Incidence and Prevalence of aSAH

Considerable variation in the annual incidence of aSAH exists in different regions of the world. A World Health Organization study found a 10-fold variation in the age-adjusted annual incidence in countries in Europe and Asia, from 2.0 cases per 100 000 population in China to 22.5 cases per 100 000 in Finland.³ A later systematic review supported a high incidence of aSAH in Finland and Japan, a low incidence in South and Central America, and an intermediate incidence of 9.1 per 100 000 population in other regions.⁴ In a more recent systematic review of population-based studies, the incidence of aSAH ranged from 2 to 16 per 100 000.⁵ In that review, the pooled age-adjusted incidence rate of aSAH in low- to middle-income countries was found to be almost double that of high-income countries.⁵ Although some reports have suggested the incidence of aSAH in the United States to be 9.7 per 100 000,⁶ the 2003 Nationwide Inpatient Sample provided an annual estimate of 14.5 discharges for aSAH per 100 000 adults.⁷ Because death resulting from aSAH often occurs before hospital admission (an estimated 12% to 15% of cases),^8,9 the true incidence of aSAH might be even higher. Although a number of population-based studies have indicated that the incidence of aSAH has remained relatively stable over the past 4 decades,^5,10–16 a recent review that adjusted for age and sex suggested a slight decrease in incidence between 1950 and 2005 for regions other than Japan, South and Central America, and Finland.⁴ These data are consistent with studies that show that the incidence of aSAH increases with age, with a typical average age of onset in adults ≥50 years of age.^3,7,17,18 aSAH is relatively uncommon in children; incidence rates increase as children get older, with incidence ranging from 0.18 to 2.0 per 100 000.^4,19 The majority of studies also indicate a higher incidence of aSAH in women than in men.^{7,11–13,20–22} Most recent pooled figures report the incidence in women to be 1.24 (95% confidence interval, 1.09–1.42) times higher than in men.⁴ This is lower than a previous estimate of 1.6 (95% confidence interval, 1.1–2.3) for the years 1960 to 1994.²³ Evidence of a sex-age effect on aSAH incidence has emerged from pooled study data, with a higher incidence reported in younger men (25–45 years of age), women between 55 and 85 years of age, and men >85 years of age.⁴ Differences in incidence of aSAH by race and ethnicity appear to exist. Blacks and Hispanics have a higher incidence of aSAH than white Americans.^6,24,25

Risk Factors for and Prevention of aSAH

Behavioral risk factors for aSAH include hypertension, smoking, alcohol abuse, and the use of sympathomimetic drugs (eg, cocaine). In addition to female sex (above), the risk of aSAH is increased by the presence of an unruptured cerebral aneurysm (particularly those that are symptomatic, larger in size, and located either on the posterior communicating artery or the vertebrobasilar system), a history of previous aSAH (with or without a residual untreated aneurysm), a history of familial aneurysms (at least 1 first-degree family member with an intracranial aneurysm, and especially if ≥2 first-degree relatives are affected) and family history of aSAH,^26,27 and certain genetic syndromes, such as autosomal dominant polycystic kidney disease and type IV Ehlers-Danlos syndrome.^28,29 Novel findings reported since publication of the previous version of these guidelines include the following: (1) Aneurysms in the anterior circulation appear to be more prone to rupture in patients <55 years of age, whereas posterior communicating aneurysms ruptured more frequently in men, and basilar artery aneurysm rupture is associated with lack of use of alcohol.³⁰ (2) The size at which aneurysms rupture appears to be smaller in those patients with the combination of hypertension and smoking than in those with either risk factor alone.³¹ (3) Significant life events such as financial or legal problems within the past month may increase the risk of aSAH.³² (4) Aneurysm size >7 mm has been shown to be a risk factor for rupture.³³ (5) There does not appear to be an increased risk of aSAH in pregnancy, delivery, and puerperium.^34,35

Inflammation appears to play an important role in the pathogenesis and growth of intracranial aneurysms.³⁶ Prominent mediators include the nuclear factor κ-light-chain enhancer of activated B cells (NF-κB),³⁷ tumor necrosis factor, macrophages, and reactive oxygen species. Although there are no controlled studies in humans, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statin”)³⁸ and calcium channel blockers may retard aneurysm formation through the inhibition of NF-κB and other pathways. Among the risk factors for aSAH, clearly attributable and modifiable risks are very low body mass index, smoking, and high alcohol consumption.^31,39,40 Yet, despite marked improvements in the treatment of hypertension and hyperlipidemia and the decrease in rates of smoking over time, the incidence of aSAH has not changed appreciably in 30 years.¹⁶

It is possible that diet increases the risk of stroke in general and aSAH in particular. In an epidemiological study of Finnish smokers who were monitored for >13 years, increased consumption of yogurt (but not all dairy products) was associated with a higher risk of aSAH.⁴¹ Greater vegetable consumption is associated with a lower risk of stroke and aSAH.⁴² Higher coffee and tea consumption⁴³ and higher magnesium consumption⁴⁴ were associated with reduced risk of stroke overall but did not change the risk of aSAH.

Predicting the growth of an individual intracranial aneurysm and its potential for rupture in a given patient remains problematic. When followed up on magnetic resonance imaging, larger aneurysms (≥8 mm in diameter) tended to grow more over time,⁴⁵ which implies a higher risk of rupture. Several characteristics of aneurysm morphology (such as a bottleneck shape⁴⁶ and the ratio of size of aneurysm to parent vessel^47,48) have been associated with rupture status, but how these might be applied to individual patients to predict future aneurysmal rupture is still unclear.³³ Variability within each patient is unpredictable at this time, but such intraindividual variability markedly changes the risk of aneurysm detection and rupture and may attenuate the benefits of routine screening in high-risk patients.⁴⁹

Given such uncertainties, younger age, longer life expectancy, and higher rate of rupture all make treatment of unruptured aneurysms more likely to be cost-effective and reduce morbidity and mortality.⁵⁰ Two large observational studies of familial aneurysms suggest that screening these patients may also be cost-effective in preventing aSAH and improving quality of life.^26,27 Smaller studies have suggested that screening of those with 1 first-degree relative with aSAH may be justified as well, but it is far less clear whether patients who underwent treatment for a previous aSAH require ongoing screening.^51,52 In the Cerebral Aneurysm Rerupture After Treatment (CARAT) study, recurrent aSAH was predicted by incomplete obliteration of the aneurysm and occurred a median of 3 days after treatment but rarely after 1 year.⁵³ Repeated noninvasive screening at later times may not be cost-effective, increase life expectancy, or improve quality of life in unselected patients.⁵⁴ Patients with adequately obliterated aneurysms after aSAH have a low risk of recurrent aSAH for at least 5 years,^55,56 although some coiled aneurysms require retreatment.⁵⁷

Natural History and Outcome of aSAH

Although the case fatality of aSAH remains high worldwide,⁵ mortality rates from aSAH appear to have declined in industrialized nations over the past 25 years.^{9,11,15,58,59} One study in the United States reported a decrease of ≈1% per year from 1979 to 1994.⁶⁰ Others have shown that case fatality rates decreased from 57% in the mid-1970s to 42% in the mid-1980s,¹¹ whereas rates from the mid-1980s to 2002 are reported to be anywhere from 26% to 36%.^{6,12,13,18,20,61,62} Mortality rates vary widely across published epidemiological studies, ranging from 8% to 67%.⁵⁹ Regional variations become apparent when numbers from different studies are compared. The median mortality rate in epidemiological studies from the United States has been 32% versus 43% to 44% in Europe and 27% in Japan.⁵⁹ These numbers are based on studies that did not always fully account for cases of prehospital death. This is an important consideration because the observed decrease in case fatality is related to improvements in survival among hospitalized patients with aSAH.

The mean age of patients presenting with aSAH is increasing, which has been noted to have a negative impact on survival rates.⁵⁹ Sex and racial variations in survival may also play a role in the variable rates, with some studies suggesting higher mortality in women than in men^9,11,60 and higher mortality in blacks, American Indians/Alaskan Natives, and Asians/Pacific Islanders than in whites.⁶³

Available population-based studies offer much less information about the functional outcome of survivors. Rates of persistent dependence of between 8% and 20% have been reported when the modified Rankin Scale is used.⁵⁹ Although not population based, trial data show a similar picture, with 12% of patients in the International Subarachnoid Aneurysm Trial (ISAT) showing significant lifestyle restrictions (modified Rankin Scale 3) and 6.5% being functionally dependent (modified Rankin Scale score of 4–5) 1 year after aSAH. Furthermore, scales that are relatively insensitive to cognitive impairment, behavioral changes, social readjustment, and energy level may substantially underestimate the effect of aSAH on the function and quality of life of surviving patients. Multiple studies using diverse designs have consistently demonstrated that intellectual impairment is very prevalent after aSAH. Although cognitive function tends to improve over the first year,⁶⁴ global cognitive impairment is still present in ≈20% of aSAH patients and is associated with poorer functional recovery and lower quality of life.⁶⁵ Cognitive deficits and functional decline are often compounded by mood disorders (anxiety, depression), fatigue, and sleep disturbances.⁶⁶ Therefore, scales assessing well-being and quality of life can be particularly useful in the integral assessment of patients with aSAH, even among those who regain functional independence.^67,68 Behavioral and psychosocial difficulties, as well as poor physical and mental endurance, are some of the most commonly encountered factors accounting for the inability of otherwise independent patients to return to their previous occupations.^66,68

Much remains to be learned about the causes of cognitive and functional deficits after aSAH and the best methods to assess intellectual outcome and functional recovery in these patients. The severity of clinical presentation is the strongest prognostic indicator in aSAH. Initial clinical severity can be reliably categorized by use of simple validated scales, such as the Hunt and Hess and World Federation of Neurological Surgeons scales.^69,70 Aneurysm rebleeding is another major predictor of poor outcome, as discussed in a later section. Other factors predictive of poor prognosis include older age, preexisting severe medical illness, global cerebral edema on computed tomography (CT) scan, intraventricular and intracerebral hemorrhage, symptomatic vasospasm, delayed cerebral infarction (especially if multiple), hyperglycemia, fever, anemia, and other systemic complications such as pneumonia and sepsis.^71–77 Certain aneurysm factors, such as size, location, and complex configuration, may increase the risk of periprocedural complications and affect overall prognosis.⁷⁸ Treatment in high-volume centers with availability of neurosurgical and endovascular services may be associated with better outcomes.^79–81

Clinical Manifestations and Diagnosis of aSAH

The clinical presentation of aSAH is one of the most distinctive in medicine. The hallmark of aSAH in a patient who is awake is the complaint “the worst headache of my life,” which is described by ≈80% of patients who can give a history.⁸² This headache is characterized as being extremely sudden and immediately reaching maximal intensity (thunderclap headache). A warning or sentinel headache that precedes the aSAH-associated ictus is also reported by 10% to 43% of patients.^83,84 This sentinel headache increases the odds of early rebleeding 10-fold.⁸⁵ Most intracranial aneurysms remain asymptomatic until they rupture. aSAH can occur during physical exertion or stress.⁸⁶ Nevertheless, in a review of 513 patients with aSAH, the highest incidence of rupture occurred while patients were engaged in their daily routines, in the absence of strenuous physical activity.⁸⁷ The onset of headache may be associated with ≥1 additional signs and symptoms, including nausea and/or vomiting, stiff neck, photophobia, brief loss of consciousness, or focal neurological deficits (including cranial nerve palsies). In a retrospective study of 109 patients with proven aSAH, headache was present in 74%, nausea or vomiting in 77%, loss of consciousness in 53%, and nuchal rigidity in 35%.⁸⁸ As many as 12% of patients die before receiving medical attention.

Despite the classic presentation of aSAH, individual findings occur inconsistently, and because the type of headache from aSAH is sufficiently variable, misdiagnosis or delayed diagnosis is common. Before 1985, misdiagnosis of aSAH occurred in as many as 64% of cases, with more recent data suggesting a misdiagnosis rate of ≈12%.^89,90 Misdiagnosis was associated with a nearly 4-fold higher likelihood of death or disability at 1 year in patients with minimal or no neurological deficit at the initial visit.⁸⁹ The most common diagnostic error is failure to obtain a noncontrast head CT scan.^89,91–93 In a small subset of patients, a high degree of suspicion based on clinical presentation will lead to the correct diagnosis despite normal head CT and cerebrospinal fluid test results, as shown in a recent study in which 1.4% of patients were diagnosed with aSAH only after vascular imaging techniques were used.⁹⁴

Patients may report symptoms consistent with a minor hemorrhage before a major rupture, which has been called a sentinel bleed or warning leak.^83,84 The majority of these minor hemorrhages occur within 2 to 8 weeks before overt aSAH. The headache associated with a warning leak is usually milder than that associated with a major rupture, but it may last a few days.^95,96 Nausea and vomiting may occur, but meningismus is uncommon after a sentinel hemorrhage. Among 1752 patients with aneurysm rupture from 3 series, 340 (19.4%; range, 15%–37%) had a history of a sudden severe headache before the event that led to admission.^82,95,97 The importance of recognizing a warning leak cannot be overemphasized. Headache is a common presenting chief complaint in the emergency department, and aSAH accounts for only 1% of all headaches evaluated in the emergency department.⁹² Therefore, a high index of suspicion is warranted, because diagnosis of the warning leak or sentinel hemorrhage before a catastrophic rupture may be lifesaving.⁹³ Seizures may occur in up to 20% of patients after aSAH, most commonly in the first 24 hours and more commonly in aSAH associated with intracerebral hemorrhage, hypertension, and middle cerebral and anterior communicating artery aneurysms.^98,99

Noncontrast head CT remains the cornerstone of diagnosis of aSAH; since publication of the previous version of these guidelines,^1,2 there have been only minor changes in imaging technology for this condition. The sensitivity of CT in the first 3 days after aSAH remains very high (close to 100%), after which it decreases moderately during the next few days.^2,100 After 5 to 7 days, the rate of negative CT increases sharply, and lumbar puncture is often required to show xanthochromia. However, advances in magnetic resonance imaging of the brain, particularly the use of fluid-attenuated inversion recovery, proton density, diffusion-weighted imaging, and gradient echo sequences,^101–103 can often allow the diagnosis of aSAH to be made when a head CT scan is negative and there is clinical suspicion of aSAH, possibly avoiding the need for lumbar puncture. The role of magnetic resonance imaging in perimesencephalic aSAH is controversial.¹⁰⁴ Indications for magnetic resonance angiography in aSAH are still few because of limitations with routine availability, logistics (including difficulty in scanning acutely ill patients), predisposition to motion artifact, patient compliance, longer study time, and cost. Aneurysms <3 mm in size continue to be unreliably demonstrated on computed tomographic angiography (CTA),^105,106 and this generates continued controversy in the case of CTA-negative aSAH.¹⁰⁷ In cases of perimesencephalic subarachnoid hemorrhage (SAH), some authors claim that a negative CTA result is sufficient to rule out aneurysmal hemorrhage and that cerebral angiography is not required, but this is controversial. In 1 study, the overall interobserver and intraobserver agreement for nonaneurysmal perimesencephalic hemorrhage was good, but there was still a level of disagreement among observers, which suggests that clinicians should be cautious when deciding whether to pursue follow-up imaging.¹⁰⁸ In another study,¹⁰⁹ a negative CTA result reliably excluded aneurysms when head CT showed the classic perimesencephalic SAH pattern or no blood. Digital subtraction angiography (DSA) was indicated if there was a diffuse aneurysmal pattern of aSAH, and repeat delayed DSA was required if the initial DSA findings were negative, which led to the detection of a small aneurysm in 14% of cases. When the blood is located in the sulci, CTA should be scrutinized for vasculitis, and DSA is recommended for confirmation.¹⁰⁹ Others have shown that CTA may not reveal small aneurysms and that 2- and 3-dimensional cerebral angiography should be performed, especially when the hemorrhage is accompanied by loss of consciousness.¹¹⁰ In cases of diffuse aSAH pattern, most agree that negative CTA should be followed by 2- and 3-dimensional cerebral angiography. In older patients with degenerative vascular diseases, CTA can replace catheter cerebral angiography in most cases if the image quality is excellent and analysis is performed carefully.¹¹¹ Overlying bone can be problematic with CTA, especially at the skull base. A new technique, CTA-MMBE (multisection CTA combined with matched mask bone elimination), is accurate in detecting intracranial aneurysms in any projection without superimposed bone.¹¹² CTA-MMBE has limited sensitivity in detecting very small aneurysms. The data suggest that DSA and 3-dimensional rotational angiography can be limited to the vessel harboring the ruptured aneurysm before endovascular treatment after detection of a ruptured aneurysm with CTA. Another new technique, dual-energy CTA, has diagnostic image quality at a lower radiation dose than digital subtraction CTA and high diagnostic accuracy compared with 3-dimensional DSA (but not 2-dimensional DSA) in the detection of intracranial aneurysms.¹¹³

Cerebral angiography is still widely used in the investigation of aSAH and the characterization of ruptured cerebral aneurysms. Although CTA is sometimes considered sufficient on its own when an aneurysm will be treated with surgical clipping,¹¹⁴ substantial controversy remains about the ability of CTA to determine whether or not an aneurysm is amenable to endovascular therapy.^115–120 In 1 series,¹¹⁵ 95.7% of patients with aSAH were referred for treatment on the basis of CTA. In 4.4% of patients, CTA did not provide enough information to determine the best treatment, and those patients required DSA; 61.4% of patients were referred to endovascular treatment on the basis of CTA; and successful coiling was achieved in 92.6%. The authors concluded that CTA with a 64-slice scanner is an accurate tool for detecting and characterizing aneurysms in acute aSAH and that CTA is useful in deciding whether to coil or clip an aneurysm.¹¹⁵ Partial volume averaging phenomena may artificially widen the aneurysmal neck and may lead to the erroneous conclusion that an aneurysm cannot be treated by endovascular coiling. This controversy is likely caused by the different technological specifications (16- versus 64-detector rows), slice thickness, and data processing algorithms of various CT systems, which have different spatial resolutions. Three-dimensional cerebral angiography is more sensitive for detecting aneurysms than 2-dimensional angiography.^121,122 The combination of 3- and 2-dimensional cerebral angiography usually provides the best morphological depiction of aneurysm anatomy with high spatial resolution, and it is, of course, always used in preparation for endovascular therapy.

Flat-panel volumetric CT is a relatively recent development that allows the generation of CT-like images from a rotational 3-dimensional spin of the x-ray gantry in the angiography room. For the moment, it has no substantial role in the initial diagnosis of aSAH because its spatial and contrast resolutions are not high enough¹²³; however, this technology can be used intraprocedurally during embolizations to rule out hydrocephalus.¹²⁴ Recently, radiation dose has emerged as an important and worrisome consideration for patients with SAH.^125,126 The combination of noncontrast head CT for the diagnosis of aSAH, confirmation of ventriculostomy placement, investigation of neurological changes, CTA for aneurysmal diagnosis, CTA and CT perfusion for recognition of vasospasm, and catheter cerebral angiography for aneurysm embolization and then for endovascular therapy of vasospasm can result in substantial radiation doses to the head, with possible risk of radiation injury, such as scalp erythema and alopecia. Although some or all of these radiological examinations are often necessary, efforts need to be made to reduce the amount of radiation exposure in patients with aSAH whenever possible.

Medical Measures to Prevent Rebleeding After aSAH

Aneurysm rebleeding is associated with very high mortality and poor prognosis for functional recovery in survivors. The risk of rebleeding is maximal in the first 2 to 12 hours, with reported rates of occurrence between 4% and 13.6% within the first 24 hours.^127–130 In fact, more than one third of rebleeds occur within 3 hours and nearly half within 6 hours of symptom onset,¹³¹ and early rebleeding is associated with worse outcome than later rebleeding.¹³² Factors associated with aneurysm rebleeding include longer time to aneurysm treatment, worse neurological status on admission, initial loss of consciousness, previous sentinel headaches (severe headaches lasting >1 hour that do not lead to the diagnosis of aSAH), larger aneurysm size, and possibly systolic blood pressure >160 mm Hg.^87,129,130 Genetic factors, although related to the occurrence of intracranial aneurysms, do not appear to be related to an increased incidence of rebleeding.¹³³ Early treatment of the ruptured aneurysm can reduce the risk of rebleeding.⁷¹ Among patients who present in a delayed manner and during the vasospasm window, delayed obliteration of aneurysm is associated with a higher risk of rebleeding than early obliteration of aneurysm.¹³⁴

There is general agreement that acute hypertension should be controlled after aSAH and until aneurysm obliteration, but parameters for blood pressure control have not been defined. A variety of titratable medications are available. Nicardipine may give smoother blood pressure control than labetalol¹³⁵ and sodium nitroprusside,¹³⁶ although data showing different clinical outcomes are lacking. Although lowering cerebral perfusion pressure may lead to cerebral ischemia, a cohort study of neurologically critically ill patients did not find an association between use of nicardipine and reduced brain oxygen tension.¹³⁷ Clevidipine, a very short-acting calcium channel blocker, is another option for acute control of hypertension, but data for aSAH are lacking at this time.

Antifibrinolytic therapy has been shown to reduce the incidence of aneurysm rebleeding when there is a delay in aneurysm obliteration. One referral center instituted a policy of short-term use of aminocaproic acid to prevent rebleeding during patient transfer. Such use led to a decreased incidence in rebleeding without increasing the risk of DCI, but 3-month clinical outcomes were not affected.¹³⁸ There was an increased risk of deep venous thrombosis but not pulmonary embolism. Neither aminocaproic acid nor tranexamic acid is approved by the US Food and Drug Administration for prevention of aneurysm rebleeding.

Surgical and Endovascular Methods for Treatment of Ruptured Cerebral Aneurysms

Microsurgical clip obliteration of intracranial aneurysms was the primary modality of treatment before 1991, when Guglielmi first described occlusion of an aneurysm by an endovascular approach with electrolytically detachable coils.¹³⁹ With advancements in both microsurgical and endovascular approaches, algorithms to determine the proper patient population and aneurysmal characteristics for each treatment are continually undergoing refinement. The only multicenter randomized trial comparing microsurgical and endovascular repair, ISAT, randomized 2143 of 9559 screened patients with aSAH across 42 neurosurgical centers.¹⁴⁰ For a patient to be considered eligible for the trial, neurosurgeons and interventionalists had to agree that the aneurysm was comparably suitable for treatment with either modality. Primary outcomes included death or dependent living, and secondary outcomes included risk of seizures and risk of rebleeding. Initial 1-year outcomes revealed a reduction in death and disability from 31% in the microsurgery arm to 24% in the endovascular arm (relative risk reduction, 24%).¹⁴¹ T