Subarachnoid hemorrhage Tania Rebeiz MD (Dr. Rebeiz of the University of Chicago has no relevant financial relationships to disclose.) James R Brorson MD (Dr. Brorson of the University of Chicago received consulting fees from the National Peer Review Corporation and Medico-legal Consulting.) Steven R Levine MD, editor. (Dr. Levine of the SUNY Health Science Center at Brooklyn has received honorariums from Genentech for service on a scientific advisory committee and a research grant from Genentech as a principal investigator.) Originally released April 10, 1995; last updated April 3, 2017; expires April 3, 2020 Introduction This article includes discussion of subarachnoid hemorrhage and subarachnoid haemorrhage. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. Overview The authors review the epidemiology, pathophysiology, natural history, diagnostic evaluation, and treatment of spontaneous subarachnoid hemorrhage and its secondary complications, including aneurysm rebleeding, hydrocephalus, hyponatremia, seizures, delayed cerebral ischemia, and cardiopulmonary problems. Newer hypotheses on the mechanism of delayed cerebral ischemia following subarachnoid hemorrhage are explained. Recommendations from the Neurocritical Care Society Guidelines and the American Heart Association/American Stroke Association guidelines for the management of aneurysmal subarachnoid hemorrhage are included. Evolving trends in the emergency room diagnosis of subarachnoid hemorrhage are critically reviewed. Key points Subarachnoid hemorrhage, often occurring from rupture of an intracranial aneurysm, constitutes a life-threatening neurologic emergency. Subarachnoid hemorrhage typically presents with a sudden severe headache and neck stiffness, and can be complicated by fatal rebleeding, arterial vasospasm producing ischemia, seizures, metabolic derangements, and venous thrombosis. The diagnosis of subarachnoid hemorrhage is usually confirmed by a noncontrast head CT, which has very high sensitivity in the initial hours following headache onset. Failure to diagnose subarachnoid hemorrhage can have fatal consequences. Traditionally a lumbar puncture has been recommended to follow a negative head CT when subarachnoid hemorrhage is suspected, but in the emergency medicine literature there is an evolving acceptance of noninvasive evaluation for aneurysm with CT angiogram when initial plain CT is negative for a suspected hemorrhage. Securing of the underlying ruptured aneurysm with surgical clipping or endovascular coiling should be performed as soon as possible to limit the chance of aneurysm rebleeding. Treatment in a specialized neurointensive care setting is necessary to address the diverse possible complications including delayed cerebral ischemia and metabolic derangements. Historical note and terminology Subarachnoid hemorrhage is a devastating condition, often resulting in severe neurologic disability or death, in which blood extravasates into the subarachnoid space between the arachnoid membrane and the pia mater. The majority of nontraumatic subarachnoid hemorrhages are due to the rupture of a saccular intracranial aneurysm. Early autopsy descriptions of aneurysmal subarachnoid hemorrhage included Observations on the Sanguineous Apoplexy of Giovanni Morgagni (1682-1771) and the documentation of bilateral carotid aneurysms in a patient presenting with apoplexy and headache by Gilbert Blane (1749-1834) (DiLuna et al 2004). It was not until the end of the 19th century, due in part to the more detailed description of the signs and symptoms of subarachnoid hemorrhage and the technique of lumbar puncture, that the diagnosis of subarachnoid hemorrhage could be made. In 1927, Egaz Moniz
was the first to successfully carry out cerebral angiography, enabling confirmation of the diagnosis of ruptured intracranial aneurysm in those patients presenting with signs and symptoms of subarachnoid hemorrhage (Moniz et al 1928). In 1973, computed tomography was introduced, facilitating the diagnosis of subarachnoid hemorrhage. Craniotomy and microsurgical clip obliteration was the main treatment method for aneurysms until 1991, when Guglielmi introduced the endovascular occlusion of aneurysm with electrolytically detachable coils (Connolly et al 2012). Since then, new advances in endovascular treatment have emerged, providing a widening array of options for treating aneurysms with challenging anatomy or location. Clinical manifestations Presentation and course The most common presenting complaint in subarachnoid hemorrhage is the sudden onset of a severe headache, often described by patients as the worst headache of my life. This typical presentation with sudden, severe, thunderclap -type headache occurs in 85% to 95% of patients (Connolly et al 2012). The headache is usually followed by pain radiating into the occipital or cervical region. Meningismus develops as blood flows into the spinal subarachnoid space. Some patients complain of pain radiating down the legs due to pooling of blood in the lumbar cistern and irritation of nerve roots. Occasionally the headache can be lateralized to 1 side. Vomiting preceding the onset of headache has been frequently reported. As many as 17% of patients present with a warning headache or sentinel headache that precedes the thunderclap headache. Such warning headaches are thought to result from small sentinel bleeding from an underlying aneurysm. Sentinel bleeds increase the odds of early rebleeding after the index subarachnoid hemorrhage by 10-fold (Beck et al 2006). Increased intracranial pressure with accompanying decrease in cerebral perfusion pressure during the ictus can lead to a sudden loss of consciousness as the presenting event, and this phenomenon should be distinguished from seizures. Clinical signs that accompany the presenting symptoms often include a mild temperature elevation and hypertension. Vitreous hemorrhage, known as Terson syndrome, occurs frequently in subarachnoid hemorrhage and is associated with poor prognosis. Cranial nerve palsies and focal neurologic deficits may also be present--classically 3rd nerve compression from a posterior communicating artery aneurysm--though 3rd nerve compression can also occur with posterior cerebral or superior cerebellar artery aneurysms. Uncal herniation causing pupillary dilatation, third nerve palsy, and deteriorating mental status is an ominous sign. Unilateral or bilateral lateral rectus (6th nerve) paresis may signify increased intracranial pressure or early hydrocephalus and is generally a nonlocalizing sign. Mental status abnormalities ranging from confusion to coma can occur. Focal deficits arise particularly in the case of concomitant intracerebral hemorrhage (more common with middle cerebral artery aneurysm rupture). Finally, patients may present with various cardiac and pulmonary abnormalities, including stunned myocardium, neurogenic pulmonary edema, hypotension, various arrhythmias, ST segment changes, and even cardiopulmonary arrest. Prognosis and complications Once a definitive diagnosis of subarachnoid hemorrhage has been made, patients are classified according to a standardized grading system. The benefits of using a classification system for patients with subarachnoid hemorrhage include the potential for accurate description and communication of a patient's baseline neurologic status as well as an indication of the patient's overall prognosis. The Hunt and Hess classification system (Hunt and Hess 1968) is perhaps the best known and most widely used in the United States (Table 1). Table 1. Hunt and Hess Classification of Subarachnoid Hemorrhage Grade Clinical Examination Associated Mortality 1 Asymptomatic, mild headache, slight nuchal rigidity 2 Cranial nerve palsy, moderate to severe headache, severe nuchal rigidity 1% 4 5% 4 3 Mild focal deficit, lethargy, confusion 19% 3 Mean Glasgow Outcome Score
4 Stupor, moderate to severe hemiparesis, early decerebrate rigidity 5 Deep coma, decerebrate rigidity, moribund appearance 40% 2 77% 2 The World Federation of Neurological Surgeons (WFNS) grading system is also used and is associated with outcome (Anonymous 1988). This system uses the Glasgow Coma Scale to evaluate level of consciousness and uses the presence or absence of major focal neurologic deficits to distinguish grade 2 from grade 3 (Teasdale et al 1988). The WFNS scale has less interobserver disagreement compared to Hunt Hess score (Degen et al 2011). Table 2. World Federation of Neurologic Surgeons Grading of Subarachnoid Hemorrhage Grade GCS Score Major Focal Deficit (Aphasia, Hemiparesis) 1 2 3 4 5 15 13 to 14 13 to 14 7 to 12 3 to 6 - - + ± ± Associated Mortality 5% 9% 20% 33% 77% Mean Glasgow Outcome Score 4 4 3 2 2 Clinical vignette A 46-year-old woman with a past medical history of tobacco use and hypertension presented to the emergency room with severe headache that reached maximum intensity within moments after onset. The headache initially localized in the back of her head and quickly spread to the top of the head and behind her eyes. She had nausea, vomiting, and somnolence, which were associated with the headache. Physical examination showed a systolic blood pressure of 190 mmhg, heart rate of 85 beats per minute, and a mild systolic murmur at the apex. Neurologic examination exhibited a somnolent patient. When aroused, she was alert and oriented. She had mild paresis on the right lower half of her face and right limbs. Her sensation to pinprick and her reflexes were slightly decreased on the paretic side. Biological basis Etiology and pathogenesis Subarachnoid hemorrhage is defined as the presence of blood within the subarachnoid space between the arachnoid membrane and the pia mater. A subarachnoid hemorrhage may be categorized as traumatic or spontaneous (typically due to aneurysmal rupture). Traumatic subarachnoid hemorrhage is much more common than spontaneous or nontraumatic subarachnoid hemorrhage, and it is not associated with the same complications. The current review focuses on spontaneous subarachnoid hemorrhage. Rupture of a cerebral aneurysm, most commonly a saccular or berry aneurysm, is the most common source of spontaneous subarachnoid hemorrhage, accounting for 75% of cases. The precise pathogenesis of saccular aneurysms is not completely known. Degeneration of the internal elastic lamina occurs through mechanisms that may involve inflammation. Risk factors for aneurysm occurrence include hypertension, moderate to heavy alcohol consumption, cigarette smoking, and abuse of sympathomimetics (Connolly et al 2012). A minority of patients suffering spontaneous subarachnoid hemorrhage are found to have other conditions that increase the risk of saccular aneurysms (Table 3). These include autosomal dominant polycystic kidney disease, glucocorticoid-remediable aldosteronism, fibromuscular dysplasia, Moyamoya disease, and Ehler-Danlos type IV. Suffering a previous subarachnoid hemorrhage is 1 of the strongest predictors of subarachnoid hemorrhage. Those with a history of subarachnoid hemorrhage form new aneurysms at a rate of 1% to 2% per year (Bederson et al 2009). Ninety percent of aneurysms develop in the anterior circulation, most commonly at the bifurcation of the anterior communicating artery and the anterior cerebral artery (30%), the internal carotid artery and posterior communicating artery (25%), the middle cerebral artery bifurcation (20%), the internal carotid artery bifurcation (8%), and other locations (7%). Ten percent of aneurysms arise from the posterior circulation. Ten to twenty percent of patients with a spontaneous subarachnoid hemorrhage have an angiogram that fails to reveal
a source of the hemorrhage (Bederson et al 2009). Twenty-four percent of them have an occult aneurysm; this number increases to 50% when excluding patients with obvious causes of bleeding and those with a typical pattern of perimesencephalic bleeding (Jung et al 2006). Perimesencephalic nonaneurysmal subarachnoid hemorrhage is typically distributed in the perimesencephalic cisterns anterior to the brainstem with potential extension to the ambient cistern and basal aspect of the Sylvian fissure. When assessed in a group of Caucasian and African-American patients over 18 years old, the incidence of perimesencephalic hemorrhages was found to be 0.5 per 100,000 patients, with a mean age of presentation of 50 to 55 years of age (Flaherty et al 2005). Up to 9% of perimesencephalic hemorrhages are caused by rupture of hidden saccular aneurysms usually located in the posterior circulation (Rinkel et al 1993). A typical presentation involves a middleaged man with a sudden headache during a Valsalva maneuver. Although less proportionately, patients suffering from perimesencephalic nonaneurysmal subarachnoid hemorrhage are subject to the same clinical complications as those with aneurysmal subarachnoid hemorrhage (Jung et al 2006), but overall, these patients have a more benign clinical presentation and a much better prognosis than patients with aneurysmal subarachnoid hemorrhage, with virtually no risk of recurrence and a normal life expectancy (Rinkel et al 1991b). The source of this type of bleeding is not defined in the majority of cases. Theories include rupture of perforating arteries, bleeding from venous source, and basilar artery wall hematoma (bleeding from the basilar artery vasa vasorum) (Rinkel et al 1993). Although saccular aneurysms are responsible for the majority of spontaneous subarachnoid hemorrhages, there are other well-defined causes for this condition, including vascular malformations, intracranial arterial dissections, and vasculopathies (Table 3). Awareness of and familiarity with these entities is key in their recognition and treatment. Table 3. Etiologies of Subarachnoid Hemorrhage Beyond Saccular Aneurysms Entity Amyloid angiopathy Arteriovenous malformation -- Reversible cerebral vasoconstriction (Call-Fleming) syndrome Cavernous malformation Cerebral venous thrombosis Coagulopathy Cortical or meningeal tumors (oncotic aneurysm) Dural arteriovenous fistula Extracorporeal circulation Fusiform aneurysm Intracranial intradural arterial dissection with pseudoaneurysm Mycotic aneurysm Moyamoya disease Pituitary apoplexy Description Convexity SAH and cortical bleeding. Diagnosis and staging with brain MRI and angiography. Thunderclap headache, focal deficits, and convexity SAH. Undetectable lesions on vascular imaging, diagnosed with MRI. Thunderclap headache and convexity SAH. Convexity SAH. Convexity SAH. Convexity SAH, diagnosed with DSA that includes bilateral external carotid injections. Convexity SAH post CABG. Diagnosed with DSA, represents a therapeutic challenge. Potential therapy with flow diverter stents. More common in the vertebrobasilar system. When bleeding occurs, it is usually devastating and frequently recurs in the initial 24 hours. Typically a distal fusiform artery aneurysm. May be accompanied by vasculitis. Hemorrhage is due to fragile neovascularization in adults and saccular aneurysms in children. Retro-orbital headache, nausea, vomiting, blurred vision, extraocular muscle paresis, and SAH on CT head. The blood can obscure the diagnosis of the pituitary adenoma.
Posterior reversible encephalopathy syndrome (PRES) Postsubdural decompression Sickle cell anemia Spinal vascular malformations Vasculitis MRI FLAIR abnormalities most commonly in the posterior lobes with occasional convexity SAH; etiology of PRES must be considered. Multifocal SAH in the immediate period following drainage of subdural hematoma. Pediatric patients have coincidental aneurysms; adults have a moyamoya syndrome with fragile neovascularization. Arteriovenous malformation, saccular aneurysm, dural arteriovenous fistula presenting initially with neck pain. Occasional cervical myelopathy. Arterial beading on vascular imaging, convexity SAH. Diagnosis may require cortical and leptomeningeal biopsy. CABG = coronary artery bypass graft; DSA = digital subtraction angiography; PRES = posterior reversible encephalopathy syndrome; SAH = subarachnoid hemorrhage Genetics. Several genetic loci have been identified in association with intracranial aneurysm formation, including 1p34-36, 2p14-15, 7q11, 11q25, and 19q13.1-13.3 (Olsson et al 2011). Risk factors for aneurysm formation are listed in Table 4. Table 4. Risk Factors for Aneurysmal Subarachnoid Hemorrhage Modifiable Risk Factors Cigarette smoking (dose-dependent effect on aneurysm rupture) Cocaine use Hypertension Moderate to heavy alcohol consumption Endocarditis (mycotic aneurysm) Nonmodifiable Risk Factors Previous subarachnoid hemorrhage (new aneurysm formation rate 1% to 2% per year) Aortic coarctation Polycystic kidney disease Pseudoxanthoma elasticum Moyamoya disease Arteriovenous malformation Fibromuscular dysplasia Dissection with pseudoaneurysm Vasculitis Neurofibromatosis-1 Glucocorticoid-remediable hyperaldosteronism Family history Connective tissue disease (Ehlers-Danlos syndrome type IV, Marfan syndrome) From (Bederson et al 2009) Epidemiology" The annual incidence of spontaneous subarachnoid hemorrhage is 2 to 25 per 100,000 people, and approximately 30,000 spontaneous subarachnoid hemorrhages occur in the United States annually (Anonymous 1988; Bederson et al 2009). The mean age of rupture is 55 years, and the peak age range for aneurysmal subarachnoid hemorrhage is 40 to 60 years. Incidence of subarachnoid hemorrhage differs by race and ethnicity, being more common in African- American populations and women (Bederson et al 2009; Connolly et al 2012). The ISUIA study addressed treatment of unruptured aneurysms detected in patients with and without previous subarachnoid hemorrhage (Wiebers et al 2003). Patients older than 50 years with large posterior circulation aneurysms are at the greatest risk for both rupture and repair. The 5-year rupture risk by aneurysm location and size for patients with no history of subarachnoid hemorrhage is below: Table 5. Aneurysm Size, Location, and 5-Year Rupture Risk
Aneurysm Location Cavernous carotid artery ACOM, MCA, ICA PCOM, posterior circulation Aneurysm Size <7 mm 7 to 12 mm 13 to 24 mm >25 mm 0% 0% 2.5% 0% 2.6% 14.5% 3.0% 14.5% 18.4% 6.4% 40% 50% ACOM = anterior communicating artery; MCA = middle cerebral artery; ICA = internal carotid artery; PCOM = posterior communicating artery. From (Wiebers et al 2003) The decision whether to treat an unruptured aneurysm should involve a discussion of the risks and benefits of rupture and treatment. Small unruptured aneurysms are often followed with serial imaging to detect growth. However, there are no clear-cut data to guide how often to repeat imaging studies. The original aneurysm size has been shown to be a predictor of aneurysm growth, supporting frequent imaging follow-up studies in these cases (Burns et al 2009). A study of aneurysm growth found that initial aneurysm size, dome/neck ratio and multilobarity, and patient smoking are risk factors for aneurysm growth (Bor et al 2015). However, gender, age, hypertension, past medical history, or family history of subarachnoid hemorrhage were not associated with aneurysmal growth. Smoking deserves particular attention as a modifiable risk factor for small aneurysms. Prevention Smoking cessation, blood pressure control, and elimination of high-risk behaviors (cocaine and sympathomimetic use, heavy alcohol consumption) may help prevent aneurysm rupture (Connolly et al 2012). Education of physicians and the general public regarding signs and symptoms of subarachnoid hemorrhage might result in fewer misdiagnoses and earlier neurosurgical referral. This may reduce the high morbidity and mortality associated with a catastrophic subarachnoid hemorrhage. Familial clustering of aneurysms has been described, with studies demonstrating that first-degree relatives of patients with aneurysmal subarachnoid hemorrhage are between 2 and 5 times more likely to develop subarachnoid hemorrhage (Bor et al 2008). According to the American Heart Association/ American Stroke Association guidelines in 2012, noninvasive screening of patients with at least 1 first degree relative with aneurysmal subarachnoid hemorrhage and/or patients with previous aneurysmal subarachnoid hemorrhage may be reasonable, however more studies are needed to weigh the risks and benefits (Connolly et al 2012). Differential diagnosis Headache, the primary symptom of subarachnoid hemorrhage, is a common presenting complaint in office and emergency room settings, but only a small fraction of patients with headache have a subarachnoid hemorrhage, creating a diagnostic challenge. The headache of subarachnoid hemorrhage characteristically is severe, very rapid in onset, and holocephalic or posterior, but atypical presentations occur. Sudden onset severe headaches are often described as thunderclap headaches, and have a wide differential diagnosis that must be carefully considered with query for characteristic clinical features and performance of appropriate diagnostic testing (Table 6). The difficult challenge in the emergency setting is how to recognize which headache cases warrant further diagnostic testing, with brain imaging and lumbar puncture in particular, among all the patients presenting and seeking relief from a severe headache. In a multicenter study of 10 university-affiliated emergency departments, among alert and oriented patients with nontraumatic headache peaking in intensity within 1 hour of onset, exclusion of patients with 3 or more similar previous recurrent headaches as well as those with other known causes for headache resulted in a 6.2% rate of confirmed subarachnoid hemorrhage among remaining patients (Perry et al 2013). A selection rule was applied to this population, calling for diagnostic investigation in patients with new severe headache and any of the following high-risk variables: Age of 40 years or more Neck pain or stiffness Witnessed loss of consciousness Onset during exertion Thunderclap headache (defined as instantly peaking pain) Limited neck flexion on examination
This rule, termed the Ottawa subarachnoid hemorrhage rule, resulted in a very high sensitivity (100%) and modest specificity (15.3%) in this selected population of headache patients (Perry et al 2013). The low specificity points to the common clinical features shared by a number of other conditions that can mimic subarachnoid hemorrhage. Table 6. Differential Diagnosis of Severe Sudden Headache ( Thunderclap Headache ) Condition Clinical features (in addition to headache) Subarachnoid hemorrhage Meningismus, altered mentation, seizures, sometimes focal signs Cerebral venous sinus thrombosis Reversible cerebral vasoconstriction syndrome Craniocervical arterial dissection Pituitary apoplexy Intraparenchymal hemorrhage Subdural or epidural hematoma Infectious or aseptic meningitis Focal or bilateral deficits, seizures, papilledema Focal deficits Posterior headache and/or neck pain, focal deficits, Horner syndrome Visual field deficits and hypopituitarism Progressive focal deficits, seizures, signs of intracranial hypertension Progressive focal deficits, signs of midline shift or herniation Fever, leukocytosis, meningismus, altered mentation Key diagnostic test CT followed by lumbar puncture MR or CT venography Vasoconstriction on angiography (MRA, CTA, or DSA) Angiography (MRA, CTA, or DSA), MR vessel wall imaging MRI brain CT brain CT brain Lumbar puncture Sentinel hemorrhage Meningismus Lumbar puncture Benign coital headache Historical setting, nonfocal exam Clinical diagnosis Migraine Trigeminal neuralgia Idiopathic intracranial hypertension Cerebral vasculitis Clinical features (aura, nausea, photo/phonophobia) Characteristic distribution and time course, trigger points Global headache, postural changes, papilledema, transient visual obscurations, visual loss Premonitory symptoms, confusion, psychosis, depression, focal signs, hemorrhage Clinical diagnosis Clinical diagnosis Lumbar puncture with measurement of opening pressure Angiography (MRA, CTA, or DSA) and vessel wall imaging When brain CT imaging shows features suggesting subarachnoid hemorrhage, in addition to aneurysmal rupture and the various etiologies of spontaneous subarachnoid hemorrhage outlined in Table 3, other diagnoses must be considered: Traumatic subarachnoid hemorrhage. Traumatic subarachnoid hemorrhage is usually recognized with a clear history of trauma. It typically affects the cerebral convexities and is often accompanied by other signs of injury such as orbital frontal contusions, skull fracture, or external scalp trauma. Pseudo-subarachnoid hemorrhage. Pseudo-subarachnoid hemorrhage is defined as increased density of the basal cisterns and subarachnoid spaces on computed tomography, not due to blood products. It is due to radiographic mimics of subarachnoid hemorrhage, which could be due to pyogenic leptomeningitis, intrathecal administration of contrast material, high-dose intravenous contrast, and diffuse cerebral edema (Given et al 2003).
Diagnostic workup Misdiagnosis of subarachnoid hemorrhage is thought to be as high as 12% (particularly in good-grade patients with mild symptoms). The most common diagnostic error is failure to obtain a noncontrast head CT. Failure to diagnose subarachnoid hemorrhage is associated with 4-fold increase in risk of death or severe disability (Kowalski et al 2004). Because treatment is urgent and the consequences of misdiagnosis are severe, a high index of suspicion for subarachnoid hemorrhage should be maintained. Imaging studies. Noncontrast CT scan. Noncontrast CT scan has a sensitivity of almost 100% when performed within 6 hours of onset, 85% sensitivity at 5 days, and 50% sensitivity at 1 week (Byyny et al 2008). False negatives can occur with low hematocrit levels. The thickness of the subarachnoid hemorrhage clot and the presence of intraventricular hemorrhage both predict the risk of vasospasm and delayed cerebral ischemia. The modified Fisher scale incorporates into its grading system the risk of vasospasm or delayed cerebral ischemia due to both subarachnoid hemorrhage and intraventricular hemorrhage. Table 7. Modified Fisher Grading Scale for Subarachnoid Hemorrhage Grade Modified Fisher Percent with Vasospasm 0 1 2 3 4 No SAH or IVH Thin SAH, no IVH Thin SAH with IVH Thick SAH, no IVH Thick SAH with IVH -- 24% 33% 33% 40% SAH = subarachnoid hemorrhage; IVH = intraventricular hemorrhage; ICH = intracranial hemorrhage. Note: approximately 1-mm vertical thickness as the cutoff between thin and thick. From (Frontera et al 2006) Cerebral angiogram. Digital subtraction cerebral angiography (DSA) is the gold standard for ruling out a ruptured cerebral aneurysm, for defining the relevant neuroanatomy, and possibly for providing immediate endovascular treatment. It has very low risks, with reported complication rate of 1% to 2.6% (renal failure, arterial occlusion, pseudo-aneurysm, and hematoma formation). The angiogram must visualize all intracranial vessels with multiple views, and the origins of both posterior inferior cerebellar arteries should be demonstrated. A 6-vessel angiogram is appropriate, including contrast to the external carotid arteries, to improve the diagnostic yield for the unusual dural arteriovenous fistulas as well as aneurysms. The goals of angiography are to determine the cause of subarachnoid hemorrhage and, if aneurysmal, to delineate the anatomy of the aneurysm (neck, nearby vessels, etc.), to determine if multiple aneurysms are present, to assess the degree of vasospasm, and to consider and potentially perform a therapeutic intervention. Fifteen percent to 20% of subarachnoid hemorrhage patients have negative angiograms. Angiography should be repeated as false negative results can be due to vasospasm, thrombosis of the aneurysm, small aneurysm, or blood in the cisterns. However, when to repeat the cerebral angiogram is debatable. Some advocate repeating it within 6 to 14 days for early management, and others recommend waiting 4 to 6 weeks post ictus to allow for the vasospasm and the hematoma to subside. There is no need to repeat angiography for typical perimesencephalic bleed because they are not usually associated with underlying aneurysm (Kumar et al 2014). Though cerebral angiography remains the gold standard test for detection of aneurysms, noninvasive testing with CT angiography often is chosen as the initial vascular imaging study in patients identified with subarachnoid hemorrhage, with DSA performed in cases with negative CTA or need to better define aneurysm anatomy for treatment planning (Connolly et al 2012). CT angiography. The sensitivity of CT angiography for detecting cerebral aneurysms depends on the size of the aneurysm. Larger aneurysms are reliably detected, whereas the smallest aneurysms may require DSA for detection. Post-image processing can provide detailed 3-D images with morphologic data. Sensitivity has improved as CT technology advanced, so that modern 16 slice or 64 slice CTA techniques have approached 100% sensitivity for
aneurysms greater than 3 mm in diameter (Li et al 2014; Zhang et al 2014). CT angiography is superior to digital subtraction angiography for defining aneurysmal wall calcification, intraluminal thrombus, and the relationship of the aneurysm to bony architecture. In addition, it has fewer complications, is a noninvasive, fast, diagnostic tool, and can triage patients to endovascular versus surgical treatment of the aneurysm. In treated aneurysms, metal artifact can limit the interpretation of CT angiography. Magnetic resonance angiography. Magnetic resonance angiography is sensitive to aneurysms larger than 5 mm. A metaanalysis found evidence of improving sensitivity over time, showing a 95% sensitivity overall in 960 pooled patients, with most of the missed aneurysms being smaller than 5 mm in diameter; a trend was found towards improved sensitivity with higher field strength (3 Tesla) magnets (Sailer et al 2014). MRI has higher sensitivity than CT for the detection of subacute hemorrhage and should be used in the patient presenting 3 to 4 days after onset, with normal head CT. In addition, contrast is not needed, and MR scanning is free from radiation. Obtaining MRI of the brain and cervical spine with and without gadolinium is a key step in the diagnosis of aneurysmal negative spontaneous subarachnoid hemorrhage. Lumbar puncture. Lumbar puncture should generally be performed if the history is suspicious for subarachnoid hemorrhage with a negative head CT. Commonly the opening pressure is elevated and blood should not clear up moving from first tube to the fourth; this helps differentiate subarachnoid hemorrhage from traumatic lumbar puncture. Xanthochromia, a hemoglobin degradation product, develops 2 to 4 hours after the ictus and persists for about 2 weeks. It causes a yellow discoloration of the CSF often seen visually. It may be detected with high sensitivity by spectrophotometry. Though there is a theoretical risk of aneurysmal re-rupture due to changing transmural pressure over an aneurysm, this risk is small with diagnostic spinal taps. Typically, the CSF initially appears grossly bloody due to the rapid rise in red blood cells, followed by a subsequent rise in white blood cells. Protein is usually slightly elevated whereas glucose is ordinarily normal. With time after aneurysm rupture, chemical meningitis can develop. The CSF profile of chemical meningitis is indistinguishable from infectious meningitis and is characterized by elevated white blood cells, including elevated polymorphonuclear cells, and low glucose. Because of the very high sensitivity of noncontrast head CT for subarachnoid blood in the early hours following onset of headache, there has been increasing interest in reevaluating whether lumbar puncture is a necessary test in cases of suspected subarachnoid hemorrhage. In a meta-analysis involving almost 9000 patients, noncontrast head CT had an overall sensitivity of 98.7% for detection of subarachnoid hemorrhage when performed within 6 hours of onset of headache (Dubosh et al 2016). Lumbar puncture can be difficult to obtain in obese or resistant patients, and can sometimes produce false positive or uninterpretable results because of traumatic puncture. A number of studies have asked whether noncontrast head CT alone, or followed by CT angiography, might be sufficiently sensitive for aneurysmal subarachnoid hemorrhage in the emergency room setting and that lumbar puncture can be foregone when the CT-based imaging is negative. A structured literature review found 31 appropriate publications addressing this issue, and concluded that although on the 1 hand there is insufficient evidence to conclude that noncontrast CT head alone is a safe approach, noncontrast CT head followed by CT angiogram is a reasonable approach to the evaluation of select patients with possible subarachnoid hemorrhage in the emergency room setting (Meurer et al 2016). Although this approach bears consideration, there are several appropriate caveats that must be kept in mind. First, the high sensitivity of CT for subarachnoid blood falls with time; the data that these recommendations rest upon generally comes from studies in which CT was performed within 6 hours of headache onset. Second, the sensitivity of CT scanning depends on the skill of the reader; although many of the studies were based on interpretation of a skilled neuroradiologist, in practice the acute reading might be by a less experienced individual. Third, a low hematocrit can produce a false-negative scan for subarachnoid blood. Finally, CT angiography is not sensitive to very small aneurysms, which because of their high prevalence are the source of a large portion of subarachnoid hemorrhages, nor does it detect many of the nonaneurysmal sources of subarachnoid bleeding, so that a negative CT angiogram, although lessening the chance of a sizable aneurysm, does not rule out the presence of a subarachnoid hemorrhage. In cases of high clinical suspicion, a negative lumbar puncture is still the only way to fully rule out a subarachnoid hemorrhage due to any cause. Laboratory studies. Routine testing should include coagulation studies and platelet count. Toxicology screening should be performed in at-risk populations.
Management Early management. The initial management of subarachnoid hemorrhage is directed at diagnosis of the etiology, responding to immediate threats to the patient's survival, and prevention of life threatening complications. When a ruptured aneurysm has been identified as cause of the hemorrhage, rebleeding is generally the greatest initial risk. Rebleeding. Rebleeding following subarachnoid hemorrhage accounts for carrying about 50% of the mortality of the condition. Early management of this syndrome is focused on avoiding this preventable complication. There is a 3% to 4% risk of rebleeding during the first 24 hours, a 2% risk the second day, and ongoing risk each subsequent day, or a 15% to 20% rebleeding risk within the first 2 weeks and up to 50% risk during the first 6 months if the aneurysm is not repaired (Naidech et al 2005a; Bederson et al 2009). Rebleeding is the most treatable cause of poor outcome after subarachnoid hemorrhage. Risk factors for rebleeding include aneurysm size, longer duration to securing the aneurysm, severity of the initial bleed, elevated blood pressure (which may be causative or secondary to the rebleeding), seizure, loss of consciousness at ictus, sentinel bleed, and the presence of intraventricular hemorrhage. Although the only definitive method to prevent rebleeding is to secure the aneurysm by excluding it from the intracranial circulation by neurosurgical clipping or endovascular obliteration, initial medical management decisions can modulate this risk, as reviewed below. Blood pressure management. Elevated blood pressure may contribute to aneurysm re-rupture. Blood pressure should be monitored and controlled to balance the theoretical risk of hypertension-related rebleeding and need to maintain cerebral perfusion pressure (Bederson et al 2009). In patients who are awake, and, thus, can be inferred to have a cerebral perfusion pressure within tolerable limits, it is reasonable to control the systolic blood pressure with shortacting titratable medications, to a goal systolic blood pressure of less than 160 mmhg (Connolly et al 2012). If intracranial pressure is monitored, it is safer to lower the systolic blood pressure below 140 mmhg, provided the cerebral perfusion pressure remains over 60 mmhg. Lowering of pressure is usually done with a titratable drip such as intravenous nicardipine or labetalol. Nitroglycerine and sodium nitroprusside are vasodilators and should be avoided as they may increase cerebral blood flow and intracranial pressure. Once the aneurysm is secured, blood pressure parameters can be liberalized to as high as 220/120 mmhg as patients enter the vasospasm period (typically 3 to 14 days after rupture). Seizure prophylaxis. Because seizures can increase intracranial pressure and may lead to aneurysm re-rupture, it has been a common practice to provide seizure prophylaxis in subarachnoid hemorrhage patients, particularly prior to aneurysm repair. However, there is no high-quality evidence showing that seizure prophylaxis improves outcome in subarachnoid hemorrhage. An article studying the current practice in seizure prophylaxis in centers with high volume of subarachnoid hemorrhage showed that most (two thirds) used prophylactic antiepileptic treatment, and levetiracetam was the most used antiepileptic. Antiepileptics were mostly used for 7 to 14 days duration (Dewan and Mocco 2015). Some studies have shown that prophylactic anticonvulsive for subarachnoid hemorrhage can be associated with poor outcome. After adjustment for age, neurologic grade, and admission systolic blood pressure, an elevated odds ratio for worse outcome in patients treated with anticonvulsants was found. Anticonvulsant treatment, predominantly with phenytoin, was associated with higher odds of developing cerebral vasospasm, cerebral infarction, and neurologic deterioration (Rosengart et al. 2007). Other data have shown that patients exposed to phenytoin have worse cognitive outcomes at 3 months, although eventually these patients slowly recover to the level of those not exposed (Naidech et al 2005b). However, the American Heart Association/American Stroke Association guidelines state that antiepileptics may be considered for prophylaxis in the acute phase of subarachnoid hemorrhage and should not be routinely used as long-term treatment unless there are risk factors for future development of seizures (Connolly et al 2012). One should weigh the risks and benefits of seizure prophylaxis and consider short course (3-7 days) of antiepileptics in patients at higher risk for developing seizures, and in patients with unsecured ruptured aneurysms, given the devastating potential consequences of seizures (Diringer et al 2011). Antifibrinolytics. Rebleeding is a major cause of morbidity and mortality. Antifibrinolytics (epsilon-aminocaproic acid 4 g intravenous load, then 24 g/day continuous infusion; or tranexamic acid 1 g intravenously immediately, then 1 g every 6 hours until occlusion) have been used to reduce the incidence of early rebleeding when early definitive aneurysm treatment is not available. In some studies, these medications have reduced rebleeding from 10% to 2% (Hillman et al 2002). Because antifibrinolytics can cause vasospasm, and are associated with increased risk of thromboembolism, they are rarely used. Their use should be limited to within 72 hours of ictus (prior to typical
vasospasm onset period) and should not be used in patients with coagulopathies, history of myocardial infarction, ischemic stroke, pulmonary embolism, or deep vein thrombosis. When definitive treatment of the aneurysm is unavoidably delayed and there are no other contraindications to treatment, short-term therapy with tranexamic acid or aminocaproic acid is reasonable (Connolly et al 2012). Antifibrinolytics should be discontinued prior to catheter angiography because they can precipitate catheter-induced vasospasm. Regionalized care. Management of subarachnoid hemorrhage requires a team of experienced physicians, including vascular neurosurgeons, endovascular neurointerventionalists, and neurointensivists. Repair of the aneurysm is only the first step in the care of a patient with subarachnoid hemorrhage. Appropriate management of delayed complications is essential to good outcome. Low volume hospitals should consider transferring their patients to a high volume hospital where a multidisciplinary neurointensive care team can provide optimal care (Connolly et al. 2012). Secure the aneurysm. Untreated ruptured aneurysms portend a 1 year mortality rate of 65% with a median survival time of 20 days from symptom onset (Korja et al 2017). Rapidly securing the aneurysm is imperative. The optimal method of aneurysm protection for each patient should be individualized based on several factors, including (1) aneurysm morphology, (2) patient characteristics, and (3) the experience of the treating facility. For good-grade patients, early treatment is recommended to decrease the 67% mortality rate that is associated with rebleeding (Bederson et al 2009). It is not certain that early aneurysm control benefits the overall outcome of patients presenting with poor Hunt and Hess grades (IV and V). These patients are seldom stable enough to undergo any sort of emergent intervention. When stable, aneurysm control with percutaneous techniques is usually logistically easier to perform provided they are technically feasible. A study showed that coiling a poor grade aneurysm within 24 hours of subarachnoid hemorrhage was associated with better outcomes compared to after 24 hours (Luo et al 2015). Endovascular techniques are usually the rule for aneurysms affecting the posterior circulation. They involve coil embolization, stent-assisted coil embolization, onyx embolization, and placement of flow-diverting stents. Complications related to angiography have been reported to be less than 0.1% (Bederson et al 2009). These include the complications related to catheter access, including local hematoma, aortic and cervicocephalic vessel dissection, and myocardial infarction and the specific complications related to the coiling, including rupture of aneurysm, migration of the coil, herniation of the coil, and local thromboembolism (Pierot and Wakhloo 2013). Rupture of aneurysm is reported in up to 5% of patients. Risk factors for rupture include small aneurysm size, middle cerebral artery location, hypertension, and ruptured aneurysm. Newer, investigational endovascular techniques include flow diverter stents and liquid coiling materials (Pierot and Wakhloo 2013). Open microsurgical clipping is generally preferred for distal artery aneurysms and middle cerebral artery bifurcation aneurysms. This procedure may be favored in cases that require concomitant clot evacuation or decompressive surgery. Risks associated with surgical clipping include new or worsening neurologic deficits caused by brain retraction, temporary artery occlusion, occlusion of parent vessel, and intraoperative hemorrhage. The International Subarachnoid Aneurysm Trial (ISAT) randomized 2143 patients with spontaneous subarachnoid hemorrhage to clipping versus coiling within 28 days of subarachnoid hemorrhage onset (Molyneux et al 2005). The majority of patients were World Federation of Neurological Surgeons (WFNS) grade 1 to 2; 97% had anterior circulation aneurysms, and most aneurysms were smaller than 10 mm. At 1 year, 24% of endovascularly treated patients had disability or death (modified Rankin Scale 3 to 6) compared with 31% of surgically treated patients (p = 0.0019). At 7- year follow-up, the mortality and seizures were higher in the surgical group (p = 0.03). The early rebleeding risk (up to 30 days after the initial procedure) was higher with endovascular repair. Due to the concern of losing the beneficial effect of endovascular treatment over the long run, the UK cohort of ISAT was followed for 18 years and showed that although there is a small increased risk of rebleeding in the endovascular group, there was no significant worse outcome compared to the surgical group and the probability of survival free from disability was significantly higher in the endovascular group compared to the surgical group at 10 years (Molyneux et al 2015). Management and prevention of subarachnoid hemorrhage complications. Increased intracranial pressure and cerebral hypoperfusion. Sudden increase in intracranial pressure after subarachnoid hemorrhage can lead to a decrease in the cerebral perfusion pressure, leading to global cerebral ischemia and death of patients before reaching the emergency room. The mechanisms leading to the increase in
intracranial pressure are hydrocephalus, cerebral edema, intracranial hematoma, ischemia, and impaired autoregulation. A study showed that intracranial pressure peaks at day 3 after the aneurysmal rupture and declines after day 7. Mean intracranial pressure correlates with mortality and severity of early brain injury (Zoerle et al 2015). Elevated intracranial pressure can be treated initially with CSF diversion, mannitol 20% 1 to 2 gms/kg intravenous bolus, or 23.4% saline intravenous push (30 cc over 10 to 20 minutes via a central line). Hyperventilation to a PCO2 goal of 30 to 35 mmhg should only be used transiently until the medical and surgical measures show effect. General measures to prevent increased intracranial pressure include placing the patient's head at a centered position, elevating the head of bed 30 degrees, and avoiding tight bandages or extrinsic structures from compressing the neck. Finally, certain measures can be attempted to control the cerebral metabolic rate, including avoiding hyperglycemia and fever. The evidence is not sufficient to advocate the use of barbiturates coma or hypothermia in the treatment of refractory increased intracranial pressure. Decompressive craniotomy can be considered. Hydrocephalus. Acute hydrocephalus may occur due to blocked CSF outflow through the aqueduct of Sylvius, fourth ventricular outlet, basal cisterns, or the subarachnoid space. This can be due to increased CSF viscosity. Hydrocephalus is associated with worse clinical grade and increased blood on CT, and often occurs in association with intraventricular hemorrhage. It occurs in 15% of patients radiographically, 40% of whom are symptomatic. Temporary CSF diversion is achieved by external ventricular drain, and can lead to a significant improvement in the clinical grade. Typical indications for external ventricular drain include ventriculomegaly, a non-command following exam, or suspicion of elevated intracranial pressure. Most external ventricular drains are set to drain at 10 to 15 mmhg initially, with a goal intracranial pressure of lower than 20 mmhg. Patients who undergo surgical clipping of their aneurysm may also be treated with fenestration of the lamina terminalis, which may ameliorate hydrocephalus, though this remains controversial (Komotar et al 2009). Although placement of an external ventricular drain may change the pressure dynamics of an aneurysm and lead to rebleeding, this is a rare complication, and an external ventricular drain should nonetheless be placed if it is indicated. Chronic ventriculoperitoneal shunting is needed in 8.9% to 48% of patients suffering aneurysmal subarachnoid hemorrhage (Connolly et al 2012). Seizures. In subarachnoid hemorrhage, the incidence of nonconvulsive seizures is 7% to18%, and status epilepticus is 3% to 13%. Nonconvulsive status epileptics is associated with higher rates of mortality and morbidity (Kondziella et al 2015). Seizures may precipitate parenchymal shift and increase the intracranial pressure in noncompliant brains. Periodic epileptiform discharges, nonconvulsive status epilepticus, nonreactive background, and the absence of normal sleep architecture are independent predictors of poor outcome in patients with subarachnoid hemorrhage. About 10% of patients experience clinical seizures during the hospital course (Claassen et al 2003). An estimated 7% of patients have clinical seizures at onset of bleeding (Lin et al 2003). Middle cerebral artery aneurysm, thickness of the subarachnoid hemorrhage, presence of a hematoma, infarct or rebleed, poor grade, and past medical history of hypertension have been proposed to be risk factors for early seizure development. Endovascular treatment seems to have lower incidence of seizures (Connolly et al 2012). Hyponatremia. Hyponatremia occurs in almost half of patients sustaining spontaneous subarachnoid hemorrhage during the first 3 days of the ictus, and can be due to several causes. According to a prospective study, the syndrome of inappropriate antidiuresis (SIAD) is the most common cause of hyponatremia (Hannon et al 2014). Other implicated factors are cerebral salt wasting, acute cortisol deficiency, incorrect IV fluid administration, and hypovolemia. It may be difficult to differentiate cerebral salt wasting from SIAD given that serum osmolality is low and urine sodium is elevated in both conditions. However, volume status can help: SIAD is associated with normovolemia/ hypervolemia whereas cerebral salt wasting results in volume depletion. However, volume status estimation is difficult in critical care patients. Inferior vena cava distensibility, stroke volume variations, and pulse pressure variations are reliable measures of intravascular volume (Garg and Bar 2017). Urine output that exceeds input in subarachnoid hemorrhage patients should alert physicians to the possibility of cerebral salt wasting. Careful attention should be given to abrupt hyponatremia heralding the presence of symptomatic vasospasm or ventriculitis. Sodium should be monitored every 6 to 12 hours with volume carefully maintained, avoiding any volume depletion, which might worsen delayed cerebral ischemia. Administration of large volumes of hypotonic saline should be avoided. If volume depletion with hyponatremia is present, careful repletion with hypertonic saline (1.5%, 2%, or 3% saline) can be considered; alternatively, fludrocortisone acetate (0.5 to 2 mg by mouth or intravenously twice daily) can be utilized (Connolly et al 2012). Rapid overcorrection may result in pontine or extrapontine myelinolysis, although this is rare in patients with hyponatremia for less than 24 hours. Increases in serum sodium exceeding 8 meq per 24 hours