of ruptured intracranial aneurysms. Foreach issue, the authors provide a brief literature review as well as theconsensus opinion of the faculty participants of the 2005 J. Lawrence

Pool symposium. The collective wisdom of the audience members fromthis event represents centuries of cumulative experience and should not

be taken lightly. As for each issue presented, we would offer only thefollowing remarks.

We hardly consider centralization of care at high-volume centers tobe a controversy. However, the idea of transferring a patient in a med-ically fragile and neurologically unstable condition after severe sub-

arachnoid hemorrhage will remain problematic. Therefore, it is likelythat a significant percentage of patients with subarachnoid hemorrhagewill continue to be treated at the primary receiving hospital. This prac-tice is at variance with many recent reports demonstrating improvedoutcomes from high-volume centers.

We routinely use intraoperative mild hypothermia and neuropro-tective drugs during aneurysm surgery, as well as the liberal use oftemporary clipping during the final stages of neck dissection andclip application. Regarding cerebrospinal fluid diversion, we preferto use intraoperative placement of a ventriculostomy rather than alumbar drain.

Regarding the use of intraoperative angiography, we have imple-mented a selective strategy. The terms of this debate may soon change,however, with the adoption of indocyanine green intraoperativevideoangiography and with the rise in popularity of advanced micro-

surgical/endovascular operating suites.The authors offer wise advice that as intracranial aneurysm treat-ment continues to evolve, we must persist in evaluating and reevalu-ating adjuvant techniques and therapies. As the authors tell us, prop-erly structured and well-funded multicenter collaborative studies arethe most likely way to settle many of these controversies.

Edward Duckworth

H. Hunt BatjerChicago, Illinois

As part of the J. Lawrence Pool Symposium, Komotar et al. pre-sented a discussion on the controversies of the surgical treatmentof ruptured intracranial aneurysms. This discussion was fairly compre-hensive and certainly did highlight many of the issues, some morecontroversial than others.

The information on centralization of care is without a doubt one ofthe most important points of this manuscript, indicating that greaterexperience has clearly demonstrated improved outcome. Obviously,our colleagues in cardiac surgery were the first to demonstrate thisfact and New York State in particular has a significant amount of dataregarding volume of procedures and outcomes.

Other areas covered in the discussion, including ventricular drainage,are certainly not as controversial. Clearly its use, when symptomatichydrocephalus is present, outweighs the risks of not using it, and cer-tainly overdrainage should be avoided. The authors include a brief dis-cussion on cerebral protection during aneurysm surgery, which I wouldascertain is fairly standard at most institutions; I would not consider theuse of cerebral protection during temporary clipping controversial.Perhaps the pharmacology and methodology are open for discussion.

All in all, I think that this article is a welcome addition and certainly

highlights the spirit of the J. Lawrence Pool Symposium.Robert H. RosenwasserPhiladelphia, Pennsylvania

In an attempt to further improve the outcome after aneurysmal sub-arachnoid hemorrhage, the authors have tackled several of the cur-rent controversies in the field. The controversial adjuvant techniques,maneuvers, and therapies surrounding the surgical treatment of rup-



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tured intracranial aneurysms that were highlighted in this article willremain controversial until future multicenter trials are performed. Inthe absence of these trials, a consensus opinion from an expert panel isextremely useful in advancing the field. Each of the areas of contro-versy is described in a balanced manner with literature citations tosupport both sides of the argument. Although these consensus opin-ions do not establish a standard of care for the management of individ-

ual patients, these expert views and careful analysis of the issues doassist in the clinical decision-making required to manage patients withruptured intracranial aneurysms.

Daniel L. BarrowAtlanta, Georgia

This article presents an excellent review of controversial topics inthe management of ruptured aneurysms. Should we transferpatients from community hospitals to regional centers with high casevolumes, dedicated specialists, and lower treatment risks? Should weuse antifibrinolytic agents such as Amicar to reduce the risk of rehem-orrhage in patients transferring to these regional centers? Should wedrain cerebrospinal fluid more aggressively with ventriculostomies inHunt and Hess Grade III patients, use lumbar drains to clear subarach-

noid blood, and/or perform fenestration of the lamina terminalis tocommunicate the ventricles with the subarachnoid space? Does intra-operative hypothermia have a role in the wake of the IntraoperativeHypothermia for Aneurysm Surgery Trial results? Should we use intra-operative angiography routinely or selectively with complexaneurysms? Should we perform hemicraniectomies in our poor-gradepatients? It is interesting to see that audience experts formed clearopinions despite confusing data in the literature (e.g., intraoperativeangiography). With other issues, experts had opinions that were con-trary to good data from well-designed studies (e.g., intraoperativehypothermia). The authors conclude appropriately that multicentercollaborative trials, not consensus opinion, are needed to resolve manyof these issues. However, at the end of the day, we appear to trust ourclinical intuition more than we do our Level I evidence.

Michael T. Lawton

San Francisco, California

In this review, controversies in surgical treatment of ruptured intracra-nial aneurysms are scrutinized. Surprisingly, topics reviewed were ofmore interest in the 1980s and 1990s. Modern microneurosurgical man-agement of ruptured intracranial aneurysms include ultra-early or evenemergent surgical intervention (i.e., in the case of a space-occupyingintracranial hemorrhage) in subspecialized centers by dedicated andexperienced cerebrovascular teams (unpublished data). Discussionshould be focused on recent advances in cerebrovascular imaging modal-ities such as noninvasive computed tomographic angiography (9), whichprovides us with three-dimensional details of vascular structures,aneurysms, and neighboring bony landmarks in a few minutes.Intraoperative digital subtraction angiography (10) is being replaced byindocyanine green angiography (13), which is also noninvasive, fast, and

repeatable. Planning of nondestructive minimally invasive craniotomies(14, 6, 8), effective use of the surgical microscope, modern neuroanesthe-siological techniques (14), adaptation of microneurosurgical techniquesduring dissection towards the aneurysm (12, unpublished data), andproper use of instruments and clips are the secrets of clean, fast, andless complicated surgery. Performing clean and effective surgery willeliminate many discussions on neuroprotection and/or hypothermia asthe operative times become shorter. Those neurosurgeons who treatpatients with intracranial aneurysms should master advanced bypass

techniques and revascularization to be able to treat the complex lesionswithout disturbing blood flow distal to the aneurysm. Finally, the onlyways to markedly reduce the morbidity and mortality of subarachnoidhemorrhages is to 1) study the aneurysm wall (5, 11, 15, unpublisheddata) to better understand the complex pathobiology of the lesions, and2) try to identify aneurysm carriers (16), especially those with ruptureprone aneurysms and, thereafter, 3) treat them before rupture.

Reza Dashti

Istanbul, Turkey

Mika Niemel

Juha A. HernesniemiHelsinki, Finland

1. Dashti R, Hernesniemi J, Niemel M, Rinne J, Porras M, Lehecka M, Shen H,Albayrak BS, Lehto H, Koroknay-Pal P, Sillero R, Perra G, Ronkainen A,Koivisto T, Jskelinen JE: Microneurosurgical management of middle cere-bral artery bifurcation aneurysms. Surg Neurol 67:441456, 2007.

2. Dashti R, Hernesniemi J, Niemel M, Rinne J, Lehecka M, Shen H, Lehto H,Albayrak B, Ronkainen A, Koivisto T, Jskelinen J: Microneurosurgicalmanagement of distal middle cerebral artery aneurysms. Surg Neurol

67:553563, 2007.3. Dashti R, Hernesniemi J, Lehto H, Niemel M, Lehecka M, PornswannaphaS, Koivisto T, Jskelinen J: Microneurosurgical management of proximalanterior cerebral artery aneurysms (A1As). Surg Neurol 68:366377, 2007.

4. Dashti R, Rinne J, Hernesniemi J, Niemel M, Kivipelto L, Lehecka M, KaratasA, Avci E, Ishii K, Shen H, Pleaez J, Albayrak B, Ronkainen A, Koivisto T,Jskelinen J: Microneurosurgical management of proximal middle cerebralartery aneurysms. Surg Neurol 67:614, 2007.

5. Frsen J, Paetau A, Kangasniemi M, Piippo A, Niemel M, Hernesniemi J,Ishii K, Niemel M, Kivipelto L, Fujiki M, Shen H: Subtemporal approach tobasilar bifurcation aneurysms: advanced technique and clinical experience.Acta Neurochir Suppl 94:3138, 2005.

6. Frsen J, Paetau A, Kangasniemi M, Piippo A, Niemel M, Hernesniemi J,Jskelinen J: Remodeling of the saccular cerebral aneurysm wall is associ-ated with rupture. Histological analysis of 24 unruptured and 42 rupturedcases. Stroke 35:22872293, 2004.

7. Frsen J, Piippo A, Paetau A, Kangasniemi M, Niemel M, Hernesniemi J,

Jskelinen J: Growth factor receptor expression and remodeling of saccularcerebral artery aneurysms: Implications for biological therapy preventingrupture. Neurosurgery 58:534541, 2006.

8. Hernesniemi J, Ishii K, Karatas A, Kivipelto L, Niemel M, Nagy L, Shen H:Surgical technique to retract the tentorial edge during subtemporal approach:Technical note. Neurosurgery 57 [Suppl]:E408, 2005.

9. Hernesniemi J, Niemel M, Kivipelto L, Ishii K, Rinne J, Ronkainen J, KoivistoT, Kivisaari R, Shen H, Karatas A, Lehecka M, Frsen J, Piippo A, JskelinenJ. Some basic principles in microneurosurgery of the brain: A review. SurgNeurol 64:195-200, 2005.

10. Kangasniemi M, Mkel T, Koskinen S, Porras M, Poussa K, Hernesniemi J:Detection of intracranial aneurysms with two-dimensional and three-dimen-sional multislice helical computed tomographic angiography. Neurosurgery54:336340, 2004.

11. Kivisaari RP, Porras M, hman J, Siironen J, Ishii K, Hernesniemi J: Routinecerebral angiography after surgery for saccular aneurysms: Is it worth it?Neurosurgery 55:10151024, 2004.

12. Laaksamo E, Tulamo R, Ihalainen S, Baumann M, Hernesniemi J, Juvela S,Niemel M, Laakso A: Involvement of MAP kinase signalling in growth andrupture of human intracranial aneurysms. Stroke (In press).

13. Nagy L, Ishii K, Karatas A, Shen H, Vajda J, Niemel M, Jskelinen J,Hernesniemi J, Toth S: Water dissection technique of Toth for opening neuro-surgical cleavage planes. Surg Neurol 65:3841, 2006.

14. Niemel M, Koivisto T, Kivipelto L, Ishii K, Rinne J, Ronkainen A, KivisaariR, Shen H, Karatas A, Lehecka M, Frsen J, Piippo A, Jskelinen J,Hernesniemi J: Microsurgical clipping of cerebral aneurysms after the ISATStudy. Acta Neurochir Suppl 94:36, 2005.


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15. Raabe A, Nakaji P, Beck J, Kim LJ, Hsu FP, Kamerman JD, Seifert V, SpetzlerRF: Prospective evaluation of surgical microscope-integrated intraoperativenear-infrared indocyanine green videoangiography during aneurysm sur-gery.J Neurosurg 103:982989, 2005.

16. Randell T, Niemel M, Kytt J, Tanskanen P, Mttnen M, Karatas A, Ishii K,Dashti R, Hernesniemi J: Principles of neuroanesthesia in aneurysmal SAH:The Helsinki experience. Surg Neurol 66:382-388, 2006.

17. Tulamo R, Frsen J, Junnikkala S, Paetau A, Kangasniemi M, Niemel M,

Jskelinen J, Jokitalo E, Karatas A, Hernesniemi J, Meri S: Complementactivation associates with saccular aneurysm wall degeneration and rupture.Neurosurgery 59:1069-1076, 2006.

18. van der Voet M, Olson JM, Kuivaniemi H, Dudek DM, Skunca M, RonkainenA, Niemel M, Jskelinen J, Hernesniemi J, Helin K, Leinonen E, Biswas M,Tromp G: Intracranial aneurysms in Finnish families: Confirmation of linkageand refinement of the interval to chromosome 19q13.3. Am J Hum Genet74:564571, 2004.



The Making of a Fresco showing the Building of a City, (1931) fresco, Diego Rivera. San Francisco Art Institute, San Francisco, California. From Rochfort D:Mexican Muralists: Orozco, Rivera, Siqueiros. San Francisco, Chronicle Books LLC, 1998.

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