T h e new england journal o f medicine

review article

Medical Progress Cerebral Aneurysms

Jonathan L. Brisman, M.D., Joon K. Song, M.D., and David W. Newell, M.D.

From the Department of Cerebrovascular accular intracranial aneurysms, abnormal focal outpouchings and Endovascular , New Jer- of cerebral , cause substantial rates of morbidity and mortality. Re- sey Neuroscience Institute, JFK Medical Center, Edison, N.J. (J.L.B.); the Depart- Scently, major changes have occurred in the way we think about and treat this ment of Endovascular , Institute disease. Previous concepts about the natural history, particularly the risk of rupture for Neurology and Neurosurgery, Roosevelt of certain aneurysms, have been challenged.1,2 Medical Center, New York (J.K.S.); and the Department of Neurosurgery, Seattle When this topic was last discussed in the Journal in 1997, minimally invasive Neuroscience Institute, Swedish Medical percutaneous endovascular treatment of intracranial aneurysms (a technique known Center, Seattle (D.W.N.). Address reprint as coiling) had been introduced as an experimental procedure for patients who requests to Dr. Brisman at the Depart- 3 ment of Cerebrovascular and Endovascu- were not good candidates for surgery. After almost a decade of increased use and lar Neurosurgery, New Jersey Neuroscience evaluation, has proved to be a safe and durable alternative to Institute at JFK Medical Center, Edison, NJ the traditional neurosurgical treatment of craniotomy and clip ligation (“clipping”). 08818, or at [email protected]. Coiling has now surpassed clipping as the primary method of treatment for intra- N Engl J Med 2006;355:xxx-xx. cranial aneurysms in some centers. Since the Guglielmi detachable coil for the Copyright © 2006 Massachusetts Medical Society. treatment of intracranial aneurysms was approved in 1995 by the Food and Drug Administration (FDA), an estimated 150,000 patients have been treated with this device.4,5 In this article, the technological advances and supporting research con- tributing to this important change in practice patterns are reviewed.

EPIDEMIOLOGY AND PATHOPHYSIOLOGY

Intracranial aneurysms are common lesions; autopsy studies indicate a prevalence in the adult population between 1 and 5 percent,2 which translates to 10 million to 12 million persons in the United States.3 Fortunately, most aneurysms are small, and an estimated 50 to 80 percent of all aneurysms do not rupture during the course of a person’s lifetime.6 Intracranial aneurysms are considered to be sporadi- cally acquired lesions, although a rare familial form has been described.3 Associated conditions include autosomal dominant polycystic disease, , Marfan’s syndrome, Ehlers–Danlos syndrome type IV, and arteriovenous malformations of the . An estimated 5 to 40 percent of patients with autoso- mal dominant polycystic kidney disease have intracranial aneurysms, and 10 to 30 percent of patients have multiple3,7 aneurysms.3 Screening with intracranial magnetic resonance is indicated for people who have two immediate relatives with intracranial aneurysms and for all patients with autosomal dominant polycystic kidney disease.3,8,9 Rescreening of patients with autosomal dominant polycystic kidney dis- ease is recommended, although the frequency of the procedure depends on wheth- er other affected family members are known to have intracranial aneurysms.8 The estimated incidence of from a ruptured intracra- nial aneurysm in the United States is 1 case per 10,000 persons, yielding approxi- mately 27,000 new cases of sub-arachnoid hemorrhage each year.3,5 Subarachnoid hemorrhage in women is more common than in men (2 to 1)10; the peak incidence is in persons 55 to 60 years old.11 An estimated 5 to 15 percent of cases of

56 n engl j med 355;9 www.nejm.org august 31, 2006 medical progress are related to ruptured intracranial aneurysms.12 smoking-induced vascular changes are thought Aneurysmal subarachnoid hemorrhage, a form of to have a major role.3 The most common histo- hemorrhagic stroke, has a 30-day mortality rate logic finding is a decrease in the , of 45 percent. An estimated 30 percent of survi- the middle muscular layer of the , causing vors will have moderate-to-severe disability.13 structural defects. These defects, combined with Little is known about the cause of intracra- hemodynamic factors, lead to aneurysmal out- nial aneurysms or the process by which they form, pouchings at arterial branch points in the sub- grow, and rupture, although and arachnoid space at the base of the brain (Fig. 1).3

Additional miscellaneous aneurysm Pericallosal artery, 4% locations not shown: 3.5%

Anterior communicating artery, 30%

Internal carotid artery bifurcation, 7.5%

Middle cerebral artery, 20%

Posterior communicating artery, 25%

Basilar tip, 7%

Posterior inferior cerebellar artery, 3%

Figure 1. The Intracranial Vasculature, Showing the Most Frequent Locations of Intracranial Aneurysms. Percentages indicate the incidence of the intracranial aneurysms.

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T h e new england journal o f medicine

study (the International Study of Unruptured In- NATURAL HISTORY AND RISK tracranial Aneurysms), in which 1692 patients OF RUPTURE selected for conservative treatment were followed, The most common presentation of intracranial yielded similar results. However, the stratifica- aneurysm is rupture leading to subarachnoid hem- tion was slightly different; the subgroup with the orrhage.11 At present, aneurysms are increasingly smallest aneurysms — 7 mm or less (which in- detected before rupture, given the increased avail- cluded 62 percent of the cohort) — had a five- ability and improved sensitivity of noninvasive year cumulative rate of rupture of 0 percent.2 A imaging techniques. An unruptured aneurysm major objection to that multicenter study is that may be and thus be found inciden- the subjects entered into the study were those tally, or it may be diagnosed on the basis of symp- preselected by surgeons for observation on the toms. Unruptured aneurysms cause symptoms by basis of their opinion that these aneurysms were exerting a mass effect, leading to cranial-nerve less likely to rupture.22,23 Subsequent studies have palsies or brain-stem compression.6 One common shown higher risks of rupture for unruptured aneurysm-related syndrome is rapid onset of a intracranial aneurysms.24,25 third-nerve palsy caused by enlargement of an 3 aneurysm of the posterior communicating artery. MEDICAL DIAGNOSIS Aneurysms presenting with subarachnoid hem- AND MANAGEMENT orrhage tend to bleed again. Two to 4 percent OF SUBARACHNOID HEMORRHAGE hemorrhage again within the first 24 hours after the initial episode, and approximately 15 to 20 Clinical Presentation and Diagnosis percent bleed a second time within the first two Many patients with subarachnoid hemorrhage weeks.11 Persons with intracranial aneurysms pre- present with an acute onset of severe , senting with symptoms of compression such as often described by patients as the “worst head- cranial-nerve palsies or brain-stem dysfunction ache of my life.” However, an estimated 10 per- should be evaluated and treated promptly because cent die before reaching medical attention, and of the increased risk of rupture (6 percent per many others present in a coma or with severe year)14 in this subgroup.6 The risk of rupture of neurologic compromise.5 Clinical grading scales an that has not bled but is such as the Hunt and Hess Scale (Table 1) are found incidentally is much less certain, and these used to describe the neurologic condition on ad- intracranial aneurysms are generally managed mission and are considered good predictors of electively. In the past, unruptured intracranial ultimate outcome.26,27 Computed tomography (CT) aneurysms were viewed as posing a high risk, of the head without the administration of contrast with an estimated risk of rupture of approximate- material is the initial diagnostic test of choice for ly 1 to 2 percent per year.15-18 Before the availabil- suspected subarachnoid hemorrhage. The Fisher ity of detachable coils, most intracranial aneurysms grade uses a four-point scale to describe the were surgically clipped to prevent rupture.19-21 amount of blood on non–contrast-enhanced CT In 1998, the results of a retrospective study in- of the head and has been shown to correlate with volving 53 centers and 2621 subjects challenged the traditional thinking about the risk of rupture Table 1. Hunt and Hess Grading Scale for Subarachnoid of unruptured intracranial aneurysms.1 In this Hemorrhage. large cohort of people with unruptured aneurysms Grade Clinical Description selected for conservative treatment, the rate of 1 Asymptomatic or minimal headache and slight rupture for certain small aneurysms (less than nuchal rigidity 10 mm in diameter) was found to be as low as 2 Moderate-to-severe headache, nuchal rigidity, and no 0.05 percent per year. Among patients with a his- neurologic deficit other than cranial-nerve palsy tory of a aneurysm, the risk of hemor- 3 Drowsiness, confusion, or mild focal deficit rhage was 10 times that of patients who had no 4 Stupor, moderate-to-severe hemiparesis, and pos- sibly, early decerebrate rigidity and vegetative such history. Intracranial aneurysms larger than disturbances 10 mm and aneurysms of the basilar apex or 5 Deep coma, decerebrate rigidity, and moribund posterior communicating artery had an even high- appearance er rate of rupture. The prospective part of the

58 n engl j med 355;9 www.nejm.org august 31, 2006 medical progress the development of vasospasm.28 Lumbar punc- tients with impaired renal function, since a large ture is reserved for the approximately 5 percent of bolus of contrast material is administered. patients in whom cranial CT reveals no abnormal- MRA takes considerably longer to perform than ities, despite a history suggesting a subarachnoid does CTA (roughly 30 to 60 minutes) and is thus hemorrhage.11 Bloody that more difficult to use in critically ill patients. MRA fails to clear with continued egress of cerebrospi- is both highly sensitive and specific for the detec- nal fluid should raise a suspicion of subarachnoid tion of intracranial aneurysms (sensitivity, 0.69 to hemorrhage. The presence of xanthochromia, a 0.99; specificity, 1.00).12,33,36,35 The sensitivity of yellowish discoloration of the cerebrospinal fluid MRA, like that of CTA, diminishes for very small representing bilirubin from the breakdown of aneurysms (under 3 mm in diameter) and was hemoglobin, is even more definitive than a high 0.38 in one series.28 red-cell count in the cerebrospinal fluid. Blood In 1998, a three-dimensional form of catheter from a subarachnoid hemorrhage that occurred angiography was developed that permits refor- more than 12 hours before the spinal tap will re- matted images to be rotated. This advance over sult in xanthochromic cerebrospinal fluid, where- two-dimensional catheter angiography, known as as fresh blood, as might occur with a traumatic three-dimensional rotational angiography, per- spinal tap, will not.29 mits the aneurysm and its relation to other ves- The next step after making a definitive diag- sels to be assessed in three dimensions, over- nosis of a spontaneous subarachnoid hemorrhage coming prior imaging limitations.39,40 Catheter should be to determine whether an aneurysm is angiography, with or without the advanced three- the cause. To do so, it is important to select the dimensional capability, is more expensive and best imaging method for a given patient. invasive than either MRA or CTA. Its risks, par- ticularly in the hands of experienced operators, Imaging Methods and Options appear acceptably low (neurologic complications The three methods of choice to identify or rule occurring in 1.0 to 2.5 percent of cases, with per- out an intracranial aneurysm and to delineate the manent impairment in 0.1 to 0.5 percent),41‑44 size and morphologic features of an intracranial given the seriousness of intracranial aneurysms. aneurysm are CT angiography (CTA) after a ve- Non-neurologic risks such as femoral-artery in- nous injection, magnetic resonance angiography jury (0.05 to 0.55 percent), groin hematoma (6.9 to (MRA), and angiography by direct intraarterial 10.7 percent), and adverse renal effects induced catheterization (catheter angiography); the last is by contrast material and other allergic reactions still considered the benchmark. Several studies (1 to 2 percent) are well known and often tran- have evaluated the accuracy of detecting intracra- sient.45 Elderly patients with atherosclerotic ves- nial aneurysms by comparing CTA, MRA, and the sels or patients with impaired renal function synergistic combination of CTA and MRA with would be more likely to have complications such catheter angiography, intraoperative findings, or as a thromboembolic event or nephrotoxicity, re- both.30-35 spectively.3 CTA provides software-generated images from thin-section contrast-enhanced CT to show cere- Clinical Approach to Imaging bral vessels in three-dimensional views. The re- High-quality catheter angiography is generally constructed pictures, which are obtained in min- definitive. Thus, it is the test of choice to evaluate utes, can be rotated and allow the vasculature to subarachnoid hemorrhage,12 although CTA alone be visualized relative to the brain and the bones has been used.41 Because of the less invasive na- of the skull base, facilitating surgical planning. ture of CTA and MRA, they are recommended as Studies evaluating CTA in the management of the first approaches in the evaluation of unrup- intracranial aneurysms have reported sensitivi- tured aneurysms. ties ranging from 0.77 to 0.97 and specificities Angiographic examination fails to disclose an ranging from 0.87 to 1.00.12,30,31,33,36,37 Sensitivity aneurysm in only 10 to 20 percent of cases of drops precipitously for the detection of smaller subarachnoid hemorrhage. In cases in which the aneurysms; sensitivity for aneurysms smaller than results of angiography are negative, angiography 3 mm is estimated to be 0.40 to 0.91.30,32,38 Cau- is usually repeated in one to six weeks.26,46 The tion must be exercised when CTA is used in pa- cause of a subarachnoid hemorrhage without an

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identified aneurysm is unknown. Hypertensive antispasmodic agents result in angiographically rupture of a small artery or is one proposed confirmed arterial dilatation in a high percent- mechanism. In these circumstances, an MRI of age of patients (90 to 98 percent).49,50 Clinical the brain and cervical spine is usually obtained improvement, however, does not invariably cor- after the administration of contrast material dur- relate with radiographic success. Some observers ing the initial admission to rule out a thrombosed report a rate of neurologic improvement of 61 to aneurysm, hemorrhagic tumor, spinal arteriove- 70 percent, whereas others report no benefit as nous malformation, or dural arteriovenous fistu- compared with triple-H therapy.49,51,52 la, although the diagnostic yield is small. Evidence of cardiac abnormalities after sub- arachnoid hemorrhage is common and includes Acute Effects of Subarachnoid Hemorrhage electrocardiographic changes (25 to 100 percent Hydrocephalus develops in about 15 to 20 percent of cases),53,54 elevations of cardiac (tro- of patients who have an aneurysmal subarach- ponin in 17 to 28 percent and creatine kinase noid hemorrhage.11 Symptomatic hydrocephalus MB isoenzyme in 37 percent of cases),53,55-57 and is usually treated with ventriculostomy and drain- left ventricular dysfunction (8 to 30 percent of age of cerebrospinal fluid. cases).58,59 This combination of abnormalities, Cerebral vasospasm, a major cause of morbid- known as “cardiac stun,” appears to result from ity and mortality, refers to the intracranial vaso- excessive catecholamine release in response to constriction that may occur between 3 and 12 the . The presence of a days after a subarachnoid hemorrhage. The cause markedly decreased ejection fraction with motion of vasospasm is unknown; even with maximal abnormalities of the ventricular wall that do not therapy, vasospasm can cause and death.11 match the electrocardiographic vascular distribu- ultrasonography is a useful tion of help to make the diagnosis.56,59 noninvasive method to detect vasospasm. Levels of both creatine kinase MB isoenzyme and troponin are usually elevated, but the troponin Medical Therapy elevation is generally only a 10th of that seen Medical treatment consists of orally administered with true ischemic myocardium.56 Most cases of nimodipine (60 mg every four hours for 21 days), cardiac stun are temporary; permanent myocardial which has been shown to improve the outcome appears to be rare, irrespective of whether after subarachnoid hemorrhage.47 In patients who early treatment of the aneurysm is performed.53 have a clear increase in the transcranial Doppler velocities or in whom new neurologic deficits de- TREATMENT OPTIONS velop, triple-H (hypertension, hypervolemia, and hemodilution) therapy is initiated. Goals of this There are three options for treating intracranial treatment include a hematocrit of 30 percent, a aneurysms: observation, craniotomy with clip liga- central venous pressure of 8 to 12 mm Hg, and tion (clipping) (Fig. 2), and endovascular occlu- enough artificially induced hypertension to pre- sion with the use of detachable coils (coiling) vent or reverse new neurologic deficits.5,11,26 Such (Fig. 3). All ruptured aneurysms in patients with deficits usually correlate with the vascular terri- Hunt and Hess grades 1 to 4 are treated early tory of the vessel in spasm and may be as subtle as (generally within 72 hours). There is debate about a decrease in the level of arousal or as overt as a how to treat patients with the most severe grade, new hemiparesis. In light of the risks of triple-H Hunt and Hess grade 5; the historically high in- therapy, such as cardiac dysfunction, catheter an- cidence of poor outcome despite treatment has giography is occasionally used to confirm the prompted the suggestion of conservative manage- findings on transcranial Doppler examination. ment unless clinical improvement occurs. How- Patients with any persistent new neurologic ever, recent evidence supports the use of aggres- deficit who have no response to medical treatment sive therapy for most of these patients, including should undergo urgent catheter angiography to ventricular drain placement and aneurysm treat- confirm the presence of vasospasm, followed by ment.26 Detachable coils have been increasingly angioplasty of the narrowed vessels or intraarte- used as a less physiologically stressful alternative rial administration of smooth-muscle relaxants to clipping the aneurysm in this subgroup of pa- such as papaverine.48,49 Balloon angioplasty and tients, who already have severe brain injury.26

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Intact aneurysms that are discovered inciden- tally are either observed or treated electively, de- pending on the patient and the size and state of the aneurysm. Observation consists of routine pe- riodic follow-up imaging and physician visits to review the studies. Clipping of aneurysms requires Skin incision the performance of a craniotomy by a neurosur- geon with the patient under general anesthesia. Craniotomy segment Permanent clips made from MRI-compatible al- loys are placed across the neck of the aneurysm, excluding it from the circulation (Fig. 2). An interventional neuroradiologist, a neuro- surgeon, or a neurologist with training in inter- ventional radiology performs endovascular coil- ing.60 General anesthesia is often used during the placement of detachable coils, although some cen- Clip applied to ters prefer to use only sedation in order to moni- neck of aneurysm tor the patient’s neurologic status during the pro- cedure.61 Neurophysiologic monitoring has been described as another way to monitor neurologic function during coiling.62 With the use of angio- graphic techniques, a microcatheter is advanced into the aneurysm, and detachable coils of vari- ous sizes and shapes are deployed to decrease the amount of blood or to stop blood from filling the aneurysm (Fig. 3).

COMPARIson of CLIPPING AND COILING Risks of Clipping In one large, single-center series and two meta- analyses, the morbidity and mortality rates associ- ated with clipping an unruptured aneurysm were Aneurysm 4.0 to 10.9 percent and 1.0 to 3.0 percent, respec- tively.19-21 Although successful clipping is gener- Figure 2. Microsurgical Clipping of an Aneurysm of the Posterior Communi- ally associated with definitive protection against cating Artery. rupture, long-term studies have documented a Panel A shows the typical skin incision (unbroken curved line) and craniotomy certain small risk of technical failure, incomplete (dashed lines) needed to access the aneurysm. Panel B shows the application occlusion (5.2 percent),63 recurrence (1.5 percent), of the clip blade to the neck of the aneurysm. and hemorrhage (0.26 percent).64

The International Study of Unruptured Intra- cranial Aneurysms assessed the risk of morbid- observation. GuidelinesTitle for the management of ity associated with the clipping of unruptured unruptured intracranialME aneurysms were issued aneurysms. The risk associated with surgical re- by the Stroke CouncilDE of the American As- A SB 12 pair was reported to be 15.7 percent after one sociation in 2000. 1 year, higher than previously reported. Additional single-center reports, however, have since dem- Risks of Inserting DetachableIssue date Coils onstrated a lower risk of surgical morbidity, in Minor risks of inserting detachable coils, such as the range of 3 to 7 percent.6 In any event, the re- reactions to contrast material and groin hemato- sults of the International Study of Unruptured mas, infections, or , are similar Intracranial Aneurysms have had an important to those of diagnostic catheter angiography.67 Ma- effect on the management of unruptured aneu- jor risks include arterial (0.7 percent), rysms65,66; more aneurysms are now treated with parent-artery occlusion (2.0 percent), and throm-

n engl j med 355;9 www.nejm.org august 31, 2006 61 T h e new england journal o f medicine

A

Aneurysm

Coil

Microcatheter

B

Catheter

Coil in place

Figure 3. Endovascular Occlusion of an Aneurysm of the Posterior Communicating Artery with Guglielmi Detachable Coils. Panel A shows the route of the microcatheter into the aneurysm through the right , , and left carotid artery and the beginning of the coil deployment. Panel B shows the final occlusion of the aneurysm with coils.

68 boembolic phenomena (2.4T lepercent). Intrapro- incidence of 1.4 to 2.7 percent, with an associat- 68-70 cedural rupture of the aneurysmME during catheter ed mortality rate of 30 to 40 percent. Even advancement into the aneurysmDE or coil place- lower rates of intraprocedural rupture (1 percent)

ment is one of the most serious complications;UT OR PLE SE NOT : have recently been reported in one high-volume Figure has been redra n and typ has b eset two large series and one meta analysisP cited k f an center; in that report, the associated morbidity

62 n engl j med 355;9 www.nejm.org august 31, 2006 medical progress was low (17 percent) and the mortality rate was intended to interface with the vessel endothelium 0 percent, perhaps reflecting increasing familiar- and form a collagenous matrix at the entrance of ity and experience with coils after approval by the the aneurysm.81 Another new type of coil77,82 that FDA in 1995.71 Overall procedural morbidity and expands once inside the aneurysm to induce mortality rates for coiling have been reported as denser packing appears to reduce the incidence 3.7 to 5.3 percent and 1.1 to 1.5 percent, respec- of coil compaction in animal models.83 Another tively.72,73 It is not feasible to perform a coiling potential solution to recanalization is a new flex- procedure for some aneurysms (5 to 14.5 percent ible, self-expandable, microcatheter-delivered, ni- of cases),68,74 because unusual tortuosity of the tinol (Neuroform stent, Target Therapeutics/ vessels renders access difficult or because the con- Boston Scientific) (Fig. 4). This intracranial stent, tours of the aneurysm do not permit the coils to which was recently approved by the FDA, is placed sit safely inside. within the artery from which the aneurysm arises, Recent technologic advances, including coils thereby blocking it.76,77 that are better able to conform in aneurysms with atypical morphology, balloons,75 and intracranial Relative Risks of Coiling and Clipping , which were introduced in 2002 (Fig. 4),76,77 Several retrospective studies84-86 suggest that de- have markedly reduced the number of aneurysms spite its attendant risks, treating most ruptured that cannot be approached with the detachable- and unruptured intracranial aneurysms with de- coil procedure. Importantly, there is a greater tachable coils appears to be safer than clipping, likelihood of partial occlusion when coils are at least during the perioperative period. In sepa- used than when surgical clipping is used. In three rate reviews of a database of a university health single-center studies, 2868 subjects with intra- system consortium (60 universities),86 the Califor- cranial aneurysms underwent a coiling proce- nia statewide database of hospital discharges,85 dure; successful angiographic occlusion (defined and the hospital database of the University of as >90 to 95 percent occlusion or a neck remnant California at San Francisco,84 Johnston et al. re- only) was achieved in 85 to 90.4 percent of le- ported that outcomes associated with clipping sions. Larger aneurysms and aneurysms with were worse than those associated with detach- wider necks typically had lower rates of success- able coils. They also reported that the use of coils ful occlusion.68,72,78 was associated with a lower rate of inpatient mor- Aneurysms that have been treated with coils tality, shorter hospital stay, and lower treatment may recur, and with recurrence, they have the costs.84-86 potential to hemorrhage. Over time, blood flow More robust data favoring the safety of coil- can compress the coils within the aneurysm, a ing over clipping are available for aneurysms pre- process known as compaction; as a result, the senting with subarach