Subarachnoid haemorrhage (spontaneous aneurysmal)

Abstract

Introduction

Subarachnoid haemorrhage (SAH) may arise spontaneously or as a result of trauma. Spontaneous SAH accounts for about 5% of all strokes. Ruptured aneurysms are the cause of 85% of spontaneous SAH. The most characteristic clinical feature is sudden-onset severe headache. Other features include vomiting, photophobia, and focal neurological deficit or seizures, or both. As the headache may have insidious onset in some cases, or may even be absent, a high degree of suspicion is required to diagnose SAH with less typical presentations.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of surgical treatments for people with confirmed aneurysmal subarachnoid haemorrhage? What are the effects of medical treatments to prevent delayed cerebral ischaemia in people with confirmed aneurysmal subarachnoid haemorrhage? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 6 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: endovascular coiling; surgical clipping; timing of surgery; and oral and intravenous nimodipine.

Key Points

Subarachnoid haemorrhage (SAH) may arise spontaneously or as a result of trauma. Spontaneous SAH accounts for about 5% of all strokes. Ruptured aneurysms are the cause of 85% of spontaneous SAH. This review deals with only spontaneous aneurysmal SAH.

• Without treatment, mortality rates of about 50% at 1 month after spontaneous aneurysmal SAH have been reported.

Treatment is aimed at prevention of re-bleeding from the same aneurysm. This can be performed by surgical clipping or by endovascular coiling.

• In people suitable for either procedure, endovascular coiling has lower rates of poor functional outcome compared with surgical clipping, but it is also associated with increased rate of recurrent haemorrhage from the treated aneurysm and a higher rate of re-treatment for the same aneurysm. Most evidence is in small (<11 mm) aneurysms of the anterior circulation. Therefore, the conclusions cannot be applied to all aneurysms (particularly large and giant aneurysms, and aneurysms with broad necks).

• Factors that should be considered when deciding on the method of treatment include the morphology of the aneurysm, the age and clinical condition of the person, and the presence or absence of a space-occupying intracranial haematoma.

We do not know the optimal timeframe for carrying out surgical clipping or endovascular coiling after aneurysmal SAH. However, early surgery will prevent re-bleeding from the aneurysm, and is preferred in most people.

Oral nimodipine reduces poor outcome (death or dependence), secondary ischaemia, and CT/MRI evidence of infarction after aneurysmal SAH.

We found no evidence on the effects of intravenous nimodipine alone.

About this condition

Definition

Subarachnoid haemorrhage (SAH) is a type of haemorrhagic stroke in which there is bleeding into the subarachnoid space. It can be subdivided into traumatic SAH and spontaneous (non-traumatic) SAH. This review deals with only spontaneous aneurysmal SAH. Diagnosis: The most characteristic clinical feature is sudden-onset severe headache. Other features include vomiting, photophobia, neck stiffness, impaired level of consciousness, acute confusional state, agitation/restlessness, and focal neurological deficit or seizures, or both. As the headache may have insidious onset in some cases, or may even be absent, a high degree of suspicion is required to diagnose SAH with these less typical presentations. Examination findings may include a reduced level of consciousness, confusion/agitation, nuchal rigidity, retinal haemorrhage, or focal neurological signs (e.g., cranial nerve palsies and hemiplegia).When SAH is suspected, an unenhanced CT scan of the head should be obtained as soon as possible. However, CT scan does not always identify the haemorrhage, and the false-negative rate increases with time after the bleed. In a prospective observational study of 3451 people with confirmed SAH, 3% (51/1553) had a normal CT scan within 24 hours of ictus. By day 5, 27% (9/33) had a normal CT scan. Even if the CT scan is done within 12 hours of ictus, 2% (95% CI 0.2 to 6) of people have a normal scan. Therefore, a lumbar puncture should be performed in anyone with suspected SAH and a normal CT scan. CSF findings in SAH may include elevated opening pressure, uniformly blood-stained CSF across all tubes, excess red blood cell count, and elevated protein or lymphocytic cellular reaction, or both. However, to differentiate genuine SAH from a traumatic tap (blood introduced into the needle at the time of lumbar puncture), CSF must be analysed for presence of xanthochromia (yellow discoloration of supernatant after centrifugation of CSF, caused by the presence of bilirubin). It has been recommended that the lumbar puncture should be delayed until 12 hours after the onset of symptoms (unless meningitis is suspected) to allow sufficient time for haemoglobin to degrade into oxyhaemoglobin and bilirubin. Earlier sampling may produce false-negative results. The colour of the supernatant should be compared with water against a white background, in bright light. Yellow discoloration of the supernatant (xanthochromia) indicates SAH. To reduce the subjectivity of this test, it has been recommended that CSF should, in all cases, be examined for bilirubin and oxyhaemoglobin using spectrophotometry, rather than by visual inspection alone. In a study of 111 people with CT-confirmed SAH, the sensitivity of CSF spectrophotometry was reported to be 100% up to 2 weeks after the ictus. However, the false-negative rate of spectrophotometry in the diagnosis of SAH in CT-negative people is not known. If a person presents more than 2 weeks after the onset of symptoms, no test can rule out SAH with 100% certainty, although MRI (particularly fluid-attenuated inversion recovery [FLAIR] and gradient echo sequences) may be useful in detecting subarachnoid blood in some people. The sensitivity of CSF spectrophotometry drops significantly after 2 weeks, decreasing to 90% by 3 weeks post-bleed. These people should be referred urgently to a neuroscience unit for consideration of further investigations.The correct diagnosis of SAH is pivotal to successful outcome. Pitfalls in diagnosis include: (1) the headache of SAH does not have any specific distinguishing features and may resemble migraine; (2) the pain of SAH may be relieved by migraine acute-attack treatments such as triptans — response to a triptan may provide false and unjustified reassurance; (3) there is an over-reliance on the classical presentation of the reported feeling of a "sudden blow to the head"; (4) because SAH may often cause fever, some people may be misdiagnosed as having meningitis; (5) approximately 20% of people with SAH develop cardiac arrhythmia, and some people will have an ECG suggestive of ischaemia (thrombolysis can have disastrous consequences in this situation); (6) people may occasionally present with an isolated acute confusional state; (7) people may present in a coma; and (8) in some people the predominant feature may be vomiting, leading to gastrointestinal investigations. Once SAH has been confirmed by CT scan or CSF examination, the source of haemorrhage must be identified. The gold-standard technique is catheter cerebral angiography. However, CT angiography (CTA) and magnetic resonance angiography (MRA) provide non-invasive means of diagnosing a cerebral aneurysm. A systematic review found that, for aneurysms larger than 3 mm, the sensitivity of CTA was 96% (95% CI 94% to 98%) and of MRA was 94% (95% CI 90% to 97%). For aneurysms 3 mm or smaller, the sensitivity of CTA was 61% (95% CI 51% to 70%) and of MRA was 38% (95% CI 25% to 53%). In people with confirmed SAH in whom CTA or MRA is negative, catheter angiography must be performed.

Incidence/ Prevalence

Spontaneous SAH accounts for about 5% of all strokes. In most populations, the incidence of SAH is 7.8/100,000 population a year (95% CI 7.2/100,000 to 8.4/100,000). However, the incidence has been reported to be markedly higher in Finland (21.4/100,000 a year, 95% CI 19.5/100,000 to 23.4/100,000). The incidence in women is 1.6 times that in men (95% CI 1.1 to 2.3).

Aetiology/ Risk factors

Ruptured aneurysms are the cause of 85% of spontaneous SAHs. Other causes of spontaneous SAH include benign perimesencephalic SAH, other idiopathies, some drugs (e.g., amphetamines), coagulation disorders, vascular malformations, dural venous sinus thrombosis, tumours, and vasculitides. The exact aetiology of intracranial aneurysms remains unclear. Risk factors include smoking (RR 2.2, 95% CI 1.3 to 3.6), hypertension (RR 2.1, 95% CI 2.0 to 3.1), and excessive alcohol intake (RR 2.1, 95% CI 1.5 to 2.8). Genetic factors may also be involved. Aneurysms are associated with defined heritable disorders, including connective tissue disorders and autosomal dominant polycystic kidney disease. They may also occur in a familial setting.

Prognosis

Aneurysmal SAH has a poor prognosis, particularly if the aneurysm is not occluded. Observational studies from the 1960s reported mortality rates of 10% to 32% on day 1, 27% to 43% during the first week, and 49% to 56% at 1 month after SAH. Most deaths occur as a result of re-bleeding from the same aneurysm. If untreated, re-bleeding occurs in 15% of people on day 1, and in 40% of people by 1 month after SAH. The rate of re-bleeding decreases with time to 3% a year after the initial 6 months. A systematic review of population-based studies found that the overall case fatality rate after aneurysmal SAH ranged from 32% to 67%. It also found that the case fatality rates had decreased by +0.5% a year (95% CI –0.1% to +1.2%) between 1960 and 1992, suggesting that improved management of people with SAH may be the reason for the better outcomes. A more recent population-based study found a case fatality rate of 39% (95% CI 34% to 44%). These reported case fatality rates include people who die before reaching hospital, which was found in a meta-analysis of population-based studies to be 12.4% (95% CI 11% to 14%). Between 10% and 20% of all people with SAH (17%–46% of survivors) become dependent. As well as physical disability, SAH results in cognitive impairment in a large number of people. In a population-based study, 105/230 (46%) of survivors interviewed at 1 year reported incomplete recovery, with ongoing problems with memory (50%), mood (39%), and speech (14%).

Aims of intervention

To reduce mortality and disability (neurological and other); to reduce secondary complications of SAH, to prevent re-bleeding (recurrent haemorrhage from the same aneurysm); and to decrease rates of delayed cerebral ischaemia, with minimal adverse effects of treatment.

Outcomes

Mortality or disability: disability measured by scales such as Modified Rankin Scale, Glasgow Outcome Scale, and dependency on others to carry out daily tasks (measured as a component of scale used to rate disability); neuropsychological outcomes; quality of life; rate of re-bleeding (recurrent haemorrhage from the same aneurysm); risk of seizures/epilepsy; secondary cerebral ischaemia;cerebral infarction; and adverse effects of treatment.

Methods

Clinical Evidence search and appraisal March 2009. The following databases were used to identify studies for this systematic review: Medline 1966 to March 2009, Embase 1980 to March 2009, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2009, Issue 1 (1966 to date of issue). An additional search was carried out of the NHS Centre for Reviews and Dissemination (CRD) — for Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single-blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied, applying the same study design criteria for inclusion as for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Subarachnoid haemorrhage (spontaneous aneurysmal).

Important outcomes	Cerebral infarction, Mortality and disability, Mortality or disability, Quality of life, Rate of re-bleeding, Secondary cerebral ischaemia
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of surgical treatments for people with confirmed aneurysmal subarachnoid haemorrhage?
3 (2243)	Mortality or disability	Endovascular coiling versus surgical clipping	4	–1	0	–1	0	Low	Quality point deducted for significant difference between groups in length of time between SAH and treatment. Directness point deducted for narrowness of included population affecting generalisability
3 (2272)	Rate of re-bleeding	Endovascular coiling versus surgical clipping	4	–1	0	–1	0	Low	Quality point deducted for significant difference between groups in length of time between SAH and treatment. Directness point deducted for narrowness of included population affecting generalisability
2 (129)	Secondary cerebral ischaemia	Endovascular coiling versus surgical clipping	4	–2	0	–1	0	Very low	Quality points deducted for sparse data and significant difference between groups in length of time between SAH and treatment. Directness point deducted for narrowness of included population affecting generalisability
1 (211)	Mortality and disability	Early surgery versus intermediate surgery or late surgery	4	0	0	–2	0	Low	Directness points deducted for narrowness of included population affecting generalisability of results, and for techniques used in RCT possibly being inapplicable to modern practice
1 (211)	Rate of re-bleeding	Early surgery versus intermediate surgery or late surgery	4	–1	0	–2	0	Low	Quality point deducted for sparse data. Directness points deducted for narrowness of included population affecting generalisability of results, and for techniques used in RCT possibly being inapplicable to modern practice
1 (211)	Secondary cerebral ischaemia	Early surgery versus intermediate surgery or late surgery	4	0	0	–2	0	Low	Directness points deducted for narrowness of included population affecting generalisability of results, and for techniques used in RCT possibly being inapplicable to modern practice
What are the effects of medical treatments to prevent delayed cerebral ischaemia in people with confirmed aneurysmal subarachnoid haemorrhage?
4 (at least 899)	Mortality and disability	Oral nimodipine versus placebo	4	–1	0	0	0	Moderate	Quality point deducted for inclusion of co-intervention
4 (at least 899)	Rate of re-bleeding	Oral nimodipine versus placebo	4	–1	0	0	0	Moderate	Quality point deducted for inclusion of co-intervention
4 (390)	Secondary cerebral ischaemia	Oral nimodipine versus placebo	4	–1	0	0	0	Moderate	Quality point deducted for inclusion of co-intervention
2 (634)	Cerebral infarction	Oral nimodipine versus placebo	4	–1	0	0	0	Moderate	Quality point deducted for inclusion of co-intervention
2 (535)	Mortality and disability	Intravenous plus oral nimodipine versus placebo or no nimodipine	4	–1	0	0	0	Moderate	Quality point deducted for inclusion of co-intervention
1 (120)	Rate of re-bleeding	Intravenous plus oral nimodipine versus placebo or no nimodipine	4	–2	0	0	0	Low	Quality points deducted for sparse data and inclusion of co-intervention
2 (535)	Secondary cerebral ischaemia	Intravenous plus oral nimodipine versus placebo or no nimodipine	4	–1	0	0	0	Moderate	Quality point deducted for inclusion of co-intervention
2 (280)	Cerebral infarction	Intravenous plus oral nimodipine versus placebo or no nimodipine	4	–1	0	0	0	Moderate	Quality point deducted for inclusion of co-intervention

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Glasgow Outcome Scale (GOS)

A 5-point scale widely used to assess outcome after head injury. Score of 5 = good recovery (able to return to work or school); score of 4 = moderate disability (disabled but able to live independently); score of 3 = severe disability (dependent on daily support); score of 2 = persistent vegetative state; score of 1 = dead.

Hunt and Hess grade

A clinical grading system for subarachnoid haemorrhage. Grade 1 = asymptomatic, or mild headache and slight nuchal rigidity; Grade 2 = cranial nerve palsy, moderate-to-severe headache, nuchal rigidity; Grade 3 = mild focal deficit, lethargy or confusion; Grade 4 = stupor, moderate-to-severe hemiparesis, early decerebrate rigidity; Grade 5 = deep coma, decerebrate rigidity, moribund appearance. One grade is added for comorbid serious systemic disease (e.g., hypertension, diabetes mellitus, severe atherosclerosis, or COPD) or severe vasospasm on angiography.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Modified Rankin Score (mRS)

A 6-point scale used to assess functional outcome after stroke. Only symptoms that become apparent after stroke are considered. Grade 0 = I have no symptoms at all; Grade 1 = I have some symptoms but I am able to carry out all usual duties and activities; Grade 2 = I am unable to carry out all previous activities but I am able to look after my own affairs without help from another person; Grade 3 = I require some help, but I am able to walk without help from another person; Grade 4 = I am unable to walk without help from another person or I am unable to attend to my own bodily needs without help from another person, or both; Grade 5 = I am bedridden, incontinent, and require constant nursing care and attention.

Very low-quality evidence

Any estimate of effect is very uncertain.

World Federation of Neurosurgical Societies (WFNS) grade

A clinical grading system for subarachnoid haemorrhage based on the Glasgow Coma Scale (GCS) score, and presence or absence of focal neurological deficit. The WFNS grade is an important prognostic factor. Grade 1 = GCS 15 with no focal neurological deficit; Grade 2 = GCS 13–14 and no focal neurological deficit; Grade 3 = GCS 13–14 with focal neurological deficit; Grade 4 = GCS 7–12 with or without focal neurological deficit; Grade 5 = GCS 3–6 with or without focal neurological deficit.

Specialised care in people with acute stroke (see stroke management review)

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.