Spontaneous subarachnoid haemorrhage

Seminar

Spontaneous subarachnoid haemorrhage R Loch Macdonald, Tom A Schweizer

Subarachnoid haemorrhage is an uncommon and severe subtype of stroke affecting patients at a mean age of 55 years, leading to loss of many years of productive life. The rupture of an intracranial aneurysm is the underlining cause in 85% of cases. Survival from aneurysmal subarachnoid haemorrhage has increased by 17% in the past few decades, probably because of better diagnosis, early aneurysm repair, prescription of nimodipine, and advanced intensive care support. Nevertheless, survivors commonly have cognitive impairments, which in turn affect patients’ daily functionality, working capacity, and quality of life. Additionally, those deficits are frequently accompanied by mood disorders, fatigue, and sleep disturbances. Management requires specialised neurological intensive care units and multidisciplinary clinical expertise, which is better provided in high-volume centres. Many clinical trials have been done, but only two interventions are shown to improve outcome. Challenges that remain relate to prevention of subarachnoid haemorrhage by improved screening and development of lower-risk methods to repair or stabilise aneurysms that have not yet ruptured. Multicentre cooperative efforts might increase the knowledge that can be gained from clinical trials, which is often limited by small studies with differing criteria and endpoints that are done in single centres. Outcome assessments that incorporate finer assessment of neurocognitive function and validated surrogate imaging or biomarkers for outcome could also help to advance the specialty.

Introduction This Seminar reviews spontaneous subarachnoid haemorrhage, which accounts for 5% of strokes (range 1–6).1 Despite subarachnoid haemorrhage being less common than ischaemic stroke and intracerebral haemorrhage, the young age of those affected and the high morbidity and mortality makes its effect on years of life lost similar to that of the more common types of stroke.2 Diagnosis and management involves emergency and general physicians, specialists in neurology, neurocritical care, interventional neuroradiology, and neurosurgery, and thus requires multidisciplinary collaboration to achieve the best patient outcome.

Epidemiology The incidence of subarachnoid haemorrhage in population-based studies, including out-of-hospital deaths, is 9∙1 cases per 100 000 people per year (95% CI 8∙8–9∙5), with some regional variation.3 Finland (19∙7 cases per 100 000 people per year, 18∙1–21∙3) and Japan (22∙7 cases per 100 000 people per year, 21∙9–23∙5) have the highest reported incidences. Controversy exists as to whether these variations in incidence are real or are due to differences in case ascertainment.3 The incidence of subarachnoid haemorrhage is falling—by 0∙6% per year from 1955 to 2003.3 About 85% of spontaneous events are aneurysmal and 10% are non-aneurysmal perimesencephalic. The remaining 5% have diverse causes (figure 1, appendix). Non-aneurysmal perimesencephalic subarachnoid haemorrhage has a specific pattern on initial CT and has more favourable outcome than does the typical aneurysmal subtype.

Risk factors The occurrence of subarachnoid haemorrhage peaks between age 50 and 60 years.3 The condition is 1∙6 times more common in women than in men, but this difference becomes evident only after the fifth decade.3 Oestrogen

and, less commonly, progesterone, have been postulated to have protective effects and thus to contribute to the increased incidence in postmenopausal women.4 However, a meta-analysis4 showed that these hormones might affect the risk of subarachnoid haemorrhage but the data were conflicting and no consistent conclusions could be reached. Risk factors for aneurysm formation, rupture of an unruptured aneurysm, and subarachnoid haemorrhage are largely similar (appendix). Studies of risk factors have yielded some conflicting results that could be related to bias in the studies and point to incomplete understanding of aneurysms. Modifiable risk factors for subarachnoid haemorrhage include smoking, hypertension, and excess alcohol intake, which all roughly double the risk individually, whereas a weaker protective effect is associated with regular exercise and increased cholesterol.5–7 These factors are associated with an attributable risk for subarachnoid haemorrhage of about two-thirds.6 The data for the effect of serum lipids on incidence are inconclusive. Non-modifiable risk factors include increasing age, female sex, family history, possibly Japanese or Finnish ethnic origin, and history of subarachnoid haemorrhage.3

Published Online September 13, 2016 http://dx.doi.org/10.1016/ S0140-6736(16)30668-7 Division of Neurosurgery (Prof R L Macdonald PhD, T A Schweizer PhD) and Labatt Family Centre of Excellence in Brain Injury and Trauma Research (Prof R L Macdonald, T A Schweizer), St Michael’s Hospital, Toronto, ON, Canada; and Department of Surgery, University of Toronto, Toronto, ON, Canada (Prof R L Macdonald, T A Schweizer) Correspondence to: Prof R Loch Macdonald, Division of Neurosurgery, St Michael’s Hospital, University of Toronto, Toronto, ON M5B 1W8, Canada [email protected]

Search strategy We searched the Cochrane Library, MEDLINE, and Embase and used a library of downloaded citations on subarachnoid haemorrhage that was updated every few months and spanned all time on MEDLINE. We used the search term “subarachnoid hemorrhage”. Publications in the past 5 years were preferentially selected, but older highly cited papers or classically important publications were also included. The reference lists of articles from the last 5 years that were identified by this search strategy were reviewed and any relevant additional references were selected. The reference list was modified on the basis of comments from peer reviewers.

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Figure 1: CT of different types of subarachnoid haemorrhage CT scans of patients with aneurysmal subarachnoid haemorrhage from aneurysms of the right middle cerebral artery (A), right internal carotid artery (B), anterior communicating artery (C), left middle cerebral artery (D), and right superior cerebellar artery (E). CT of patients with non-aneurysmal perimesencephalic subarachnoid haemorrhage (F–H, J) resemble aneurysmal subarachnoid haemorrhage from a basilar bifurcation aneurysm (I), showing that CT or catheter angiography are necessary in all patients with this condition. Non-aneurysmal subarachnoid haemorrhage due to cerebral venous thrombosis (K, L), trauma (M), pituitary apoplexy (N), and pseudo-subarachnoid haemorrhage due to increased intracranial pressure, brain swelling, and compression of the basal cisterns (O). The patients’ right side is displayed on the left side of the CT scans.

The effect of these factors on the risk of rupture of a known unruptured aneurysm differs and has been studied in cohorts of patients with unruptured aneurysms who are followed up over time. In these studies, the most important factors for rupture were hypertension, age, possibly Japanese or Finnish ethnic origin, larger aneurysm, particular aneurysm locations, and irregular aneurysm shape.8–10 Patients with a family history of aneurysms might have an increased risk of rupture but this assumption is based on limited data.11,12 Aneurysms that are growing or symptomatic should be expeditiously referred for repair. Smoking, alcohol intake, exercise, serum cholesterol, and sex seem to be less important in predicting risk of rupture of an unruptured intracranial aneurysm. Risk factors for aneurysm formation would best be obtained by population-based screening or unbiased autopsy studies. Such studies suggest that aneurysms are more likely with increased age, in women, in people with autosomal dominant polycystic kidney disease (ADPKD), and in those with a history of subarachnoid haemorrhage (appendix).5,13–16 Half of subarachnoid haemorrhage cases in one study17 occurred during sleep or at rest but 19% occurred during or within 2 h of moderate or heavy exercise (odds ratio [OR] 2∙7, 95% CI 1∙6–4∙6). The absolute number of exertion-related cases was low and the benefits of regular exercise outweigh the risks.18 2

Family history and genetics Family history of subarachnoid haemorrhage, defined as two first-degree relatives with the condition, accounts for 11% of events whereas ADPKD accounts for 0·3% of cases.19 Screening of 548 relatives who were smokers or who had hypertension in families with two affected siblings or three or more affected first-degree or seconddegree relatives showed that 21% had unruptured aneurysms.12 The aneurysms of two patients subsequently ruptured, resulting in a familial risk of 1∙2% per year (95% CI 0∙14–4∙3%). This risk is 17 times higher than a non-contemporaneous matched cohort.10,12 The risk of subarachnoid haemorrhage is three-to-seven times higher in first-degree relatives of patients than in the general population, but similar to the general population in second-degree relatives.20 Genome wide association studies have identified six definite and one probable loci with common variants associated with intracranial aneurysms.21 These loci explain 5% of genetic risk, suggesting that familial clustering might equally be due to common environmental risk factors. About 10% of patients with ADPKD have asymptomatic intracranial aneurysms.22

Pathophysiology Saccular cerebral aneurysms are acquired lesions that develop at branch points of major arteries of the circle of Willis. They develop in response to haemodynamic stress-induced degeneration of the internal elastic lamina with secondary thinning and loss of the tunica media. Multiple pathophysiological mechanisms have been proposed (appendix). The average size of a ruptured aneurysm is 6–7 mm.23 Aneurysmal subarachnoid haemorrhage injects blood into the subarachnoid space in almost all cases (figure 2). Bleeding into the ventricles and brain itself are common, but bleeds into the subdural space are uncommon (<5%). This is important in diagnosis of a ruptured aneurysm, in that an acute subdural haematoma by itself is unlikely to be caused by a ruptured aneurysm. Brain injury from subarachnoid haemorrhage occurs in two phases (figure 2). There is early brain injury that is shown by the neurological grade of the patient, which is caused by transient global ischaemia and toxic effects of subarachnoid blood.24,25 Direct destruction of brain tissue by an intracerebral haemorrhage is another factor (figure 2).24 Subarachnoid haemorrhage is unique in that there is a delayed phase of brain injury in which delayed neurological deterioration due to delayed cerebral ischaemia develops in a third of patients 3–14 days after the haemorrhage.26 There is a systemic response to subarachnoid haemorrhage that can affect the lungs (pulmonary oedema, acute respiratory distress syndrome), heart (arrhythmias, contractility abnormalities), and fluid and electrolyte balance, and can cause systemic inflammatory response syndrome.27 Common mechanisms for this systemic response are increased sympathetic nervous

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system activity, with increased catecholamines, natriuretic peptides, renin or angiotensin system activation, and inflammatory cytokines.

A Ruptured intracranial aneurysm

Diagnosis Sudden onset of the “most severe headache of a person’s life” is the cardinal symptom of subarachnoid haemorrhage.28 About 70% of patients present with headache, which is of sudden onset (thunderclap headache, defined as reaching maximum severity within 1 min of onset) in 50% of these patients. Sudden onset is a more important feature for diagnosis than severity.29 Headache is the only symptom in about half of cases; in the remainder there is nausea, vomiting, transient or ongoing loss of consciousness, or focal neurological deficits. 56 (12%) of 482 patients with subarachnoid haemorrhage between 1996 and 200130 were initially misdiagnosed, most commonly as having migraine or tension headache. Misdiagnosis is most common in neurologically intact patients who complain only of headache and is associated with increased risk of death and severe disability. Decision rules help to identify which patients with headache to investigate for subarachnoid haemorrhage.29 Of 2131 neurologically healthy patients older than 15 years with non-traumatic acute headache reaching maximum intensity within 1 h, 132 (6%) had subarachnoid haemorrhage.29 The use of the Ottawa subarachnoid haemorrhage rule (including age ≥40 years, neck pain or stiffness, witnessed loss of consciousness, onset of headache during exertion, instantaneous onset of headache, or limited neck flexion on examination) resulted in a diagnosis with a sensitivity of 100% (95% CI 97–100%) and a specificity of 15% (14–17%). Clinical judgment is required when applying these criteria and in deciding whether or not to investigate the patient, but in general a low threshold for investigation is appropriate given the high morbidity and mortality of subarachnoid haemorrhage and the low risk of the investigations required to make the diagnosis. Non-contrast CT is the diagnostic test of choice for subarachnoid haemorrhage.31 Failure to obtain a CT scan is the most common diagnostic error leading to missed diagnosis.30 A prospective multicentre study assessed CT scans on 3132 neurologically normal patients with non-traumatic headache reaching maximum severity within 1 h.31 For 953 patients scanned within 6 h, the sensitivity of CT for subarachnoid haemorrhage was 100%, but declined with increasing time from headache onset. This study made use of third generation, multidetector CT scanners, and imaging interpretation was done by qualified radiologists. Although multidetector CT scanners are highly accurate, sensitivity depends on the interval between symptom onset and image acquisition. In the first 72 h, sensitivity is greater than 97% but is only 50% after 5 days. The high sensitivity within 6 h suggests that subarachnoid haemorrhage can be effectively ruled out by CT and that lumbar puncture

Subarachnoid haemorrhage

Transient global ischaemia

Early brain injury

• Microcirculatory constriction • Endothelial cell apoptosis • Blood–brain barrier disruption • Impaired autoregulation • Cerebral oedema

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• Excitotoxicity • Ion channel dysfunction • Thrombin activation • Oxidative stress • Inflammation • Increased MMPs • Altered nitric oxide Midline shift or herniations: Increased intracranial pressure Posterior cerebral artery infarction

Subdural haematoma (<5%)

Intraventricular haemorrhage (>50%)

Ruptured aneurysm

Intracerebral haematoma (30%)

Duret brainstem haemorrhage

Subarachnoid haemorrhage (>99%) • Pulmonary oedema • Acute respiratory distress syndrome • Arrhythmias • Contractility • Systemic inflammatory response

• Sympathetic hyperactivity • Increased catecholamines • Increased natriuretic peptides • Increased renin/angiotensin • Inflammatory cytokines

Figure 2: Pathophysiology of subarachnoid haemorrhage Haemorrhage into various compartments (subarachnoid, intraventricular, intracerebral, subdural) can cause brain shift, increased intracranial pressure, herniation, Duret brainstem haemorrhages, and death. Systemic effects of subarachnoid haemorrhage include cardiac and pulmonary complications. Brain injury from this condition initially is due to transient global ischaemia and effects of the haemorrhage. Delayed neurological complications can ensue. MMPs=matrix metalloproteinases.

is not necessary. Lumbar puncture findings support the diagnosis of subarachnoid haemorrhage if erythrocytes or xanthochromia are present in the cerebrospinal fluid (CSF). However, omitting the use of lumbar puncture from diagnosis is controversial, and if subarachnoid

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Subarachnoid haemorrhage

Aneurysmal pattern

Non-aneurysmal perimesencephalic pattern or no SAH on CT but positive LP

CTA

Cause of SAH found

DSA

No cause for SAH found

Repair aneurysm or responsible lesion, DSA required as part of endovascular treatment or if neurosurgeon needs it for surgical planning

Cause of SAH found

Non-aneurysmal, non-perimesencephalic pattern (eg, convexity SAH)

CTA

No cause for SAH found

Repeat CTA or DSA days later if no cause for SAH is found, MRI/A is sometimes done but yield is very low

No cause for SAH found, no further investigations, some advocate repeat delayed angiography

CTA

Cause of SAH found

No cause for SAH found

Cause of SAH found

Repair aneurysm or responsible lesion, DSA required as part of endovascular treatment or if neurosurgeon needs it for surgical planning

Consider DSA if CTA unavailable or it does not disclose a cause for SAH

Repair aneurysm or treat responsible lesion such as PRES, venous thrombosis, vasculitis, DSA required as part of endovascular treatment or if neurosurgeon needs it for surgical planning

No cause for SAH found

Consider DSA if CTA unavailable or it does not disclose a cause for SAH

No cause for SAH found

No cause for SAH found

No further investigations necessary

MRI/A, additional medical investigations may be indicated

Figure 3: An algorithm for investigation of patients with subarachnoid haemorrhage with CT or lumbar puncture An algorithm for investigation of patients with subarachnoid haemorrhage present on CT scan or LP. SAH=subarachnoid haemorrhage. CTA=CT angiography. MRA=MR angiography. DSA=digital subtraction angiography. LP=lumbar puncture. PRES=posterior reversible encephalopathy syndrome.

haemorrhage is suspected and CT scan does not result in a definitive diagnosis, then additional testing by lumbar puncture is recommended.32 Any erythrocytes or haemoglobin breakdown product in the CSF is evidence of subarachnoid haemorrhage. However, extraneous blood can contaminate the sample (traumatic tap), which can make the diagnosis problematic (appendix). None of the methods to differentiate these possibilities is infallible and subarachnoid haemorrhage cannot be ruled out unless a CSF sample has no erythrocytes and no xanthochromia as measured by spectrophotometry. Xanthochromia is a yellow discolouration of CSF, and occurs more than 12 h after diagnosis because of formation in vivo of bilirubin.32 Erythrocytes will lyse in vitro and release haemoglobin that will colour the supernatant fluid so CSF should be centrifuged immediately and the supernatant fluid removed for analysis. The sample should then be stored in the dark to avoid the degradation of bilirubin. Spectrophotometry should be done as soon as possible, and a clear CSF sample would rule out a subarachnoid haemorrhage diagnosis. Unfortunately diagnosis with this method is difficult, since spectrophotometry is not available in many countries, the 12 h time is likely to be 4

variable, and visual inspection (in the absence of spectrophotometry) is unreliable.33 If subarachnoid haemorrhage cannot be excluded, a CT angiogram can be useful to exclude an aneurysm. Once a diagnosis of subarachnoid haemorrhage is made, vascular imaging is required to identify the source of the bleed. Digital subtraction angiography with three dimensional (3D) reconstructions is the gold standard for detection of the cause of the haemorrhage and for planning treatment, but the procedure is invasive, expensive, time consuming, and has risks.34 Complications with digital subtraction angiography occurred in 3·2% of cases in one series,34 which were mostly transient and included rare instances of death, permanent neurological deficits, and aneurysm rebleeding. The main imaging advance for diagnosis has been CT angiography, which can replace digital subtraction angiography in some cases (figure 3).35 A systematic review and meta-analysis showed that CT angiography had a pooled sensitivity of 97–98% (95% CI 95–98) compared with digital subtraction angiography with or without the use of 3D reconstruction.35 The decision to clip or coil the ruptured aneurysm can often be made on the basis of CT angiography and many neurosurgeons proceed to neurosurgical clipping without

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the need for invasive digital subtraction angiography in uncomplicated cases. Digital subtraction angiography is required for endovascular coiling, complex aneurysms, and if CT angiography does not show a cause for subarachnoid haemorrhage that is not the perimesencephalic pattern. For patients with an aneurysmal pattern of haemorrhage and no cause identified, digital subtraction angiography should be repeated days to weeks later. This repeated angiography shows an aneurysm in 10% of patients (7∙4–13∙6).36 Investigation of perimesencephalic subarachnoid haemorrhage is controversial since CT angiography is almost as sensitive as 3D digital subtraction angiography for detecting aneurysms, and it has been questioned whether patients with perimesencephalic haemorrhage and normal CT angiography require such angiography.37 About 10% of posterior circulation aneurysms haemorrhage with a perimesencephalic pattern and about 10% of perimesencephalic subarachnoid haemorrhage are due to posterior circulation aneurysms (figure 1). The decision to obtain digital subtraction angiography should be individualised. Most would not advocate follow-up imaging in such patients if initial studies are normal.37 A systematic review and meta-analysis38 of MRI and magnetic resonance (MR) angiography (usually time-offlight MR angiography) for detection of aneurysms showed that sensitivity was 95% (95% CI 89–98) and pooled specificity was 89% (80–95). Newer methods such as contrast enhanced MR angiography and imaging with higher resolution, 3 Tesla scanners, might be more sensitive. The limitations of MRI and MR angiography are the difficulties in imaging critically ill patients who might have monitoring devices (eg, pacemakers) in place that are not MR compatible and that the sensitivity for detecting aneurysms is lower than that of CT angiogram methods. Haemosiderin-sensitive MRI sequences, such as gradient-echo T2*-weighted and susceptibility-weighted images, could be useful to detect subarachnoid haemorrhage in patients who present weeks after a possible haemorrhage.39 Other applications for MRI and MR angiogram are for investigation of subarachnoid haemorrhage with unknown cause, follow-up of coiled aneurysms to assess for recanalisation, and as a research method to examine brain structure and function after subarachnoid haemorrhage.40 Patients are graded clinically and by volume of subarachnoid haemorrhage and intraventricular haemorrhage on admission, which is important for communication between the treating team, predicting and detecting neurological deterioration, and estimating prognosis (tables 1, 2).41–50

Management Once initial emergency support has been administered and diagnosis made, treatable causes of ongoing primary brain injury need to be addressed. The first procedure is surgical evacuation of space-occupying acute subdural

Hunt and Hess41

WFNS42

PAASH43

Grade #1

Asymptomatic or mild headache and GCS 15 slight nuchal rigidity

Grade #2

Moderate to severe headache, nuchal rigidity, no focal neurological deficit other than cranial nerve palsy

Grade #3

GCS 14–13 with major focal deficit GCS 8–10 Confusion, lethargy, or mild focal neurological deficit other than cranial nerve palsy

Grade #4

Stupor or moderate to severe hemiparesis

Grade #5

Coma, extensor posturing, moribund GCS 6–3 with or without major appearance focal deficit

GCS 14–13 without major focal deficit (aphasia or hemiparesis/hemiplegia)

GCS 12–7 with or without major focal deficit

GCS 15 GCS 11–14

GCS 4–7 GCS 3

These scales are the Hunt and Hess, WFNS, and PAASH scales.41–44 The WFNS and PAASH scores rely on the GCS and have similar interobserver agreement that is higher than the Hunt and Hess scale.43 GCS=Glasgow coma score. PAASH=prognosis on admission of aneurysmal subarachnoid haemorrhage. WFNS=World Federation of Neurological Surgeons. SAH=subarachnoid haemorrhage.

Table 1: Commonly used clinical grading scales for SAH

and intracerebral haemorrhages, which is best accompanied by clipping the ruptured aneurysm (figure 4).51–53 Second, insertion of a ventricular catheter can be life saving in patients with acute hydrocephalus. The main causes of early death include brain damage from the initial subarachnoid haemorrhage and rebleeding of the aneurysm before it is repaired. Death in the 3–14 day interval is usually due to rebleeding, medical complications, delayed cerebral ischaemia, or withdrawal of care in patients who fail to improve over time or who develop complications that preclude functional recovery.54,55 Rebleeding is reported within 72 h of subarachnoid haemorrhage in 8–23% of cases,56 50–90% of which occur within the first 6 h. Rebleeding occurs at 3% per year after the first month. This rebleeding has a mortality of 20–60%, which does not include patients who die before hospital admission.56 Risk factors for rebleeding are poor neurological grade, admission hypertension, a large aneurysm, and an association has been suggested with the use of antiplatelet drugs.56 Catheter angiography done within 6 h of haemorrhage was also associated with rebleeding but this is probably related to the natural history rather than to angiography.56,57 The negative effect of rebleeding on outcome suggests that early aneurysm repair should improve outcome. Guidelines recommend this procedure should be done as soon as possible or within 72 h in all but the most severely affected patients.58–60 Another potential treatment to reduce rebleeding is antifibrinolytic drugs such as tranexamic acid. A randomised clinical trial61 suggested a short course (1 g every 6 h up to 72 h) of tranexamic acid given until the aneurysm is repaired reduced the risk of rebleeding, although a significant improvement in outcome was not shown. Tranexamic acid and similar antifibrinolytic lysine derivatives increase the risk of thromboembolic complications and might induce seizures.62,63 Additional studies of short-term antifibrinolytic administration are needed.

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Fisher scale44

Claassen scale46

Modified Fisher scale47

Hijdra scale, grade each of ten cisterns and each of the four ventricles48

Grade #0

··

No SAH or intraventricular haemorrhage

No SAH or intraventricular haemorrhage

No blood in cistern, no blood in ventricle

Grade #1

No SAH or intraventricular haemorrhage

Minimum or thin SAH, no intraventricular haemorrhage in either lateral ventricle

Localised or diffuse thin SAH with no intraventricular haemorrhage

Small amount of blood in cistern, sedimentation of blood in posterior part of ventricle

Grade #2

Diffuse deposition of thin layer with Minimal or thin SAH, with intraventricular haemorrhage in all vertical layers of blood both lateral ventricles (interhemispheric fissure, insular cistern, ambient cistern) <1 mm thick

No or localised or diffuse thin SAH but with intraventricular haemorrhage

Moderate amount of blood in cistern, ventricle partly filled with blood

Grade #3

Vertical layers of blood ≥1 mm thick or localised clots (clots defined as >3 × 5 mm)

Thick SAH completely filling two or more cisterns or fissures, no intraventricular haemorrhage in both lateral ventricles

Localised or diffuse thick SAH with no intraventricular haemorrhage

Cistern completely filled with blood, ventricle completely filled with blood

Grade #4

Diffuse or no subarachnoid blood, but with intracerebral or intraventricular clots

Localised or diffuse thick SAH with Thick SAH completely filling intraventricular haemorrhage two or more cisterns or fissures, with intraventricular haemorrhage in both lateral ventricles

··

The severity of subarachnoid and intraventricular haemorrhage on the initial CT scan is the most important factor predicting delayed cerebral ischaemia and cerebral infarction and is a prognostic factor for outcome.47 Qualitative, semiquantitative, and quantitative scales have been proposed to measure the extent of damage.49,50 SAH=subarachnoid haemorrhage.

Table 2: Scales used to determine severity of SAH and intraventricular haemorrhage using the Fisher, Claassen, Modified Fisher, and Hijdra scales

US guidelines58 suggest that treatment in centres that manage a high number of patients improves outcome from subarachnoid haemorrhage, and this observation has been supported by a meta-analysis.64 Although it is unclear whether patients at different sites are matched for prognostic factors for outcome, referral to high-volume centres is recommended. Whether to repair an aneurysm by endovascular coiling or neurosurgical clipping depends on patient age; clinical condition, including presence of large intracranial haematomas that need urgent extraction; associated illnesses; the size, shape, and location of the ruptured aneurysm; any additional aneurysms present and the certainty that exists as to which one bled; estimated risks of treatment of the aneurysm by clipping or coiling; and the available equipment and skills of the individuals doing the procedure.65 For aneurysms treatable by either endovascular coiling or neurosurgical clipping, endovascular repair is recommended. A meta-analysis of four randomised trials66 showed that coiling reduced the risk of unfavourable outcome at 1 year to 23% compared with 34% after clipping (OR 1∙48, 95% CI 1∙24–1∙76), with no difference in mortality. In the largest trial,67 the odds of being alive and independent after 10 years were significantly better after coiling (1·34, 1·07–1·67) than after clipping. Acute hydrocephalus occurs in 20% of patients with aneurysmal subarachnoid haemorrhage.68,69 Insertion of a ventricular catheter is indicated in patients with grade 2 or higher on the World Federation of Neurosurgical Surgeons scale and can be life saving.70 Hydrocephalus resolves spontaneously within 24 h in 30% of patients but can worsen and be rapidly lethal (figure 4).71 Deterioration 6

occurred in 143 (22%) of 660 patients in one study72 and was predicted by further subarachnoid haemorrhages identified by CT, intraventricular haemorrhage, hydrocephalus, and use of tranexamic acid. Reluctance to insert a ventricular catheter is based on the risks of infection, intracerebral haemorrhage or intraventricular haemorrhage, and precipitating rebleeding of the aneurysm. Dey and colleagues73 analysed 33 studies with 9667 cases from the scientific literature and showed a pooled infection prevalence of 7∙9% (95% CI 6∙3–8∙4) and haemorrhage prevalence of 8∙4% (5∙7–11∙1). Most infections are readily treatable and haemorrhage associated with ventricular drainage that is symptomatic is rare, with a prevalence of 0∙7% (0∙4–1∙1).73 Rebleeding from the aneurysm is reported in association with ventricular drainage in 0–43% of cases but many believe that this rebleeding is rarely due to the ventricular drainage itself.70 With the risks of untreated hydrocephalus and low risk of ventricular drainage, one should not hesitate to insert a ventricular catheter if in doubt. Rebleeding could be minimised by avoidance of excessive intracranial pressure reduction and by early aneurysm repair. Patients unable to be weaned from drainage or who develop delayed hydrocephalus require permanent CSF diversion (figure 4). In a retrospective Australian cohort74 of 10 807 patients with subarachnoid haemorrhage, 701 (7%) required shunts. This figure varies widely dependent on physician practice. Multivariate analysis showed that poor grade at admission, acute hydrocephalus, intraventricular haemorrhage, ruptured vertebral artery aneurysm, meningitis, and long-lasting ventricular drainage were predictors of shunt dependency.74 Fenestration of the

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lamina terminalis and third ventriculostomy have been used to try to reduce the need for permanent CSF diversion.75,76 There are no randomised trials that make use of these techniques and a meta-analysis of studies of fenestration of the lamina terminalis showed that the technique was ineffective.75 An alternative to ventricular drainage is lumbar drainage but this technique can be done only when there are no intracranial space-occupying haematomas or substantial intraventricular haemorrhage. Even in the absence of these conditions there is risk of neurological deterioration after this procedure due to herniation. Lumbar drainage was studied in a randomised trial77 and shown to reduce delayed cerebral ischaemia but to have no effect on outcome at 6 months. Increased intracranial pressure (>20 mm Hg) occurs in more than 50% of patients with aneurysmal subarachnoid haemorrhage.78 Causes include brain swelling from the initial haemorrhage, acute hydrocephalus, cerebral infarction, and cerebral oedema. Reducing increased intracranial pressure associated with acute hydrocephalus or intracerebral haemorrhage can be life saving and increases the chances of favourable outcome (figure 4).79 However, in cases of extensive cerebral infarction and brain swelling, this increased pressure could indicate irreversible brain damage and treatment might be futile. There are few studies of treatments for increased intracranial pressure after subarachnoid haemorrhage and most recommendations are derived from traumatic brain injury, which recommend some combination of maintaining intracranial pressure at less than 20 mm Hg and cerebral perfusion pressure at 50–70 mm Hg.80 Extrapolation of these recommendations to subarachnoid haemorrhage is speculative and might require revision when studies of intracranial pressure and cerebral perfusion pressure thresholds are done in this condition. Partial or generalised seizures or abnormal movements occur at the time of aneurysmal subarachnoid haemorrhage in 4–26% of patients and later in the acute hospital course in 1–28% of patients.81 In one randomised trial,82 nine (65%) of 14 seizures that occurred after admission but before aneurysm repair were associated with rebleeding, probably as a result rather than as a cause of rebleeding. Long-term epilepsy develops in 2% of patients with subarachnoid haemorrhage but severity of the haemorrhage is a key factor in the risk for developing epilepsy, with more than 25% risk in patients with a severe haemorrhagic outcome. Risk factors for seizures in hospital and in the long term include younger age, loss of consciousness at ictus, history of hypertension, middle cerebral artery aneurysm, severe subarachnoid haemorrhage on CT, intracerebral haematoma, subdural haematoma, aneurysm repair by clipping compared with coiling, and delayed cerebral ischaemia.81,83 To our knowledge, no randomised trials have been done of anticonvulsant drugs in patients with aneurysmal subarachnoid haemorrhage, so drug selection, duration

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Figure 4: Management of acute and chronic hydrocephalus and intracerebral haemorrhage in three cases A 56-year-old woman collapsed and was brought to hospital. Initial modified Glasgow Coma Score was 6T or 9 (imputed). She was intubated and CT scan showed subarachnoid haemorrhage (A) and acute hydrocephalus (B), measured as above the 95th percentile for age by the ventriculocranial or bicaudate ratio (VCR), measured by thewidth of the frontal horns at the level of the foramen of Monro where the lateral walls of the frontal horns are parallel, divided by the internal diameter of the skull at the same level (VCR 2·15/10·11 = 0·21).51 The upper 95th percentile is 0·16 for less than 30 years old, 0·18 for 50 years old, 0·19 at 60 years old, 0·21 for 80 years old, and 0·25 for 100 years old. A ventricular catheter was inserted 11 h after the ictus and the left middle cerebral aneurysm clipped through a pterional craniotomy 17 h after the ictus. Preoperative CT angiography (C) showed that the aneurysm that was repaired as supported by intraoperative indocyanine green angiography. The patient remained in poor condition and was transferred to chronic care. The patient remained bedridden and minimally responsive to her family 3 months later, when a CT scan (D) showed chronic hydrocephalus (VCR 3·14/9·86 = 0·32). A ventriculoperitoneal shunt was inserted. 8 months later, a year after subarachnoid haemorrhage, the patient almost fully recovered and was at home, independent, and functioning normally apart from fatigue and anxiety about having another subarachnoid haemorrhage (E, VCR 1·97/9·99 = 0·20). A 28-year-old woman had sudden onset severe headache. She had a modified Glasgow Coma Score of 15 and a CT scan (F, G) showed diffuse subarachnoid haemorrhage with mild ventricular enlargement (VCR 1·42/11·34 = 0·13). A CT angiography showed an anterior communicating artery aneurysm (H). Her consciousness deteriorated 11 h later. A CT scan showed dilation of the left lateral ventricle and obliteration of the subarachnoid sulci. (I). Mannitol did not result in improvement. Both pupils became dilated 14 h later and a ventricular catheter was inserted. The intracranial pressure progressively increased, was intractable to medical management, and the patient was brain dead 2 days later (J). A 49-year-old woman developed sudden headache and right hemiparesis. Modified Glasgow Coma Score was 12 and CT scan showed subarachnoid haemorrhage and intracerebral haemorrhage (K, L) consistent with left middle cerebral artery aneurysm. During transport to the neurosurgical centre, she deteriorated and had a modified Glasgow Coma Score of 4. She was intubated on arrival 4 h after ictus and underwent CT and CT angiography that showed an increase in the left intracerebral haemorrhage and a left middle cerebral artery aneurysm (M, N). She underwent immediate craniotomy, clipping of the aneurysm, evacuation of the haemorrhage, insertion of a ventricular catheter, and decompressive craniectomy. The bone flap was replaced 3 months later (O). She was ambulatory with a cane but had residual dysphasia and hemiparesis and was unable to resume work 30 months later.

of treatment, type of patient population, and drug dosage are open to question. Anticonvulsants, particularly phenytoin, have been associated with unfavourable outcome after subarachnoid haemorrhage.84 We recommend anticonvulsants only in patients with documented seizures. Patients might deteriorate days after subarachnoid haemorrhage for many reasons (appendix).26 Delayed cerebral ischaemia occurs 3–14 days after haemorrhage and is the most important complication because no

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highly effective treatment exists.85 Delayed cerebral ischaemia is diagnosed when other causes are ruled out or deemed insufficient to cause the neurological changes.86 Cerebral infarction from delayed cerebral ischaemia remains the most important cause of morbidity in patients surviving the initial haemorrhage.87,88 The pathophysiology of delayed cerebral ischaemia is postulated to include an interaction of delayed onset of angiographic vasospasm, impaired autoregulation, microthrombosis, capillary transit time heterogeneity, and cortical spreading ischaemia.26,89–91 The strongest predictors of delayed cerebral ischaemia are the severity of subarachnoid haemorrhage on admission CT scan and poor neurological grade, but multiple factors contribute and prediction remains inaccurate.26,92 Diagnosis also is imprecise and made more difficult since many patients are sedated or already neurologically impaired.93 Algorithms for diagnosis of delayed cerebral ischaemia vary from clinical examination alone to invasive monitoring and frequent CT angiography, CT perfusion studies, and even routine digital subtraction angiography.26,59 Despite many randomised trials,26,94 the only pharmacological drug shown to reduce the risk of delayed cerebral ischaemia and unfavourable outcome is nimodipine. Guidelines suggest oral nimodipine be started within 96 h of subarachnoid haemorrhage.58–60 Meta-analyses53,95,96 of fasudil, intrathecal fibrinolytics, and cilostazol randomised trials hint at efficacy but these findings require further study. In an effort to understand why many treatments have not shown efficacy, an international cooperative group has pooled individual patient data from multiple randomised trials and databases to inform clinical trial design, develop common data elements, and promote conduct of early stage trials at multiple centres rather than independent, staggered designs with incomparable protocols.97–99 Principles of management of delayed cerebral ischaemia are to counteract reduced delivery of oxygen and glucose to the brain.26,59 These principles include monitoring of the neurological exam and maintaining normal body temperature, body fluid volumes, haemoglobin, glucose, electrolytes (particularly sodium and magnesium), maintain adequate nutrition, and mobilise the patient (panel). Aneurysmal subarachnoid haemorrhage is associated with natriuresis (salt wasting) and decreased body water secondary to raised natriuretic peptides, renin activity, aldosterone, catecholamines, and arginine vasopressin.100 Maintenance of normovolaemia and normal serum sodium is recommended, but how monitoring of these variables can be achieved is not defined.58–60 Prophylactic treatments for delayed cerebral ischaemia, such as inducing hypervolaemia, hypertension, hypermagnesaemia, and hypothermia, have not been beneficial and are not recommended.58–60 Treatment of a patient who deteriorates from delayed cerebral ischaemia 8

is one of the most controversial areas in management of aneurysmal subarachnoid haemorrhage. None of the widely used so-called rescue therapies have been studied or proven efficacious in randomised trials; their use varies greatly between countries and centres and they might be ineffective or even detrimental.101 Guidelines from the American Heart Association state that induced hypertension is recommended for patients with delayed cerebral ischaemia unless their blood pressure is already raised. In this case, endovascular pharmacological or mechanical angioplasty is a reasonable option.58 The European Stroke Organization simply states that there is no evidence from controlled studies for use of induced hypertension and does not address endovascular therapies.60 Probably the most common approach for delayed cerebral ischaemia is to institute induced hypertension and angioplasty with balloons or selective vasodilator drug infusions.26,59 Guidelines from several countries and associations have been created to address the management of systemic complications (panel).58–60 Rebleeding and delayed cerebral ischaemia have declined as causes of morbidity and mortality and as a result, medical complications are an increasingly important factor in outcome.54,55 Up to 80% of patients will develop a serious medical complication, which increases the risk of secondary brain injury and delayed cerebral ischaemia.102 In one series102 of 580 patients, fever, hyperglycaemia, or anaemia occurred in 30–54% of patients and were independently associated with poor outcome after adjustment for the prognostic variables of age, clinical grade, aneurysm size, rebleeding, and cerebral infarction due to angiographic vasospasm.

Prognosis Regarding short-term outcome, a meta-analysis103 of 33 studies found a case fatality of 8∙3–66∙7% in patients with subarachnoid haemorrhage. The median of patients who died before arrival to hospital was 8·3%. In another meta-analysis,104 there was an absolute annual reduction rate in 30 day mortality of 0∙9% (95% CI 0∙3–1∙5) between 1980 and 2005, for an overall 50% reduction. Data for functional outcome in population-based studies are scarce. It is estimated that 55% of patients regain independent function, 19% remain dependent, and 26% die.103 Many outcome scales have been developed to assess neurological and cognitive outcomes and quality of life after brain injury, including the Glasgow and extended Glasgow outcome scales, modified Rankin scale, Short Form-36, Mini-Mental Status Examination, Montreal cognitive assessment, and Barthel index. None of these tests were developed specifically for subarachnoid haemorrhage. Patients with favourable outcome (eg, modified Rankin scale ≤3 or Glasgow outcome scale ≥4) frequently have deficits in cognitive domains (eg, verbal memory, language, and executive function), decreased decision-making capacity expressed

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by cognitive inflexibility, enhanced risk-taking behaviour, and decreased quality of life for years after subarachnoid haemorrhage.105 Additionally, these deficits are frequently accompanied by mood disorders, fatigue, and sleep disturbances.105 A systematic review106 identified factors at hospital admission that were associated with unfavourable outcome according to the Glasgow outcome score or modified Rankin score and included worse admission neurological condition, older age, aneurysm repair by clipping rather than coiling, more severe subarachnoid haemorrhage on CT scan, history of hypertension, larger aneurysm, and posterior circulation aneurysm. Only 25% of the variation in outcome is explained by these variables, indicating that other factors (eg, genetic, epigenetic, disease-related factors) have substantial effects on outcome or that outcome scales are imprecise. In the long term, many patients who survive subarachnoid haemorrhage continue to have the abovenoted deficits in cognition, quality of life, mood, and fatigue.105 Patients who have had subarachnoid haemorrhage have a 15 times higher risk of a second haemorrhagic event than do the general population.107 Their long-term standardised mortality ratio is 1·5, in excess of the general population, and mostly related to cardiovascular and cerebrovascular disease.108

Prevention Subarachnoid haemorrhage could be prevented by repairing aneurysms before they rupture or by reducing aneurysm formation. Unruptured aneurysms had a prevalence of 3·2% in 83 study populations.11 No randomised trials exist on which to base the decision to repair an unruptured aneurysm, and the risks of rupture have to be weighed against the risks of repair.11 Several systems have been developed to aid the clinician in decision making. A systematic review8 pooled analysis of 8382 patients who had 230 subarachnoid haemorrhages during 29 166 combined years of follow-up and showed that age, hypertension, aneurysm size and location, and geographical location were associated with rupture. These factors were used to develop a risk score (PHASES: population, hypertension, age, size, earlier subarachnoid haemorrhage, site). Another system developed by Delphi consensus by a panel of experts and included these factors plus family history, medical comorbidities, life expectancy, presence of daughter loci, growth or de-novo aneurysm formation, symptoms other than rupture, and risk of repair, which was not addressed in PHASES.109 Formation of new aneurysms in patients who have had subarachnoid haemorrhage is increasingly recognised. In one study110 of 752 patients followed up for 6016 patientyears, recurrent subarachnoid haemorrhage occurred in 3∙2% (95% CI 1∙5–4∙9) or about 22 times more frequently than in the general population. Increased likelihood of recurrence was observed with smoking (hazard ratio [HR] 6·5, 95% CI 1·7–24·0), increased age

Panel: Recommended management of subarachnoid haemorrhage • Admit to hospital and monitor patient with frequent clinical and neurological assessments in critical care settings. • CT and vascular imaging (CT or catheter angiography) and aneurysm repair to be done as soon as possible. • Urgent surgery to evacuate space-occupying intracerebral haemorrhage and clip aneurysm or insert ventricular catheter to drain symptomatic hydrocephalus. • Administer enteral nimodipine. • Administer antihypertensives to reduce blood pressure before aneurysm repair, but should be avoided after aneurysm repair unless blood pressure is substantially raised. • Maintain normal body temperature and avoid fever, hypothermia, extremes in glucose concentration, hypercarbia, hypoxia, hypomagnesaemia, decreased cerebral perfusion pressure, hypovolaemia, and hyponatraemia. • Maintain normovolaemia and use measures necessary to do so (intravenous fluids, monitor volume status, possible central venous access, bodyweights). • Rapidly investigate neurological deterioration and treat underlying causes and consider perfusion imaging to find out whether arterial narrowing is a cause of deterioration. • Apply graduated compression stockings or intermittent pneumatic compression devices on lower limbs and consider pharmacological prophylaxis for venous thromboembolism beginning 24 h after aneurysm repair. • Give anticonvulsants for the treatment of seizures (not prophylaxis). • After electrocardiography on admission, consider investigation for cardiac injury if there are clinical signs of this or there is stunned myocardium, takotsubo cardiomyopathy, or increased cardiac troponin I. • Minimise blood loss, maintain normal haemoglobin, or transfuse for anaemia, but transfusion thresholds are unknown. • If a patient develops delayed cerebral ischaemia, treat with induced hypertension. Endovascular balloon or pharmacological angioplasty are reasonable. Both are of unproven effectiveness and carry substantial risks. • Follow up the patient after discharge and provide physical, neurological, occupational, and cognitive rehabilitation. Consider diagnosis and treatment of depression, anxiety, and post-traumatic stress disorder and whether patient and family members should be screened for aneurysms in follow up. • Support adequate and well-controlled randomised clinical trials since other than enteral nimodipine and timely aneurysm repair by coiling, none of the above recommendations are based on robust data. The history of subarachnoid haemorrhage is similar to other areas of medicine in which anecdote leads to adoption of management that is of unproven efficacy and safety until shown in high-quality randomised trials.

(0·5 per 10 years, 0·3–0·8), and multiple aneurysms at time of their first haemorrhage (5·5, 2·2–14·1).110 In another series,111 220 patients with subarachnoid haemorrhage were followed up for 3–17 years (mean of 11 years). The cumulative risk of recurrence was 2·2% at 10 years and 9·0% at 20 years, rates that were more than ten times higher than those in the general population. The incidence of aneurysms identified by screening depends on the population screened such as the number with a positive family history and risk factors for aneurysm formation and rupture (appendix). In a study from Sweden, 112 the odds ratio for subarachnoid haemorrhage was 2 (95% CI 1∙8–2∙6) if the patient had one first-degree relative with the disorder, and 51 (9–1117) if there were two first-degree relatives.

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Bor and colleagues113 screened 458 patients with a family history of aneurysms or subarachnoid haemorrhage and showed that 10% had aneurysms. Screening every 5 years in subsets of these patients detected new aneurysms in about 5%, even if no aneurysms were initially seen. A familial aneurysm study12 identified aneurysms in 21% of family members of a high-risk subgroup of hypertensive smokers. Screening is recommended for first-degree relatives if the patient has two or more first-degree relatives with aneurysms or subarachnoid haemorrhage.11 Angiography with CT or MR are acceptable methods for screening these patients. Patients with coarctation of the aorta, ADPKD, and twins if one twin has an aneurysm or subarachnoid haemorrhage, are suggested for screening at an arbitrary interval of 5 years.114 The screening interval, whether to screen other lower-risk groups, and the effect of screening on quality of life have been controversial.11 Screening might be done in lower-risk groups if siblings of patients who have had a subarachnoid haemorrhage at a young age volunteer and if an unruptured aneurysm is identified and not repaired. Patients who have a subarachnoid haemorrhage at a young age, especially if they are female, smokers, or have multiple aneurysms also fulfil this criteria.11,114,115 Screening should be repeated yearly for 1–3 years, and then less frequently if the aneurysm remains unchanged in size and shape.11,115 Contributors TS searched the literature, wrote the initial draft of the manuscript and made revisions. RLM searched the literature, rewrote the initial draft, made multiple revisions, designed the illustrations and submitted the manuscript. Declaration of interest RLM is Chief Scientific Officer of Edge Therapeutics, Inc. TAS declares no competing interests.

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Acknowledgments TAS receives grant support from the Canadian Institutes of Health Research, Ministry of Research and Development, and the Heart and Stroke Foundation of Canada. RLM receives grant support from the Physicians Services Incorporated Foundation, Brain Aneurysm Foundation, Canadian Stroke Network, and the Heart and Stroke Foundation of Ontario. This work was conducted independently of the funders and does not necessarily reflect their opinions.

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www.thelancet.com Published online September 13, 2016 http://dx.doi.org/10.1016/S0140-6736(16)30668-7