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Diagnosis and Treatment of Unruptured Intracranial Aneurysms and Aneurysmal Subarachnoid Hemorrhage

      Abstract

      Unruptured intracranial aneurysms (UIAs) are commonly acquired vascular lesions that form an outpouching of the arterial wall due to wall thinning. The prevalence of UIAs in the general population is 3.2%. In contrast, an intracranial aneurysm may be manifested after rupture with classic presentation of a thunderclap headache suggesting aneurysmal subarachnoid hemorrhage (SAH). Previous consensus suggests that although small intracranial aneurysms (<7 mm) are less susceptible to rupture, aneurysms larger than 7 mm should be treated on a case-by-case basis with consideration of additional risk factors of aneurysmal growth and rupture. However, this distinction is outdated. The PHASES score, which comprises data pooled from several prospective studies, provides precise estimates by considering not only the aneurysm size but also other variables, such as the aneurysm location. The International Study of Unruptured Intracranial Aneurysms is the largest observational study on the natural history of UIAs, providing the foundation to the current guidelines for the management of UIAs. Although SAH accounts for only 3% of all stroke subtypes, it is associated with considerable burden of morbidity and mortality. The initial management is focused on stabilizing the patient in the intensive care unit with close hemodynamic and serial neurologic monitoring with endovascular or open surgical aneurysm treatment to prevent rebleeding. Since the results of the International Subarachnoid Aneurysm Trial, treatment of aneurysmal SAH has shifted from surgical clipping to endovascular coiling, which demonstrated higher odds of survival free of disability at 1 year after SAH. Nonetheless, aneurysmal SAH remains a public health hazard and is associated with high rates of disability and death.

      Abbreviations and Acronyms:

      aRR (adjusted risk ratio), aSAH (aneurysmal subarachnoid hemorrhage), CPP (cerebral perfusion pressure), CSF (cerebrospinal fluid), CSW (cerebral salt wasting), CT (computed tomography), CTA (computed tomography angiography), DC (decompressive craniectomy), DCI (delayed cerebral ischemia), DSA (digital subtraction angiography), EVD (external ventricular drain), FDA (Food & Drug Administration), GCS (Glasgow Coma Scale), ICA (internal carotid artery), ICP (intracranial pressure), ISAT (International Subarachnoid Aneurysm Trial), ISUIA (International Study of Unruptured Intracranial Aneurysms), MAP (mean arterial pressure), MCA (middle cerebral artery), MMP (matrix metalloproteinase), MRA (magnetic resonance angiography), mRS (modified Rankin scale), PAASH (Prognosis on Admission of Aneurysmal Subarachnoid Hemorrhage), RCT (randomized controlled trial), SAH (subarachnoid hemorrhage), SBP (systolic blood pressure), SIADH (syndrome of inappropriate antidiuretic hormone secretion), SUAVe (Small Unruptured Intracranial Aneurysm Verification study), TBI (traumatic brain injury), UCAS (Unruptured Cerebral Aneurysm Study), UIA (unruptured intracranial aneurysm), WEB (Woven EndoBridge), WFNS (World Federation of Neurosurgical Societies)

      Unruptured Intracranial Aneurysms

      Approximately 85% of intracranial saccular (berry) aneurysms are acquired lesions within the anterior circulation and are characterized by an outpouching of the arterial wall due to thinning. They commonly occur at bifurcating arteries (Figure 1), including the junction of the anterior communicating artery with the anterior cerebral artery, the junction of the posterior communicating artery with the internal carotid artery (ICA), and the bifurcation of the middle cerebral artery (MCA). Whereas aneurysms in the posterior circulation are less common, they are more likely to rupture and to lead to poor outcomes, including cognitive disability and sudden death. Unruptured intracranial aneurysms (UIAs) are often asymptomatic when measuring 7 mm or less and are detected incidentally on neuroimaging. With modern advancements in noninvasive modalities including computed tomography angiography (CTA) and magnetic resonance angiography (MRA), the incidental detection of UIAs has significantly increased. Although the feared presentation of an intracranial aneurysm is subarachnoid hemorrhage (SAH), most intracranial aneurysms do not ever rupture. The natural history of UIAs remains poorly understood, but intracranial aneurysm formation is more common among women, with increased age, and in the presence of multiple aneurysms, genetic syndromes, and a strong family history.
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      • Algra A.
      • van Gijn J.
      Prevalence and risk of rupture of intracranial aneurysms: a systematic review.
      The 2015 American Heart Association and American Stroke Association guidelines provide recommendations for the management of UIAs, including risk reduction strategies, screening recommendations, appropriate imaging modalities for intermittent imaging, selection of appropriate candidates for screening and intervention, and recommendations on the mode of intervention (endovascular or surgical clipping).
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      Guidelines for the management of patients with unruptured intracranial aneurysms: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      Figure thumbnail gr1
      Figure 1Common locations of unruptured intracranial aneurysms within the circle of Willis. (Mayo Clinic Foundation for Medical Education and Research.
      All rights reserved.)

      Pathogenesis

      Intracranial aneurysms are most often saccular type, although fusiform type is not uncommon. Normal intracranial arteries are composed of the intima (basal membrane and endothelial cells), the media (smooth muscle cells and elastin fibers), and the adventitia, including collagen, which provides structural integrity to the vessel wall.
      • Lasheras J.C.
      The biomechanics of arterial aneurysms.
      Hemodynamic stress has been shown to trigger localized inflammatory infiltration, thereby weakening the vessel wall and leading to formation of intracranial aneurysms.
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      • Hoi Y.
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      Complex hemodynamics at the apex of an arterial bifurcation induces vascular remodeling resembling cerebral aneurysm initiation.
      Degeneration of the internal elastic lamina, which separates the intima and media, is a key structural process in the development of an intracranial aneurysm.
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      The biomechanics of arterial aneurysms.
      Moreover, inflammation has been shown to play a pivotal role in the formation, progression, and rupture of intracranial aneurysms. Endothelial dysfunction induced by hemodynamic stress, followed by an inflammatory response by macrophages through a release of proinflammatory cytokines as well as matrix metalloproteinases (MMPs) that digest the extracellular matrix and lead to apoptosis of the vascular smooth muscle cells, results in loss of vessel wall integrity and aneurysmal formation.
      • Chalouhi N.
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      Biology of intracranial aneurysms: role of inflammation.
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      The role of oxidative stress in cerebral aneurysm formation and rupture.
      • Chalouhi N.
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      • Starke R.M.
      • et al.
      Cigarette smoke and inflammation: role in cerebral aneurysm formation and rupture.
      In one study, aneurysmal growth was associated with the presence of macrophages and macrophage-derived MMPs, whereas selective inhibition of MMPs was shown to hinder aneurysmal progression.
      • Aoki T.
      • Kataoka H.
      • Morimoto M.
      • Nozaki K.
      • Hashimoto N.
      Macrophage-derived matrix metalloproteinase-2 and -9 promote the progression of cerebral aneurysms in rats.
      Remarkably, ruptured aneurysms have demonstrated higher immunohistochemical staining for cyclooxygenase 2 and microsomal prostaglandin E2 synthase 1,
      • Hasan D.M.
      • Mahaney K.B.
      • Brown Jr., R.D.
      • et al.
      Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture.
      whereas in vivo studies have demonstrated a reduction in experimental cerebral aneurysms by the use of anti-inflammatory medications.
      • Frenzel T.
      • Lee C.Z.
      • Kim H.
      • et al.
      Feasibility of minocycline and doxycycline use as potential vasculostatic therapy for brain vascular malformations: pilot study of adverse events and tolerance.
      ,
      • Makino H.
      • Tada Y.
      • Wada K.
      • et al.
      Pharmacological stabilization of intracranial aneurysms in mice: a feasibility study.
      Thus, aspirin has been suggested to have a protective role in the development and progression of intracranial aneurysms by attenuating inflammation through the inhibition of cyclooxygenase 2 and microsomal prostaglandin E2 synthase 1. Macrophages may be of 2 types (proinflammatory M1 and anti-inflammatory M2), exerting opposite effects on inflammation, and may be associated with aneurysmal rupture. In UIAs, both M1 and M2 are equally present, whereas an imbalance favoring M1 cells has been implicated in ruptured intracranial aneurysms.
      • Hasan D.
      • Chalouhi N.
      • Jabbour P.
      • Hashimoto T.
      Macrophage imbalance (M1 vs. M2) and upregulation of mast cells in wall of ruptured human cerebral aneurysms: preliminary results.
      Consecutive stages of degeneration of saccular aneurysm walls have been demonstrated histologically, with a greater risk of rupture with each increasing stage (Table 1).
      • Frosen J.
      • Piippo A.
      • Paetau A.
      • et al.
      Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases.
      There also are likely to be genetic predispositions to aneurysm formation. For instance, a meta-analysis of genetic studies identified 19 single-nucleotide polymorphisms associated with sporadic UIAs, and the strongest associations were found on chromosome 9 (CDKN2B antisense inhibitor gene), chromosome 8 (SOX17 transcription regulator gene), and chromosome 4 (EDNRA gene; for expansion of gene symbols, use search tool at www.genenames.org).
      • Alg V.S.
      • Sofat R.
      • Houlden H.
      • Werring D.J.
      Genetic risk factors for intracranial aneurysms: a meta-analysis in more than 116,000 individuals.
      Table 1Histologic Examination of a Saccular Aneurysm Wall
      StageHistologic features
      1Endothelialized wall with linearly organized smooth muscle wall
      2Thickened wall with disorganized smooth muscle cells
      3Hypocellular wall with organizing luminal thrombosis or intimal hyperplasia
      4Extremely thin thrombosis-lined hypocellular wall

      Epidemiology and Risk Factors

      The prevalence of UIAs is approximately 3.2% of the general population, with a mean age of 50 years and with 20% to 30% of patients having multiple aneurysms.
      • Weir B.
      Unruptured intracranial aneurysms: a review.
      • Vernooij M.W.
      • Ikram M.A.
      • Tanghe H.L.
      • et al.
      Incidental findings on brain MRI in the general population.
      • Vlak M.H.
      • Algra A.
      • Brandenburg R.
      • Rinkel G.J.
      Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis.
      Nearly 3.6% to 6% of the population have been shown to harbor an intracranial aneurysm on prospective autopsy and angiographic studies.
      • Rinkel G.J.
      • Djibuti M.
      • Algra A.
      • van Gijn J.
      Prevalence and risk of rupture of intracranial aneurysms: a systematic review.
      Approximately 50% to 80% of all UIAs do not rupture in a patient’s lifetime.
      • Connolly E.S.
      • Solomon R.A.
      Management of unruptured aneurysms.
      The annual rate of de novo aneurysm formation ranges between 0.3% and 1.8%,
      • Juvela S.
      • Poussa K.
      • Porras M.
      Factors affecting formation and growth of intracranial aneurysms: a long-term follow-up study.
      • Sprengers M.E.
      • van Rooij W.J.
      • Sluzewski M.
      • et al.
      MR angiography follow-up 5 years after coiling: frequency of new aneurysms and enlargement of untreated aneurysms.
      • Wermer M.J.
      • van der Schaaf I.C.
      • Velthuis B.K.
      • Algra A.
      • Buskens E.
      • Rinkel G.J.
      ASTRA Study Group
      Follow-up screening after subarachnoid haemorrhage: frequency and determinants of new aneurysms and enlargement of existing aneurysms.
      whereas the annual incidence of aneurysmal growth ranges between 1.51% and 22.7%.
      • Ferns S.P.
      • Sprengers M.E.
      • van Rooij W.J.
      • et al.
      De novo aneurysm formation and growth of untreated aneurysms: a 5-year MRA follow-up in a large cohort of patients with coiled aneurysms and review of the literature.
      A female predominance, which increases to a 2:1 ratio after 50 years of age, is likely to be related to reduction in collagen after menopause in the absence of estrogen.
      • Vlak M.H.
      • Algra A.
      • Brandenburg R.
      • Rinkel G.J.
      Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis.
      Although UIAs are often sporadically acquired lesions, familial forms have been linked with conditions such as arteriovenous malformations, coarctation of the aorta, fibromuscular dysplasia, Marfan syndrome, Ehlers-Danlos syndrome type IV, autosomal dominant polycystic kidney disease, familial aldosteronism type 1, sickle cell disease, and moyamoya.
      • Vlak M.H.
      • Algra A.
      • Brandenburg R.
      • Rinkel G.J.
      Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis.
      ,
      • Schievink W.I.
      Intracranial aneurysms [erratum appears in N Engl J Med. 1997;336(17):1267].
      Family history is an important risk factor for development of UIAs, such that the risk is 3.6 times greater.
      • Vlak M.H.
      • Algra A.
      • Brandenburg R.
      • Rinkel G.J.
      Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis.
      Patients with 1 affected family member have a 4% risk for development of an aneurysm, whereas those with 2 or more affected first-degree family members have a risk of 8% to 10%.
      • Nieuwkamp D.J.
      • Setz L.E.
      • Algra A.
      • Linn F.H.
      • de Rooij N.K.
      • Rinkel G.J.
      Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis.
      Location of aneurysms may also be similar within families,
      • Mackey J.
      • Brown Jr., R.D.
      • Moomaw C.J.
      • et al.
      Familial intracranial aneurysms: is anatomic vulnerability heritable?.
      and aneurysmal rupture tends to occur in the same decade of life among siblings.
      • St Jean P.
      • Hart B.
      • Webster M.
      • et al.
      Alpha-1-antitrypsin deficiency in aneurysmal disease.
      Compared with sporadic aneurysms, familial UIAs often rupture at a younger age and at smaller sizes.
      • St Jean P.
      • Hart B.
      • Webster M.
      • et al.
      Alpha-1-antitrypsin deficiency in aneurysmal disease.
      • Ronkainen A.
      • Hernesniemi J.
      • Puranen M.
      • et al.
      Familial intracranial aneurysms.
      • Broderick J.P.
      • Brown Jr., R.D.
      • Sauerbeck L.
      • et al.
      Greater rupture risk for familial as compared to sporadic unruptured intracranial aneurysms.
      Hypertension, tobacco smoking, and alcohol consumption increase the risk for development of UIAs.
      • Brown Jr., R.D.
      • Huston J.
      • Hornung R.
      • et al.
      Screening for brain aneurysm in the Familial Intracranial Aneurysm study: frequency and predictors of lesion detection.
      Hypertension is more prevalent in patients with UIAs and is also a significant risk factor for future SAH. Currently, there have been no prospective studies demonstrating that blood pressure control prevents aneurysm development. However, a study in Finland found indirect evidence that antihypertensive agents were more frequently used in the UIA group, whereas untreated hypertension was more frequent in patients with ruptured aneurysms.
      • Lindgren A.E.
      • Kurki M.I.
      • Riihinen A.
      • et al.
      Hypertension predisposes to the formation of saccular intracranial aneurysms in 467 unruptured and 1053 ruptured patients in Eastern Finland.
      Similarly, another study provided indirect evidence that blood pressure control decreases the risk of aneurysmal rupture.
      • Etminan N.
      • Chang H.S.
      • Hackenberg K.
      • et al.
      Worldwide incidence of aneurysmal subarachnoid hemorrhage according to region, time period, blood pressure, and smoking prevalence in the population: a systematic review and meta-analysis.
      Thus, whereas blood pressure control may not affect the development of intracranial aneurysms, it may effectively reduce the risk of rupture. The risk for development of a UIA has been shown to increase with the number of cigarettes smoked daily. Tobacco smoking may predispose to intracranial aneurysm formation by decreasing α1-antitrypsin,
      • Schievink W.I.
      Intracranial aneurysms [erratum appears in N Engl J Med. 1997;336(17):1267].
      and similarly, individuals with α1-antitrypsin deficiency are at a greater risk.
      • St Jean P.
      • Hart B.
      • Webster M.
      • et al.
      Alpha-1-antitrypsin deficiency in aneurysmal disease.
      Smoking and hypertension combined yield a higher risk for UIA than expected by their independent risks, which suggests synergism between these risk factors.
      • Vlak M.H.
      • Rinkel G.J.
      • Greebe P.
      • Algra A.
      Independent risk factors for intracranial aneurysms and their joint effect: a case-control study.
      Statin therapy for hypercholesterolemia may also reduce the risk of aneurysm formation as demonstrated in an animal study
      • Aoki T.
      • Kataoka H.
      • Ishibashi R.
      • et al.
      Pitavastatin suppresses formation and progression of cerebral aneurysms through inhibition of the nuclear factor κB pathway.
      ; however, a study in humans found no beneficial effect on UIA formation.
      • Marbacher S.
      • Schlappi J.A.
      • Fung C.
      • Husler J.
      • Beck J.
      • Raabe A.
      Do statins reduce the risk of aneurysm development? A case-control study.
      Although some studies have shown that physical exercise may decrease the risk of UIA,
      • Vlak M.H.
      • Rinkel G.J.
      • Greebe P.
      • Algra A.
      Independent risk factors for intracranial aneurysms and their joint effect: a case-control study.
      ,
      • Vlak M.H.
      • Rinkel G.J.
      • Greebe P.
      • Greving J.P.
      • Algra A.
      Lifetime risks for aneurysmal subarachnoid haemorrhage: multivariable risk stratification.
      other studies have shown that during the acute phase, physical exercise can trigger the rupture of an existing intracranial aneurysm.
      • Vlak M.H.
      • Rinkel G.J.
      • Greebe P.
      • van der Bom J.G.
      • Algra A.
      Trigger factors and their attributable risk for rupture of intracranial aneurysms: a case-crossover study.
      ,
      • Anderson C.
      • Ni Mhurchu C.
      • Scott D.
      • Bennett D.
      • Jamrozik K.
      • Hankey G.
      Australasian Cooperative Research on Subarachnoid Hemorrhage Study Group
      Triggers of subarachnoid hemorrhage: role of physical exertion, smoking, and alcohol in the Australasian Cooperative Research on Subarachnoid Hemorrhage Study (ACROSS).
      However, the consensus is to recommend continuation of regular physical exercise as this risk for rupture remains small.

      Clinical Presentation

      The UIA is often asymptomatic and discovered incidentally on neuroimaging performed for other indications. Symptomatic UIAs may be manifested with vague or nonspecific symptoms, including headache, dizziness, and visual changes. Large UIAs may compress adjacent brain structures, such that ICA aneurysms may cause visual field defects or hemiparesis, whereas aneurysms of the basilar artery or posterior communicating artery may cause oculomotor nerve palsy.
      • Broderick J.P.
      • Brown Jr., R.D.
      • Sauerbeck L.
      • et al.
      Greater rupture risk for familial as compared to sporadic unruptured intracranial aneurysms.
      Clinical features characterizing oculomotor nerve palsy may be ptosis of the upper eyelid due to lack of action of the levator palpebrae superioris, pupillary dilation due to loss of sphincter pupillae function, and lateral deviation of the affected eye. Furthermore, patients may complain of facial pain in the presence of cavernous carotid aneurysms
      • Gagliardi D.
      • Faravelli I.
      • Villa L.
      • et al.
      Bilateral cavernous carotid aneurysms: atypical presentation of a rare cause of mass effect. A case report and a review of the literature.
      or even ischemic symptoms when an embolus originates from within the aneurysmal sac and is dislodged distally. A retrospective study of 111 patients outlined the clinical features of symptomatic UIAs and reported that 51% were asymptomatic, 17% presented with acute symptoms (37% with ischemia, 37% with headache, 15.7% with seizures, and 10.5% with cranial neuropathies), and 32% presented with chronic symptoms due to mass effect (51% with headache, 29% with visual deficits, 11% with weakness, and 9% with facial pain).
      • Raps E.C.
      • Rogers J.D.
      • Galetta S.L.
      • et al.
      The clinical spectrum of unruptured intracranial aneurysms.
      Of note, these data may not be representative of intracranial aneurysms in general as this study comes from a tertiary care university hospital, with many patients being referred by physicians in community centers often because they had symptomatic aneurysms.

      Diagnosis

      The UIA may be diagnosed on MRA, CTA, and catheter angiography, with each modality harboring its advantages and disadvantages at various stages of evaluation and management. After the initial diagnosis of a UIA, the anatomic details of the aneurysm are noted to appropriately categorize the aneurysm for a suitable management.
      The initial diagnostic modality for aneurysm detection is often CTA as intravenous administration of contrast material helps visualize cerebral vessels in a 3-dimensional view, and CTA can be completed in minutes. The sensitivity of CTA ranges from 77% to 97%, and specificity ranges from 87% to 100%
      • Chappell E.T.
      • Moure F.C.
      • Good M.C.
      Comparison of computed tomographic angiography with digital subtraction angiography in the diagnosis of cerebral aneurysms: a meta-analysis.
      ; for aneurysms smaller than 3 mm, the sensitivity decreases to 40% to 91%.
      • White P.M.
      • Wardlaw J.M.
      • Easton V.
      Can noninvasive imaging accurately depict intracranial aneurysms? A systematic review.
      Multidetector CTA has higher sensitivity and specificity (>97% for both) and better detection of aneurysms 4 mm and larger compared with single-detector CTA.
      • Menke J.
      • Larsen J.
      • Kallenberg K.
      Diagnosing cerebral aneurysms by computed tomographic angiography: meta-analysis.
      The CTA examination uses iodinated contrast agents with risk of anaphylaxis and is contraindicated in patients with impaired renal function. In patients with coiled aneurysms, CTA has significant coil artifacts and generally fails to show the anatomy of an aneurysm in the same section of the coil artifacts. Although clipped aneurysms can still be visualized, the aneurysm neck and adjacent vessels can be masked with multiple clips.
      • Hirai T.
      • Korogi Y.
      • Ono K.
      • et al.
      Preoperative evaluation of intracranial aneurysms: usefulness of intraarterial 3D CT angiography and conventional angiography with a combined unit—initial experience.
      The MRA study can be completed with contrast enhancement or with time of flight, a technique to visualize blood flow within the vasculature without the use of contrast material. The sensitivity of MRA is 74% to 98%, and specificity is 100% for aneurysms 3 mm and larger.
      • Sailer A.M.
      • Wagemans B.A.
      • Nelemans P.J.
      • de Graaf R.
      • van Zwam W.H.
      Diagnosing intracranial aneurysms with MR angiography: systematic review and meta-analysis.
      ,
      • White P.M.
      • Teasdale E.M.
      • Wardlaw J.M.
      • Easton V.
      Intracranial aneurysms: CT angiography and MR angiography for detection prospective blinded comparison in a large patient cohort.
      However, similar to CTA, the sensitivity of MRA for aneurysms smaller than 3 mm decreases to 40%.
      • White P.M.
      • Teasdale E.M.
      • Wardlaw J.M.
      • Easton V.
      Intracranial aneurysms: CT angiography and MR angiography for detection prospective blinded comparison in a large patient cohort.
      In a meta-analysis of contrast-enhanced MRA, the sensitivity and specificity to identify residual aneurysm in post-coiled patients were 92% and 96%, respectively.
      • Weng H.H.
      • Jao S.Y.
      • Yang C.Y.
      • Tsai Y.H.
      Meta-analysis on diagnostic accuracy of MR angiography in the follow-up of residual intracranial aneurysms treated with Guglielmi detachable coils.
      Our preferred imaging modality for follow-up of coiled aneurysms is MRA with contrast enhancement. It is commonly used in patients allergic to iodinated contrast agents or when radiation exposure is avoided, but it is more difficult to obtain in critically ill or anxious patients because of long imaging times. Gadolinium-induced nephrogenic systemic fibrosis in patients with end-stage renal disease is not a concern anymore with new contrast agents.
      Catheter angiography is the “gold standard” modality for intracranial aneurysms. It provides a detailed evaluation of the aneurysm and adjacent vessels and has high sensitivity in detecting aneurysms smaller than 3 mm
      • Yoon D.Y.
      • Lim K.J.
      • Choi C.S.
      • Cho B.M.
      • Oh S.M.
      • Chang S.K.
      Detection and characterization of intracranial aneurysms with 16-channel multidetector row CT angiography: a prospective comparison of volume-rendered images and digital subtraction angiography.
      • Teksam M.
      • McKinney A.
      • Casey S.
      • Asis M.
      • Kieffer S.
      • Truwit C.L.
      Multi-section CT angiography for detection of cerebral aneurysms.
      • Dammert S.
      • Krings T.
      • Moller-Hartmann W.
      • et al.
      Detection of intracranial aneurysms with multislice CT: comparison with conventional angiography.
      • McKinney A.M.
      • Palmer C.S.
      • Truwit C.L.
      • Karagulle A.
      • Teksam M.
      Detection of aneurysms by 64-section multidetector CT angiography in patients acutely suspected of having an intracranial aneurysm and comparison with digital subtraction and 3D rotational angiography.
      and in visualization of small perforator vessels.
      • Kucukay F.
      • Okten R.S.
      • Tekiner A.
      • et al.
      Three-dimensional volume rendering digital subtraction angiography in comparison with two-dimensional digital subtraction angiography and rotational angiography for detecting aneurysms and their morphological properties in patients with subarachnoid hemorrhage.
      • van Rooij W.J.
      • Sprengers M.E.
      • de Gast A.N.
      • Peluso J.P.
      • Sluzewski M.
      3D rotational angiography: the new gold standard in the detection of additional intracranial aneurysms.
      • Wong S.C.
      • Nawawi O.
      • Ramli N.
      • Abd Kadir K.A.
      Benefits of 3D rotational DSA compared with 2D DSA in the evaluation of intracranial aneurysm.
      Three-dimensional angiography provides even more details about the aneurysm compared with 2-dimensional planar imaging. Catheter angiography is often used when there is a high clinical suspicion of an aneurysm with normal findings on noninvasive imaging.
      • Friedman J.A.
      • Piepgras D.G.
      • Pichelmann M.A.
      • Hansen K.K.
      • Brown Jr., R.D.
      • Wiebers D.O.
      Small cerebral aneurysms presenting with symptoms other than rupture.
      Compared with CTA and MRA, it is more expensive and carries procedural risks, including neurologic complications (1.0%-2.5%), injury to the femoral artery (0.05%-0.55%), groin hematoma (6.9%-10.7%), and contrast-induced nephropathy (1%-2%).
      • Rinkel G.J.
      Intracranial aneurysm screening: indications and advice for practice.

      Risk Factors of Aneurysm Growth

      The risk factors for aneurysmal growth can be divided into patient-specific factors, including female sex, hypertension, and smoking, and aneurysm-specific factors, including posterior circulation location, irregular shape, and large size.
      • Backes D.
      • Rinkel G.J.
      • Laban K.G.
      • Algra A.
      • Vergouwen M.D.
      Patient- and aneurysm-specific risk factors for intracranial aneurysm growth: a systematic review and meta-analysis.
      Aneurysmal growth tends to occur more with larger aneurysms
      • Burns J.D.
      • Huston 3rd, J.
      • Layton K.F.
      • Piepgras D.G.
      • Brown Jr., R.D.
      Intracranial aneurysm enlargement on serial magnetic resonance angiography: frequency and risk factors.
      ; UIAs are more likely to grow at an inconstant, nonlinear rate, and periods of growth appear to be shorter and less frequent than periods of no growth.
      • Etminan N.
      • Buchholz B.A.
      • Dreier R.
      • et al.
      Cerebral aneurysms: formation, progression, and developmental chronology.
      ,
      • Koffijberg H.
      • Buskens E.
      • Algra A.
      • Wermer M.J.
      • Rinkel G.J.
      Growth rates of intracranial aneurysms: exploring constancy.
      Aneurysms between 5 and 10 mm are at an increased risk of growth,
      • Ferns S.P.
      • Sprengers M.E.
      • van Rooij W.J.
      • et al.
      De novo aneurysm formation and growth of untreated aneurysms: a 5-year MRA follow-up in a large cohort of patients with coiled aneurysms and review of the literature.
      and the observed growth of aneurysms less than 8 mm compared with more than 12 mm is increased by 12 times.
      • Burns J.D.
      • Huston 3rd, J.
      • Layton K.F.
      • Piepgras D.G.
      • Brown Jr., R.D.
      Intracranial aneurysm enlargement on serial magnetic resonance angiography: frequency and risk factors.
      ICA and basilar artery aneurysms are more likely to grow than those located in other areas.
      • Matsubara S.
      • Hadeishi H.
      • Suzuki A.
      • Yasui N.
      • Nishimura H.
      Incidence and risk factors for the growth of unruptured cerebral aneurysms: observation using serial computerized tomography angiography.
      The presence of multiple aneurysms is also associated with aneurysmal growth.
      • Chien A.
      • Liang F.
      • Sayre J.
      • Salamon N.
      • Villablanca P.
      • Vinuela F.
      Enlargement of small, asymptomatic, unruptured intracranial aneurysms in patients with no history of subarachnoid hemorrhage: the different factors related to the growth of single and multiple aneurysms.
      Similarly, when intracranial aneurysms coexist with intracranial arteriovenous malformations, these UIAs are more likely to grow and to rupture.
      • Wiebers D.O.
      • Torres V.E.
      Screening for unruptured intracranial aneurysms in autosomal dominant polycystic kidney disease.

      Risk of Rupture and Natural History

      The natural history of UIAs has been widely discussed but is still not fully defined. The International Study of Unruptured Intracranial Aneurysms (ISUIA),
      • Wiebers D.O.
      • Whisnant J.P.
      • Huston 3rd, J.
      • et al.
      Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment.
      the Unruptured Cerebral Aneurysm Study (UCAS),
      • Morita A.
      • Kirino T.
      • Hashi K.
      • et al.
      UCAS Japan Investigators
      The natural course of unruptured cerebral aneurysms in a Japanese cohort.
      and the Small Unruptured Intracranial Aneurysm Verification (SUAVe) study
      • Sonobe M.
      • Yamazaki T.
      • Yonekura M.
      • Kikuchi H.
      Small unruptured intracranial aneurysm verification study: SUAVe study.
      offered management decisions in UIAs by noting that aneurysm size and location are associated with increased risk of rupture (Table 2). These studies were not true natural history studies because many of the patients were treated during the follow-up period. Nonetheless, they are the best data we currently have.
      Table 2Landmark Studies on the Natural History of UIAs
      ISUIA
      • Wiebers D.O.
      • Whisnant J.P.
      • Huston 3rd, J.
      • et al.
      Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment.
      UCAS
      • Morita A.
      • Kirino T.
      • Hashi K.
      • et al.
      UCAS Japan Investigators
      The natural course of unruptured cerebral aneurysms in a Japanese cohort.
      SUAVe study
      • Sonobe M.
      • Yamazaki T.
      • Yonekura M.
      • Kikuchi H.
      Small unruptured intracranial aneurysm verification study: SUAVe study.
      Type of studyProspective, epidemiologic cohortProspective, cohortProspective, cohort
      No. of patients16925720446
      Annual risk of rupture (%)0.7 (overall)0.95 (≥3 mm UIA)
      • 0.54 for <5 mm UIA
      • 0.34 for single UIA
      • 0.95 for multiple UIAs
      Risk of rupture by location
      • Group 1: CCA (lowest risk)
      • Group 2: ACommA, ACA, MCA, and ICA (intermediate risk)
      • Group 3: vertebrobasilar, posterior cerebral arterial system, and PCommA (highest risk)
      • Compared with UIA in MCA
        • HR 1.9 for PCommA
        • HR 2.0 for ACommA
      Not a significant predictive factor for rupture of small aneurysms
      Risk of rupture by size
      • UIA 7-12 mm
        • Group 1: 0%
        • Group 2: 2.6%
        • Group 3: 14.5%
      • UIA 13-24 mm
        • Group 1: 3%
        • Group 2: 14.5%
        • Group 3: 18.4%
      • UIA >25 mm
        • Group 1: 6.4%
        • Group 2: 40%
        • Group 3: 50%
      • HR 3.3 for UIA 7-9 mm
      • HR 9.1 for UIA 10-24 mm
      • HR 76.3 for UIA ≥25 mm
      • HR 1.00 for UIA <4 mm
      • HR 5.51 for UIA ≥4 mm
      ACA, anterior cerebral artery; ACommA, anterior communicating artery; CCA, cavernous carotid artery; HR, hazard ratio; ICA, internal carotid artery; ISUIA, International Study of Unruptured Intracranial Aneurysms; MCA, middle cerebral artery; PCommA, posterior communicating artery; SUAVe, Small Unruptured Intracranial Aneurysm Verification; UCAS, Unruptured Cerebral Aneurysm Study; UIA, unruptured intracranial aneurysm.
      The risk of rupture for growing aneurysms (recent growth) is 3.1% compared with 0.1% for stable aneurysms.
      • Brinjikji W.
      • Zhu Y.Q.
      • Lanzino G.
      • et al.
      Risk factors for growth of intracranial aneurysms: a systematic review and meta-analysis.
      For example, an aneurysm of 8 mm in size may have had multiple episodes of growth in the past, which can be followed by a long period of stability. Furthermore, the risk of rupture for UIAs 3 mm and smaller is considerably low but not nil
      • Malhotra A.
      • Wu X.
      • Forman H.P.
      • et al.
      Growth and rupture risk of small unruptured intracranial aneurysms: a systematic review.
      ; the risk is found to increase with UIAs larger than 7 mm, located on the anterior or posterior communicating artery, in patients younger than 50 years, in patients with hypertension, with multiple aneurysms, and with presence of a daughter sac.
      • Wiebers D.O.
      • Whisnant J.P.
      • Huston 3rd, J.
      • et al.
      Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment.
      ,
      • Morita A.
      • Kirino T.
      • Hashi K.
      • et al.
      UCAS Japan Investigators
      The natural course of unruptured cerebral aneurysms in a Japanese cohort.
      A Japanese prospective study reported the natural history of patients with aneurysms 3 mm and larger with an annual rupture rate of 0.95%.
      • Morita A.
      • Kirino T.
      • Hashi K.
      • et al.
      UCAS Japan Investigators
      The natural course of unruptured cerebral aneurysms in a Japanese cohort.
      A large meta-analysis showed that age older than 60 years, female sex, Finnish or Japanese descent, size larger than 5 mm, posterior circulation location, and symptomatic aneurysms are other factors associated with a higher risk of rupture.
      • Wermer M.J.
      • van der Schaaf I.C.
      • Algra A.
      • Rinkel G.J.
      Risk of rupture of unruptured intracranial aneurysms in relation to patient and aneurysm characteristics: an updated meta-analysis.
      An aneurysm to vessel size ratio of 3.1 has demonstrated greater risk of rupture for aneurysms smaller than 5 mm.
      • Kashiwazaki D.
      • Kuroda S.
      Sapporo SAH Study Group
      Size ratio can highly predict rupture risk in intracranial small (<5 mm) aneurysms.
      The role of racial differences in the natural history of UIA is unclear. The ISUIA was largely performed in white individuals in North America and Europe. There are also limited data on the natural history of familial intracranial aneurysms, with some studies showing a propensity for rupture at smaller sizes and at a younger age than with sporadic aneurysms.
      • Ronkainen A.
      • Hernesniemi J.
      • Puranen M.
      • et al.
      Familial intracranial aneurysms.
      ,
      • Broderick J.P.
      • Brown Jr., R.D.
      • Sauerbeck L.
      • et al.
      Greater rupture risk for familial as compared to sporadic unruptured intracranial aneurysms.
      Individuals with a history of aneurysmal SAH (aSAH) are also at a higher risk for another aneurysmal rupture. In the ISUIA, UIAs smaller than 7 mm ruptured at 0.5% and 0.1% per year with and without a history of aSAH rupture, respectively.
      • Wiebers D.O.
      • Whisnant J.P.
      • Huston 3rd, J.
      • et al.
      Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment.
      The PHASES score (population, hypertension, age, size of aneurysm, earlier SAH from another aneurysm, site of aneurysm) was used to predict a patient’s 5-year risk of rupture based on aneurysmal and patient factors (Table 3).
      • Greving J.P.
      • Wermer M.J.
      • Brown Jr., R.D.
      • et al.
      Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies.
      The PHASES score was developed from a systematic review and pooled analysis of 6 prospective cohort studies comprising individual data of 8382 patients with SAH as the outcome.
      • Greving J.P.
      • Wermer M.J.
      • Brown Jr., R.D.
      • et al.
      Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies.
      Aneurysmal rupture occurred in 230 patients during 29,166 person-years of follow-up. The mean observed 1-year risk of aneurysmal rupture was 1.4% (95% CI, 1.1 to 1.6); the 5-year risk was 3.4% (95% CI, 2.9 to 4.0).
      • Greving J.P.
      • Wermer M.J.
      • Brown Jr., R.D.
      • et al.
      Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies.
      A score of 3 or less was associated with a low but not absent risk of aneurysmal rupture.
      • Bijlenga P.
      • Gondar R.
      • Schilling S.
      • et al.
      PHASES score for the management of intracranial aneurysm: a cross-sectional population-based retrospective study.
      Table 3PHASES Aneurysmal Risk Score
      • Greving J.P.
      • Wermer M.J.
      • Brown Jr., R.D.
      • et al.
      Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies.
      ACA, anterior cerebral artery; ICA, internal carotid artery; MCA, middle cerebral artery; PCommA, posterior communicating artery; SAH, subarachnoid hemorrhage.
      CriteriaPoints
      PopulationNorth American, European (other than Finnish)0
      Japanese3
      Finnish5
      HypertensionNo0
      Yes1
      Age<70 years0
      ≥70 years1
      Size of aneurysm<7.0 mm0
      7.0-9.9 mm3
      10.0-19.9 mm6
      ≥20.0 mm10
      Earlier SAH from another aneurysmNo0
      Yes1
      Site of aneurysmICA0
      MCA2
      ACA, PCommA, posterior circulation
      ACA includes anterior cerebral arteries, anterior communicating artery, and pericallosal artery; posterior circulation is composed of the vertebral artery, basilar artery, cerebellar arteries, and posterior cerebral artery.
      4
      a ACA, anterior cerebral artery; ICA, internal carotid artery; MCA, middle cerebral artery; PCommA, posterior communicating artery; SAH, subarachnoid hemorrhage.
      b ACA includes anterior cerebral arteries, anterior communicating artery, and pericallosal artery; posterior circulation is composed of the vertebral artery, basilar artery, cerebellar arteries, and posterior cerebral artery.
      The role of antiplatelets and anticoagulants in UIAs has been debated. Retrospective studies have reported that patients taking aspirin long term have a reduced risk of rupture, whereas dipyridamole and new aspirin use may be associated with SAH.
      • Schmidt M.
      • Johansen M.B.
      • Lash T.L.
      • Christiansen C.F.
      • Christensen S.
      • Sørensen H.T.
      Antiplatelet drugs and risk of subarachnoid hemorrhage: a population-based case-control study.
      ,
      • Toussaint 3rd, L.G.
      • Friedman J.A.
      • Wijdicks E.F.
      • et al.
      Influence of aspirin on outcome following aneurysmal subarachnoid hemorrhage.
      In a subanalysis of the untreated ISUIA cohort, aspirin administered 3 times or more per week was protective against aneurysmal rupture
      • Hasan D.M.
      • Mahaney K.B.
      • Brown Jr., R.D.
      • et al.
      Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture.
      ; in another study, the rate of hemorrhage was found to be lower in patients taking aspirin (28%) compared with those not taking aspirin (40%).
      • Brown Jr., R.D.
      • Broderick J.P.
      Unruptured intracranial aneurysms: epidemiology, natural history, management options, and familial screening.
      Aspirin was also not found to worsen the outcomes after SAH.
      • Toussaint 3rd, L.G.
      • Friedman J.A.
      • Wijdicks E.F.
      • et al.
      Influence of aspirin on outcome following aneurysmal subarachnoid hemorrhage.
      On the contrary, anticoagulants have been associated with poor outcome after SAH
      • Rinkel G.J.
      • Prins N.E.
      • Algra A.
      Outcome of aneurysmal subarachnoid hemorrhage in patients on anticoagulant treatment.
      but do not increase the risk of aneurysmal rupture.
      • Wiebers D.O.
      • Whisnant J.P.
      • Huston 3rd, J.
      • et al.
      Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment.
      ,
      • Tarlov N.
      • Norbash A.M.
      • Nguyen T.N.
      The safety of anticoagulation in patients with intracranial aneurysms.
      The PROTECT-U trial of patients with UIA not qualifying for preventive endovascular or neurosurgical intervention is the first randomized controlled trial (RCT) to evaluate whether treatment with aspirin 100 mg/d plus intensive blood pressure treatment with a target systolic blood pressure (SBP) of less than 120 mm Hg, measured with a home blood pressure device, reduces the risk of aneurysmal rupture or growth compared with standard care therapy (no aspirin and target office SBP <140 mm Hg).
      • Vergouwen M.D.
      • Rinkel G.J.
      • Algra A.
      • et al.
      Prospective Randomized Open-label Trial to evaluate risk faCTor management in patients with Unruptured intracranial aneurysms: study protocol.
      The primary outcome of the study is aneurysmal rupture or growth of 1 mm or more in diameter on repeated MRA or CTA within 36±6 months from randomization.
      • Vergouwen M.D.
      • Rinkel G.J.
      • Algra A.
      • et al.
      Prospective Randomized Open-label Trial to evaluate risk faCTor management in patients with Unruptured intracranial aneurysms: study protocol.

      Management

      The optimal management of UIAs is controversial as the natural history remains poorly understood and given the lack of RCTs comparing conservative management with modern treatment with endovascular and microsurgical techniques. Therefore, all patients with UIAs should be counseled on the importance of blood pressure control and smoking cessation. Management of UIAs should be individualized and involves comparing the risk of rupture with the risk of treatment and selection of the optimal treatment modality for each patient. In addition to the PHASES score, the UIA treatment score can be used for clinical decision-making in patients with UIAs.
      • Etminan N.
      • Brown Jr., R.D.
      • Beseoglu K.
      • et al.
      The unruptured intracranial aneurysm treatment score: a multidisciplinary consensus.
      The UIA treatment score was developed and validated on the basis of the opinion of a large group of international and multidisciplinary experts in the field (neurosurgery, neuroradiology, neurology, and clinical epidemiology) and gives an idea of how these experts might manage a patient with a UIA. On the contrary, the PHASES score is a pooled analysis of prospective cohort studies.

      Screening

      Screening for UIAs is often reserved for high-risk patients, including those with 2 first-degree family members with a history of intracranial aneurysm, autosomal dominant polycystic kidney disease, coarctation of the aorta, and history of aSAH.
      • Williams L.N.
      • Brown Jr., R.D.
      Management of unruptured intracranial aneurysms [erratum appears in Neurol Clin Pract. 2014;4(2):98].
      Screening in patients with 1 affected family member is performed on a case-by-case basis.
      • Bederson J.B.
      • Awad I.A.
      • Wiebers D.O.
      • et al.
      Recommendations for the management of patients with unruptured intracranial aneurysms: a statement for healthcare professionals from the Stroke Council of the American Heart Association.
      • Xu H.W.
      • Yu S.Q.
      • Mei C.L.
      • Li M.H.
      Screening for intracranial aneurysm in 355 patients with autosomal-dominant polycystic kidney disease.
      • Connolly H.M.
      • Huston 3rd, J.
      • Brown Jr., R.D.
      • Warnes C.A.
      • Ammash N.M.
      • Tajik A.J.
      Intracranial aneurysms in patients with coarctation of the aorta: a prospective magnetic resonance angiographic study of 100 patients.
      Magnetic Resonance Angiography in Relatives of Patients with Subarachnoid Hemorrhage Study Group
      Risks and benefits of screening for intracranial aneurysms in first-degree relatives of patients with sporadic subarachnoid hemorrhage.
      Patients with a history of new onset of headaches also deserve special attention with imaging. Once a patient is diagnosed with UIA and the decision has been made to pursue observation, follow-up imaging at 6 to 12 months is recommended. If the aneurysm remains stable, imaging is repeated annually for 2 or 3 years and then every 2 to 5 years as long as the aneurysm remains stable.
      • Thompson B.G.
      • Brown Jr., R.D.
      • Amin-Hanjani S.
      • et al.
      Guidelines for the management of patients with unruptured intracranial aneurysms: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      Serial imaging is crucial as there is evidence that newly formed small aneurysms may be at a greater risk for growth and rupture.
      • Williams L.N.
      • Brown Jr., R.D.
      Management of unruptured intracranial aneurysms [erratum appears in Neurol Clin Pract. 2014;4(2):98].
      ,
      • Wiebers D.O.
      • Piepgras D.G.
      • Meyer F.B.
      • et al.
      Pathogenesis, natural history, and treatment of unruptured intracranial aneurysms.
      If follow-up imaging demonstrates aneurysmal enlargement, treatment should be considered, and long-term follow-up with imaging is warranted because of an increased risk of aneurysm recurrence and de novo aneurysmal formation.
      • Thompson B.G.
      • Brown Jr., R.D.
      • Amin-Hanjani S.
      • et al.
      Guidelines for the management of patients with unruptured intracranial aneurysms: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      Repeated imaging can also be performed with changes in headaches. The role of routine imaging for UIAs of 3 mm or less is not as robustly defined, but repeated imaging every 5 years may be reasonable.
      • Malhotra A.
      • Wu X.
      • Forman H.P.
      • Matouk C.C.
      • Gandhi D.
      • Sanelli P.
      Management of Tiny unruptured intracranial aneurysms: a comparative effectiveness analysis.

      Patient Selection for Intervention

      Data on the natural history of UIAs report that most patients remain asymptomatic for extended periods. Deciding whether to pursue conservative management vs treatment is multifactorial. Although treatment is associated with a high rate of success, there are inherent risks of complications and death despite ongoing advances in the field, whereas managing asymptomatic UIAs conservatively carries the risk of rupture. Of note, many patients who undergo preventive aneurysm treatment do not return to work and experience significantly reduced life satisfaction.
      • Backes D.
      • Rinkel G.J.
      • van der Schaaf I.C.
      • et al.
      Recovery to preinterventional functioning, return-to-work, and life satisfaction after treatment of unruptured aneurysms.
      Therefore, it is important to individualize care on the basis of the patient’s overall medical condition, specifics of each aneurysm, and risk of treatment. Age is an important factor in deciding whether to treat a UIA as there is increased morbidity and mortality of both endovascular treatment and clipping in older patients.
      • Wiebers D.O.
      • Piepgras D.G.
      • Meyer F.B.
      • et al.
      Pathogenesis, natural history, and treatment of unruptured intracranial aneurysms.
      Aneurysm location is also an important factor, and cavernous ICA aneurysms are usually followed conservatively because they are extradural and do not result in SAH; however, large symptomatic intracavernous aneurysms can cause cranial neuropathy and may require treatment.
      • Williams L.N.
      • Brown Jr., R.D.
      Management of unruptured intracranial aneurysms [erratum appears in Neurol Clin Pract. 2014;4(2):98].
      Intradural aneurysms can cause SAH and are best differentiated from extradural lesions on coronal imaging as they are located distal to the optic strut. Symptomatic intradural aneurysms of all sizes warrant treatment unless patients have high procedural risk or limited life expectancy,
      • Williams L.N.
      • Brown Jr., R.D.
      Management of unruptured intracranial aneurysms [erratum appears in Neurol Clin Pract. 2014;4(2):98].
      and most symptomatic cases can be treated endovascularly. Larger aneurysms with irregularities or presence of daughter sacs confer a higher risk of rupture and deserve consideration for treatment. Previous consensus suggests that although it is common to monitor UIAs smaller than 7 mm,
      • Yamaki V.N.
      • Brinjikji W.
      • Murad M.H.
      • Lanzino G.
      Endovascular treatment of very small intracranial aneurysms: meta-analysis.
      aneurysms between 7 and 12 mm are often treated,
      • Williams L.N.
      • Brown Jr., R.D.
      Management of unruptured intracranial aneurysms [erratum appears in Neurol Clin Pract. 2014;4(2):98].
      and aneurysms in patients with a prior aSAH are treated even when small. However, this distinction is outdated. The PHASES score provides more precise estimates by considering not only the aneurysm size but also other variables, such as the aneurysm location. For instance, a 6-mm basilar tip aneurysm has a higher risk of rupture than an 8-mm ophthalmic aneurysm.
      In a meta-analysis of 114 studies,
      • Algra A.M.
      • Lindgren A.
      • Vergouwen M.D.I.
      • et al.
      Procedural clinical complications, case-fatality risks, and risk factors in endovascular and neurosurgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis.
      current procedural clinical 30-day complications and the case-fatality rate from endovascular and neurosurgical treatment of UIA and risk factors of clinical complications were assessed. For endovascular therapy (74 studies), the pooled complication risk was 4.96% (95% CI, 4.00% to 6.12%), and the case-fatality rate was 0.30% (95% CI, 0.20% to 0.40%).
      • Algra A.M.
      • Lindgren A.
      • Vergouwen M.D.I.
      • et al.
      Procedural clinical complications, case-fatality risks, and risk factors in endovascular and neurosurgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis.
      The factors associated with complications from endovascular therapy were female sex, diabetes, hyperlipidemia, cardiac comorbidity, wide aneurysm neck (>4 mm or dome to neck ratio >1.5), posterior circulation aneurysm, stent-assisted coiling, and stenting.
      • Algra A.M.
      • Lindgren A.
      • Vergouwen M.D.I.
      • et al.
      Procedural clinical complications, case-fatality risks, and risk factors in endovascular and neurosurgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis.
      Similarly, for neurosurgical treatment (54 studies), the pooled complication risk was 8.34% (95% CI, 6.25% to 11.10%), and the case-fatality rate was 0.10% (95% CI, 0.00% to 0.20%).
      • Algra A.M.
      • Lindgren A.
      • Vergouwen M.D.I.
      • et al.
      Procedural clinical complications, case-fatality risks, and risk factors in endovascular and neurosurgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis.
      The factors associated with complications of neurosurgical therapy were age, female sex, coagulopathy, use of anticoagulation, smoking, hypertension, diabetes, congestive heart failure, posterior aneurysm location, and aneurysm calcification.
      • Algra A.M.
      • Lindgren A.
      • Vergouwen M.D.I.
      • et al.
      Procedural clinical complications, case-fatality risks, and risk factors in endovascular and neurosurgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis.

      Microsurgical Clipping

      Microsurgical clipping represents the benchmark for treatment of intracranial aneurysms and is now tailored to the location and type of aneurysm. The principle of clipping involves an open craniotomy, gaining proximal vascular control, identifying the aneurysm neck and adjacent branches, and securing the aneurysm neck or base with microsurgical clips. This excludes the aneurysm from the parent circulation and eliminates the risk of rupture. Alternative techniques include wrapping of the aneurysm to enforce the walls when clipping cannot be performed safely. On occasion, exclusion of the vessel harboring the aneurysm is required with proximal and distal vessel occlusion or with hunterian ligation (proximal vessel occlusion). The safety of vascular sacrifice can be predetermined with balloon test occlusion, which is a preoperative angiographic test used to estimate the risk of stroke and to assess the integrity of the cerebral blood flow when an artery is being considered for permanent therapeutic occlusion because of an inoperable aneurysm. Nonetheless, a bypass procedure for flow supplement is considered when patients cannot tolerate the balloon test occlusion. Aneurysm clips are available in various shapes and sizes, and clip reconstruction results in complete aneurysm obliteration in more than 90%,
      • David C.A.
      • Vishteh A.G.
      • Spetzler R.F.
      • Lemole M.
      • Lawton M.T.
      • Partovi S.
      Late angiographic follow-up review of surgically treated aneurysms.
      with a low recurrence rate for saccular aneurysms. Ideal candidates for surgical clipping include young patients with low surgical risks; anterior circulation aneurysms, especially those in a superficial location (MCA aneurysms); and small lesions (<10 mm).
      • Ajiboye N.
      • Chalouhi N.
      • Starke R.M.
      • Zanaty M.
      • Bell R.
      Unruptured cerebral aneurysms: evaluation and management.
      Several meta-analyses have been performed of outcomes after microsurgical clipping. A meta-analysis of 28 studies reported mortality and morbidity rates of 1% and 4.1%, respectively.
      • King Jr., J.T.
      • Berlin J.A.
      • Flamm E.S.
      Morbidity and mortality from elective surgery for asymptomatic, unruptured, intracranial aneurysms: a meta-analysis.
      Another meta-analysis of 61 studies reported mortality and morbidity rates of 2.6% and 10.9%, respectively.
      • Raaymakers T.W.
      • Rinkel G.J.
      • Limburg M.
      • Algra A.
      Mortality and morbidity of surgery for unruptured intracranial aneurysms: a meta-analysis.
      A meta-analysis of 60 studies from 1990 to 2011 reported mortality and morbidity rates of 1.7% and 6.7%, respectively.
      • Kotowski M.
      • Naggara O.
      • Darsaut T.E.
      • et al.
      Safety and occlusion rates of surgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis of the literature from 1990 to 2011.
      In the ISUIA, the morbidity at 1 year was 9.8%, and the mortality at 30 days and 1 year was 2.3% and 3.0%, respectively.
      • Wiebers D.O.
      • Whisnant J.P.
      • Huston 3rd, J.
      • et al.
      Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment.
      The variable morbidity rates in these studies may be attributed to the definition of morbidity and aneurysm characteristics.
      • Thompson B.G.
      • Brown Jr., R.D.
      • Amin-Hanjani S.
      • et al.
      Guidelines for the management of patients with unruptured intracranial aneurysms: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      The results of neuropsychological testing after microsurgical clipping have been debatable. Whereas impaired cognition independently accounted for 55% of the overall morbidity in the ISUIA, several prospective studies reported no cognitive dysfunction after clipping.
      • Ohue S.
      • Oka Y.
      • Kumon Y.
      • et al.
      Importance of neuropsychological evaluation after surgery in patients with unruptured cerebral aneurysms.
      ,
      • Pereira-Filho A.A.
      • Pereira A.G.
      • Faria M.B.
      • Lima L.C.
      • Portuguez M.W.
      • Kraemer J.L.
      Microsurgical clipping in forty patients with unruptured anterior cerebral circulation aneurysms: an investigation into cognitive outcome.
      Poor outcomes after surgery were associated with age (>50 years), aneurysm size (4.0%, 12.1%, and 26.5% for aneurysms <10 mm, 10-24 mm, and ≥25 mm, respectively) and location (posterior circulation confers a risk ratio of 4.1), history of prior stroke, and presence of symptoms (new-onset oculomotor nerve palsy as it suggests aneurysm growth and impending rupture).
      • Wiebers D.O.
      • Whisnant J.P.
      • Huston 3rd, J.
      • et al.
      Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment.
      The risks of microsurgical clipping include stroke (6.7%-10%) and hemorrhagic complications (2.4%-4.1%),
      • Alshekhlee A.
      • Mehta S.
      • Edgell R.C.
      • et al.
      Hospital mortality and complications of electively clipped or coiled unruptured intracranial aneurysm.
      ,
      • McDonald J.S.
      • McDonald R.J.
      • Fan J.
      • Kallmes D.F.
      • Lanzino G.
      • Cloft H.J.
      Comparative effectiveness of unruptured cerebral aneurysm therapies: propensity score analysis of clipping versus coiling.
      incomplete aneurysm obliteration (5%) and recurrence (1.5%),
      • King Jr., J.T.
      • Berlin J.A.
      • Flamm E.S.
      Morbidity and mortality from elective surgery for asymptomatic, unruptured, intracranial aneurysms: a meta-analysis.
      infection, and seizures (0.1% for status epilepticus and 9.2% for any seizure).
      • Alshekhlee A.
      • Mehta S.
      • Edgell R.C.
      • et al.
      Hospital mortality and complications of electively clipped or coiled unruptured intracranial aneurysm.
      ,
      • Hoh B.L.
      • Nathoo S.
      • Chi Y.Y.
      • Mocco J.
      • Barker 2nd, F.G.
      Incidence of seizures or epilepsy after clipping or coiling of ruptured and unruptured cerebral aneurysms in the nationwide inpatient sample database: 2002-2007.
      Improved outcomes correlate with high volume of intracranial aneurysm procedures performed per year and the individual surgeon’s volume, with higher rates of home disposition and lower mortality rates for hospitals with more than 20 cases vs fewer than 4 cases annually.
      • Berman M.F.
      • Solomon R.A.
      • Mayer S.A.
      • Johnston S.C.
      • Yung P.P.
      Impact of hospital-related factors on outcome after treatment of cerebral aneurysms.
      • Chyatte D.
      • Porterfield R.
      Functional outcome after repair of unruptured intracranial aneurysms.
      • Barker 2nd, F.G.
      • Amin-Hanjani S.
      • Butler W.E.
      • Ogilvy C.S.
      • Carter B.S.
      In-hospital mortality and morbidity after surgical treatment of unruptured intracranial aneurysms in the United States, 1996-2000: the effect of hospital and surgeon volume.

      Endovascular Management

      Endovascular treatment of UIAs has become increasingly common compared with open surgery.
      • Brinjikji W.
      • Rabinstein A.A.
      • Nasr D.M.
      • Lanzino G.
      • Kallmes D.F.
      • Cloft H.J.
      Better outcomes with treatment by coiling relative to clipping of unruptured intracranial aneurysms in the United States, 2001-2008.
      The positive outcomes of the International Subarachnoid Aneurysm Trial (ISAT), which compared microsurgical clipping and endovascular coiling in ruptured aneurysms, resulted in favoring of endovascular treatment over open surgery.
      • Molyneux A.
      • Kerr R.
      • Stratton I.
      • et al.
      International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial.
      As a result, endovascular treatment has become popular for the treatment of unruptured aneurysms and continues to take momentum. Patients with aneurysms in the anterior circulation and aneurysms smaller than 10 mm are excellent candidates for endovascular treatment. The most common form of endovascular repair involves introducing platinum coils into the aneurysm sac through a microcatheter to promote aneurysm thrombosis and occlusion and isolation of the aneurysm from the circulation. Currently, most intracranial aneurysms are treated endovascularly with use of intrasaccular (aneurysm sac) or intraluminal (parent vessel) devices, and this can be achieved by obliteration of the aneurysm sac or by flow-diverting stents.
      • Ajiboye N.
      • Chalouhi N.
      • Starke R.M.
      • Zanaty M.
      • Bell R.
      Unruptured cerebral aneurysms: evaluation and management.
      The presence of coils in the aneurysm alters the blood flow pattern, which then leads to thrombosis. Adjunct techniques can be used in wide-neck (>4 mm) aneurysms and include balloon-assisted coiling, whereby a balloon is inflated in the parent artery, and stent-assisted coiling, whereby a stent is deployed to prevent coil protrusion into the parent artery that can lead to thrombus formation and stroke.
      • Naggara O.N.
      • Lecler A.
      • Oppenheim C.
      • Meder J.F.
      • Raymond J.
      Endovascular treatment of intracranial unruptured aneurysms: a systematic review of the literature on safety with emphasis on subgroup analyses.
      Whereas these techniques are targeted toward the aneurysm sac, flow diverters have been used for small, distal aneurysms since the initial approval of the Pipeline (Medtronic) embolization device by the Food and Drug Administration (FDA) for treatment of giant, wide-necked intracranial ICA aneurysms.
      • Kan P.
      • Siddiqui A.H.
      • Veznedaroglu E.
      • et al.
      Early postmarket results after treatment of intracranial aneurysms with the pipeline embolization device: a U.S. multicenter experience.
      Flow diversion devices are placed within the parent artery bridging the aneurysm neck and diverting the blood flow away from the aneurysm sac, resulting in gradual thrombosis of the aneurysm over time. Subsequent inflammatory response, healing, and endothelial growth lead to shrinking of the aneurysm and reconstruction of the parent artery lumen while perforators and side branches are preserved. Flow diverters are self-expanding, which allows treatment of previously untreatable wide-neck and giant aneurysms. Patients are typically prescribed dual antiplatelet therapy (aspirin and clopidogrel) before the procedure, with clopidogrel for 3 to 6 months and aspirin for life after the procedure.
      • Naggara O.N.
      • Lecler A.
      • Oppenheim C.
      • Meder J.F.
      • Raymond J.
      Endovascular treatment of intracranial unruptured aneurysms: a systematic review of the literature on safety with emphasis on subgroup analyses.
      The main risks associated with flow diverters include in-stent thrombosis, stroke, perianeurysmal edema, distant and delayed hemorrhages, and perforator occlusions. Although several techniques have emerged in past years, some, like liquid embolic agents, did not gain popularity because of risk-benefit profile or evolving technology.
      • Naggara O.N.
      • Lecler A.
      • Oppenheim C.
      • Meder J.F.
      • Raymond J.
      Endovascular treatment of intracranial unruptured aneurysms: a systematic review of the literature on safety with emphasis on subgroup analyses.
      Flow disruption is the latest intrasaccular technique for wide-neck aneurysms using a Woven EndoBridge (WEB) device placed within the aneurysm sac. The WEB aneurysm embolization system (Terumo) is a permanent, self-expanding mesh ball implant for the treatment of wide-neck intracranial aneurysms located at or near branching arteries. The implant disrupts the blood flow entering the aneurysm and promotes thrombosis. Its use is indicated for aneurysms at the MCA bifurcation, ICA terminus, anterior communicating artery complex, or basilar artery apex, with a dome diameter between 3 and 10 mm and either neck size of 4 mm or more or dome to neck ratio of more than 1 and less than 2. This technology requires no antiplatelet therapy and may be used for ruptured aneurysms. In several studies, the WEB device has demonstrated good long-term stable occlusion rates, with good procedural safety and efficacy of the treatment.
      • Behme D.
      • Berlis A.
      • Weber W.
      Woven EndoBridge intrasaccular flow disrupter for the treatment of ruptured and unruptured wide-neck cerebral aneurysms: report of 55 cases.
      • Pierot L.
      • Costalat V.
      • Moret J.
      • et al.
      Safety and efficacy of aneurysm treatment with WEB: results of the WEBCAST study.
      • Pierot L.
      • Klisch J.
      • Liebig T.
      • et al.
      WEB-DL endovascular treatment of wide-neck bifurcation aneurysms: long-term results in a European series [erratum appears in AJNR Am J Neuroradiol. 2016;37(2):E19].
      • Pierot L.
      • Moret J.
      • Barreau X.
      • et al.
      Safety and efficacy of aneurysm treatment with WEB in the cumulative population of three prospective, multicenter series.
      • Pierot L.
      • Moret J.
      • Turjman F.
      • et al.
      WEB treatment of intracranial aneurysms: clinical and anatomic results in the French observatory.
      • Pierot L.
      • Spelle L.
      • Molyneux A.
      • Byrne J.
      Webcast and French Observatory Imvestigators
      Clinical and anatomical follow-up in patients with aneurysms treated with the WEB device: 1-year follow-up report in the cumulated population of 2 prospective, multicenter series (WEBCAST and French Observatory).
      Furthermore, in the WEB-IT study, which prospectively evaluated the safety and effectiveness of the WEB device in 150 patients, 1 primary safety event (0.7%), delayed ipsilateral parenchymal hemorrhage, occurred on postoperative day 22, but no primary safety events occurred after 30 days and through 1 year.
      • Arthur A.S.
      • Molyneux A.
      • Coon A.L.
      • et al.
      The safety and effectiveness of the Woven EndoBridge (WEB) system for the treatment of wide-necked bifurcation aneurysms: final 12-month results of the pivotal WEB Intrasaccular Therapy (WEB-IT) study.
      Angiographic follow-up at 12 months demonstrated that 53.8% had complete aneurysm occlusion, whereas adequate occlusion was achieved in 84.6% of the patients.
      • Arthur A.S.
      • Molyneux A.
      • Coon A.L.
      • et al.
      The safety and effectiveness of the Woven EndoBridge (WEB) system for the treatment of wide-necked bifurcation aneurysms: final 12-month results of the pivotal WEB Intrasaccular Therapy (WEB-IT) study.
      A retrospective multicenter series demonstrated 100% technical feasibility, 4.8% morbidity, and 0% mortality,
      • Pierot L.
      • Liebig T.
      • Sychra V.
      • et al.
      Intrasaccular flow-disruption treatment of intracranial aneurysms: preliminary results of a multicenter clinical study.
      and the device was recently approved by the FDA.
      Whereas endovascular techniques continue to evolve rapidly, they have inherent drawbacks, with failed procedure rates of 0% to 10%,
      • Wanke I.
      • Doerfler A.
      • Dietrich U.
      • et al.
      Endovascular treatment of unruptured intracranial aneurysms.
      • Soeda A.
      • Sakai N.
      • Sakai H.
      • et al.
      Thromboembolic events associated with Guglielmi detachable coil embolization of asymptomatic cerebral aneurysms: evaluation of 66 consecutive cases with use of diffusion-weighted MR imaging.
      • Grunwald I.Q.
      • Papanagiotou P.
      • Politi M.
      • Struffert T.
      • Roth C.
      • Reith W.
      Endovascular treatment of unruptured intracranial aneurysms: occurrence of thromboembolic events.
      • Gonzalez N.
      • Murayama Y.
      • Nien Y.L.
      • et al.
      Treatment of unruptured aneurysms with GDCs: clinical experience with 247 aneurysms.
      complications in 5% to 10%,
      • Weir B.
      Unruptured intracranial aneurysms: a review.
      ,
      • Gonzalez N.
      • Murayama Y.
      • Nien Y.L.
      • et al.
      Treatment of unruptured aneurysms with GDCs: clinical experience with 247 aneurysms.
      ,
      • Goddard A.J.
      • Annesley-Williams D.
      • Gholkar A.
      Endovascular management of unruptured intracranial aneurysms: does outcome justify treatment?.
      unfavorable outcomes in 4% to 5%, and mortality of 1% to 2% of patients.
      • Naggara O.N.
      • Lecler A.
      • Oppenheim C.
      • Meder J.F.
      • Raymond J.
      Endovascular treatment of intracranial unruptured aneurysms: a systematic review of the literature on safety with emphasis on subgroup analyses.
      ,
      • Naggara O.N.
      • White P.M.
      • Guilbert F.
      • Roy D.
      • Weill A.
      • Raymond J.
      Endovascular treatment of intracranial unruptured aneurysms: systematic review and meta-analysis of the literature on safety and efficacy.
      The main risks include thromboembolism (2.5%), arterial dissection (0.7%), parent artery occlusion (2%), groin hematoma, infection, reaction to contrast material, and pseudoaneurysms.
      • Friedman J.A.
      • Nichols D.A.
      • Meyer F.B.
      • et al.
      Guglielmi detachable coil treatment of ruptured saccular cerebral aneurysms: retrospective review of a 10-year single-center experience.
      ,
      • Murayama Y.
      • Nien Y.L.
      • Duckwiler G.
      • et al.
      Guglielmi detachable coil embolization of cerebral aneurysms: 11 years' experience.
      The ISUIA reported 1-year morbidity and mortality rates of 6.4% and 3.1%, respectively.
      • Wiebers D.O.
      • Whisnant J.P.
      • Huston 3rd, J.
      • et al.
      Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment.
      Poor outcomes are more common in posterior circulation aneurysms and in those larger than 12 mm.
      • Wiebers D.O.
      • Whisnant J.P.
      • Huston 3rd, J.
      • et al.
      Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment.
      In terms of durability, successful aneurysm obliteration is seen in 86.1%, with recurrence in 24.4%, need for re-treatment in 9.1%, and annual risk of bleeding in 0.2% of patients.
      • Naggara O.N.
      • White P.M.
      • Guilbert F.
      • Roy D.
      • Weill A.
      • Raymond J.
      Endovascular treatment of intracranial unruptured aneurysms: systematic review and meta-analysis of the literature on safety and efficacy.
      Recanalization can be associated with recurrent hemorrhage,
      • Molyneux A.J.
      • Kerr R.S.
      • Birks J.
      • et al.
      Risk of recurrent subarachnoid haemorrhage, death, or dependence and standardised mortality ratios after clipping or coiling of an intracranial aneurysm in the International Subarachnoid Aneurysm Trial (ISAT): long-term follow-up.
      and the risk is greater in previously ruptured aneurysms than in UIAs.
      • Nguyen T.N.
      • Hoh B.L.
      • Amin-Hanjani S.
      • Pryor J.C.
      • Ogilvy C.S.
      Comparison of ruptured vs unruptured aneurysms in recanalization after coil embolization.
      Although there is a higher rate of aneurysm recurrence with endovascular treatment, it is superior to surgical clipping in terms of disability and complications.
      • Hwang J.S.
      • Hyun M.K.
      • Lee H.J.
      • et al.
      Endovascular coiling versus neurosurgical clipping in patients with unruptured intracranial aneurysm: a systematic review.
      A subanalysis of the ISUIA cohort found an overall morbidity and mortality of 12.6% (no history of SAH) and 10.1% (history of SAH) for surgical clipping and 9.8% (no history of SAH) and 7.1% (history of SAH) for endovascular coiling at 1 year.
      • Wiebers D.O.
      • Whisnant J.P.
      • Huston 3rd, J.
      • et al.
      Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment.
      However, in a randomized trial of 260 patients, there was no difference in morbidity at 1 year between treatment modalities for UIA.
      • Darsaut T.E.
      • Findlay J.M.
      • Magro E.
      • et al.
      Surgical clipping or endovascular coiling for unruptured intracranial aneurysms: a pragmatic randomised trial.

      Conservative Management

      In the absence of symptoms from UIAs or a strong family history of SAH, most UIAs can be managed conservatively, especially in elderly patients.
      • Korja M.
      • Lehto H.
      • Juvela S.
      Lifelong rupture risk of intracranial aneurysms depends on risk factors: a prospective Finnish cohort study.
      A conservative approach is justified in patients for whom the risk of treatment complications is higher than the 5-year rupture risk. In such patients, a wait-and-scan policy is recommended. Patients with UIAs should be counseled on reduction of risk factors for aneurysm growth and rupture. Blood pressure control to normotensive levels with periodic assessment is encouraged, and patients should be advised to quit smoking and to avoid secondhand smoking. Whereas routine physical activities including participation in aerobic activities and contact sports are safe, some studies report that activities involving the Valsalva maneuver, such as weightlifting and strenuous physical activities, should be restricted.
      • Flemming K.D.
      • Lanzino G.
      Management of unruptured intracranial aneurysms and cerebrovascular malformations.
      Needless to say, only a minority of all UIAs will rupture during the patient’s lifetime, and imposing restrictions for daily living may make patients anxious, and they may carry the feeling that aneurysmal rupture is pending. In one editorial, the authors reevaluated the discussion on lifestyle modifications in the setting of a UIA. They calculated how many episodes of coffee drinking and sexual intercourse need to be avoided to prevent 1 aneurysmal rupture, such that people at a high risk (aneurysm >7 mm) need to avoid approximately 670,000 cups of coffee or 64,000 episodes of sexual intercourse, whereas people at a low risk (aneurysm of ≤7 mm) need to avoid 13.4 million cups of coffee or 1.3 million episodes of sexual intercourse to prevent 1 SAH.
      • Vlak M.H.
      • Rinkel G.J.
      • Greebe P.
      • van der Bom J.G.
      • Algra A.
      Trigger factors and their attributable risk for rupture of intracranial aneurysms: a case-crossover study.
      ,
      • Macleod M.R.
      • White P.M.
      Not tonight, darling, I might get a headache.
      As a result, putting life restrictions on patients with UIAs has only a minor impact on aneurysmal rupture while having a significant negative impact on quality of life. Furthermore, follow-up imaging is warranted at regular intervals as outlined earlier to assess for aneurysmal growth and progression. Recent literature has suggested that several groups of aneurysms have a higher risk of growth than others, and these patients may benefit from shorter intervals of repeated surveillance imaging.
      • Backes D.
      • Rinkel G.J.E.
      • Greving J.P.
      • et al.
      ELAPSS score for prediction of risk of growth of unruptured intracranial aneurysms.
      ,
      • Sanchez van Kammen M.
      • Greving J.P.
      • Kuroda S.
      • et al.
      External validation of the ELAPSS score for prediction of unruptured intracranial aneurysm growth risk.
      The ELAPSS score has been used to predict the risk of aneurysmal growth, such that earlier SAH, location of aneurysm, age >60 years, population, and size and shape of the UIA were found to be predictors of aneurysmal growth.
      • Backes D.
      • Rinkel G.J.E.
      • Greving J.P.
      • et al.
      ELAPSS score for prediction of risk of growth of unruptured intracranial aneurysms.
      This score was externally validated and was found to show accurate calibration for 3- and 5-year risks of aneurysm growth. As a result, this score may assist patients and clinicians in predicting the growth of a UIA and in planning for follow-up imaging accordingly.
      • Sanchez van Kammen M.
      • Greving J.P.
      • Kuroda S.
      • et al.
      External validation of the ELAPSS score for prediction of unruptured intracranial aneurysm growth risk.
      Furthermore, in elderly patients (>75 years) and those with significant comorbidities or a limited life expectancy, conservative management and no follow-up may be needed, even with large aneurysms, because it is highly unlikely that these patients will undergo preventive aneurysm treatment.
      In patients with UIAs that remain stable in size, observation is recommended. There is also no evidence to suggest restricting a patient’s level or type of activity or refraining from surgical procedures or any required medications.
      • Flemming K.D.
      • Lanzino G.
      Management of unruptured intracranial aneurysms and cerebrovascular malformations.
      When there is evidence of aneurysmal growth, treatment is recommended. The role of antiplatelets is not clear; however, human and animal studies of aspirin suggested protective effects against aneurysmal development, progression, and rupture by attenuating inflammation without worsening the outcomes in patients with SAH. It is hoped that the results of the PROTECT-U trial will shed light on the role of aspirin plus intensive blood pressure control in reducing the risk of aneurysmal rupture or growth in patients who do not qualify for preventive endovascular or microsurgical intervention.
      • Vergouwen M.D.
      • Rinkel G.J.
      • Algra A.
      • et al.
      Prospective Randomized Open-label Trial to evaluate risk faCTor management in patients with Unruptured intracranial aneurysms: study protocol.
      Whereas anticoagulation does not increase the risk of aneurysmal rupture, it increases morbidity and mortality in aSAH. Therefore, an individualized approach is warranted in patients with conditions that require anticoagulation (eg, pulmonary embolism or atrial fibrillation). On the other hand, anticoagulation may be considered safe in patients with small UIAs as the benefit outweighs the risk, but the same would not be true in symptomatic, enlarging, or high-risk aneurysms.

      Aneurysmal Subarachnoid Hemorrhage

      Acute aSAH is characterized by the extravasation of blood within the subarachnoid space from a ruptured intracranial aneurysm. Subarachnoid hemorrhage is associated with a substantial burden of morbidity and mortality.
      • Feigin V.L.
      • Lawes C.M.
      • Bennett D.A.
      • Barker-Collo S.L.
      • Parag V.
      Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review.
      The average age of patients with SAH is substantially lower than for other types of stroke, peaking in the sixth decade, and it accounts for 3% of all stroke types.
      • Go A.S.
      • Mozaffarian D.
      • Roger V.L.
      • et al.
      Heart disease and stroke statistics—2014 update: a report from the American Heart Association.
      Whereas the worldwide case-fatality rate has reportedly improved over the years, speculated to be secondary to more rapid recognition and improved treatment strategies, the prehospital and 30-day mortality rates remain high (15% and 35%, respectively).
      • Nieuwkamp D.J.
      • Setz L.E.
      • Algra A.
      • Linn F.H.
      • de Rooij N.K.
      • Rinkel G.J.
      Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis.
      ,
      • Lovelock C.E.
      • Rinkel G.J.
      • Rothwell P.M.
      Time trends in outcome of subarachnoid hemorrhage: population-based study and systematic review.
      In one study, the 90-day case-fatality rate was found to decline from 39% in 1999-2002 to 30% in 2009-2012 (adjusted risk ratio [aRR], 0.74; 95% CI, 0.62 to 0.88).
      • Vergouwen M.D.
      • Jong-Tjien-Fa A.V.
      • Algra A.
      • Rinkel G.J.
      Time trends in causes of death after aneurysmal subarachnoid hemorrhage: a hospital-based study.
      In 2009-2012, the specific causes of in-hospital death were death from the initial bleeding (aRR, 1.06; 95% CI, 0.72 to 1.56), death from rebleeding (aRR, 0.47; 95% CI, 0.31 to 0.71), and death from delayed cerebral ischemia (DCI; aRR, 0.91; 95% CI, 0.50 to 1.65).
      • Vergouwen M.D.
      • Jong-Tjien-Fa A.V.
      • Algra A.
      • Rinkel G.J.
      Time trends in causes of death after aneurysmal subarachnoid hemorrhage: a hospital-based study.
      Nonetheless, over time, the rate of in-hospital rebleeding declined from 24% to 17%, leading to a decline in in-hospital death, which was likely to be attributed to earlier aneurysm treatment.
      • Vergouwen M.D.
      • Jong-Tjien-Fa A.V.
      • Algra A.
      • Rinkel G.J.
      Time trends in causes of death after aneurysmal subarachnoid hemorrhage: a hospital-based study.

      Epidemiology

      Spontaneous SAH is attributed to intracranial aneurysmal rupture in 85%, and 10% are perimesencephalic with unknown etiology.
      • Macdonald R.L.
      • Schweizer T.A.
      Spontaneous subarachnoid haemorrhage.
      ,
      • van Gijn J.
      • Kerr R.S.
      • Rinkel G.J.
      Subarachnoid haemorrhage.
      The remaining causes include infection, inflammatory conditions, and vascular malformations. The global incidence of SAH has been estimated at 6.1 per 100,000 persons.
      • Etminan N.
      • Chang H.S.
      • Hackenberg K.
      • et al.
      Worldwide incidence of aneurysmal subarachnoid hemorrhage according to region, time period, blood pressure, and smoking prevalence in the population: a systematic review and meta-analysis.
      The incidence of SAH has been relatively stable,
      • van Gijn J.
      • Kerr R.S.
      • Rinkel G.J.
      Subarachnoid haemorrhage.
      with a modest decline in recent years.
      • Macdonald R.L.
      • Schweizer T.A.
      Spontaneous subarachnoid haemorrhage.
      ,
      • Linn F.H.
      • Rinkel G.J.
      • Algra A.
      • van Gijn J.
      Incidence of subarachnoid hemorrhage: role of region, year, and rate of computed tomography: a meta-analysis.
      Within the United States, the incidence between ethnic groups varies, and nonwhites may have a higher incidence than whites.
      • Zacharia B.E.
      • Hickman Z.L.
      • Grobelny B.T.
      • et al.
      Epidemiology of aneurysmal subarachnoid hemorrhage.
      A relationship between SAH and low socioeconomic class has also been observed.
      • Feigin V.L.
      • Lawes C.M.
      • Bennett D.A.
      • Barker-Collo S.L.
      • Parag V.
      Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review.
      ,
      • Hughes J.D.
      • Bond K.M.
      • Mekary R.A.
      • et al.
      Estimating the global incidence of aneurysmal subarachnoid hemorrhage: a systematic review for central nervous system vascular lesions and meta-analysis of ruptured aneurysms.
      ,
      • Nichols L.
      • Stirling C.
      • Otahal P.
      • Stankovich J.
      • Gall S.
      Socioeconomic disadvantage is associated with a higher incidence of aneurysmal subarachnoid hemorrhage.
      There is a higher incidence in countries like Finland and Japan.
      • Macdonald R.L.
      • Schweizer T.A.
      Spontaneous subarachnoid haemorrhage.
      ,
      • Linn F.H.
      • Rinkel G.J.
      • Algra A.
      • van Gijn J.
      Incidence of subarachnoid hemorrhage: role of region, year, and rate of computed tomography: a meta-analysis.
      ,
      • de Rooij N.K.
      • Linn F.H.
      • van der Plas J.A.
      • Algra A.
      • Rinkel G.J.
      Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends.
      The incidence increases with age,
      • de Rooij N.K.
      • Linn F.H.
      • van der Plas J.A.
      • Algra A.
      • Rinkel G.J.
      Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends.
      and the average age at diagnosis is 50s to 60s,
      • Zacharia B.E.
      • Hickman Z.L.
      • Grobelny B.T.
      • et al.
      Epidemiology of aneurysmal subarachnoid hemorrhage.
      ,
      • de Rooij N.K.
      • Linn F.H.
      • van der Plas J.A.
      • Algra A.
      • Rinkel G.J.
      Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends.
      with half younger than 55 years at diagnosis.
      • Macdonald R.L.
      • Schweizer T.A.
      Spontaneous subarachnoid haemorrhage.
      The affected young population accounts for the high and costly number of lost productive years. Women are 1.6 times more affected than men,
      • Macdonald R.L.
      • Schweizer T.A.
      Spontaneous subarachnoid haemorrhage.
      ,
      • de Rooij N.K.
      • Linn F.H.
      • van der Plas J.A.
      • Algra A.
      • Rinkel G.J.
      Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends.
      with a male predominance in young years and a transition to female sex after the fifth decade.
      • Linn F.H.
      • Rinkel G.J.
      • Algra A.
      • van Gijn J.
      Incidence of subarachnoid hemorrhage: role of region, year, and rate of computed tomography: a meta-analysis.
      ,
      • de Rooij N.K.
      • Linn F.H.
      • van der Plas J.A.
      • Algra A.
      • Rinkel G.J.
      Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends.
      Early (21-30 days) case-fatality from SAH is estimated to be at 25% to 35%.
      • Feigin V.L.
      • Lawes C.M.
      • Bennett D.A.
      • Barker-Collo S.L.
      • Parag V.
      Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review.
      A large meta-analysis demonstrated a decrease in case-fatality of 0.8% per year,
      • Nieuwkamp D.J.
      • Setz L.E.
      • Algra A.
      • Linn F.H.
      • de Rooij N.K.
      • Rinkel G.J.
      Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis.
      and this has been attributed to improved diagnosis, use of nimodipine, endovascular treatment, and specialized neurocritical care.
      • Galea J.P.
      • Dulhanty L.
      • Patel H.C.
      UK and Ireland Subarachnoid Hemorrhage Database Collaborators
      Predictors of outcome in aneurysmal subarachnoid hemorrhage patients: observations from a multicenter data set.

      Clinical Presentation

      The classic description at presentation is a sudden and severe headache, often termed thunderclap headache, typically described as “the worst headache of my life.”
      • Mac Grory B, Vu L.
      • Cutting S.
      • Marcolini E.
      • Gottschalk C.
      • Greer D.
      Distinguishing characteristics of headache in nontraumatic subarachnoid hemorrhage.
      Thunderclap headache is defined as a severe headache with abrupt onset to maximum intensity in less than 1 minute.
      Headache Classification Committee of the International Headache Society
      The International Classification of Headache Disorders, 3rd edition (beta version).
      Approximately 50% of SAHs are manifested with thunderclap headache, and SAH is found in 25% of patients who present with thunderclap headache.
      • Ducros A.
      • Bousser M.G.
      Thunderclap headache.
      The headache is distinctly different from previous headaches and often accompanied by loss of consciousness, nausea, vomiting, photophobia, and neck pain.
      • Petridis A.K.
      • Kamp M.A.
      • Cornelius J.F.
      • et al.
      Aneurysmal subarachnoid hemorrhage.
      Any new headache with these “red flags” merits further evaluation. The clinical manifestations of SAH are variable, and a small percentage of patients may experience headache with few or no other symptoms.
      • Mac Grory B, Vu L.
      • Cutting S.
      • Marcolini E.
      • Gottschalk C.
      • Greer D.
      Distinguishing characteristics of headache in nontraumatic subarachnoid hemorrhage.
      Patients with “sentinel headache” may not seek medical attention right away or may be misdiagnosed, putting them at high risk for rebleeding within a short time.
      • Linn F.H.
      • Wijdicks E.F.
      • van der Graaf Y.
      • Weerdesteyn-van Vliet F.A.
      • Bartelds A.I.
      • van Gijn J.
      Prospective study of sentinel headache in aneurysmal subarachnoid haemorrhage.
      The Ottawa SAH rule is a validated tool designed for patients emergently presenting with headache. It includes age of 40 years or older, neck pain or stiffness, witnessed loss of consciousness, onset during exertion, instantly peaking pain, and limited neck flexion and has 100% sensitivity and approximately 15% specificity for the detection of SAH.
      • Perry J.J.
      • Stiell I.G.
      • Sivilotti M.L.
      • et al.
      Clinical decision rules to rule out subarachnoid hemorrhage for acute headache.
      Terson syndrome is recognized as intraocular hemorrhage associated with SAH; it can be diagnosed on funduscopic examination and is thought to be related to sudden elevation in intracranial pressure (ICP). Terson syndrome is associated with increased mortality and is seen in up to 40% of patients with SAH.
      • Hassan A.
      • Lanzino G.
      • Wijdicks E.F.
      • Rabinstein A.A.
      • Flemming K.D.
      Terson's syndrome.

      Diagnosis

      Computed tomography (CT) of the head is the most rapidly available and appropriate initial diagnostic test in patients suspected to have SAH. The sensitivity of CT within 6 hours of symptom onset may be as high as 100%
      • Perry J.J.
      • Stiell I.G.
      • Sivilotti M.L.
      • et al.
      Sensitivity of computed tomography performed within six hours of onset of headache for diagnosis of subarachnoid haemorrhage: prospective cohort study.
      • Backes D.
      • Rinkel G.J.
      • Kemperman H.
      • Linn F.H.
      • Vergouwen M.D.
      Time-dependent test characteristics of head computed tomography in patients suspected of nontraumatic subarachnoid hemorrhage.
      • Blok K.M.
      • Rinkel G.J.
      • Majoie C.B.
      • et al.
      CT within 6 hours of headache onset to rule out subarachnoid hemorrhage in nonacademic hospitals.
      ; CT of the head shows retinal nodularity and crescentic hyperdensities in most patients with Terson syndrome. In patients with normal findings on CT and with a high index of suspicion for aSAH, lumbar puncture is recommended.
      • Connolly Jr., E.S.
      • Rabinstein A.A.
      • Carhuapoma J.R.
      • et al.
      Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      ,
      • Edlow J.A.
      • Panagos P.D.
      • Godwin S.A.
      • Thomas T.L.
      • Decker W.W.
      American College of Emergency Physicians
      Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute headache.
      A retrospective study demonstrated that cerebrospinal fluid (CSF) analysis identified all cases of CT-negative SAH, although with a very low prevalence (0.7%) of aSAH.
      • Gangloff A.
      • Nadeau L.
      • Perry J.J.
      • Baril P.
      • Émond M.
      Ruptured aneurysmal subarachnoid hemorrhage in the emergency department: clinical outcome of patients having a lumbar puncture for red blood cell count, visual and spectrophotometric xanthochromia after a negative computed tomography.
      The CSF is typically collected in 4 consecutive tubes and is inspected visually or with spectroscopy for xanthochromia. The tubes are also assessed for erythrocytosis; typically, the number of red blood cells in all tubes is comparable in aSAH and decreases consecutively with traumatic taps. Spectrophotometry can be used to differentiate xanthochromia from a traumatic tap. Xanthochromia, which reflects bilirubin converted from oxyhemoglobin released from red blood cells, takes approximately 12 hours to develop, so it may not be present early in the clinical course. Spectrophotometry has been shown to be highly sensitive (>95%) if it is performed after 12 hours of onset of the SAH
      • Vermeulen M.
      • van Gijn J.
      • Blijenberg B.G.
      Spectrophotometric analysis of CSF after subarachnoid hemorrhage: limitations in the diagnosis of rebleeding.
      and therefore is recommended by some experts. Although it is not a widely available test in North America, visual inspection remains a commonly employed method of SAH detection. Moreover, the accuracy of spectroscopy has varied in the literature. For instance, a prospective cohort study found spectrophotometric definitions of xanthochromia to be only low to moderately specific for SAH.
      • Beetham R.
      • Lhatoo S.
      Should spectrophotometry be used to identify xanthochromia in the cerebrospinal fluid of alert patients suspected of having subarachnoid hemorrhage?.
      Vascular imaging is performed once a diagnosis of SAH is established with CT or lumbar puncture; CTA is sufficient in most cases and is commonly used for the identification of intracranial aneurysms and to guide management.
      • Connolly Jr., E.S.
      • Rabinstein A.A.
      • Carhuapoma J.R.
      • et al.
      Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      It must be recalled that the prevalence of intracranial aneurysms is 3.2% in the general population,
      • Vlak M.H.
      • Algra A.
      • Brandenburg R.
      • Rinkel G.J.
      Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis.
      and the frequency of multiple aneurysms in patients with SAH can be as high as 20.2% in women. Nonetheless, in one study, the largest aneurysm had not ruptured in 29% of the patients with multiple aneurysms.
      • Backes D.
      • Vergouwen M.D.
      • Velthuis B.K.
      • et al.
      Difference in aneurysm characteristics between ruptured and unruptured aneurysms in patients with multiple intracranial aneurysms.
      Therefore, it is essential to determine the culprit aneurysm, and this is often established by identification of the pattern and the epicenter of the SAH on CT. Whereas it is often presumed that the larger aneurysm within the SAH epicenter is usually the culprit, a small aneurysm, often with irregularities, is occasionally the cause of the SAH. Also, the pattern and epicenter of the SAH can change over time in patients who present in a delayed fashion. Digital subtraction angiography (DSA) is the gold standard for cerebrovascular imaging and for treatment planning, especially in complex cases,
      • Connolly Jr., E.S.
      • Rabinstein A.A.
      • Carhuapoma J.R.
      • et al.
      Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      as it provides detailed visualization of the intracranial vasculature and is particularly helpful in detection of small (<2 mm) and blister aneurysms and dissections. The DSA examination has a 1.8% risk of neurologic complications and 1% to 2% risk of aneurysm rebleeding.
      • van Gijn J.
      • Kerr R.S.
      • Rinkel G.J.
      Subarachnoid haemorrhage.
      Treatment can be based on CTA without DSA in cases with imminent risk of brain herniation that require urgent decompression and in cases with hematoma in which evacuation is needed and can be performed during clipping (eg, ruptured MCA aneurysm with hematoma). Brain magnetic resonance imaging is reliable in identifying acute subarachnoid blood products
      • Mitchell P.
      • Wilkinson I.D.
      • Hoggard N.
      • et al.
      Detection of subarachnoid haemorrhage with magnetic resonance imaging.
      ,
      • Wiesmann M.
      • Mayer T.E.
      • Yousry I.
      • Medele R.
      • Hamann G.F.
      • Bruckmann H.
      Detection of hyperacute subarachnoid hemorrhage of the brain by using magnetic resonance imaging.
      ; however, it is not routinely performed in the acute phase because of time constraints and availability. High-resolution magnetic resonance vessel wall imaging may be helpful in identifying the aneurysm that has ruptured in patients with multiple intracranial aneurysms.
      • Matouk C.C.
      • Mandell D.M.
      • Gunel M.
      • et al.
      Vessel wall magnetic resonance imaging identifies the site of rupture in patients with multiple intracranial aneurysms: proof of principle.
      Magnetic resonance imaging may also be helpful in the evaluation of alternative causes of SAH, such as arteriovenous malformations or infectious, inflammatory, and neoplastic processes.
      Perimesencephalic SAH is a subtype of nontraumatic SAH with blood mostly isolated anterior to the midbrain or surrounding cisterns without intraventricular extension.
      • van Gijn J.
      • van Dongen K.J.
      • Vermeulen M.
      • Hijdra A.
      Perimesencephalic hemorrhage: a nonaneurysmal and benign form of subarachnoid hemorrhage.
      ,
      • Mensing L.A.
      • Vergouwen M.D.I.
      • Laban K.G.
      • et al.
      Perimesencephalic hemorrhage: a review of epidemiology, risk factors, presumed cause, clinical course, and outcome.
      The clinical course is typically benign, and rebleeding, hydrocephalus, and DCI are uncommon because the source of bleeding is not aneurysmal but may be venous.
      • van Gijn J.
      • van Dongen K.J.
      • Vermeulen M.
      • Hijdra A.
      Perimesencephalic hemorrhage: a nonaneurysmal and benign form of subarachnoid hemorrhage.
      ,
      • Mensing L.A.
      • Vergouwen M.D.I.
      • Laban K.G.
      • et al.
      Perimesencephalic hemorrhage: a review of epidemiology, risk factors, presumed cause, clinical course, and outcome.
      The radiologic criteria for the pattern of perimesencephalic hemorrhage are traditionally agreed on as follows: the center of the hemorrhage is located immediately anterior to the midbrain, including those with extension of blood to the anterior perimesencephalic cistern or the basal part of the sylvian fissure; there is no complete filling of the anterior interhemispheric fissure and no extension to the lateral sylvian fissure, except for minute amounts of blood; and there is no evidence of frank intraventricular hemorrhage.
      • Rinkel G.J.
      • Wijdicks E.F.
      • Vermeulen M.
      • et al.
      Nonaneurysmal perimesencephalic subarachnoid hemorrhage: CT and MR patterns that differ from aneurysmal rupture.
      After a negative initial assessment for non-perimesencephalic SAH, an aneurysm can be found in up to 10% of patients on repeated DSA.
      • Bakker N.A.
      • Groen R.J.
      • Foumani M.
      • et al.
      Repeat digital subtraction angiography after a negative baseline assessment in nonperimesencephalic subarachnoid hemorrhage: a pooled data meta-analysis.
      Among patients with SAH, imaging shows no clear source of bleeding in 15%, and 38% have perimesencephalic SAH.
      • Kapadia A.
      • Schweizer T.A.
      • Spears J.
      • Cusimano M.
      • Macdonald R.L.
      Nonaneurysmal perimesencephalic subarachnoid hemorrhage: diagnosis, pathophysiology, clinical characteristics, and long-term outcome.
      In patients with acute SAH and no obvious source of bleeding, vascular imaging is often repeated to rule out intracranial aneurysm. The false-negative rate for CTA has been shown to be exceedingly low, so it is reasonable to forego DSA after CTA with normal findings as it may not add additional diagnostic value if these criteria for perimesencephalic hemorrhage are met.
      • Mohan M.
      • Islim A.
      • Dulhanty L.
      • Parry-Jones A.
      • Patel H.
      CT angiogram negative perimesencephalic subarachnoid hemorrhage: is a subsequent DSA necessary? A systematic review.
      ,
      • Andaluz N.
      • Zuccarello M.
      Yield of further diagnostic work-up of cryptogenic subarachnoid hemorrhage based on bleeding patterns on computed tomographic scans.
      Despite the reliability of CTA to rule out aneurysm, some centers advocate for at least 1 follow-up CTA or DSA study because of the potential for an initial CTA study with falsely normal findings.
      • Andaluz N.
      • Zuccarello M.
      Yield of further diagnostic work-up of cryptogenic subarachnoid hemorrhage based on bleeding patterns on computed tomographic scans.

      Management of SAH

      Initial Treatment

      Initial management of patients with SAH should focus on the airway, breathing, and circulation. Patients unable to protect their airway or in acute respiratory failure should be intubated immediately. Patients are at a high risk for development of cardiopulmonary instability, often due to sympathetic nervous system surges. Therefore, patients should be stabilized at local hospitals and transferred to high-volume centers (>35 SAH cases per year with experienced neurosurgeons and endovascular and neurocritical care specialists) where they are admitted to the intensive care unit for close hemodynamic and neurologic monitoring. The initial management should focus on control of blood pressure to reduce the risk of repeated rupture until the aneurysm is secured and intracranial hypertension has been treated. Aneurysm rebleeding has a mortality rate of 20% to 60%, excluding patients who die before hospital arrival, and is associated with poor clinical grades, larger aneurysms, and hypertension.
      • Macdonald R.L.
      • Schweizer T.A.
      Spontaneous subarachnoid haemorrhage.
      The highest rate of rebleeding is within 72 hours, with the majority (50%-90%) in the first 6 hours, especially when the SBP is higher than 160 mm Hg.
      • Larsen C.C.
      • Astrup J.
      Rebleeding after aneurysmal subarachnoid hemorrhage: a literature review.
      Hypertension due to sympathetic activation, pain, and anxiety is common.
      • Diringer M.N.
      Management of aneurysmal subarachnoid hemorrhage.
      Whereas the magnitude of blood pressure control to reduce the risk of rebleeding has not been established, studies suggest that the SBP be kept below 160 mm Hg until the aneurysm is secured (class IIa; level of evidence C).
      • Connolly Jr., E.S.
      • Rabinstein A.A.
      • Carhuapoma J.R.
      • et al.
      Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      Currently, there are no RCTs available showing that SBP should be lowered to below 160 mm Hg. It remains unclear whether a potential lower risk of rebleeding is offset by an increased risk of cerebral ischemia, even if the SBP is between 140 and 160 mm Hg. Monitoring with an arterial line is often done until the aneurysm is secured, and titratable and short-acting medications should be used as intravenous pushes or infusions (nicardipine or labetalol) as needed to prevent fluctuations in blood pressure. Hypotension should be avoided because of the risk of cerebral ischemia. Blood pressure is carefully monitored and titrated to optimize the balance between the mean arterial pressure (MAP), ICP, and cerebral perfusion pressure (CPP). Short-acting opiates and acetaminophen are often used to control pain and to prevent secondary hypertension. Use of gabapentin was recently reported to reduce narcotic requirements in the few weeks of pain management.
      • Dhakal L.P.
      • Hodge D.O.
      • Nagel J.
      • et al.
      Safety and tolerability of gabapentin for aneurysmal subarachnoid hemorrhage (SAH) headache and meningismus [erratum appears in Neurocrit Care. 2015;22(3):422].
      When aneurysm obliteration by endovascular or surgical techniques is delayed, such as when a patient is transferred to a tertiary care center with this expertise, short-term antifibrinolytics (tranexamic acid or ε-aminocaproic acid) have been administered in an attempt to reduce the risk of rebleeding during this vulnerable time.
      • Connolly Jr., E.S.
      • Rabinstein A.A.
      • Carhuapoma J.R.
      • et al.
      Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      ,
      • Diringer M.N.
      • Bleck T.P.
      • Claude Hemphill 3rd, J.
      • et al.
      Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society's Multidisciplinary Consensus Conference.
      Only one RCT has demonstrated a decrease in recurrent bleeding after administration of tranexamic acid, and its effect on functional outcomes and DCI is not well defined.
      • Hillman J.
      • Fridriksson S.
      • Nilsson O.
      • Yu Z.
      • Saveland H.
      • Jakobsson K.E.
      Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study.
      The recently completed ULTRA (ULtra-early TRanexamic Acid after SAH) trial seeks to investigate the effect of early administration of tranexamic acid on functional outcomes and DCI.
      • Post R.
      • Germans M.R.
      • Coert B.A.
      • Rinkel G.J.E.
      • Vandertop W.P.
      • Verbaan D.
      Update of the ULtra-early TRranexamic Acid after Subarachnoid Hemorrhage (ULTRA) trial: statistical analysis plan.
      Long-term infusions should be avoided, given the increased risk of stroke, myocardial infarction, venous thromboembolism, and deep venous thrombosis.
      • Germans M.R.
      • Coert B.A.
      • Vandertop W.P.
      • Verbaan D.
      Time intervals from subarachnoid hemorrhage to rebleed.
      • Baharoglu M.I.
      • Germans M.R.
      • Rinkel G.J.
      • et al.
      Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage.
      • Foreman P.M.
      • Chua M.
      • Harrigan M.R.
      • et al.
      Antifibrinolytic therapy in aneurysmal subarachnoid hemorrhage increases the risk for deep venous thrombosis: a case-control study.

      Aneurysm Treatment

      Once the patient is medically stabilized, aneurysm obliteration is habitually performed as soon as possible because rebleeding, which most commonly occurs in the first 72 hours, is the leading cause of morbidity and poor outcome.
      • Connolly Jr., E.S.
      • Rabinstein A.A.
      • Carhuapoma J.R.
      • et al.
      Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      ,
      • Diringer M.N.
      • Bleck T.P.
      • Claude Hemphill 3rd, J.
      • et al.
      Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society's Multidisciplinary Consensus Conference.
      Although guidelines recommend that aneurysms be secured as soon as feasible,
      • Connolly Jr., E.S.
      • Rabinstein A.A.
      • Carhuapoma J.R.
      • et al.
      Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      there is no consensus on the optimal time of securement or whether early obliteration actually improves outcomes as there is no large RCT on the topic. For instance, in 1 meta-analysis, treatment within 1 day was associated with better outcomes than treatment after 1 day. However, there was no difference in outcome with treatment on day 1 compared with days 1 to 3.
      • Rawal S.
      • Alcaide-Leon P.
      • Macdonald R.L.
      • et al.
      Meta-analysis of timing of endovascular aneurysm treatment in subarachnoid haemorrhage: inconsistent results of early treatment within 1 day.
      In a study comparing aneurysm treatment before 24 hours and 24 to 72 hours after ictus, the aRR for poor outcome in the pooled analysis was 1.37 (95% CI, 1.11 to 1.68). Furthermore, a “worst case scenario” analysis was performed, in which all patients with rebleeding more than 3 hours after admission were recategorized into the 24- to 72-hour group, which resulted in a similar aRR of 1.24 (95% CI, 1.01 to 1.52), suggesting that aneurysm treatment can be performed within 72 hours after ictus rather than emergently.
      In the ISAT, the treatment of ruptured aneurysms within 24 hours was associated with improved clinical outcomes, and the benefit was more pronounced for coiling than for clipping.
      • Molyneux A.J.
      • Kerr R.S.
      • Yu L.M.
      • et al.
      International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion.
      ,
      • Qureshi A.I.
      • Vazquez G.
      • Tariq N.
      • Suri M.F.
      • Lakshminarayan K.
      • Lanzino G.
      Impact of International Subarachnoid Aneurysm Trial results on treatment of ruptured intracranial aneurysms in the United States. Clinical article.
      The proportion of patients with a poor outcome at 1 year (defined as a modified Rankin scale [mRS] score of >2) was 23.5% among patients assigned to coil embolization vs 30.9% in those allocated to clip ligation (P=.0019). Whereas the ruptured aneurysm had to be judged amenable to either surgical or endovascular treatment, the surgical group had a lower risk of rebleeding and fewer aneurysms with incomplete occlusion. However, with newer endovascular techniques and devices, most ruptured aneurysms are now treated endovascularly, except for aneurysms with associated hematoma that require evacuation and aneurysms with a broad neck that are not amenable to balloon-assisted coiling treated at centers with advanced microsurgical skills. Although broad-neck aneurysms can be treated with stent-assisted coiling, the use of stents requires dual antiplatelet therapy, and this can become a problem, especially with bleeding from the external ventricular drain (EVD) and if placement of a ventriculoperitoneal shunt is required. Therefore, the choice of treatment depends on the patient’s overall condition, the characteristics of the aneurysm, the presence of an associated hematoma and mass effect, and the overall microsurgical vs endovascular expertise at the treating center.

      Common Complications During Management of SAH

      Increased ICP

      More than 50% of patients with aSAH are estimated to have an ICP of more than 20 mm Hg during their hospitalization, and in patients in poor clinical condition, it may be present in 60% to 70%.
      • Heuer G.G.
      • Smith M.J.
      • Elliott J.P.
      • Winn H.R.
      • LeRoux P.D.
      Relationship between intracranial pressure and other clinical variables in patients with aneurysmal subarachnoid hemorrhage.
      The sudden onset of bleeding in SAH causes a surge of ICP, thereby lowering CPP, and can lead to global ischemia or transient cerebral circulatory arrest.
      • Zoerle T.
      • Lombardo A.
      • Colombo A.
      • et al.
      Intracranial pressure after subarachnoid hemorrhage.
      Outside of the initial surge of ICP with aneurysmal rupture, hydrocephalus is the most common cause of increased ICP. Hydrocephalus occurs in 20% of patients,
      • Macdonald R.L.
      • Schweizer T.A.
      Spontaneous subarachnoid haemorrhage.
      in the form of either communicating or obstructive hydrocephalus. Intraventricular extension of bleeding occurs in up to 50% of patients and can cause acute obstructive hydrocephalus due to direct blockage of CSF drainage, leading to further elevation in the ICP. The presence of blood within the subarachnoid space leads to impairment of CSF absorption through the arachnoid granulations, therefore resulting in communicating hydrocephalus.
      • Macdonald R.L.
      • Schweizer T.A.
      Spontaneous subarachnoid haemorrhage.
      Increased ICP has consistently served as a predictor of higher mortality and worse functional outcomes in aSAH. Despite this, there are no consensus guidelines on the management of ICP in aSAH, and the management of ICP in aSAH is therefore commonly deduced from the Brain Trauma Foundation guidelines.
      • Carney N.
      • Totten A.M.
      • O'Reilly C.
      • et al.
      Guidelines for the management of severe traumatic brain injury, fourth edition.
      In patients with limited neurologic examination (eg, coma), treatment of elevated ICP and maintenance of normal CPP are essential to prevent neurologic deterioration and poor outcomes.
      • de Oliveira Manoel A.L.
      • Goffi A.
      • Marotta T.R.
      • Schweizer T.A.
      • Abrahamson S.
      • Macdonald R.L.
      The critical care management of poor-grade subarachnoid haemorrhage.
      Initial medical treatment involves head elevation to 30 to 45 degrees in neutral position, normocapnic ventilation, sedation with or without drainage of CSF, and osmotherapy with either mannitol or hypertonic saline if deemed appropriate.
      • de Oliveira Manoel A.L.
      • Goffi A.
      • Marotta T.R.
      • Schweizer T.A.
      • Abrahamson S.
      • Macdonald R.L.
      The critical care management of poor-grade subarachnoid haemorrhage.
      The traumatic brain injury (TBI) guidelines recommend ICP monitoring in patients with Glasgow Coma Scale (GCS) score of 8 or lower with a goal of maintaining ICP below 22 mm Hg and CPP between 60 and 70 mm Hg.
      • Carney N.
      • Totten A.M.
      • O'Reilly C.
      • et al.
      Guidelines for the management of severe traumatic brain injury, fourth edition.
      In acute hydrocephalus, insertion of an EVD can be lifesaving. Despite EVD placement, 93% of patients continue to have elevated ICP, especially in the acute phase,
      • Lv Y.
      • Wang D.
      • Lei J.
      • Tan G.
      Clinical observation of the time course of raised intracranial pressure after subarachnoid hemorrhage.
      and the optimal duration of drainage is not known. Hyperosmolar therapy with mannitol and hypertonic saline is routinely applied in the management of ICP in aSAH; their osmotic properties create a gradient across the blood-brain barrier that reduces brain fluid content and therefore volume and ICP.
      • Ropper A.H.
      Hyperosmolar therapy for raised intracranial pressure.
      Mannitol is a diuretic that has suggested level IIB evidence at doses of 0.25 to 1 g/kg for reduction of ICP per TBI guidelines.
      • Carney N.
      • Totten A.M.
      • O'Reilly C.
      • et al.
      Guidelines for the management of severe traumatic brain injury, fourth edition.
      One must recall the significant clinical, pathophysiologic, and hemodynamic differences in aSAH vs TBI when extrapolating these recommendations for aSAH. Mannitol is associated with hypotension as it decreases peripheral vascular resistance, and its diuretic properties could contribute to hypovolemia, both of which have the theoretical potential to contribute to DCI and decreased CPP as these adverse effects are at odds with guideline recommendations to maintain euvolemia and to induce hypertension in DCI.
      • Connolly Jr., E.S.
      • Rabinstein A.A.
      • Carhuapoma J.R.
      • et al.
      Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.
      ,
      • Mak C.H.
      • Lu Y.Y.
      • Wong G.K.
      Review and recommendations on management of refractory raised intracranial pressure in aneurysmal subarachnoid hemorrhage.
      Because of its efficacy in reducing ICP, mannitol remains an option for ICP management in aSAH; however, its application should be implemented on an individualized patient basis with the goal of optimizing the balance of maintaining euvolemia with reduction of ICP. In contrast to mannitol, hypertonic saline provides intravascular volume expansion with positive ionotropic effects, has minimal diuretic properties, and may improve cerebral along with systemic hemodynamics,
      • Mak C.H.
      • Lu Y.Y.
      • Wong G.K.
      Review and recommendations on management of refractory raised intracranial pressure in aneurysmal subarachnoid hemorrhage.
      ,
      • Thongrong C.
      • Kong N.
      • Govindarajan B.
      • Allen D.
      • Mendel E.
      • Bergese S.D.
      Current purpose and practice of hypertonic saline in neurosurgery: a review of the literature.
      which may be more in line with the so-called triple-H therapy. When hypertonic saline is used, parameters including volume status, blood pressure, and serum sodium concentration and osmolality must be monitored closely to prevent secondary injury, such as DCI.
      • Alotaibi N.M.
      • Wang J.Z.
      • Pasarikovski C.R.
      • et al.
      Management of raised intracranial pressure in aneurysmal subarachnoid hemorrhage: time for a consensus?.
      The use of hypertonic saline in poor-grade aSAH has been shown to increase regional cerebral blood flow, blood tissue oxygenation, and pH.
      • Al-Rawi P.G.
      • Tseng M.Y.
      • Richards H.K.
      • et al.
      Hypertonic saline in patients with poor-grade subarachnoid hemorrhage improves cerebral blood flow, brain tissue oxygen, and pH.
      The TBI guidelines acknowledge, however, that there is insufficient evidence on clinical outcomes to formally recommend any specific hyperosmolar agent or optimal means of administration.
      • Carney N.
      • Totten A.M.
      • O'Reilly C.
      • et al.
      Guidelines for the management of severe traumatic brain injury, fourth edition.
      Recent guidelines by the Neurocritical Care Society have conditionally recommended, because of the low quality of evidence, symptom-based bolus dosing of hypertonic saline rather than sodium target–based dosing for the management of ICP or cerebral edema in SAH.
      • Cook A.M.
      • Morgan Jones G.
      • Hawryluk G.W.J.
      • et al.
      Guidelines for the acute treatment of cerebral edema in neurocritical care patients.
      For intracranial hypertension refractory to initial medical management, induction of barbiturate coma or decompressive craniectomy (DC) can be considered if a salvageable prognosis is suspected. Barbiturates are believed to reduce ICP by suppressing cerebral metabolism, thus reducing blood volume and therefore ICP.
      • Roberts I.
      • Sydenham E.
      Barbiturates for acute traumatic brain injury.
      There are, however, multiple limiting adverse effects, including hypotension that may adversely reduce CPP, cardiorespiratory depression, and metabolic derangements. The induced coma may also make it difficult to accurately perform neurologic assessments and to identify complications, such as DCI.
      • Alotaibi N.M.
      • Wang J.Z.
      • Pasarikovski C.R.
      • et al.
      Management of raised intracranial pressure in aneurysmal subarachnoid hemorrhage: time for a consensus?.
      There are no dedicated cohort studies investigating the role of barbiturate coma in aSAH, and like hyperosmolar therapy, it has been much more thoroughly evaluated in TBI. A systematic review in 2012 involving 7 RCTs concluded that despite the fact that barbiturates do reduce ICP, hypotension was observed in 25% of patients, and overall there was no evidence that the use of barbiturates in TBI improves outcomes.
      • Roberts I.
      • Sydenham E.
      Barbiturates for acute traumatic brain injury.
      In contrast, TBI guidelines do recommend high-dose barbiturate administration if ICP is refractory to maximum standard medical and surgical therapies, with the caveats that hemodynamic stability is essential before and during barbiturate therapy and that it should not be used as a prophylactic therapy to prevent increased ICP.
      • Carney N.
      • Totten A.M.
      • O'Reilly C.
      • et al.
      Guidelines for the management of severe traumatic brain injury, fourth edition.
      Decompressive craniectomy has been applied as a prophylactic and salvage method for various underlying clinical indications of cerebral edema and increased ICP, including infarction, traumatic and nontraumatic hemorrhage, and infection.
      • Schirmer C.M.
      • Hoit D.A.
      • Malek A.M.
      Decompressive hemicraniectomy for the treatment of intractable intracranial hypertension after aneurysmal subarachnoid hemorrhage.
      The surgical removal of the skull allows the brain to expand, which reduces compression and midline shift while improving ICP and therefore CPP and cerebral blood flow.
      • Crudele A.
      • Shah S.O.
      • Bar B.
      Decompressive hemicraniectomy in acute neurological diseases.
      For instance, in TBI, DC has been shown to lower ICP, to reduce length of stay in the intensive care unit, and to reduce mortality, but it is associated with higher rates of vegetative state.
      • Hutchinson P.J.
      • Kolias A.G.
      • Timofeev I.S.
      • et al.
      Trial of decompressive craniectomy for traumatic intracranial hypertension.
      ,
      • Cooper D.J.
      • Rosenfeld J.V.
      • Murray L.
      • et al.
      Decompressive craniectomy in diffuse traumatic brain injury [erratum appears in N Engl J Med. 2011;365(21):2040].
      Early DC appears to reduce mortality and to improve functional outcomes in malignant MCA ischemic strokes.
      • Vahedi K.
      • Hofmeijer J.
      • Juettler E.
      • et al.
      Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials.
      Unlike in TBI and malignant stroke, the role of DC in aSAH has not been well established as the available data are sparse and with mixed results. Although there are no large RCTs on the topic, a systematic review and meta-analysis including 15 studies investigated the effect of DC on functional outcome and death in patients with poor-grade aSAH. At approximately 12 months, the pooled rate was 61.2% (95% CI, 52% to 69%) for poor outcome and 27.8% (95% CI, 21% to 35%) for death. In the 3 studies with matched controls, there was a trend of decreased mortality at 1 to 3 months for patients who did not undergo DC (odds ratio, 0.58 [95% CI, 0.27 to 1.25]; P=.168); however, there was no difference in the likelihood of poor outcome observed at early or 1-year follow-up. Primary (early) DC resulted in lower rates of poor outcome in comparison to secondary (delayed) DC (47% vs 74%, respectively). In this review, anisocoria, high World Federation of Neurosurgical Societies (WFNS) grade, severity of midline shift, volume of hematoma, and delayed surgical treatment were associated with poor outcomes in multiple studies.
      • Alotaibi N.M.
      • Elkarim G.A.
      • Samuel N.
      • et al.
      Effects of decompressive craniectomy on functional outcomes and death in poor-grade aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.
      In one study of aSAH patients who underwent DC for ICP management, neurologic outcome was found to be significantly related to the underlying pathologic process leading to increased ICP, not by timing. In patients with large hematomas, significantly improved outcomes were found in comparison to those treated for edema or delayed ischemic infarctions, regardless of whether the DC was a primary, secondary, or repeated effort.
      • Dorfer C.
      • Frick A.
      • Knosp E.
      • Gruber A.
      Decompressive hemicraniectomy after aneurysmal subarachnoid hemorrhage.
      These results must be considered, however, with the retrospective design and lack of a comparison group in mind. In contrast, another study investigating DC in 4 groups of patients with aSAH (group 1, primary DC; group 2, secondary DC due to hematoma; group 3, secondary DC due to increased ICP/edema without infarction; group 4, secondary DC due to increased ICP/edema with infarction) found that timing of DC may influence functional outcomes. For instance, patients with good outcomes were treated earlier by secondary DC (within 3.6±1.6 days) than those who died or those who survived with at least moderate disability who were treated later (within 5.9±5.5 days; P=.12). This study was limited to patients who received early clipping of the aneurysm, and most patients (55%) enrolled were in the primary DC group.
      • Buschmann U.
      • Yonekawa Y.
      • Fortunati M.
      • Cesnulis E.
      • Keller E.
      Decompressive hemicraniectomy in patients with subarachnoid hemorrhage and intractable intracranial hypertension.
      Another study also stratified according to indication (ranging from primary to secondary with infarcts or rebleeding) found that the time of onset of intractable ICP to DC was crucial for favorable outcomes, and outcomes did not differ according to whether the DC was categorized as primary or secondary or by specific indication for DC. Early hydrocephalus and clinical signs of herniation (eg, pupillary dilation) were associated with worse outcomes. Similar to other studies, this study had limitations due to retrospective data analysis and small number of patients in certain groups.
      • Guresir E.
      • Schuss P.
      • Vatter H.
      • Raabe A.
      • Seifert V.
      • Beck J.
      Decompressive craniectomy in subarachnoid hemorrhage.
      Prospective RCTs are certainly warranted to clarify the role of DC in aSAH, with identification of factors that guide selection of patients, timing, and specific indications and thresholds for DC.

      Seizures

      The incidence of seizures in patients with SAH is unknown, and seizures often represent a sign of rebleeding before the aneurysm is secured. The SAFARI score was predictive of early seizure in a 1500-patient cohort and comprised 4 variables to help individualize treatment: age 60 years and older, seizure before hospitalization, SAH bleeding in the anterior circulation, and hydrocephalus requiring EVD.
      • Jaja B.N.R.
      • Schweizer T.A.
      • Claassen J.
      • et al.
      The SAFARI score to assess the risk of convulsive seizure during admission for aneurysmal subarachnoid hemorrhage.
      In comatose patients, nonconvulsive seizures are associated with DCI and worse outcomes.
      • Claassen J.
      • Albers D.
      • Schmidt J.M.
      • et al.
      Nonconvulsive seizures in subarachnoid hemorrhage link inflammation and outcome.
      Therefore, continuous electroencephalography monitoring is used in high-grade SAH to aid in early diagnosis and treatment. Despite lack of evidence, antiepileptic drugs are used for seizure prophylaxis before aneurysm treatment, especially in patients with intraparenchymal hemorrhage. However, tapering of these drugs after aneurysm treatment is recommended without extending prophylaxis beyond 3 to 7 days unless patients present with seizures.
      • Macdonald R.L.
      • Schweizer T.A.
      Spontaneous subarachnoid haemorrhage.
      Levetiracetam is commonly used as the antiepileptic drug of choice because of its low adverse effect profile, lack of drug-drug interactions, and adverse effects of phenytoin on cognition in SAH survivors as well as reduced nimodipine levels.
      • Naidech A.M.
      • Kreiter K.T.
      • Janjua N.
      • et al.
      Phenytoin exposure is associated with functional and cognitive disability after subarachnoid hemorrhage.
      ,
      • Muck W.
      • Ahr G.
      • Kuhlmann J.
      Nimodipine. Potential for drug-drug interactions in the elderly.
      Epilepsy develops in approximately 2% of patients with SAH and is associated with higher severity of SAH.
      • Macdonald R.L.
      • Schweizer T.A.
      Spontaneous subarachnoid haemorrhage.

      Fever

      Fever in SAH is associated with DCI and poor outcome independently of hemorrhage severity or presence of infection. It occurs in approximately 70% of SAH patients, especially in high-grade SAH.
      • Diringer M.N.
      • Bleck T.P.
      • Claude Hemphill 3rd, J.
      • et al.
      Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society's Multidisciplinary Consensus Conference.
      Fever is often related to systemic inflammatory response syndrome and aseptic chemical meningitis, and diligent work-up for infectious causes and treatment is essential. The combination of pharmacologic treatment and external cooling devices is usually sufficient to maintain normothermia. Treatment-refractory fever during the first 10 days after SAH is predicted by poor clinical grade and intraventricular hemorrhage and is associated with increased mortality and functional disability and cognitive impairment among survivors. Whether fever is individually causative rather than simply being associated with poor outcomes is not clear. It has been shown, however, that inducing normothermia in patients with aSAH and refractory fever attenuates cerebral metabolic distress and decreases ICP.
      • Oddo M.
      • Frangos S.
      • Milby A.
      • et al.
      Induced normothermia attenuates cerebral metabolic distress in patients with aneurysmal subarachnoid hemorrhage and refractory fever.

      Hypothermia

      Hypothermia, a well-established neuroprotective treatment for survivors of out-of-hospital cardiac arrest that improves mortality and neurologic outcomes,
      • Bernard S.A.
      • Gray T.W.
      • Buist M.D.
      • et al.
      Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia.
      ,
      Hypothermia after Cardiac Arrest Study Group
      Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest [erratum appears in N Engl J Med. 2002;346(22):1756].
      has also been studied in ischemic stroke and TBI.
      • Hemmen T.M.
      • Lyden P.D.
      Hypothermia after acute ischemic stroke.
      • Hemmen T.M.
      • Lyden P.D.
      Multimodal neuroprotective therapy with induced hypothermia after ischemic stroke.