Non-traumatic Subarachnoid Haemorrhage

Non-traumatic subarachnoid haemorrhage (SAH) accounts for about 5% of all strokes with an incidence in Western populations of 6-10 cases per 100,000 person years [1-3].

Many people die from SAH before reaching hospital [4] and the overall case fatality rate is 45-50% [5,6]. Of those that do survive about a third are significantly disabled [6] both physically and cognitively.

Compared with other types of stroke, SAH affects a younger age group [7] (mean 50 years) and thereby has an even greater impact in terms of human and financial cost.

Patients with SAH are likely to present to the emergency department (ED) but misdiagnosis is often a problem [8,9]. Misdiagnosis of SAH is most likely in the neurologically pristine [9], the very population who have most to gain from timely treatment, with resultant human, financial and litigation cost [10]. Correct and early diagnosis is vital as it enables early definitive treatment and improved clinical outcomes [11].

Learning Bite

The overall mortality of SAH is 50%. Of survivors, one-third are significantly disabled [1-7].

Introduction

There are three main classes of non-traumatic SAH. These are:

• Aneurysmal SAH
• Non-aneurysmal SAH
• Vascular rarities such as arterio-venous malformations (AVMs), dissections, tumours and vasculitides

This session looks at aneurysmal and non-aneurysmal SAH. Vascular rarities will be covered in other sessions.

Aneurysmal SAH

About 75-80% of cases of non-traumatic SAH are due to rupture of a saccular aneurysm in the cerebral circulation [12].

Incidence

These aneurysms are found in approximately 2-3% of the population and are more common in older people [13].

Only 2% of relatives of patients with SAH are similarly affected and an increased risk is only attributed if two or more first degree relatives are involved [14].

The genetic predisposition to form intracerebral aneurysms has been studied with links found with polycystic kidney disease [15] and, rarely, with other connective tissue diseases.

Risk factors

Modifiable risk factors include [16]:

In most cases of SAH, the bleed is arterial with free communication between blood at arterial pressure and the subarachnoid space resulting in the characteristic abrupt onset of symptoms especially headache and loss of consciousness.

It has been proposed that perimesencephalic bleeds may be venous [20], the lower pressures causing a slower onset of symptoms and a smaller haemorrhage thus resulting in a better clinical picture and outcome.

The spread of blood in the subarachnoid space can lead to:

• Meningism
• Hydrocephalus
• Intraventricular haemorrhage
• Cerebral oedema
• Raised intracranial pressure (ICP)

In those patients who survive the initial insult, rebleeding and vasospasm are the major causes of morbidity and mortality. Attempts to prevent rebleeding (that is often catastrophic) are primarily directed at the timely identification and treatment of the cause of the SAH (usually an aneurysm).

Vasospasm can be apparent radiologically or clinically [21] and is a difficult phenomenon to understand. Though many theories have been postulated the only consistent predictor is that the severity of the vasospasm is related to the size of the haemorrhage [21].

Learning Bite

In patients who survive the initial haemorrhage the primary complications are rebleeding and vasospasm [14].

Other frequent complications of SAH include neurogenic cardiac dysfunction and electrolyte problems, particularly hyponatraemia, hyperglycaemia and hypomagnesaemia. Though these can be treated individually, the primary goal should always be the treatment of the anatomical cause for the SAH [11].

SAH can present in a number of different ways: from collapse with a reduced level of consciousness to acute confusion or seizures but, in those able to speak, the primary complaint is usually of sudden and severe headache [22].

Initial presentation and causes of non-traumatic SAH

Presentation to the ED with headache is common and represents 1-4% of attendances [23-25]. Causes range from benign tension headache or migraine to a catastrophic secondary cause including SAH.

Table 1: Important causes of secondary headache

Vascular	Stroke (ischaemic or haemorrhagic) Dissection of cranio-cervical arteries Hypertensive encephalopathy Giant cell arteritis Cerebral venous sinus thrombosis Pituitary apoplexy
Infective	Meningitis Encephalitis Abscess
Intracranial mass	Tumour Haematoma
Idiopathic intracranial hypertension
Acute angle closure glaucoma
CO poisoning
Spontaneous intracranial hypotension

SAH represents only 1-3% of all cases of ED headache though this may be as high as 12% if only worst ever headache is considered [26].

For more information on these topics, please see the sessions on Primary Headache and Secondary Headache in the Learning Curriculum.

Likelihood of SAH

The likelihood of SAH correlates well with a reduced Glasgow Coma Score (GCS) or the presence of abnormal neurological signs [27] but up to 50% of SAH patients have normal neurology at presentation [7,28].

Important correlates in the history are worst ever headache [26,27] particularly of rapid onset [28,29] and perhaps with associated seizure [27]. Additionally, it has recently been described that the findings of age > 40 years, neck pain and stiffness, limited neck flexion or transient loss of consciousness are associated with increased chance of SAH [30].

Onset of SAH

Usually, the onset is within seconds though sometimes minutes [27]. Expert opinion holds that, though the headache is usually awful, the suddenness of onset is more important than the severity in making the diagnosis [18].

A headache failing to reach maximal intensity within a few minutes is unlikely to be due to SAH [31,32]. Characteristically, the headache will last at least an hour [31,32] and usually 1-2 weeks [18].

Site and character of the headache are generally not helpful in making the diagnosis though, in the patient known to suffer from headaches, it is important to carefully elicit whether the onset, severity, quality and associated symptoms are typical or whether this presentation is different. Occasionally, the headache may be mild [33] or relieved with simple analgesia [34].

Associations

Association with physical exertion has been demonstrated [30,35] but most episodes of SAH occur at periods of relative inactivity [36].

The concept of the sentinel headache or herald bleed due to presumed aneurysm stretching or a small warning haemorrhage is a matter of some conjecture [37] and there are no other historical features that are helpful in the diagnosis [18,27].

The spectrum of clinical signs

Fig 3: ECG in a lady with SAH showing widespread T wave inversion

SAH may produce a wide spectrum of clinical signs. These may be specific e.g. subhyaloid haemorrhage and cranial nerve palsies or non-specific e.g. vomiting, pyrexia, meningism and visual disturbance.

SAH may cause hypertension or neurogenic pulmonary oedema and can mimic the ECG changes of acute myocardial ischaemia (Fig 3) or infarction leading to treatment delays. SAH is also a known cause of cardiac arrest [38].

Learning bite

Emergency physicians need to carefully assess all patients suspected of having a SAH. They should be aware of the potential pitfalls in assessment and investigation as well as understanding of the treatment measures that can be instituted within the ED to benefit the patient prior to arranging prompt transfer to a high volume neurosciences centre.

Should I Investigate for SAH?

The decision to investigate a patient for SAH rests largely on the history. The requirement to fully evaluate patients with reduced consciousness or a focal neurological deficit presents little difficulty. The challenge is greatest in patients with milder symptoms who are neurologically pristine [9]. Misdiagnosis in this group results in increased morbidity and mortality in those who have most to benefit from timely treatment.

The question of which ED patients with acute headache and a normal neurological examination should proceed to investigation for exclusion of SAH has led to initial work in Canada on the development of clinical decision rules. These are highly sensitive for the detection of SAH in patients with certain specific clinical characteristics but are not yet generalisable [30,39,40].

Studies have shown the misdiagnosis rate of SAH over the past 30 years to be in excess of 10% [8,9]. Three reasons for misdiagnosis recur repeatedly [41,42]:

• Failure to consider the diagnosis of SAH
• Failure to obtain and correctly interpret the results of a CT brain scan
• Failure to perform and correctly interpret the results of a lumbar puncture (LP)

The diagnosis of SAH should be considered in all patients presenting with first or worst headache, particularly of sudden onset. Failure to entertain this possibility is still a regular cause of medical mishap.

Learning Bite

Failure to consider and properly investigate patients with a suspected SAH is still a significant cause of medical error [42].

Non-contrast CT Head

The first investigation should be a non-contrast CT scan of the head [11,18].

Indications

If there is abnormal neurology or a reduced conscious level this should take place as soon as possible after the index episode. Ideally, this would hold true for all patients as the sensitivity of CT scanning is higher the closer it is performed to the index episode.

The largest studies on ED patients reveal an overall sensitivity of 92-93% though this may be substantially higher, perhaps even 100%, if performed in the first 6 hours [43-45] The sensitivity drops off to about 85% at 3 days and 50% at 1 week [7] as blood diffuses away from the site of haemorrhage.

Interpretation of the results of the CT scan may also be subject to spectrum bias (patients who are neurologically well will likely have smaller bleeds harder to see on CT) and the fact that neuroradiology reporting is superior to that of a general radiologist [46].

CT appearances of SAH

The distribution of blood on the initial CT Head scan can be helpful in distinguishing aneurysmal SAH (Fig 4) from perimesencephalic haemorrhage (Fig 5) [18,19,37].

Fig 4: aneurysmal SAH	Fig 5: Perimesencephalic haemorrhage

Ruptured aneurysms are most often found in the anterior communicating artery (blood in interhemispheric fissure) (Fig 4) followed by the internal carotid artery, middle cerebral artery (blood in the Sylvian fissure) and vertebrobasilar circulation.

About 20% of patients with SAH will have multiple aneurysms so the CT pattern of blood is important in identifying the probable culprit [37].

Patients with perimesencephalic patterns of SAH (blood localised to the midbrain cisterns) do very well [20] with no specific treatment. However, non-contrast CT brain appearances are not unique [20] and CT angiography (CTA) is required in these patients to exclude a ruptured vertebrobasilar aneurysm [47,48].

Learning Bite

All patients with CT-proven SAH should undergo CT or formal angiography to identify the aneurysm responsible or confirm the absence of such in cases of perimesencephalic haemorrhage [47-51].

NICE NG228 states that if a CT head scan is done within 6 hours of symptom onset and is reported and documented by a radiologist as showing no evidence of a subarachnoid haemorrhage:

Do not routinely offer a lumbar puncture.

Think about alternative diagnoses and seek advice from a specialist.

However, if the CT head scan is done more than 6 hours after symptom onset and shows no evidence of a subarachnoid haemorrhage, consider a lumbar puncture.

Learning bite

A negative CT scan alone within 6 hours of onset of symptoms can be enough to exclude SAH.

Lumbar Puncture

Procedure

LP is an invasive and often uncomfortable procedure that can be technically challenging. Post-dural puncture headache (PDPH) is reported in up to 38% of cases [52] though other complications are uncommon [53].

The incidence of PDPH can be reduced by replacing the stylet before withdrawing the needle [54] or with the use of an atraumatic Sprotte [55] or Whitacre [56] needle.

It is generally recommended that CSF opening pressure be measured for patients with sudden onset headache [46]. This is principally to diagnose cerebral venous sinus thrombosis (CVST) or idiopathic intracranial hypertension (IIH) if elevated and to detect low pressure headache if reduced. Measurement requires the use of larger needles (potentially increasing the likelihood of PDPH) to allow rapid pressure transduction and necessitates the patient being in the lateral position.

CVST should certainly be considered as a cause of severe headache, especially in people with a prothrombotic risk factor [57]. However, it is much rarer than SAH and is an unusual cause of thunderclap headache. If suspected after a normal CT brain, CT venography or MRI would be a more helpful test.

There is no evidence that the practice of enforcing a period of bed rest post LP has any bearing on the development of PDPH [58].

CSF analysis

It is important to understand the problems that can arise during CSF sampling, transport and interpretation in order to make a correct clinical judgement.

Traumatic LP taps occur regularly [59] and often mandate further investigations that may be unnecessary [13].

Unfortunately, none of the methods of distinguishing a traumatic tap from SAH are 100% reliable [60] though there is general consensus that CSF should always be assessed for the presence of xanthochromia [11,49,51]. Xanthochromia refers to the yellow discolouration of the CSF supernatant seen with haemoglobin breakdown to methaemoglobin, oxyhaemoglobin and bilirubin. Oxyhaemoglobin may develop in 2-3 hours but can occur as a result of a traumatic tap [61] whereas the appearance of bilirubin takes longer but only occurs in vivo.

For this reason, traditional teaching has held that LP should not be performed before 12 hours from the index episode of headache [62-64]. Samples taken earlier may not reliably demonstrate the presence of bilirubin and hence be falsely negative.

Learning Bite

Patients in whom the diagnosis of SAH is considered but in whom the CT is normal must subsequently undergo an LP at least 12 hrs after the onset of symptoms [64].

Consequently, in the UK, clear national guidance (NEQAS) has been issued on how CSF specimens should be handled and analysed [64]. The LP should ideally be performed by an experienced practitioner, the last sample protected from the light (to prevent in vitro degradation of bilirubin to deoxyhaemoglobin) and analysed in the lab as soon as possible, ideally within the hour, avoiding pneumatic delivery systems that can cause haemolysis [65].

Method of Analysis

UK recommendations [64] strongly advocate the use of spectrophotometry to detect bilirubin in the CSF believing this to be the finding most suggestive of SAH [64,66]. However, Perry et al [67] found that each of 4 different spectrophotometric methods (including NEQAS) had an unacceptably high false positive rate. This led to renewed concerns about unnecessary invasive investigation [66] and the possibility of the detection of incidental aneurysm that, in the context of acute headache, may lead to patient anxiety, difficult management decisions and perhaps to unnecessary endovascular or surgical intervention.

In contrast, in the US, analysis for xanthochromia is performed almost exclusively by visual inspection of the CSF supernatant [68]. This technique has been demonstrated to be very specific for SAH [69] but with questionable sensitivity [70-72]. However, the largest prospective trial on 592 patients supports the practice of using visual CSF analysis, demonstrating a sensitivity of 100% (95%CI 94%-100%) for the diagnosis of SAH [73].

Learning Bite

There is concern that spectrophotometric analysis of CSF may lead to false positive results and unnecessary investigation whereas visual inspection for xanthochromia may lead to false negatives and missed cases of SAH [64,73].

Whatever the method of analysis, it is important the clinician has a clear understanding of the interpretation of the CT and CSF results and balances this against good clinical judgement [42].

Other Diagnostic Strategies

Table 2: Other diagnostic strategies

Primary CT angiography (CTA)	Some have suggested use of CTA as the initial investigation [75]. However, it does not lead to an improvement in the diagnostic yield of SAH over standard work up [75].
Primary MR angiography (MRA)	Detection of acute SAH by MRA has a sensitivity of 94% within 4 days. Sensitivity may increase as time passes making this a useful tool for the investigation of patients with a delayed (>2 weeks) presentation [75].
Lumbar puncture first	An LP first strategy has been postulated in patients with and no clinical evidence of raised intracranial pressure [76]. However, CT first may point to SAH or another significant diagnosis without recourse to an invasive LP.

 

Investigations Summary

At present, evidence and opinion dictate that all patients presenting with acute severe headache <2 weeks from the index episode should undergo non-contrast CT scanning of the brain.

If this is reported as normal (ideally by a neuroradiologist) then an LP should be undertaken at least 12 hours from the start of the headache.” to “If this CT scan is completed within 6 hours of onset of symptoms, and reported by a radiologist, then further investigation should not be routinely offered. If the scan is more than 6 hours from the onset of symptoms, an LP should be undertaken at least 12 hours from the start of the headache.

Once SAH is diagnosed, the severity of the initial bleed should be determined as it is the most useful indicator of outcome of aneurysmal SAH [11]. Clinical grading systems include the Hunt and Hess classification (Table 3) [78] and that of The World Federation of Neurosurgical Societies (Table 4) [79].

Table 3: Hunt and Hess SAH classification system

Clinical picture	Grade
Asymptomatic, mild headache, slight nuchal rigidity	1
Moderate to severe headache, nuchal rigidity, no neurological deficit other than cranial nerve palsy	2
Drowsiness / confusion, mild focal neurological deficit	3
Stupor, moderate-severe hemiparesis	4
Coma, decerebrate posturing	5

Table 4: World Federation of Neurosurgeons SAH grading system

Glasgow Coma Score	Motor deficit*	Grade
15	Absent	1
13-14	Absent	2
13-14	Present	3
7-12	Present or absent	4
3-6	Present or absent	5

* Where a motor deficit refers to a major focal deficit

Learning Bite

The outcome of SAH is correlated directly with the degree of neurological dysfunction at time of first presentation [78,79].

Fig 6: Basilar tip aneurysm on CTA

Fig 7: Internal carotid aneurysm seen on conventional catheter angiography

Once the diagnosis of SAH is confirmed, patients should be transferred to a neurosciences unit that performs a high volume of SAH related surgical and endovascular procedures as outcomes in such centres are better [80,81].

In many centres CTA is used as a first line investigation in aneurysmal SAH to define the relevant anatomy and plan intervention because it is quick and convenient (Fig 6).

Catheter angiography is then reserved for selective cases after a risk assessment [37]. Catheter angiography remains the gold standard investigation in the detection of aneurysmal SAH (Fig 7). It may be normal in cases of perimesencephalic haemorrhage, thrombosed aneurysm or severe vasospasm. It has a neurological complication rate of 1.3% though only 0.5% have permanent neurological dysfunction [82].

Initial management of all patients with headache should include adequate analgesia, and antiemetics, if required. There is no reason to avoid opiate analgesia in SAH, though its use should be clearly documented and taken into account during any neurological assessment. However, once a diagnosis of aneurysmal SAH is established, the priorities shift to ensuring timely definitive treatment of the causative lesion. Meticulous attention is paid to resuscitation principles, in particular airway protection with rapid sequence induction if required and fluid resuscitation to euvolaemia with intravenous crystalloid, whilst trying to prevent the development of complications, particularly rebleeding and vasospasm.

Urgently discuss with a specialist neurosurgical centre the need for transfer of care of a person with a diagnosis of subarachnoid haemorrhage to a specialist neurosurgical centre.

Do not use a subarachnoid haemorrhage severity score in isolation to determine the need for, or timing of, transfer of care to a specialist neurosurgical centre. Be aware that the risk of rebleeding is highest within 24 hours of the onset of symptoms.

NICE recommends that patients be offered CT angiography of the head without delay to people with a confirmed diagnosis of subarachnoid haemorrhage to identify the cause of the bleeding and to guide treatment, but this may be more effectively completed in a neurosurgical centre with specialist neuroradiologists available to review images routinely.

Rebleeding

Aneurysmal SAH has been demonstrated to have a rebleed rate of 2-4% in the first 24 hours and 15-20% in the first two weeks [83]. After rebleeding the prognosis is very poor with many dying or permanently disabled.

Medical prevention of rebleeding

The administration of antifibrinolytics can reduce rebleeding but clinical outcomes are not affected and their use is not recommended following SAH [84]. Though most clinicians would ensure bed rest, there is no good evidence that this practice reduces the rate of rebleeding. The AHA/ASA management guidance suggests that a systolic BP of >160mmHg should be controlled with a titratable agent to balance the risk of hypertension-related rebleeding and maintain cerebral perfusion pressure, however this should be discussed with your local neurosciences centre [11].

Surgical and endovascular prevention of rebleeding

The decision regarding definitive treatment of a ruptured aneurysm is taken with reference to the clinical grade of the patient, the presence of co-morbidities and relevant clinical anatomy. Where possible, aneurysm occlusion by endovascular coil embolisation or microsurgical aneurysm clipping is undertaken as soon as practicable (ideally within 72 hours) to prevent rebleeding.

For aneurysms amenable to both treatments, endovascular coiling is superior and has replaced surgical clipping in most cases (ARR 7% for dependency and death with sustained benefit at 7 years, NNT 14 (95%CI 9-25) [85,86].

Learning Bite

When SAH is diagnosed, patients should be transferred promptly to a neurosciences centre with both endovascular and neurosurgical capabilities as clinical outcomes are better [80,81].

Vasospasm

Vasospasm is a common but poorly understood entity that occurs with greatest frequency at 5-14 days [18] after the primary SAH. It may be asymptomatic and visible only as an angiographic phenomenon but in one third of patents [87] it is clinically apparent as delayed cerebral ischaemia (DCI) manifesting as focal neurological deficits or a reduction in level of conscious level [88]. Unlike a thromboembolic stroke, clinical signs usually present gradually [18] and can occur across vascular territories [89]. The main independent predictors of the development of vasospasm are the size of the SAH [21] and initial loss of consciousness [90].

A Cochrane review has demonstrated calcium channel antagonists, i.e. nimodipine 60 mg 4 hourly orally, to be effective in the prevention and treatment of cerebral vasospasm. Its use is associated with a significant improvement in clinical outcome [91]. Magnesium sulphate may also have benefits [92] though further work is needed [18,46].

NICE recommends to consider enteral nimodipine for people with a confirmed subarachnoid haemorrhage.

Intravenous nimodipine should only be used within a specialist setting and if enteral treatment is not suitable.

The role of antiplatelet agents [93] and statins [94] in the treatment of vasospasm is not clear and Cochrane reviews on the use of volume expansion [95], endothelin receptor antagonists [96] and corticosteroids [97] demonstrated no benefit.

Learning Bite

The only medical treatment for vasospasm with proven clinical benefit is the administration of oral nimodipine 60 mg 4-hourly [91].

Other neurological complications

Other neurological complications include hydrocephalus which, if symptomatic, is best treated by ventriculostomy [98].

1. Linn FH, Rinkel GJ, Algra A, van Gijn J. Incidence of subarachnoid hemorrhage: role of region, year, and rate of computed tomography: a meta-analysis. Stroke. 1996 Apr;27(4):625-9.
2. Epidemiology of aneurysmal subarachnoid hemorrhage in Australia and New Zealand: incidence and case fatality from the Australasian Cooperative Research on Subarachnoid Hemorrhage Study (ACROSS). Stroke. 2000 Aug;31(8):1843-50.
3. Mitchell P, Hope T, Gregson BA, Mendelow AD. Regional differences in outcome from subarachnoid haemorrhage: comparative audit. BMJ 2004 May 22;328(7450):1234-1235.
4. Huang J, van Gelder JM. The probability of sudden death from rupture of intracranial aneurysms: a meta-analysis. Neurosurgery 2002 discussion 1105-7; Nov;51(5):1101-1105.
5. Stegmayr B, Eriksson M, Asplund K. Declining mortality from subarachnoid hemorrhage: changes in incidence and case fatality from 1985 through 2000. Stroke 2004 Sep;35(9):2059-2063.
6. Hop JW, Rinkel GJ, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke 1997 Mar;28(3):660-664.
7. Kassell NF, Torner JC, Haley EC,Jr, Jane JA, Adams HP, Kongable GL. The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: Overall management results. J.Neurosurg. 1990 Jul;73(1):18-36.
8. Mayer PL, Awad IA, Todor R, Harbaugh K, Varnavas G, et al. Misdiagnosis of symptomatic cerebral aneurysm. Prevalence and correlation with outcome at four institutions. Stroke 1996 Sep;27(9):1558-1563.
9. Kowalski RG, Claassen J, Kreiter KT, Bates JE, Ostapkovich ND, et al. Initial misdiagnosis and outcome after subarachnoid hemorrhage. JAMA 2004 Feb 18;291(7):866-869.
10. Johnston SC, Selvin S, Gress DR. The burden, trends, and demographics of mortality from subarachnoid hemorrhage. Neurology 1998;50(5):1413-1418.
11. Bederson JB, Connolly ES,Jr, Batjer HH, Dacey RG, Dion JE, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 2009 Mar;40(3):994-1025.
12. Cioffi F, Pasqualin A, Cavazzani P, Da Pian R. Subarachnoid haemorrhage of unknown origin: clinical and tomographical aspects. Acta Neurochir. 1989;97(1-2):31-39.
13. Rinkel GJ, Djibuti M, Algra A, van Gijn J. Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke 1998 Jan;29(1):251-256.
14. Teasdale GM, Wardlaw JM, White PM, Murray G, Teasdale EM, Easton V, et al. The familial risk of subarachnoid haemorrhage. Brain 2005 Jul;128(Pt 7):1677-1685.
15. Gieteling EW, Rinkel GJ. Characteristics of intracranial aneurysms and subarachnoid haemorrhage in patients with polycystic kidney disease. J.Neurol. 2003 Apr;250(4):418-423.
16. Feigin VL, Rinkel GJ, Lawes CM, Algra A, Bennett DA, van Gijn J, et al. Risk factors for subarachnoid hemorrhage: an updated systematic review of epidemiological studies. Stroke 2005 Dec;36(12):2773-2780.
17. Ruigrok YM, Buskens E, Rinkel GJ. Attributable risk of common and rare determinants of subarachnoid hemorrhage. Stroke 2001 May;32(5):1173-1175.
18. van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet 2007 Jan 27;369(9558):306-318.
19. van Gijn J, van Dongen KJ, Vermeulen M, Hijdra A. Perimesencephalic hemorrhage: a nonaneurysmal and benign form of subarachnoid hemorrhage. Neurology 1985 Apr;35(4):493-497.
20. Rinkel GJ, Wijdicks EF, Hasan D, Kienstra GE, Franke CL, et al. Outcome in patients with subarachnoid haemorrhage and negative angiography according to pattern of haemorrhage on computed tomography. Lancet 1991 Oct 19;338(8773):964-968.
21. Harrod CG, Bendok BR, Batjer HH. Prediction of cerebral vasospasm in patients presenting with aneurysmal subarachnoid hemorrhage: a review. Neurosurgery 2005 discussion 633-54; Apr;56(4):633-654.
22. Perry JJ, Stiell I, Wells GA, Spacek A. Diagnostic test utilization in the emergency department for alert headache patients with possible subarachnoid hemorrhage. CJEM 2002;4(5):333-337.
23. Leicht MJ. Non-traumatic headache in the emergency department. Ann.Emerg.Med. 1980 Aug;9(8):404-409.
24. Ramirez-Lassepas M, Espinosa CE, Cicero JJ, Johnston KL, Cipolle RJ, Barber DL. Predictors of intracranial pathologic findings in patients who seek emergency care because of headache. Arch.Neurol. 1997 Dec;54(12):1506-1509.
25. Goldstein JN, Camargo CA,Jr, Pelletier AJ, Edlow JA. Headache in United States emergency departments: demographics, work-up and frequency of pathological diagnoses. Cephalalgia 2006 Jun;26(6):684-690.
26. Morgenstern LB, Luna-Gonzales H, Huber JC,Jr, Wong SS, Uthman MO, Gurian JH, et al. Worst headache and subarachnoid hemorrhage: prospective, modern computed tomography and spinal fluid analysis. Ann.Emerg.Med. 1998 Sep;32(3 Pt 1):297-304.
27. Linn FH, Rinkel GJ, Algra A, van Gijn J. Headache characteristics in subarachnoid haemorrhage and benign thunderclap headache. Journal of Neurology, Neurosurgery & Psychiatry 1998 Nov;65(5):791-793.
28. Kassell NF, Kongable GL, Torner JC, Adams HP,Jr, Mazuz H. Delay in referral of patients with ruptured aneurysms to neurosurgical attention. Stroke 1985 Jul-Aug;16(4):587-590.
29. Landtblom AM, Fridriksson S, Boivie J, Hillman J, Johansson G, Johansson I. Sudden onset headache: a prospective study of features, incidence and causes. Cephalalgia 2002 Jun;22(5):354-360.
30. Perry JJ, Stiell IG, Sivilotti ML, Bullard MJ, Hohl CM, Sutherland J, et al. Clinical decision rules to rule out subarachnoid hemorrhage for acute headache. JAMA 2013 Sep 25;310(12):1248-1255.
31. Locker TE, Thompson C, Rylance J, Mason SM. The utility of clinical features in patients presenting with nontraumatic headache: an investigation of adult patients attending an emergency department. Headache 2006 Jun;46(6):954-961.
32. Davenport R. Acute headache in the emergency department. Journal of Neurology, Neurosurgery & Psychiatry 2002 Jun;72(Suppl 2):33-37.
33. Weir B. Headaches from aneurysms. Cephalalgia 1994 Apr;14(2):79-87.
34. Seymour JJ, Moscati RM, Jehle DV. Response of headaches to nonnarcotic analgesics resulting in missed intracranial hemorrhage. Am.J.Emerg.Med. 1995 Jan;13(1):43-45.
35. Fann JR, Kukull WA, Katon WJ, Longstreth WT,Jr. Physical activity and subarachnoid haemorrhage: a population based case-control study. Journal of Neurology, Neurosurgery & Psychiatry 2000 Dec;69(6):768-772.
36. Matsuda M, Watanabe K, Saito A, Matsumura K, Ichikawa M. Circumstances, activities, and events precipitating aneurysmal subarachnoid hemorrhage. Journal of Stroke & Cerebrovascular Diseases 2007 Jan-Feb;16(1):25-29.
37. Al-Shahi R, White PM, Davenport RJ, Lindsay KW. Subarachnoid haemorrhage. BMJ 2006 Jul 29;333(7561):235-240.
38. Toussaint LG,3rd, Friedman JA, Wijdicks EF, Piepgras DG, Pichelmann MA, McIver JI, et al. Survival of cardiac arrest after aneurysmal subarachnoid hemorrhage. Neurosurgery 2005 discussion 25-31; Jul;57(1):25-31.
39. Perry JJ, Stiell IG, Wells GA, Mortensen M, Sivilotti M, Bullard M, et al. A clinical decision rule to safely rule out subarachnoid hemorrhage in acute headache patients in the emergency department. (Abstract). Acad Emerg Med 2006;13(5):Suppl 1:S9.
40. Perry JJ, Stiell IG, Sivilotti ML, Bullard MJ, Lee JS, Eisenhauer M, et al. High risk clinical characteristics for subarachnoid haemorrhage in patients with acute headache: prospective cohort study. BMJ 2010;341:5204.
41. Vermeulen MJ, Schull MJ. Missed diagnosis of subarachnoid hemorrhage in the emergency department. Stroke 2007 Apr;38(4):1216-1221.
42. Edlow JA, Caplan LR. Avoiding pitfalls in the diagnosis of subarachnoid hemorrhage. N.Engl.J.Med. 2000 Jan 6;342(1):29-36.
43. Perry JJ, Stiell IG, Wells GA, Mortensen M, Lesuik H, Sivilotti M, et al. The sensitivity of computed tomography for the diagnosis of subarachnoid hemorrhage in ED patients with acute headache. (Abstract). Acad Emerg Med 2004;11(5):435-436.
44. Perry JJ, Stiell IG, Sivilotti ML, Bullard MJ, Emond M, Symington C, et al. Sensitivity of computed tomography performed within six hours of onset of headache for diagnosis of subarachnoid haemorrhage: prospective cohort study. BMJ 2011;343:4277.
45. Perry JJ, Spacek A, Forbes M, Wells GA, Mortensen M, Symington C, et al. Is the combination of negative computed tomography result and negative lumbar puncture result sufficient to rule out subarachnoid hemorrhage? Ann Emerg Med 2008 Jun;51(6):707-713.
46. Edlow JA, Malek AM, Ogilvy CS. Aneurysmal subarachnoid hemorrhage: update for emergency physicians. J Emerg Med 2008 Apr;34(3):237-251.
47. Velthuis BK, Rinkel GJ, Ramos LM, Witkamp TD, van Leeuwen MS. Perimesencephalic hemorrhage. Exclusion of vertebrobasilar aneurysms with CT angiography. Stroke 1999 May;30(5):1103-1109.
48. Ruigrok YM, Rinkel GJ, Buskens E, Velthuis BK, van Gijn J. Perimesencephalic hemorrhage and CT angiography: A decision analysis. Stroke 2000 Dec;31(12):2976-2983.
49. “Scottish Intercollegiate Guidelines Network.”. Diagnosis and management of headache in adults;2008. view link
50. Guidelines in Emergency Medicine Network (GEMNet). A cliinical guideline for the managment of lone acute severe headache. Dec, 2009. View link
51. Edlow JA, Panagos PD, Godwin SA, Thomas TL, Decker WW, American College of Emergency P. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute headache. Ann Emerg Med 2008 Oct;52(4):407-436.
52. Kuntz KM, Kokmen E, Stevens JC, Miller P, Offord KP, Ho MM. Post-lumbar puncture headaches: experience in 501 consecutive procedures. Neurology 1992 Oct;42(10):1884-1887.
53. Evans RW. Complications of lumbar puncture. Neurol.Clin. 1998 Feb;16(1):83-105.
54. Strupp M, Brandt T, Muller A. Incidence of post-lumbar puncture syndrome reduced by reinserting the stylet: a randomized prospective study of 600 patients. J.Neurol. 1998 Sep;245(9):589-592.
55. Braune HJ, Huffmann GA. A prospective double-blind clinical trial, comparing the sharp Quincke needle (22G) with an “atraumatic” needle (22G) in the induction of post-lumbar puncture headache. Acta Neurol.Scand. 1992 Jul;86(1):50-54.
56. Vallejo MC, Mandell GL, Sabo DP, Ramanathan S. Postdural puncture headache: a randomized comparison of five spinal needles in obstetric patients. Anesthesia & Analgesia 2000 Oct;91(4):916-920.
57. Stam J. Thrombosis of the cerebral veins and sinuses. N.Engl.J.Med. 2005 Apr 28;352(17):1791-1798.
58. Sudlow CLM, Warlow CP. Posture and fluids for preventing post-dural puncture headache. Cochrane Database of Systematic Reviews 2001(2).
59. Shah KH, Richard KM, Nicholas S, Edlow JA. Incidence of traumatic lumbar puncture. Acad.Emerg.Med. 2003 Feb;10(2):151-154.
60. Shah KH, Edlow JA. Distinguishing traumatic lumbar puncture from true subarachnoid hemorrhage. J.Emerg.Med. 2002 Jul;23(1):67-74.
61. Graves P, Sidman R. Xanthochromia is not pathognomonic for subarachnoid hemorrhage. Acad.Emerg.Med. 2004 Feb;11(2):131-135.
62. Vermeulen M, van Gijn J. The diagnosis of subarachnoid haemorrhage. Journal of Neurology, Neurosurgery & Psychiatry 1990 May;53(5):365-372.
63. Vermeulen M, Hasan D, Blijenberg BG, Hijdra A, van Gijn J. Xanthochromia after subarachnoid haemorrhage needs no revisitation. Journal of Neurology, Neurosurgery & Psychiatry 1989 Jul;52(7):826-828.
64. UK National External Quality Assessment Scheme for Immunochemistry Working,Group. National guidelines for analysis of cerebrospinal fluid for bilirubin in suspected subarachnoid haemorrhage. Ann.Clin.Biochem. 2003 Sep;40(Pt 5):481-488.
65. Wenham PR, Hanson T, Ashby JP. Interference in spectrophotometric analysis of cerebrospinal fluid by haemolysis induced by transport through a pneumatic tube system. Ann.Clin.Biochem. 2001 Jul;38(Pt 4):371-375.
66. Gunawardena H, Beetham R, Scolding N, Lhatoo SD. Is cerebrospinal fluid spectrophotometry useful in CT scan-negative suspected subarachnoid haemorrage?. Eur.Neurol. 2004;52(4):226-229.
67. Perry JJ, Sivilotti ML, Stiell IG, Wells GA, Raymond J, Mortensen M, et al. Should spectrophotometry be used to identify xanthochromia in the cerebrospinal fluid of alert patients suspected of having subarachnoid hemorrhage?. Stroke 2006 Oct;37(10):2467-2472.
68. Edlow JA, Bruner KS, Horowitz GL. Xanthochromia. Arch.Pathol.Lab.Med. 2002 Apr;126(4):413-415.
69. Sidman R, Spitalnic S, Demelis M, Durfey N, Jay G. Xanthrochromia? By what method? A comparison of visual and spectrophotometric xanthrochromia. Ann.Emerg.Med. 2005 Jul;46(1):51-55.
70. Arora S, Swadron SP, Dissanayake V. Evaluating the sensitivity of visual xanthochromia in patients with subarachnoid haemorrhage. J Emerg Med Article in Press 24th June 2008.
71. Cruickshank A, Beetham R, Holbrook I, Watson I, Wenham P, Keir G, et al. Spectrophotometry of cerebrospinal fluid in suspected subarachnoid haemorrhage. BMJ 2005 Jan 15;330(7483):138.
72. Dupont SA, Wijdicks EF, Manno EM, Rabinstein AA. Thunderclap headache and normal computed tomographic results: value of cerebrospinal fluid analysis. Mayo Clin.Proc. 2008 Dec;83(12):1326-1331.
73. Perry JJ, Spacek A, Forbes M, Wells GA, Mortensen M, Symington C, et al. Is the combination of negative computed tomography result and negative lumbar puncture result sufficient to rule out subarachnoid hemorrhage?. Ann.Emerg.Med. 2008 Jun;51(6):707-713.
74. Nijjar S, Patel B, McGinn G, West M. Computed tomographic angiography as the primary diagnostic study in spontaneous subarachnoid hemorrhage. Journal of Neuroimaging 2007 Oct;17(4):295-299.
75. Carstairs SD, Tanen DA, Duncan TD, Nordling OB, Wanebo JE, Paluska TR, et al. Computed tomographic angiography for the evaluation of aneurysmal subarachnoid hemorrhage. Acad.Emerg.Med. 2006 May;13(5):486-492.
76. Mitchell P, Wilkinson ID, Hoggard N, Paley MN, Jellinek DA, Powell T, et al. Detection of subarachnoid haemorrhage with magnetic resonance imaging. Journal of Neurology, Neurosurgery & Psychiatry 2001 Feb;70(2):205-211.
77. Schull MJ. Lumbar puncture first: an alternative model for the investigation of lone acute sudden headache. Acad.Emerg.Med. 1999 Feb;6(2):131-136.
78. Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J.Neurosurg. 1968 Jan;28(1):14-20.
79. Teasdale GM, Drake CG, Hunt W, Kassell N, Sano K, Pertuiset B, et al. A universal ubarachnoid hemorrhage scale: report of a committee of the World Federation of Neurosurgical Societies. Journal of Neurology, Neurosurgery & Psychiatry 1988 Nov;51(11):1457.
80. Bardach NS, Zhao S, Gress DR, Lawton MT, Johnston SC. Association between subarachnoid hemorrhage outcomes and number of cases treated at California hospitals. Stroke 2002 Jul;33(7):1851-1856.
81. Berman MF, Solomon RA, Mayer SA, Johnston SC, Yung PP. Impact of hospital-related factors on outcome after treatment of cerebral aneurysms. Stroke 2003 Sep;34(9):2200-2207.
82. Willinsky RA, Taylor SM, TerBrugge K, Farb RI, Tomlinson G, Montanera W. Neurologic complications of cerebral angiography: prospective analysis of 2,899 procedures and review of the literature. Radiology 2003 May;227(2):522-528.
83. Kassell NF, Torner JC. Aneurysmal rebleeding: a preliminary report from the Cooperative Aneurysm Study. Neurosurgery 1983 Nov;13(5):479-481.
84. Baharoglu MI, Germans MR, Rinkel GJ, Algra A, Vermeulen M, van Gijn J, et al. Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database of Systematic Reviews 2013;8:001245.
85. van der Schaaf I, Algra A, Wermer M, Molyneux A, Clarke M, van Gijn J, et al. Endovascular coiling versus neurosurgical clipping for patients with aneurysmal subarachnoid haemorrhage. Cochrane Database of Systematic Reviews 2005(4):003085.
86. Molyneux AJ. Kerr RS. Yu LM. Clarke M. Sneade M. Yarnold JA. Sandercock P. International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet 2005 Sep 3-9;366(9488):809-817.
87. Roos YB, de Haan RJ, Beenen LF, Groen RJ, Albrecht KW, Vermeulen M. Complications and outcome in patients with aneurysmal subarachnoid haemorrhage: a prospective hospital based cohort study in the Netherlands. Journal of Neurology, Neurosurgery & Psychiatry 2000 Mar;68(3):337-341.
88. Hijdra A, Van Gijn J, Stefanko S, Van Dongen KJ, Vermeulen M, Van Crevel H. Delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: clinicoanatomic correlations. Neurology 1986 Mar;36(3):329-333.
89. Rabinstein AA, Weigand S, Atkinson JL, Wijdicks EF. Patterns of cerebral infarction in aneurysmal subarachnoid hemorrhage. Stroke 2005 May;36(5):992-997.
90. Hop JW, Rinkel GJ, Algra A, van Gijn J. Initial loss of consciousness and risk of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Stroke 1999 Nov;30(11):2268-2271.
91. Dorhout Mees SM, Rinkel GJ, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, et al. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database of Systematic Reviews 2007(3):000277.
92. van den Bergh WM, Algra A, van Kooten F, Dirven CM, van Gijn J, Vermeulen M, et al. Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial. Stroke 2005 May;36(5):1011-1015.
93. Dorhout Mees SM, van den Bergh WM, Algra A, Rinkel GJ. Antiplatelet therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database of Systematic Reviews 2007(4):006184.
94. Vergouwen MD, de Haan RJ, Vermeulen M, Roos YB. Effect of statin treatment on vasospasm, delayed cerebral ischemia, and functional outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis update. Stroke 2010 Jan;41(1):e47-52.
95. Rinkel GJ, Feigin VL, Algra A, van Gijn J. Circulatory volume expansion therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database of Systematic Reviews 2004(4):000483.
96. Guo J, Shi Z, Yang K, Tian JH, Jiang L. Endothelin receptor antagonists for subarachnoid hemorrhage. Cochrane Database of Systematic Reviews 2012;9:008354.
97. Feigin VL, Anderson N, Rinkel GJ, Algra A, van Gijn J, Bennett DA. Corticosteroids for aneurysmal subarachnoid haemorrhage and primary intracerebral haemorrhage. Cochrane Database of Systematic Reviews 2005(3):004583.
98. Hasan D, Vermeulen M, Wijdicks EF, Hijdra A, van Gijn J. Management problems in acute hydrocephalus after subarachnoid hemorrhage. Stroke 1989 Jun;20(6):747-753.
99. Claiborne Johnston S, Rothwell PM, Nguyen-Huynh MN et al. Validation and refinement of scores to predict early stroke risk after transient ischaemic attack. Lancet 2007;369(9558):283-292.