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SUBARACHNOID HAEMORRHAGE -A BRIEF REVIEW Introduction A subarachnoid haemorrhage is bleeding into the subarachnoid space—the area between the arachnoid mater and the pia mater surrounding the brain. This may occur spontaneously, usually from a ruptured cerebral aneurysm, or may result from head injury. SAH is a form of stroke and comprises 1–7% of all strokes. It is a medical emergency and can lead to death or severe disability—even when recognized and treated at an early stage. Up to half of all cases of SAH are fatal and 10–15% dies before reaching a hospital, and those who survive often have neurological or cognitive impairment. The 20th century has seen great advances in diagnosis, starting with the ability to recognize the condition at all during life. Advances in treatment and prevention of complications have also occurred, but these have led to only modest improvement in overall outcome; hence there are still formidable challenges ahead for neurologists, neurosurgeons and radiologists.

In the recent years, there are various researches, clinical trials, review works about every aspects of subarachnoid haemorrhage including its risk factors, path physiology, clinical features and management sides. So, the aim of this review article is to boost up our thinking about subarachnoid haemorrhage with the updated knowledge.

Epidemiological aspects

The incidence of SAH has remained stable over the last 30 years. In a meta-analysis of relevant studies in 1996, the pooled incidence rate was 10.5 per 100 000 person per year. [4]

There seemed to be a decline over time, but this was caused by diagnostic bias. That more

recent studies reported lower incidence rates than older studies could be entirely explained by the increasing proportion of patients investigated with CT scanning. In a virtual study in which CT is applied to all patients, the incidence is calculated to be 5.6 per 100 000 patient years [4] (Table 1).

Table 1 Epidemiological characteristics of SAH [4, 5] Incidence

n/100 000 patient years (95% CI)

Overall Finland Japan Other regions Virtual study with 100% CT Women Men

10.5 (9.9–11.2) 22.0 (20.0–23.0) 23.0 (19.0–28.0) 7.8 (7.2–8.4) 5.7 7.1 (5.4–8.7) 4.5 (3.1–5.8)

To update 1996 review on the incidence of subarachnoid haemorrhage (SAH), another study published in 2007 (December) which reveals the overall incidence of SAH is approximately 9 per 100 000 person-years. Studies from Japan and Finland show higher rates in those countries (22.7 and 19.7, respectively), for reasons that are not entirely understood. South and Central America, in contrast, have a rate of 4.2 per 100,000 on average.[6] The decline in incidence of SAH over the past 45 years is relatively moderate compared with that for stroke in general. Between 1950 and 2005, the incidence decreased by 0.6% per year. [6]


Although the group of people at risk for SAH is younger than the population usually affected by stroke,[1] the risk still increases with age, with a mean age at presentation of 55 years.[7] Young people are much less likely than middle-aged people to suffer a subarachnoid haemorrhage.[6] The risk continues to rise with age and is 60% higher in the very elderly (over 85) than in those between 45 and 55. [6]

The incidence is 1.6 times higher in women than in men,[8,9] although this difference does not carry across all populations.[10] Studies have suggested that the gender difference is related to hormonal status. Premenopausal women are at reduced risk for subarachnoid haemorrhage, especially those without a history of smoking or hypertension. [11] Increased SAH risk was associated with (1) earlier age at menarche and (2) null gravidity. No significant association of SAH risk was found with regularity of menstrual cycle, age at pregnancy, age at first birth, and number of births. [12] There appear to be racial differences in risk of SAH. Black people have a 2.1 times higher risk than whites. [13]

Fig.1. Average number of people with SAH per 100,000 person-years, broken down by age. [6]

Risk factors Familial predisposition An important, but non-modifiable risk factor is familial predisposition to SAH. Between five and 20% of patients with SAH have a positive family history.[14] First-degree relatives of patients with SAH have a 3- to 7-fold increased risk of being struck by the same disease.[15-19] In second-degree relatives, the incidence of SAH is similar to that found in the general population.[15] In a review in 2007, study showed three- to fivefold increased risk in first-degree relatives of people who have suffered a subarachnoid haemorrhage. [20]

Disease association The occurrence of SAH is also associated with specific heritable disorders of connective tissue, but these patients account for only a minority of all patients with SAH. Even though autosomal dominant polycystic kidney disease (ADPKD) is the most common heritable disorder associated with SAH, it is found in only 2% of all patients with SAH.[21] Other genetically determined disorders that have been associated with SAH are Ehlers– Danlos disease IV and neurofibromatosis type 1, but these associations are weaker than between ADPKD and these syndromes are seldom found in patients with SAH.[22,23] Marfan's syndrome has often been associated with SAH, but in a clinical cohort of 129 patients with Marfan's syndrome, none had a history of SAH.[24]


Modifiable risk factors To identify modifiable risk factors for subarachnoid haemorrhage (SAH), Teunissen et al performed a Medline search from 1966 through 1994. Significant risk factors were as follows: (1) smoking, (2) hypertension and (3) drinking 150 g or more of alcohol per week. Use of oral contraceptives, hormone replacement therapy, hypercholesterolemia, and physical activity were not significantly related to the risk of SAH. [25]

After a 1996 review, there is review study by the same group in 2005. Results reveal Smoking, hypertension, and excessive alcohol again remain the most important risk factors for SAH. Having smoked in the past confers a doubled risk of SAH compared to those who have never smoked. The seemingly protective effects of white ethnicity compared to nonwhite ethnicity, hormone replacement therapy, hypercholesterolemia, and diabetes in the etiology of SAH are uncertain.[1]

Causes of subarachnoid haemorrhage According to the recent review study report, in 85% of cases of spontaneous SAH, the cause is rupture of a cerebral aneurysm—a weakness in the wall of one of the arteries in the brain that becomes enlarged. They tend to be located in the circle of Willis and its branches. While most cases of SAH are due to bleeding from small aneurysms, larger aneurysms (which are less common) are more likely to rupture.[2] In 15–20% of cases of spontaneous SAH, no aneurysm is detected on the first angiogram.[26] About half of these are attributed to non-aneurysmal perimesencephalic haemorrhage, in which the blood is limited to the subarachnoid spaces around the midbrain (i.e. mesencephalon). In these, the origin of the blood is uncertain. [2] The remainder are due

to other disorders affecting the blood vessels (such as arteriovenous malformations), disorders of the blood vessels in the spinal cord, and bleeding into various tumors.[2] Cocaine abuse and sickle cell anemia (usually in children) and, rarely, anticoagulant therapy, problems with blood clotting and pituitary apoplexy can also result in SAH.[26, 27] Subarachnoid blood can be detected on CT scanning in as many as 60% of people with traumatic brain injury.[28] Traumatic SAH (tSAH) usually occurs near the site of a skull fracture or intracerebral contusion.[26]

Clinical features Subarachnoid haemorrhage should always be suspected in patients with a typical presentation which includes a sudden onset of severe headache (frequently described as the "worst ever") associated with nausea, vomiting, neck pain, photophobia, seizures (1 in 14) and loss of consciousness. Physical examination may reveal meningismus, a diminished level of consciousness, and localizing neurologic signs. In patients with such neurological deficits, it is straightforward that they should be referred for further investigation. [29] About one-third of sufferers have no symptoms apart from the characteristic headache, and about one in ten people who seek medical care with this symptom are later diagnosed with a subarachnoid haemorrhage. [2] In patients in whom headache is the only symptom, it is often more difficult to recognize the seriousness of the underlying condition.

Classically, the headache from aneurysmalrupture develops in seconds. Therefore it is important to make specific enquiries about how quickly the headache developed; patients often complain only about the severity of the headache and do not know that the speed of onset is a pivotal piece of information. However, even an accurate history does not reliably


distinguish between aneurysmalrupture and innocuous forms of headache, such as benign vascular headache or a muscle contraction headache. First, only half the patients with aneurysm rupture describe the onset as instantaneous, the other half describe it as coming on in seconds to even a few minutes.[30] Secondly, in the group of patients whose headache came on within a split second, innocuous forms of headache outnumber SAH by 10 to one. [31]

Other features are equally unhelpful in making the distinction: the severity of headache is

rated similar, vomiting occurs in 70% of patients with aneurysmalrupture, but also in 43% of patients with innocuous thunderclap headache. Also, preceding bouts of similar headaches are recalled in 20% of patients with aneurysmalrupture and 15% of patients with innocuous thunderclap headache.[30] Neck stiffness is a common sign in SAH of any cause, but takes hours to develop and therefore cannot be used to exclude the diagnosis if a patient is seen soon after the sudden-onset headache. It does not occur if patients are in deep coma. If explosive headache is the only symptom, the chance of SAH being the cause is only 10%.[31] Nevertheless, the lack of clinical features that distinguish reliably and at an early stage between SAH and innocuous types of sudden headache necessitate a brief consultation in hospital for all patients with an episode of severe headache that comes on within minutes. Such an approach serves the patient's best interests and is also cost effective. The discomfort and cost of referring the 90% of patients with innocuous headache is outweighed by avoidance of the disaster in the other 10% so that a ruptured aneurysm is avoided. [32] It is even more difficult to suspect aneurysmalrupture if the patient does not report a history of sudden headache, or if other symptoms seem to prevail over the headache, such as in patients presenting with a seizure or a confusional state, or if there is an associated head trauma. Epileptic seizures at the onset of aneurysmalSAH occur in ~6–16% of patients.


Of course the majority of patients with de novo epilepsy above age 25 years will have

underlying conditions other than SAH, but the diagnosis should be suspected if the post-ictal headache is unusually severe. One to 2% of patients with SAH present with an acute confusional state and in most such patients a history of sudden headache is lacking.[34] The differential diagnosis of acute confusional state is extensive and SAH accounts for, at most, a few percent of all patients seen in an emergency ward because of an acute confusional state.[35] In such patients, the diagnosis emerges only if the careful history of an eyewitness reveals the sudden onset of the symptoms; also detection of focal deficits or absence of a psychiatric history should raise the index of suspicion and lead to a brain imaging study. Trauma and spontaneous SAH are sometimes difficult to disentangle. Patients may be found alone after having been beaten in a brawl or hit by a drunken driver who made away, without external wounds to indicate an accident, with a decreased level of consciousness or with retrograde amnesia, making it impossible to obtain a history and with neck stiffness, causing the patient to be worked up for SAH. Conversely, patients may cause an accident whilst riding a bicycle or driving a car at time of the aneurysmalrupture. The diagnostic conundrum is particularly difficult when patients sustain a skull fracture having fallen after aneurysm rupture[36] or when head trauma causes an aneurysm to burst.[37] Meticulous reconstruction of traffic or sports accidents may therefore be rewarding, especially in patients with disproportionate headache or neck stiffness.

Signs Patient may have confusion, decreased level of consciousness or coma, neck stiffness and other signs of meningism.[2] Neck stiffness usually presents six hours after initial onset of SAH.[38] Localizing neurologic signs include third-nerve palsy (posterior communicating aneurysm), sixth-nerve palsy (increased intracranial pressure), bilateral 8

lower-extremity weakness or abulia (anterior communicating aneurysm), and the combination of hemi paresis and aphasia or visuospatial neglect (middle cerebral-artery aneurysm).[39] Intraocular haemorrhage (bleeding into the eyeball) may occur in response to the raised pressure: subhyaloid haemorrhage (bleeding under the hyaloid membrane, which envelops the vitreous body of the eye) and vitreous haemorrhage may be visible on fundoscopy. This is known as Terson syndrome (occurring in 3–13% of cases) and is more common in more severe SAH.[40] As a result of the bleeding, the body releases large amounts of adrenaline and similar hormones. This leads to a sharp increase in the blood pressure; the heart comes under substantial strain and neurogenic pulmonary edema (accumulation of fluid in the lungs), cardiac arrhythmias (irregularities in the heart rate and rhythm) [41] and cardiac arrest (in 3% of cases) may occur rapidly after the onset of haemorrhage. [2,42]

Clinical clues to the cause of SAH Past history may contain useful information. Patients may report symptoms consistent with a minor haemorrhage before a major rupture, which has been called a sentinel bleed or warning leak. [43] The majority of these minor haemorrhages occur within 2 to 8 weeks before overt SAH. The headache associated with a warning leak is usually milder than that associated with a major rupture, but it may last for a few days.

[44, 45]

Nausea and

vomiting may occur, but meningismus is uncommon after a sentinel haemorrhage. In patients with previous head injury, and particularly with a skull fracture, a Dural arteriovenous malformation (AVM) should be suspected, since healing of the fracture may

be accompanied by the development of such a malformation.[46] Although SAH from a septic aneurysm is a rare presentation of infective endocarditic in patients not known to have a disorder of the heart valves,[47,48] this diagnosis should be considered in patients with a history of malaise in the days or weeks preceding the haemorrhage, even more so if the haemorrhage is located at the convexity of the brain. Usually it will not be hard for the physician to get acquainted with the existence of sickle cell disease, a history of cardiac myxoma, or coagulation disorders. Pain at onset in the lower part of the neck (upper neck pain is common also with ruptured intracranial aneurysms), or a sudden and stabbing pain between the shoulder blades (coup de poignard or dagger thrust), with or without radiation to the arms, suggests a spinal AVM or fistula as the source of SAH.[49]A history of even quite minor neck trauma or of sudden, unusual head movements before the onset of headache may provide a clue to the diagnosis of vertebral artery dissection as a cause of SAH. Cocaine ingestion as a risk factor may not immediately be known in the case of an unconscious patient. Even if the family turns up in large numbers, one may find that not every relative is aware of illicit drugs being used or willing to volunteer this information even if they are. In cocaine-associated SAH there is often an underlying aneurysm. [50, 51] The physical examination can also provide an indication about the cause of SAH. Monocular blindness may result from anterior communicating artery aneurysms if it is exceptionally large.[52] Complete or partial third nerve palsy is a well-recognized sign after rupture of an aneurysm of the internal carotid artery at the origin of the posterior communicating artery.[53] The third nerve can also be involved with aneurysms of the basilar bifurcation or the superior cerebellar artery, but these are relatively infrequent sites.[54] Sixth nerve palsies, often bilateral in the acute stage, usually result from a non-specific and sustained rise of cerebrospinal fluid pressure, either at the time of rupture or later. A 10

combination of visual and occulomotor deficits should raise the suspicion of a pituitary apoplexy.


Usually, the underlying adenoma has insidiously manifested itself before the

dramatic occurrence of the haemorrhage by a dull retro-orbital pain, fatigue, gradual decrease of visual acuity or a constriction of the temporal fields. Lower cranial nerve palsies point to dissection of the vertebral artery, through direct compression of the ninth or tenth nerve.[56] Lower cranial nerve palsies (ninth to twelfth nerve) may also accompany dissection of the carotid artery in the neck, but this is an extremely uncommon cause of SAH.[57] Deficits indicating lesions of the cerebellum or brainstem, such as dysmetria, scanning speech, rotatory nystagmus or Horner's syndrome, also strongly suggest vertebral artery dissection. [58]

The presence or absence of hemiparesis does not contribute much to the diagnosis of

uncommon causes, because the rare occurrence of hemiparesis with a ruptured aneurysm (mostly of the middle cerebral artery) will still outnumber all other potential causes of SAH, in which hemiparesis may be relatively common, for example with septic aneurysms.

Missed diagnosis & deferential diagnosis In the absence of the classic signs and symptoms, subarachnoid haemorrhage may be misdiagnosed. [59, 60] The frequency of misdiagnosis may be up to 50 percent in patients presenting for their first visit to a physician. The common incorrect diagnoses are migraine and tension-type headaches. Failure to obtain the appropriate imaging study accounts for 73 percent of cases of misdiagnosis, and failure to perform or correctly interpret the results of a lumbar puncture accounts for 23 percent. Misdiagnosed patients tend to be less ill and have a normal neurologic examination. However, in such cases, neurologic complications occur later in as many as 50 percent of patients, and these patients have an associated higher risk of death and disability. [59, 60]

Up to 40 percent of patients headache may be the only presenting symptom and may abate completely within minutes or hours;


these are called sentinel or thunderclap

headaches or "warning leaks." Emergency evaluation of sentinel headaches is required since patients may have a serious subarachnoid haemorrhage within three weeks.


In many

instances, no reliable clinical features distinguish a sentinel headache from a benign headache. As only 10% of people admitted to the emergency department with a thunderclap headache are suffering from an SAH, other possible causes are usually considered simultaneously, such as meningitis, migraine, tension headache and cerebral venous sinus thrombosis.[63] Intracerebral haemorrhage, in which bleeding occurs within the brain itself, is twice as common as SAH and is often misdiagnosed as the latter.[64]

Investigation Brain scanning (CT and MRI)

If SAH is suspected, CT scanning is the first line in investigation because of the characteristically hyperdense appearance of extravagated blood in the basal cisterns.[65] The pattern of haemorrhage often suggests the location of any underlying aneurysm[66], although with variable degrees of certainty. [67] Head CT scanning can also demonstrate intraparenchymal hematomas, hydrocephalus, and cerebral edema . This has a high sensitivity and will correctly identify over 95% of cases—especially on the first day after the onset of bleeding. [2] Because of rapid clearance of blood, delayed head CT scanning may be normal despite a suggestive history. In the first 12 hours after SAH, the 12

sensitivity of CT for SAH is 98% to 100%, declining to 93% at 24 hours [68-72] and to 57% to 85% 6 days after SAH. [73, 74]

Fig.2.CT scans of the brain showing subarachnoid haemorrhage as a white area in the center A false-positive diagnosis of SAH on CT is possible in the presence of generalized brain edema, with or without brain death, which causes venous congestion in the subarachnoid space and in this way may mimic SAH.


The CT scan should be carefully

scrutinized because small amounts of subarachnoid blood may easily be overlooked (Fig.3). If after a thorough review no blood is found, aneurysmal SAH cannot be excluded even if CT is performed within 12 h because studies are negative in ~2% of patients with SAH. [76]

Fig. 3 Sedimentation in the left occipital horn as the only sign of SAH on CT.

Brain CT may also help in distinguishing primary SAH from traumatic brain injury, but the aneurysmalpattern of haemorrhage is not always immediately appreciated in patients admitted with a trauma.[77] If trauma is the cause of SAH, the blood is usually confined to the superficial sulci at the convexity of the brain, adjacent to a fracture or to an intracerebral contusion; these findings dispel any lingering concern about the possibility of a ruptured aneurysm. Nevertheless, patients with basal-frontal contusions may show a pattern of haemorrhage resembling that of a ruptured anterior communicating artery aneurysm,[78] and in patients with blood confined to the sylvian fissure or ambient cistern it may also be difficult to distinguish trauma from aneurysmalrupture by the pattern of haemorrhage alone.[79] In patients with direct trauma to the neck or with head injury associated with vigorous neck movement, the trauma can immediately be followed by massive haemorrhage into the basal cisterns resulting from a tear or even a complete rupture of one of the arteries of the posterior circulation, which is often rapidly fatal.[80,81] MRI with FLAIR (fluid attenuated inversion recovery) techniques demonstrates SAH in the acute phase as reliably as CT, [82] but MRI is impracticable because the facilities are less


readily available than CT scanners, and restless patients cannot be studied unless anaesthesia is given. After a few days (up to 40), however, MRI is increasingly superior to CT in detecting extravagated blood.[83,84] This makes MRI a unique method for identifying the site of the haemorrhage in patients with a negative CT scan but a positive lumbar puncture (see below), such as those who are not referred until 1 or 2 weeks after symptom onset.[85]

Lumbar puncture Lumbar puncture, in which cerebrospinal fluid (CSF) is removed with a needle from the lumbar sac, will show evidence of haemorrhage in 3% of people in whom CT was found normal; lumbar puncture is therefore regarded as mandatory in people with suspected SAH if imaging is negative.[2] At least three tubes of CSF are collected. [86] If an elevated number of red blood cells is present equally in all bottles, this indicates a subarachnoid haemorrhage. If the number of cells decreases per bottle, it is more likely that it is due to damage to a small blood vessel during the procedure (known as a "traumatic tap"). [87] The CSF sample is also examined for xanthochromia—the yellow appearance of centrifugated fluid. More sensitive is spectrophotometry (measuring the absorption of particular wavelengths of light) for detection of bilirubin, a breakdown product of hemoglobin from red blood cells.[2,88] Xanthochromia and spectrophotometry remain reliable ways to detect SAH several days after the onset of headache.[88] An interval of at least 12 hours between the onset of the headache and lumbar puncture is required, as it takes several hours for the hemoglobin from the red blood cells to be metabolized into bilirubin. [2,88]

A normal CT scan and CSF examination exclude a subarachnoid haemorrhage and predict a more favorable prognosis in the setting of severe and/or sudden headache.[89,90]It

has been recommended that patients with a normal CT scan and CSF examination be offered reassurance, symptomatic headache treatment, and appropriate consultative referral as indicated.[91]

Other investigations Transcranial droppler ultrasound assessment of proximal middle, anterior and posterior cerebral and basilar artery flow is helpful in detecting the onset of vasospasm, even prior to symptoms and following its course and response to therapy.



radiographs sometimes reveal calcification in the AVM or increased vascular markings in the overlying bone.[93]

Associated Systemic Changes Acute subarachnoid haemorrhage is associated with several characteristic responses in the systemic circulation, water balance, and cardiac function. The ECG changes include symmetrically large peaked T waves and other alterations suggesting subendocardial ischemia. Also there is a tendency to develop hyponatremia; this abnormality and its relationship to intravascular volume depletion play a key role in treatment. Albuminuria and glycosuria may be present for a few days. Rarely, diabetes insipidus occurs in the acute stages, but water retention or a natriuresis is more frequent. There may be a leukocytosis of 15,000 to 18,000 cells per cubic millimeter, but the sedimentation rate is usually normal. [94] According to the AHA/ASA guideline published in 2009[95]



Recommendations: 16






1. SAH is a medical emergency that is frequently misdiagnosed. A high level of suspicion for SAH should exist in patients with acute onset of severe headache (Class I, Level of Evidence B). 2. CT scanning for suspected SAH should be performed (Class I, Level of Evidence B), and lumbar puncture for analysis of CSF is strongly recommended when the CT scan is negative (Class I, Level of Evidence B). 3. Selective cerebral angiography should be performed in patients with SAH to document the presence and anatomic features of aneurysms (Class I, Level of Evidence B). 4. MRA and CTA may be considered when conventional angiography cannot be performed in a timely fashion (Class IIb, Level of Evidence B).

The main cause Saccular aneurysms

Approximately 85% of all spontaneous haemorrhages into the subarachnoid space arise from rupture of saccular aneurysms at the base of the brain. [96-98] such aneurysms are not congenital, but develop during the course of life. Cerebral aneurysms almost never occur in neonates and they are also rare in children.


In those exceptional cases, there is usually a

specific underlying cause for the aneurysm, such as trauma, infection or connective-tissue disorder. [100,101]

Location [103] Approximately 90 to 95 percent of saccular aneurysm lies on the anterior part of the circle of Willis. The four most common sites are

1. The proximal portions of the anterior communicating artery. 2. At the origin of the posterior communicating artery from the stem of the internal carotid. 3. At the first major bifurcation of the middle cerebral artery. 4. At the bifurcation of the internal carotid into middle and anterior cerebral arteries. Other sites include the internal carotid artery in the cavernous sinus, at the origin of the ophthalmic artery, the junction of the posterior communicating and posterior cerebral arteries, the bifurcation of the basilar artery, and the origins of the three cerebeller arteries. Aneurysms that rupture in the cavernous sinus may give rise to an arteriovenous fistula.


Fig.4. Common sites of berry aneurysms in the circle of Willis Source: Robin's Patholgy (6th edn)

Pathogenesis The etiology and pathogenesis of intracranial aneurysms are clearly multifactorial. It is largely unknown why only some adults develop aneurysms at arterial bifurcations and most do not. The once popular notion of a congenital defect in the muscle layer of the wall (tunica media) being a weak spot through which the inner layers of the arterial wall would bulge has been largely dispelled by a number of contradictory observations. First, gaps in the muscle layer of intracranial arteries are equally common in patients with and without aneurysms[104] and are usually strengthened by densely packed collagen fibrils.[105,106] Secondly, if an aneurysm has formed, any defect in the muscle layer is located not at the neck of the aneurysm, but somewhere in the wall of the aneurysmalsac.[107] Evidence suggests that both genetic and environmental factors contribute to the development of saccular aneurysms. A role of acquired changes in the arterial wall is likely because hypertension, smoking and alcohol abuse are risk factors for SAH in general.[108] It may well be the influence of these factors that leads to local thickening of the intimal layer (intimal pads') in the arterial wall, distal and proximal to a branching site, changes that some investigators regard as the earliest stage in the formation of aneurysms. [109,110] The formation of these pads, in which the intimal layer is inelastic, may cause increased strain in the more elastic portions of the vessel wall.[111] Also, structural abnormalities in structural proteins of the extracellular matrix have been identified in the arterial wall at a distance from the aneurysm itself.[112]

Some neoplastic conditions may lead to the formation of aneurysms, i.e. cerebellar haemangioblastoma[113] or metastasis from bronchial carcinoma. [114] Iatrogenic causes include radiation therapy,[115] acrylate applied externally for microvascular decompression [116] and operation for a superficial temporal artery-middle cerebral artery bypass, with the aneurysm at the site of the anastomosis.[117]

Morphology [118] An unruptured berry aneurysm is a thin-walled out pouching at arterial branch points along the circle of Willis or major vessels just beyond. Berry aneurysms measure a few mm to 2 to 3 cm and have a bright red, shiny surface and a thin translucent wall. Athermanous plaques, calcification, or thrombotic occlusion of the sac may be found in the wall or lumen of the aneurysm. Brownish discoloration of the adjacent brain and meanings is evidence of prior haemorrhage. The neck of the aneurysm may be either wide or narrow. Rupture usually occurs at the apex of the sac with extravasations of blood into the subarachnoid space, the substances of the brain, or both. The arterial wall adjacent to the neck of the aneurysm often shows some intimal thicking and gradual attenuation of the media as it approaches the neck. At the neck of the aneurysm, the muscular wall and intimal elastic lamina are usually absent or fragmented, and the wall of the sac is made up of thickened hyalinized intima. The adventitia covering the sac is continuous with that of the parent artery.

Unruptured aneurysm 20

Risk of rupture: Between 3.6 and 6% of the population harbour an unruptured intracranial aneurysm. Risk of rupture is related to aneurysm site and size and whether or not the patient has already had a subarachnoid haemorrhage from another aneurysm. [119] In ISUIA 2, the rupture rate for anterior circulation aneurysms <7 mm was 0% per year in patients with no prior sub arachnoids haemorrhage and 0.3% per year in patients with previous subarachnoid haemorrhage; 7-12 mm aneurysms, 0.5% per year (both groups); 1324 mm aneurysms, 3% per year; and gaint aneurysms 8% per year. Rupture rate for posterior circulation is higher at all sizes; <7mm was 0.5% per year in subjects with no prior SAH, 0.7% in those with prior SAH; 7-12 mm, 3% per year; 13-24 mm, 3.7% per year; and giant aneurysms, 10% per year.[120] Non-invasive tests like contrast enhanced magnetic resonance angiography (MRA) and multislice computered tomographic angiography (CTA) are alternatives to intra-arterial digital subtraction angiography to detect aneurysms. Although there are promising techniques, the quality of data testing their accuracy remains limited and single slice CTA and time-of-flight MRA are poorer at detecting aneurysms <5mm diameter, which account for up to 1/3 of unroptured aneurysms. [119] Management: For ruptured aneurysms, the only large scale randomized controlled trial comparing surgical and endovascular treatment (ISAT) by coiling, resulted in an absolute 8.8% reduction (updated figure as of June 2003 for 1888) in death or dependency at 1 year compared with surgical clipping. [121] For unruptured aneurysms, the best available data so far comparing coiling and clipping is form the prospective (but non randomized) arm of ISUIA. [120] Elective surgical clipping had combined morbidity and mortality at 1 year of 12.2% versus 9.5% for coiling, although the groups were not matched with more high risks patients in the endovascular treatment cohorts.


Nevertheless these data are

encouraging for future long term durability of coiling treatment and the fact that complete aneurysm occlusion is not always achieved remain obstacles to its wider use in unruptured aneurysms. Screening: There is an increased risk of SAH in relative of patients with SAH (highest in those with two or more first degree relatives affected), but most SAH is sporadic and therefore the balance of available evidence indicates that mass screening for aneurysms is not cost effective. There may be a limited role for investigation of high-risk subgroups and ideally such screening should be tested in a randomized trial. The avoidance and active management of vascular risk factors should also be part of the management of at risk subjects. [119]

Detection of ruptured aneurysms MRA MR angiography in SAH has evolved over the past decade but has not replaced catheter-based angiography as the initial test for aneurysm identification and localization. MRA is safe, but less suitable in the acute stage, because in the acute stage patients are often restless or need extensive monitoring.[122] Factors such as aneurysm size, acquisition sequences used, and the type of post processed images used for MRA interpretation can influence MRA results. The sensitivity of 3-dimensional time-of-flight MRA for cerebral aneurysms is between 55% and 93%. [122-125] With aneurysms 5 mm, the sensitivity is 85% to 100%, whereas the sensitivity of MRA for detecting aneurysms <5 mm drops to 56%. [122,123,126,127]

MRA also has limitations in the characterization of the aneurysm neck and its

relationship to the parent vessels. MRA does not require iodinated contrast and ionizing 22

radiation. This may be helpful in the evaluation of patients during pregnancy. MRA may also be an acceptable modality for initial screening in patients without SAH, as described above. [128,129]

CTA CT angiography is a rapid, readily available, less invasive alternative to catheter angiography and has demonstrated sensitivities approaching equivalence to catheter angiography for larger aneurysms. The technique uses a rapid intravenous injection of iodinated contrast with image acquisition during the arterial phase in the area of interest. Images from a CTA should extend from just below the foramen magnum to above the circle of Willis and middle cerebral artery bifurcation. The success of CTA depends in part on imaging through the area of interest during maximal contrast dose. Postâ&#x20AC;&#x201C;image processing techniques can provide valuable 3-dimensional information for developing treatment strategies. Interpretation of CTA should not be based on reconstructed images alone. The source images should be the major basis of interpretation, and the 3-dimensional reconstructed images should be used to clarify specific questions.[130] CTA has a reported sensitivity for aneurysms between 77% and 100% and a specificity between 79% and 100%. [131-137]

The sensitivity and specificity of CTA for aneurysm detection depend on aneurysm

location and size, radiologist experience, image acquisition, and the presentation of the images. For aneurysms 5 mm, CTA has a sensitivity between 95% and 100% compared with between 64% and 83% when aneurysms are <5 mm. [131-137] Vessel tortuosity decreases the specificity of CTA, leading to misinterpretation as an intracranial aneurysm. This occurs most frequently in the region of the middle cerebral artery bifurcation, anterior communicating artery, and the posterior inferior cerebellar arteries. Radiologist experience is an important

factor in the practical accuracy of CTA in detecting cerebral aneurysms. The sensitivity and specificity for the detection of cerebral aneurysms are increased with more experienced observers.[131,132] Among aneurysms detected on CTA and then undergoing surgery, 100% correlation was observed between CTA and catheter angiography.[132,138] Velthuis and colleagues[138] found that CTA is equal to catheter angiography in 80% to 83% of cases. In 74% of patients, catheter angiography performed after CTA did not reveal any additional information.[134] From these data, many neurosurgeons operate on the basis of CTA alone in cases in which the risk of delaying surgery for a catheter study is not justified. A smaller number of neurosurgeons have used these data to justify routine surgery on CTA alone. [139] CTA can also be used to supplement information obtained by catheter angiography. CTA is better able to define aneurysmalwall calcification, intraluminal aneurysm thrombosis, orientation of aneurysm with respect to intraparenchymal haemorrhage, and the relationship of the aneurysm with bony landmarks. CTA has been shown to be effective in determining the presence of severe vasospasm but is less accurate in detecting mild and moderate vasospasm.[140] CTA has advantages related to rapid image acquisition and its widespread availability, which can make it suitable for critically ill patients. Disadvantages of CTA include the need for iodinated contrast dye administration, the possibility of bony artifact that interferes with image quality, and the inability to study small distal vessels. Artifact interference from metal limits the use of CTA in patients with previous aneurysm clips or coils. The use of CTA continues to evolve, and in the future, CTA will increasingly supplement or selectively replace conventional angiography in the management of acute SAH. [141]

Conventional angiography 24

The gold standard for detecting aneurysms is conventional angiography, but this procedure can be time consuming and it is not an innocuous procedure. The aneurysm may re-rupture during the procedure, as occurs in 1â&#x20AC;&#x201C;2% of cases overall.[142] The rupture rate in the 6 h period following angiography has been estimated at 5%.[142] Causes other than saccular aneurysms Non-aneurysmalperimesencephalic haemorrhage

Perimesencephalic haemorrhage constitutes ~10% of all episodes of SAH and twothirds of those with a normal angiogram. [143-148] In this radiologically distinct and strikingly harmless variety of SAH, the extravagated blood is confined to the cisterns around the midbrain, and the centre of the bleeding is immediately anterior to the midbrain (Fig. 5).[149151]

In some cases, the only evidence of blood is found anterior to the pons. [152] For this

reason some have proposed the term pre-truncal haemorrhage,[153] but in other patients the blood is found mainly in the ambient cistern (Fig. 6) or only in the quadrigeminal cistern. [153,154,155]

There is no extension of the haemorrhage to the lateral Sylvain fissures or to the

anterior part of the interhemispheric fissure. Some sedimentation of blood in the posterior horns of the lateral ventricles may occur, but frank intraventricular haemorrhage or extension of the haemorrhage into the brain parenchyma indicates arterial haemorrhage and rules out this particular condition.[156] this disease entity is defined only by the characteristic distribution of the extravagated blood on brain CT, in combination with the absence of an aneurysm.

Fig. 5 Upper panels: a typical perimesencephalic pattern of haemorrhage. The centre of the bleeding is in the interpeduncular cistern; the haemorrhage extends into both ambient cisterns and the basal parts of the sylvian fissure, but not into the lateral parts of the Sylvain fissures or the anterior interhemispheric fissure. The angiogram shows neither basilar aneurysm, nor a vertebral artery aneurysm on the right. Angiography of the left vertebral artery was also normal (not shown). Lower panels: a patient with the centre of the haemorrhage in the interpeduncular cistern, but with extension into the lateral part of the sylvian fissures and into the anterior interhemispheric fissure. CT angiography shows a basilar tip aneurysm.


Fig. 6 Perimesencephalic haemorrhage, mainly in the ambient cistern. Perimesencephalic haemorrhage can occur in any patient over the age of 20 years, but most patients are in their sixth decade, as with aneurysmal haemorrhage. A history of hypertension was obtained more often than expected in a single study,


but not in

another.[158] In one-third of the patients, strenuous activities immediately precede the onset of symptoms, a proportion similar to that found in aneurysmal haemorrhage.[143,159] Clinically, there is little to distinguish idiopathic perimesencephalic haemorrhage from aneurysmal haemorrhage. The headache onset is more often gradual (minutes rather than seconds) than with aneurysmal haemorrhage,


but the predictive value of this

feature is poor. Loss of consciousness and focal symptoms are exceptional and then only transient; a seizure at onset virtually rules out the diagnosis.


On admission, all patients

are, in fact, in perfect clinical condition, apart from their headache. [143,157] Transient amnesia is found in about one-third and is associated with enlargement of the temporal horns on the initial CT scan.[160] Typically, the early course is uneventful: rebleeds and delayed cerebral ischaemia simply do not occur. Approximately 20% of patients have enlarged lateral ventricles on their admission brain CT scan, associated with extravasations of blood in all perimesencephalic cisterns, which probably causes blockage of the CSF circulation at the tentorial hiatus.[161] Only few have symptoms from this ventricular dilatation and even then

an excellent outcome can be anticipated.[161,162] The period of convalescence is short and almost invariably patients are able to resume their previous work and other activities.[162,163] Rebleeds after the hospital period have not been documented thus far[163] and the quality of life in the long term is excellent.[164] A perimesencephalic pattern of haemorrhage may occasionally (in 2.5â&#x20AC;&#x201C;5% of cases) be caused by rupture of a posterior fossa aneurysm.[165,166] The chance of finding an aneurysm in 5% of patients has to be weighed against the risks of complications from angiography imposed upon the remaining 95% of patients. In recent years, CTA has been studied as a method to confirm or exclude the presence of an aneurysm in patients with a perimesencephalic pattern of haemorrhage on CT. In a prospectively collected series of 40 patients with either a perimesencephalic haemorrhage or a posterior circulation aneurysm in whom CTA and conventional angiography were performed, radiologists detected an aneurysm in 16 patients and no aneurysm in the remaining 24 patients. These findings were confirmed after reading the angiograms.


A formal decision analysis based on these

observations indicated that a strategy where CTA is performed and not followed by conventional angiography, if negative, results in a better utility than a strategy where CTA is followed by conventional angiography or if all patients are initially investigated by conventional angiography (Y. M. Ruigrok, G. J. E. Rinkel, E. Buskens, B. K. Velthuis and J. van Gijn, unpublished data).

Arterial dissection Dissection, in general, tends to be recognized more often in the carotid than in the vertebral artery, but SAH from a dissected artery occurs mostly in the vertebral artery (Fig. 7).[168,169] It is unknown what precise proportion of all SAH cases arise from a dissected


vertebral artery. All miscellaneous causes together account for only ~5%, against 85% for aneurysmalhaemorrhages and 10% for idiopathic perimesencephalic haemorrhages. In a post-mortem study of fatal SAH, dissection was found in five of 110 patients [170]

Fig. 7 Subarachnoid haemorrhage from dissection of a vertebral artery. CT angiogram on the day of admission shows irregular narrowing of the left vertebral artery. Intra-arterial angiography 1 week later shows absence of retrograde filling on injection of the right vertebral artery (lower left panel) and a string sign on injection of the left vertebral artery (lower centre and right panels).

Neurological deficits that may accompany SAH from vertebral artery dissection are palsies of the ninth and tenth cranial nerves, by subadventitial dissection, Wallenberg's syndrome.


Rebreeds occur in between 30 and 70% of cases.



or The

interval can be as short as a few hours or as long as a few weeks. The second episode is fatal in approximately half of the patients. Dissection of the intracranial portion of the internal carotid artery or one of its branches as a cause of SAH is much less common than with the vertebral artery. Reported cases have affected the terminal portion of the internal carotid artery, cerebral artery [177] and the anterior cerebral artery.[178]


the middle

Cerebral AVMs Subarachnoid bleeding at the convexity of the brain may occur from superficial AVMs, but only in <5% of all ruptured AVMs are the extravasations only in the subarachnoid space, without intracerebral haematoma (Fig. 8).


Saccular aneurysms form on feeding

arteries of 10â&#x20AC;&#x201C;20% of AVMs, presumably because of the greatly increased flow and the attendant strain on the arterial wall. If bleeding occurs in these cases, it is more often from the aneurysm than from the malformation. In those cases the site of the aneurysms is different from the classical sites of saccular aneurysms on the circle of Willis and again the haemorrhage is more often into the brain itself than into the subarachnoid space. [180,181]

Fig. 8 Subarachnoid haemorrhage from an arteriovenous malformation on the left middle cerebral artery.

Dural arteriovenous fistulae

Dural arteriovenous fistulae of the tentorium can give rise to a basal haemorrhage that is indistinguishable on CT from aneurysmalhaemorrhage (Fig. 9).[182] The anomaly is rare and can be found from adolescence to old age. The risk of haemorrhage from dural AVMs


depends on the pattern of venous drainage. Patients with direct cortical venous drainage have a relatively high risk, which is further increased if a venous ectasia is present. Patients with drainage into a main sinus have a low risk of haemorrhage and if no reflux occurs into the smaller sinuses or cortical veins, it is negligible. [183] After a first rupture, rebleeding may occur; in a series of five patients presenting with SAH, three had one or more rebleeds.[184]

Fig. 9 Subarachnoid haemorrhage in a patient with a Dural arteriovenous malformation. Apart from this malformation no aneurysm was found.

Cervical AVMs

Spinal AVMs present with SAH in ~10% of cases; in >50% of these patients, the first haemorrhage occurs before the age of 20 years.[185] Clues pointing to a cervical origin of the haemorrhage are onset with a sudden and excruciating pain in the lower part of the neck, or pain radiating from the neck to the shoulders or arms. [186]In the absence of such symptoms, the true origin of the haemorrhage emerges only when spinal cord dysfunction develops, after a delay that may be as short as a few hours or as long as a few years. [185] Rebleeds may occur, even repeatedly.[187] CT scanning of the brain in patients with a ruptured cervical AVM may show blood throughout the basal cisterns and ventricles. [186] If a cervical origin of the haemorrhage is suspected, MRI or MRA angiography are the first line of investigation, because spinal angiography is impractical without localizing signs or symptoms.

Saccular aneurysms of spinal arteries Saccular aneurysms of spinal arteries are extremely rare, with recorded incidents in ~12 patients.[188] As with AVMs of the spinal cord, the clinical features of spinal SAH may be accompanied by those of a transverse lesion of the cord, either partial or complete.

Cardiac myxoma Cardiac myxoma are uncommon to start with, and if present they may in exceptional cases metastasize to an intracranial artery, infiltrate the wall and thus cause an aneurysm to develop, even >1 year after operation on the primary tumour. [189]

Septic aneurysms Infected tissue debris entering the blood stream may lodge in the wall of cerebral arteries and lead to aneurysmal dilatation. The traditional term `mycotic aneurysms' refers only to fungi and should perhaps be discarded; after all, bacterial endocarditis is more common as an underlying condition than aspergillosis. Most strokes in the context of infective endocarditis are not SAH but (haemorrhagic) infarcts or intracerebral haemorrhages from pyogenic arteritis.[190] Aneurysms associated with infective endocarditis are most often located on distal branches of the middle cerebral artery, but ~10% of the aneurysms develop at more proximal sites.[191] Therefore, rupture of a septic aneurysm causes an intracerebr al haematoma in most patients, but some have a basal pattern of haemorrhage on CT that is very similar to that of a ruptured saccular aneurysm (Fig. 10). CTdocumented rebleeds have been reported.[192] Usually patients present with clinical features 32

of infected heart valves before SAH occurs, but sometimes rupture of a septic aneurysm is the initial manifestation of infective endocarditis. [193] Septic aneurysms can be obliterated by surgical or endovascular treatment,[192,194] or they may resolve after adequate antibiotic therapy.[195]

Fig. 10 Subarachnoid haemorrhage and an intracerebral haemorrhage in a patient with multiple septic aneurysms from infective endocarditis. Septic aneurysms in patients with aspergillosis are usually located on the proximal part of the basilar or carotid artery. [196] Rupture of such an aneurysm causes a massive SAH in the basal cisterns, indistinguishable from that of a saccular aneurysm.[197] Aspergillosis is difficult to diagnose, but should particularly be suspected in patients undergoing long-term treatment


antibiotics or






haematogenous dissemination have pulmonary lesions, but X-ray films of the chest may be normal early in the course.


Severely HIV-infected children may develop cerebral

aneurysms secondary to generalized arteriopathy. [198,199] In HIV-infected adults, aneurysmal SAH can also be coincidental.

Pituitary apoplexy The precipitating event of arterial haemorrhage occurring in a pituitary tumour is thought to be tissue necrosis, involving one of the hypophyseal arteries. Several contributing

factors may precipitate haemorrhagic infarction of a pituitary tumour, such as pregnancy, raised intracranial pressure, anticoagulant treatment, cerebral angiography or the administration of gonadotrophin-releasing hormone.[200] The initial features are a sudden and severe headache,[201] with or without nausea, vomiting, neck stiffness or a depressed level of consciousness.[202] The hallmark of pituitary apoplexy is that most patients have a sudden decrease in visual acuity: in one series of 15 patients, only two had normal visual acuity. In most patients with pituitary apoplexy eye movements are disturbed as well, because the haemorrhage compresses the oculomotor, trochlear and abducens nerves in the adjacent cavernous sinus. [203] Brain CT or MRI scanning indicate the pituitary fossa as the source of the haemorrhage and in most instances the adenoma itself is visible. [203]

Cocaine abuse In patients with SAH related to the use of HCl (`crack') cocaine, ~70% have an underlying aneurysm, against 30â&#x20AC;&#x201C;40% of those who used the alkaloid form. [204] The pattern of haemorrhage on brain CT may be comparable to that of a ruptured saccular aneurysm[205] and the diagnosis rests on a confirmatory history or on the results of toxicological tests. Rebleeds do occur, even in patients with a normal angiogram, and the outcome is often poor.


the source of the haemorrhage in patients without an aneurysm is unknown.

Although biopsy-proven vasculitis has been found, [207] changes suggestive of vasculitis often fail to show up on angiograms, admittedly a very insensitive test. [206,208]

Anticoagulants Anticoagulant drugs are seldom the sole cause for SAH. In a series of 116 patients with intracranial, extracerebral haemorrhage while on anticoagulant treatment, seven had 34

only SAH and in only three of these patients was there no cause for the haemorrhage other than anticoagulation.[209] Severe coagulopathy other than by anticoagulant drugs, e.g. congenital deficiency of factor VII, is also a rare cause of haemorrhage confined to the subarachnoid space.[210] If aneurysmal haemorrhage occurs in a patient on anticoagulants, the outcome is relatively poor.[211]

Sickle cell disease Thirty per cent of patients with sickle cell disease and SAH are children. [212] CT scans in these children show blood in the superficial cortical sulci; angiograms show no aneurysm, but often show multiple distal branch occlusions and a leptomeningeal collateral circulation. The SAH is attributed to rupture of these collaterals.


the outcome is poor: only three of

11 recently reviewed children recovered in a good functional state. [212] Most adult patients in whom sickle cell disease underlies SAH have a ruptured aneurysm at the base of the brain.

Superficial siderosis of the CNS This condition is characterized by iron overload of the pial membranes, through chronic oozing of blood from any source in the subarachnoid space. It has been included in this review only for semantic reasons; the clinical picture is completely different from that with sudden haemorrhages and does not include sudden headache. The clinical syndrome is characterized by sensorineural deafness (95%), furthermore by cerebellar ataxia (88%) and pyramidal signs (76%). Possible other features include dementia, bladder disturbance and anosmia. Men are more often affected than women (3:1). A source of bleeding has been identified in a little more than half of the cases reported up to 1995.


Causes of chronic

bleeding include a CSF cavity lesion or cervical root lesion, a vascular tumour (such as an ependymoma) or any other vascular abnormality. Probably the remaining cases are also caused by chronic haemorrhage. The high iron content of the pial membranes causes a characteristic signal on MRI scanning. [214]

Assessment There are several grading scales available for SAH. The Glasgow Coma Scale is ubiquitously used for assessing consciousness. Three specialized scores are used to evaluate SAH; in each, a higher number is associated with a worse outcome. [215] These scales have been derived by retrospectively matching characteristics of patients with their outcomes. The first scale of severity was described by Hunt and Hess in 1968: [216] Grade Signs and symptoms Survival Asymptomatic or minimal headache and slight neck 1 70% stiffness Moderate to severe headache; neck stiffness; no 2 60% neurologic deficit except cranial nerve palsy 3 Drowsy; minimal neurologic deficit 50% Stuporous; moderate to severe hemiparesis; 4


possibly early decerebrate rigidity and vegetative 20% disturbances Deep coma; decerebrate rigidity; moribund 10% The Fisher Grade classifies the appearance of subarachnoid haemorrhage on CT

scan.[217] This scale has been modified by Claassen and coworkers, reflecting the additive risk from SAH size and accompanying intraventricular haemorrhage.[218]

Grade Appearance of haemorrhage 1 2 3 4 36

None evident Less than 1 mm thick More than 1 mm thick Any thickness with intraventricular haemorrhage or

parenchymal extension The World Federation of Neurosurgeons (WFNS) classification uses Glasgow coma score (GCS) and focal neurological deficit to gauge severity of symptoms.[219] Grade 1 2 3 4 5 A

GCS Focal neurological deficit 15 Absent 13–14 Absent 13–14 Present 7–12 Present or absent <7 Present or absent comprehensive classification scheme has been suggested by Ogilvy and Carter to

predict outcome and gauge therapy. [220] The system consists of five grades and it assigns one point for the presence or absence of each of five factors: age greater than 50; Hunt and Hess grade 4 or 5; Fisher scale 3 or 4; aneurysm size greater than 10 mm; and posterior circulation aneurysm 25 mm or more.[220]

Complications of aneurysmal SAH [221] Intracranial complications 1. Recurrent haemorrhage. 2. Vasospasm- induced ischemic stroke. 3. Hydrocephalus. 4. Seizures. 5. Global cerebral ischaemia

Extra cranial complications 1. Systemic Arterial hypotension or hypertension Electrolyte disturbances (hyponatremia, hypernatremia, hypokalemia)

Cardiac (myocardial infraction, arrhythmia, congestive heart failure) 2. Pulmonary (neurogenic pulmonary edema, adult respiratory distress syndrome, atelectasis, pneumonia) 3. Gastrointestinal bleeding. 4. Sepsis 5. Renal or hepatic dysfunction 6. Venous thromboembolism 7.

Bleeding disorders, including thrombocytopenia

Rebleeding Recurrent haemorrhage is a feared complication of SAH because it is a leading cause of death or neurologic morbidity during the first 2 weeks after SAH.


within hours of the initial haemorrhage, occurs in at least 15% of patients.

Early rebleeding,


At present it is

virtually impossible to prevent this from happening, but medical or surgical intervention can prevent recurrent haemorrhage occurring later. In patients who survive the first day, the risk of rebleeding is more or less evenly distributed over the next 4 weeks, although there may be a second peak early in the third week. Rebleeding risk remains around 40% over the subsequent four weeks, suggesting that interventions should be aimed at reducing this risk as soon as possible.[2] Recurrent haemorrhage usually causes a sudden headache and a rapid change in neurologic condition, including a drop in consciousness. Extensor spasm and posturing are important early signs. A "convulsion" that occurs immediately after SAH also can mark a recurrent haemorrhage. [224] However, rebleeding in a comatose patient may be overlooked. It may be manifested only by a sudden change in respiratory pattern or vital signs.


Recurrent haemorrhage should be sought whenever a patient experiences a new headache or worsens neurologically. [221]

Vasospasm Vasospasm, in which the blood vessels constrict and thus restrict blood flow, is a serious complication of SAH. It can cause ischemic brain injury (referred to as "delayed ischemia") and permanent brain damage due to lack of oxygen in parts of the brain. It can be fatal if severe. Delayed ischemia is characterized by new neurological symptoms, and can be confirmed by transcranial Doppler or cerebral angiography. Cerebral vasospasm is most likely an inflammatory reaction in the blood-vessel wall and develops between days 4 and 12 after subarachnoid haemorrhage in up to one-third of patients. [225] The best predictor of vasospasm is the amount of blood seen on the initial head CT scan.[226-228] Angiographic vasospasm is more common (occurring in about two thirds of patients) than is symptomatic vasospasm (with clinical evidence of cerebral ischemia). Transcranial Doppler ultrasonography is performed either daily or every other day to monitor for vasospasm, which is defined as a mean velocity of cerebral blood flow of more than 120 cm per second in a major vessel. Doppler ultrasonography has a sensitivity that is similar to that of cerebral angiography for the detection of narrowed vessels, particularly in the middle cerebral and internal cerebral arteries. [229]

Global cerebral ischaemia In few patients, irreversible brain damage may have occurred immediately after aneurysm rupture. In a consecutive series of 31 patients who died on the first day, six patients had neither a supratentorial haematoma nor intraventricular haemorrhage. The

most likely explanation is a prolonged period of global cerebral ischaemia at the time of haemorrhage, as a result of the pressure in the cerebrospinal fluid spaces being elevated to the level of that in the arteries, for as long as a few minutes. This is quite distinct from delayed ischaemia, which is focal or multifocal. Such an immediate and potentially lethal arrest of the circulation to the brain is indeed suggested by autopsy evidence and by the recording of intracranial pressure or transcranial Doppler sonography at the time of recurrent aneurysmal haemorrhage. [230]

Acute Management Stabilizing the patient is the first priority. Those with a depressed level of consciousness may need to be intubated and mechanically ventilated. Blood pressure, pulse, respiratory rate and Glasgow Coma Scale are monitored frequently. Once the diagnosis is confirmed, patients should be transferred to centers with neurovascular expertise and preferably with a dedicated neurologic critical care unit to optimize care.[231,232] Once in the critical care setting, the main goals of treatment are the prevention of rebleeding, the prevention and management of vasospasm, and the treatment of other medical and neurologic complications.

General measures Forced bed rest is a traditional part of management. Visitors and external stimuli are restricted. Passive range-of-motion exercises and frequent turning are performed. A water mattress or an alternating- pressure pneumatic bed can reduce the risk of pressure sores . Nutrition is an early priority, with oral or nasogastric tube feeding being preferable over 40

parenteral routes. Alert patients are usually given a soft, high-fiber diet supplemented by stool softener. Caffeinated beverages are avoided. Stuporous and comatose patients are not fed during the acute treatment period. If a seriously ill person is stable several days after SAH and the airway is secured, nasogastric feedings can be instituted. A bladder catheter is usually inserted to monitor fluid balance.

Symptomatic treatment Patients with SAH are often confused or agitated as a result of brain injury, hydrocephalus, or increased intracranial pressure. Pain or nausea can also lead to irritability. Agitation










pressure. Analgesia (pain control) is generally restricted to less sedating agents such as codeine, as sedation may impact on the mental status and thus interfere with the ability to monitor the level of consciousness

. Some patients have photophobia; a quiet, dark


environment can help relieve some of these conditions, which otherwise might worsen the head pain. Aspirin affects platelet aggregation and prolongs the bleeding time; there is concern that aspirin might potentiate rebleeding. Benzodiazepines may be administered to help relieve distress.[233] Antiemetic drugs should be given to awake persons.[234] Glucocorticoids may help reduce the head and neck ache caused by the irritative effect of the subarachnoid blood. There is no good evidence they reduce cerebral edema, are neuroprotective, or reduce vascular injury, and their routine use therefore is controversial. Two important factors that are associated with poor outcome are hyperglycemia and hyperthermia, and both should be corrected.[235,236] Deep vein thrombosis is prevented with

compression stockings, intermittent pneumatic compression of the calves or both[2] and subcutaneous heparin should be added after the aneurysm is treated. Gastrointestinal bleeding can result from hemorrhagic gastritis, stress gastric ulcers, or an esophageal tear secondary to vomiting. Because of the risk of bleeding, patients are often given intravenous histamine2-receptor antagonists or proton pump inhibitors via nasogastric tube.[237] Sucralfate does not have central nervous system side effects, so it has potential advantages in preventing gastrointestinal side effects among critically ill patients prone to depression in consciousness.[238]

Prevention of rebleeding Medical Measures Bed rest is a prescribed element in the treatment protocol of SAH aimed at reducing rebleeding. Despite continued inclusion in current treatment protocols, by itself it does not abate the risk of rebleeding. [239] it may be included as a component of a broader treatment strategy, along with more definitive measures.

Antihypertensive Treatment Arterial hypertension is common in SAH, resulting from elevations of catecholamines and renin produced by hypothalamic disturbances. [240] Additionally, increased intracranial pressure can induce arterial hypertension as a means to maintain adequate cerebral perfusion pressure. Arterial hypertension also can be secondary to seizures, vomiting, agitation, or pain. In addition, the patient may have preexisting hypertension. To date, no well-controlled studies exist that answer whether blood pressure control in acute SAH influences rebleeding. A retrospective review of the influence of rebleeding showed that it occurred less frequently in patients treated with antihypertensive medication, yet blood pressures were still higher in the treated group.[241] Alternately, 42

rebleeding may be related to variations or changes in blood pressure rather than to absolute blood pressure[242]; 1 report found an increase in blood pressure before rebleeding. [243] In a retrospective review of 179 patients admitted within 24 hours of SAH, 17% experienced rehaemorrhage that was associated with a systolic blood pressure >150 mm Hg. [244] Interpretation of this finding is confounded, however, by the observation that blood pressure was higher closer to the time of initial SAH, as was the incidence of rebleeding. Another study found a rehaemorrhage rate of 13.6% in the ambulance or referring hospital with a peak incidence within 2 hours of the initial bleed. Rebleeding was more common in those with a systolic blood pressure >160 mm Hg.[243] Another large retrospective study reported a rebleeding rate of 6.9% after admission but no relationship to blood pressure. [245] Interpretation of these studies is limited by variable times of observation and variable use of antihypertensives,[246] although all attempted to repair the aneurysm within 24 hours of admission. So blood pressure should be monitored and controlled to balance the risk of stroke, hypertension-related rebleeding, and maintenance of cerebral perfusion pressure The levels of arterial hypertension that mandates treatment is not known. Patients with moderate hypertension (mean arterial blood pressure lower than 120 mm hg) probably do not need to be treated. On the other hand, patients whose mean blood pressure is 120 or higher or whose systolic blood pressure is higher than 180 mm hg should receive medication. When blood pressure is elevated, short-acting continuous-infusion intravenous agents with a reliable dose-response relationship and favorable safety profile are desirable. To reduce blood pressure, nicardipine, labetalol, and esmolol appear to meet these criteria best. It is reasonable to avoid sodium nitroprusside in many neurological emergencies because of its tendency to raise intracranial pressure and cause toxicity with prolonged infusion.

Antifibrinolytic drug Treatment with antifibrinolytic agents does reduce the rebleed rate, but fails to improve overall outcome. By far the largest study was a Dutchâ&#x20AC;&#x201C;Scottish trial.[247] In this metaanalysis, antifibrinolytic treatment did not provide any evidence of benefit on outcome. The risk of rebleeding was significantly reduced by antifibrinolytic therapy, but this was offset by a similar increase of the risk of secondary cerebral ischaemia. In other words, antifibrinolytic drugs work, but they do not help. However, because all trials in this meta-analysis had been performed before the nineties, at a time when prevention or treatment of secondary cerebral ischaemia had yet to be developed, a new clinical trial on antifibrinolytic therapy has recently been completed in The Netherlands. In this trial, all 492 patients were maximally protected against ischaemia by means of calcium antagonists and normovolaemia. Tranexamic acid again significantly reduced the rate of rebleeding, yet the overall outcome was not different between the two groups, mainly because of cerebral ischaemia. [248] However, increased use of early aneurysm treatment combined with prophylactic treatment of cerebral vasospasm may reduce the ischemic complications of antifibrinolytic agents while maintaining the benefit of reduced preoperative bleeding rates. In a prospective, randomized trial of the antifibrinolytic drug tranexamic acid, early rebleeding rates and adverse outcomes were reduced when the drug was administered immediately after the diagnosis of SAH. [249] According to the AHA/ASA guideline published in 2009[95]

Medical Measures to Prevent Rebleeding After SAH: Summary and Recommendations according to the AHA/ASA guideline [95]: 44

1. Blood pressure should be monitored and controlled to balance the risk of stroke, hypertension-related rebleeding, and maintenance of cerebral perfusion pressure (Class I, Level of Evidence B). 2. Bed rest alone is not enough to prevent rebleeding after SAH. It may be considered a component of a broader treatment strategy, along with more definitive measures (Class IIb, Level of Evidence B). 3. Although older studies demonstrated an overall negative effect of antifibrinolytics, recent evidence suggests that early treatment with a short course of antifibrinolytic agents combined with a program of early aneurysm treatment followed by discontinuation of the antifibrinolytic and prophylaxis against hypovolemia and vasospasm may be reasonable (Class IIb, Level of Evidence B), but further research is needed. Furthermore, antifibrinolytic therapy to prevent rebleeding may be considered in certain clinical situations, eg, in patients with a low risk of vasospasm and/or a beneficial effect of delaying surgery (Class IIb, Level of Evidence B

Surgical and Endovascular Methods People whose CT scan shows a large hematoma, depressed level of consciousness or focal neurologic symptoms may benefit from urgent surgical removal of the blood or occlusion of the bleeding site. The remainders are stabilized more extensively and undergo a transfemoral angiogram or CT angiogram later. It is hard to predict who will suffer a rebleed, yet it may happen at any time and carries a dismal prognosis. After the first 24 hours have passed, rebleeding risk remains around 40% over the subsequent four weeks, suggesting that interventions should be aimed at reducing this risk as soon as possible. [2]

If a cerebral aneurysm is identified on angiography, two measures are available to reduce the risk of further bleeding from the same aneurysm: clipping[250] and coiling.[251] Clipping requires a craniotomy (opening of the skull) to locate the aneurysm, followed by the placement of clips around the neck of the aneurysm. Coiling is performed through the large blood vessels (endovascularly): a catheter is inserted into the femoral artery in the groin and advanced through the aorta to the arteries (both carotid arteries and both vertebral arteries) that supply the brain. When the aneurysm has been located, platinum coils are deployed that cause a blood clot to form in the aneurysm, obliterating it. The decision as to which treatment is undertaken is typically made by a multidisciplinary team consisting of a neurosurgeon, neuroradiologist and often other health professionals.[2] The International Subarachnoid Aneurysm Trial (ISAT) prospectively examined patients with ruptured aneurysms who were considered equally suitable for either endovascular coiling or microsurgical clipping.


The authors found that for this

particular subgroup of patients, a favorable outcome, which was defined as survival free of disability at one year, occurred significantly more often in patients treated with endovascular coiling than with surgical placement of clips. The risk of epilepsy was substantially lower in patients who underwent endovascular coiling, but the risk of rebleeding was higher. Also, in patients who underwent follow-up cerebral angiography, the rate of complete occlusion of the aneurysm was greater with surgical clipping. ISAT was a landmark study that validated the technique of endovascular coiling. However, many aneurysms are not equally suitable for either microsurgical clipping or endovascular coiling. In individual cases, several factors â&#x20AC;&#x201D; such as the patient's age and overall medical condition and the aneurysm's location, morphology, and relationship to adjacent vessels â&#x20AC;&#x201D; need to be analyzed to decide on the most appropriate treatment.[254-256] 46

In general, elderly patients or patients in poor medical condition are often better suited for endovascular coiling. Aneurysms of the vertebrobasilar circulation or aneurysms deep in the skull base, such as paraophthalmic aneurysms, may be more easily accessed by an endovascular approach. Wide-neck aneurysms (in which the ratio of the neck diameter to that of the largest dome is more than 0.5) tend to be less suitable for endovascular coiling. Aneurysms associated with large parenchymal hematomas and those that have normal branches arising from the base or dome are often more suitable for microsurgical clipping. In addition, for aneurysms causing a local mass effect, surgical therapy may be more efficacious. Owing to the complex analysis of specific variables among patients and types of aneurysms that is needed to determine the most appropriate treatment for individual patients, we recommend evaluation by practitioners who have detailed knowledge of neurovascular surgery, endovascular techniques, and neurologic critical care. According to the recently published "Guidelines for the Management of Aneurysmal Subarachnoid Haemorrhage" by American Heart Association (AHA) in 2009, they suggests

Surgical/Endovascular Treatment of Ruptured Aneurysms: Summary and Recommendations [95] 1. Surgical clipping or endovascular coiling should be performed to reduce the rate of rebleeding after aneurysmal SAH (Class I, Level of Evidence B). 2. Wrapped or coated aneurysms and incompletely clipped or coiled aneurysms have an increased risk of rehaemorrhage compared with those that are completely occluded and therefore require long-term follow-up angiography. Complete obliteration of the aneurysm is recommended whenever possible (Class I, Level of Evidence B).

3. For patients with ruptured aneurysms judged by an experienced team of cerebrovascular surgeons and endovascular practitioners to be technically amenable to endovascular coiling and neurosurgical clipping, endovascular coiling can be beneficial (Class I, Level of Evidence B). Nevertheless, it is reasonable to consider individual characteristics of the patient and the aneurysm in deciding the best means of repair, and management of patients in centers offering both techniques is probably indicated (Class IIa, Level of Evidence B). 4. Although previous studies showed that overall outcome was not different for early versus delayed surgery after SAH, early treatment reduces the risk of rebleeding after SAH, and newer methods may increase the effectiveness of early aneurysm treatment. Early aneurysm treatment is reasonable and is probably indicated in the majority of cases (Class IIa, Level of Evidence B).

Prevention of secondary cerebral ischaemia Fluid balance and electrolytes Fluid management in SAH is important to prevent a reduction in plasma volume, which may contribute to the development of cerebral ischaemia. Nevertheless, the arguments for a liberal (some might say aggressive) regimen of fluid administration are indirect. In approximately one-third of the patients, plasma volume drops by >10% within the preoperative period, which is significantly associated with a negative sodium balance; in other words, there is loss of sodium as well as of water. [257,258] Moreover, fluid restriction in patients with hyponatraemia is associated with an increased risk of cerebral ischaemia. [259] Fluid restriction was applied in the past because hyponatraemia was erroneously attributed to water retention, via inappropriate secretion of antidiuretic hormone. Two non48

randomized studies with historical controls suggested that a daily intake of at least 3 l of saline (against 1.5–2.0 l in the past) was associated with a lower rate of delayed cerebral ischaemia and a better overall outcome.[260,261] The interpretation of these two studies is difficult not only because of their observational nature, but also because the liberal administration of saline in the second period was confounded by avoidance of antihypertensive drugs. The only randomized study of hypervolaemia that has been published included only 30 patients.[262] Treatment allocation was not blinded (personal information obtained from the authors) and outcome was not assessed beyond the time of operation (day 7–10). At that time, the rate of delayed ischaemia had been reduced by twothirds (67%; 95% CI 1–89%). Despite the incomplete evidence, it seems reasonable to prevent hypovolaemia. Van Gijn and Rinkel (2001) favoured giving 2.5–3.5 l/day of normal saline, unless contraindicated by signs of impending cardiac failure. Nevertheless, it appeared that many patients need a daily fluid intake of 4–6 l (sometimes as much as 10 l) to balance the production of urine plus estimated insensible losses (via perspiration and expired air). Fluid requirements may be guided by recording of central venous pressure (directly measured value should be >8 mmHg) or pulmonary wedge pressures (to be maintained at >7 mmHg), but frequent calculation of fluid balance (four times per day until approximately day 10) is the main measure for estimating how much fluid should be given. Fluid intake should be increased proportionally in patients with fever, whatever the cause. [263]

Calcium antagonists Calcium antagonists reduce the influx of calcium into the cell through blocking calcium channels. Thus, a rationale for the use of calcium antagonists for prevention of

secondary ischaemia was based on the notion that these drugs can counteract the influx of calcium into the vascular smooth-muscle cell, thereby decreasing the rate of vasospasm. After their introduction into clinical practice it was discovered that calcium antagonists also have neuroprotective properties. Another important effect of calcium antagonists is the induction









Magnesium sulphate acts as a non-competitive antagonist of voltage-dependent calcium channels, as a NMDA-receptor antagonist, and has neuroprotective and vasodilatory properties.[268] It has been shown to reduce cerebral vasospasm and infarct volume after experimental SAH. [269,270] Also, hypomagnesaemia occurs in more than 50% of patients with SAH and is related to the occurrence of secondary ischaemia. [271] These observations have led to the hypothesis that magnesium sulphate can decrease the occurrence









Several trials with nimodipine and other calcium antagonists have been performed in patients with SAH. In recent years magnesium sulphate has been added to the list of calcium antagonists that have been tested. There are 27 trials of treatment with calcium antagonists in patients with subarachnoid haemorrhage: 20 trials of any calcium antagonist versus placebo and seven trials of magnesium sulphate in addition to nimodipine. The trials were performed between 1983 and 2006. Analysing those previous trails, Mees et al (2007) published a review article in 2007. According to their recommendation, they suggest oral nimodipine (60 mg every four hours, to be continued for three weeks) as standard treatment in patients with aneurysmal subarachnoid haemorrhage. Although the evidence about the beneficial effect of nimodipine is not beyond all doubt, they recommend oral nimodipine given the potential benefits and modest risks associated with it. Intravenous 50

administration of calcium antagonists is more expensive and potentially hazardous in view of hypotensive effects, and is therefore not recommended. There is no evidence that nicardipine or AT877 has a significant effect on functional outcome after aneurysmal subarachnoid haemorrhage. Magnesium is another calcium antagonist with promising results, but larger trials with this drug are needed before we can be certain about a beneficial effect. [272]

Neuroprotective drugs other than calcium antagonists Tirilazad has been studied in four randomized, controlled trials, totalling >3500 patients.[273-275] This drug belongs to the category of 21 amino steroids that inhibit irondependent lipid peroxidation. The only beneficial effect on overall outcome was seen in a single subgroup of a single trial, i.e. those treated with 6 mg/kg/day (two other groups received 0.2 or 2 mg/kg/day). [273] This possible benefit could not be reproduced in the corresponding subgroup from a parallel trial,[274]or in two further trials with an even higher dose (15 mg/kg/day) in women;[275] the gender distinction was made because in the first two trials, women had seemed to respond less than men to tirilazad mesylate. A single trial with another hydroxyl radical scavenger, N'-propylenedinicotinamide (nicaraven), in 162 patients showed a decreased rate of delayed cerebral ischaemia but not of poor outcome at 3 months after SAH.[276] Curiously enough, the opposite was found in a trial of 286 patients with ebselen, a seleno-organic compound with antioxidant activity through a glutathione peroxidase-like action: improved outcome at 3 months after SAH, but without any reduction in the frequency of delayed ischaemia. [277] Aspirin and other antiplatelet agents

Several studies have found that blood platelets are activated from day three after SAH, mostly through increased levels of thromboxane B2, the stable metabolite of thromboxane A2, a substance that promotes platelet aggregation and vasoconstriction. 280]


The practical question is whether interventions aimed at counteracting platelet activation

are therapeutically useful. A retrospective analysis of 242 patients who had survived the first 4 days after SAH showed that patients who had used salicylates before their haemorrhage (as detected by history and urine screening) had a significantly decreased risk of delayed cerebral ischaemia, with or without permanent deficits (relative risk 0.40; 95% CI 0.18â&#x20AC;&#x201C;0.93). [281]

A first clinical trial was done in as early as 1982, which failed to show benefit from aspirin


, but the number of patients was small (53), un-operated patients were also included and

all were treated with tranexamic acid, which increases the risk of ischaemia (see above). There is a need for a prospective and randomized study of salicylates or other antiplatelet drugs as a preventive measure against delayed cerebral ischaemia, preferably after clipping of the aneurysm to avoid rebleeding being precipitated by the antiplatelet and so antihaemostatic action. Four antiplatelet agents other than aspirin have been tested in separate trials of patients with SAH: dipyridamole (100 mg/day orally or 10 mg/day intravenously) in 320 patients; [283] the thromboxane A2 synthetase inhibitor nizofenone (10 mg/day intravenously) in 77 patients;[284] the thromboxane A2 synthetase inhibitor cataclot (1 g/kg/min intravenously) in 24 patients;[285] and the experimental antiplatelet agent OKY-46 (160 or 800 mg orally) in 256 patients.[286] In a systematic overview of these four trials and the two aspirin trials mentioned above, the rate of poor outcome was not significantly different between patients treated with antiplatelet agents and controls (S. Raup, J. W. Hop, G. J. E. Rinkel, A. Algra and J. van Gijn, unpublished review). A pilot study of aspirin after early operation in 50 patients has shown that this treatment is feasible and probably safe.[287] 52

Other strategies to prevent delayed cerebral ischaemia Using a stratified treatment randomization scheme, which took into account the number of days since the SAH and the postoperative Hunt-Hess grade, Lennihan and colleagues[288] showed that those treated with hypervolemic therapy (n=41) received significantly more fluid and exhibited higher pulmonary artery diastolic pressures and central venous pressures than normovolemic patients (n=41), there was no difference between the two groups in mean global CBF (xenon washout), minimal regional CBF, or symptomatic spasm during the treatment period. In addition, 14- and 90-day functional outcomes were similar. Egge et al [289] also performed a randomized prospective trial (n=32 patients) to consider the issue of prophylactic volume expansion and hyperdynamic therapy before the onset of symptoms. Sixteen patients received hypervolemic therapy; the other half received normovolemic therapy. All patients were monitored for a minimum of 12 days and followed up with single-photon emission CT scanning and clinical observation. They also did not observe any difference between the two groups with respect to cerebral vasospasm, as observed clinically, on TCD recordings, or in CBF. One-year clinical follow-up, according to the Glasgow Coma Scale, did not demonstrate any significant group differences. In their study, costs were higher and complications were more frequent for the hyperdynamic therapy group. Taken together, these two small, single-centers, prospective randomized studies strongly suggest that avoiding hypovolemia is advisable, but there is no evidence that prophylactic hyperdynamic therapy is of any utility. Nevertheless, given the inability of these small studies to detect small improvements owing to a lack of statistical power, many centers in North America continue to advocate prophylactic volume expansion as a means to improve CBF, and numerous reports advocate

the use of either in-dwelling pulmonary artery catheters to maximize cardiac output and cardiac index or central venous catheters in patients with no preexisting cardiac disease. [290,291-295]

Calcitonin-gene-related peptide is a potent vasodilatator, but in a randomized clinical trial, no effect of this drug was found.


Another strategy aimed at reducing the frequency

of vasospasm is lysis of the intra-cisternal blood clot with intrathecally administered recombinant tissue plasminogen activator, but a clinical trial in 100 patients failed to show a reduction in the rate of secondary ischaemia or improvement in outcome.[297] Prophylactic transluminal balloon angioplasty has been advocated,


but there are

no controlled studies to support this.

Treatment of delayed cerebral ischaemia The most widely accepted therapy for symptomatic cerebral vasopasm is to increase the cerebral perfusion pressure by raising mean arterial pressure through plasma volume expansion and the judicious use of vasopressor agents, usually phenylephrine or dopamine. Raised perfusion pressure has been associated with clinical improvement in many patients, but high arterial pressure may promote rebleeding in unprotected aneurysms. Treatment with induced hypertension and hypervolemia generally requires monitoring of arterial and central venous pressures and in severe cases, the pulmonary artery wedge pressure. Volume expansion helps prevent hypotension, augments cardiac output, and reduces blood viscosity by reducing hematocrit. This method is called â&#x20AC;&#x153;triple-Hâ&#x20AC;? (hypertension, hemodilution, and hypervolemic) therapy.[299] Nevertheless, despite reportsindicating


improvement in neurological status after the institution of this regimen, only 1 randomized study has been performed to assess efficacy.[,300,301] Balloon angioplasty has been shown to be effective in reversing cerebral vasospasm in large proximal conducting vessels with thick muscular walls, whereas angioplasty is not effective or safe in distal perforating branches beyond second-order segments.[302-304] Although many advances have been made in interventional procedures, there are still significant risks associated with angioplasty of cerebral vessels such as vessel occlusion, vessel rupture, thrombus formation, and aneurysm clip displacement.[302-304] With microcatheter technology improving and superselective techniques having advanced over the last decade, it has become possible to selectively catheterize third- and fourth-order cerebral vessels and to administer high doses of vasodilators such as papaverine into vessels that cannot be treated with balloon angioplasty.[305-308] Superselective slow infusion of vasodilators has been reported to reduce the risks associated with earlier methods of delivery, including brainstem depression, hypotension, aggravation of vasospasm, seizures, respiratory arrest, transient hemiparesis, and elevated intracranial pressure.[309,310] There are numerous reports in the literature in which a combination of balloon angioplasty and vasodilator infusion was used to treat vasospastic cerebral vessels distal to vessels that can be treated with mechanical angioplasty. [311] However, there are no reports indicating that the two treatments delivered together are superior in terms of outcome.[312] The major complication associated with papaverine is elevated intracranial pressure. All reports have indicated that intracranial pressure can be controlled with brief hyperventilation, mannitol, barbiturate therapy, and/or ventricular drainage. Reported rates of serious complications range from 2% to 5%. [313,314]

According to the AHA/ASA guideline published in 2009:







Recommendations [95] 1. Oral nimodipine is indicated to reduce poor outcome related to aneurysmal SAH (Class I, Level of Evidence A). The value of other calcium antagonists, whether administered orally or intravenously, remains uncertain. 2. Treatment of cerebral vasospasm begins with early management of the ruptured aneurysm, and in most cases, maintaining normal circulating blood volume and avoiding hypovolemia are probably indicated (Class IIa, Level of Evidence B). 3. One reasonable approach to symptomatic cerebral vasospasm is volume expansion, induction of hypertension, and hemodilution (triple-H therapy) (Class IIa, Level of Evidence B). 4. Alternatively, cerebral angioplasty and/or selective intraarterial vasodilator therapy may be reasonable after, together with, or in the place of triple-H therapy, depending on the clinical scenario (Class IIb, Level of Evidence B).

Management of Hydrocephalus Associated With SAH The literature regarding hydrocephalus in SAH consists of a number of case series, most of which are retrospective. Acute hydrocephalus (ventricular enlargement within 72 hours) is reported to occur in 20% to 30% of patients.[315-318] The ventricular enlargement is often, but by no means always, accompanied by intraventricular blood;[319,320] hydrocephalus without intraventricular haemorrhage is associated with the amount and distribution of cisternal blood.[321,322] Acute hydrocephalus is more frequent in patients with poor clinical grade and higher Fischer Scale scores. 56


The clinical significance of acute

ventriculomegaly after SAH is uncertain because many patients are apparently asymptomatic and do not deteriorate.[323] If the level of consciousness is decreased, drainage of the excess fluid is performed by therapeutic lumbar puncture, extraventricular drain (a temporary device inserted into the one of the ventricles) or occasionally a permanent shunt.[2,3]

In patients with a

diminished level of consciousness, 40% to 80% had some degree of improvement after ventriculostomy.[319,320,324]] On the basis of two small series, the placement of a ventriculostomy may[325] or may not[326] be associated with rebleeding. Chronic ventriculomegaly requiring permanent shunting procedures is reported at rates of 18% to 26% of surviving patients. [318,326,327] The need for permanent CSF diversion has been associated with older age, early ventriculomegaly, intraventricular haemorrhage, poor clinical condition on presentation, and female sex. [328,329-332] Two single-center series have suggested that routine fenestration of the lamina terminalis reduces the incidence of chronic hydrocephalus.[333,334] In comparison, rates are no different in patients undergoing clipping






aneurysms. [326,327]


ventriculoperitoneal, or lumboperitoneal shunts may improve clinical status in this group of patients.[335,336] Nevertheless, the speed with which the ventriculostomy is weaned does not appear to affect the need for ultimate shunt placement.[337] According to the AHA/ASA guideline published in 2009:

Management of Hydrocephalus: Summary and Recommendations [95] 1. Ventriculostomy can be beneficial in patients with ventriculomegaly and diminished level of consciousness after acute SAH (Class IIa, Level of Evidence B).

2. Temporary or permanent CSF diversion is recommended in symptomatic patients with chronic hydrocephalus after SAH (Class I, Level of Evidence B).

Management of Seizures Associated With SAH The risk and implications of seizures associated with SAH are not well defined, and the need for and efficacy of routinely administered anticonvulsants after SAH are not well established. More recent retrospective reviews report a low frequency of seizures ranging from 6% to 18%.[338-340] Another retrospective review found that the majority of early seizures occurred before medical presentation.[339] Delayed seizures occurred in

7% of

patients in another series.[341] The relationship between seizures and outcome is uncertain because they have been reported to have no impact on outcome[339] or to be associated with worse outcome.[338] Risk factors for seizures after SAH have been noted in several retrospective studies, including middle cerebral artery aneurysms,[342,343] intraparenchymal hematoma,[342,344,345] infarcts,[346] and a history of hypertension.[347] A large number of seizure-like episodes have been associated with aneurysmal rupture.[348,349] It is unclear, however, whether all these episodes are truly epileptic in origin. [349,350]

One series of selected patients who underwent continuous EEG monitoring found that

19% of stuporous or comatose patients had nonconvulsive seizures an average of 18 days after SAH.[351] Many believe that patients might benefit from prevention with antiepileptic drugs. [352]

Although this is widely practiced, [353] it is controversial and not based on good evidence.


In some studies, use of these drugs was associated with a worse prognosis; this might

be because they actually cause harm, or because they are used more often in persons with a


poorer prognosis.[356,357] there is a possibility of a gastric haemorrhage due to stress ulcers. [358]

According to the AHA/ASA guideline published in 2009

Management of Seizures: Summary and Recommendations [95] 1. The administration of prophylactic anticonvulsants may be considered in the immediate posthemorrhagic period (Class IIb, Level of Evidence B). 2. The routine long-term use of anticonvulsants is not recommended (Class III, Level of Evidence B) but may be considered for patients with risk factors such as prior seizure, parenchymal hematoma, infarct, or middle cerebral artery aneurysms (Class IIb, Level of Evidence B).

Treatment of Myocardial ischemia and cardiac arrhythmias Cardiac arrhythmias can be detected in almost all patients during the first few hours after SAH; in approximately 20% of cases, the arrhythmias can be severe or life-threatening. [360,361]

Ventricular arrhythmias are a potential cause of sudden death after SAH. Di Pasquale

and coworkers (1988) noted torsades de points in 3.8% of 132 patients with SAH who underwent Holter monitoring. Changes resembling those seen in acute myocardial ischemia can be noted in 25% to 80% of patients.[362,363]

Presumably, the markedly elevated levels of norepinephrine lead to hypokalemia, systemic hypertensive effects, left ventricular strain, coronary artery vasospasm, a "stunned" myocardium, or cardiac toxicity. [364] Administration of a B-blocking medication might reduce the number and severity of cardiac sequelae.[365]

Prognosis During the last three decades, new management strategies have been developed for patients with aneurysmal subarachnoid haemorrhage. To assess whether the casefatality rate has improved after the introduction of new management strategies, there is a study report published in 1997 by hop et al on outcome from all population-based studies from 1960 onward. According to them the case-fatality rate after subarachnoid haemorrhage has decreased during the last three decades which was between 32% and 67%, the average case fatality rate for subarachnoid haemorrhage is 51 percent. The case-fatality rate decreased by 0.5% per year (95% confidence interval, -0.1 to 1.2). Most deaths occur within two weeks after the ictus, with 10 percent occurring before the patient receives medical attention and 25 percent within 24 hours after the event.[366] An estimated 6700 annual in-hospital deaths from aneurysmal SAH occur in the United States,[367]with evidence that incidence rates remain relatively stable, but death rates from SAH may have declined during the past several decades. The mortality rate for SAH in the 1966 Cooperative Study on Intracranial Aneurysms was 50% at 29 days [368] and 33% in a recent analysis of in-hospital deaths among SAH patients admitted through an emergency department (ED).[369] In a population-based study by Broderick et al,[370] the 30-day mortality rate among all patients who suffered SAH was 45%, with the majority of deaths occurring in the first days after SAH. Other studies have suggested slightly declining mortality rates in this and other countries.[371-373] According to the recent review, trends for survival from subarachnoid haemorrhage are improving.[2] Of those who survive hospitalization, more than a quarter have significant restrictions in their lifestyle, and less than a fifth have no residual symptoms whatsoever. [374] 60

Delay in diagnosis of minor SAH (mistaking the sudden headache for migraine) contributes to poor outcome.[375] Factors found on admission that are associated with poorer outcome include poorer neurological grade; systolic hypertension; a previous diagnosis of heart attack or SAH; liver disease; more blood and larger aneurysm on the initial CT scan; location of an aneurysm in the posterior circulation; and higher age.[376] Factors that carry a worse prognosis during the hospital stay include occurrence of delayed ischemia resulting from vasospasm, development of intracerebral hematoma or intraventricular haemorrhage (bleeding into the ventricles of the brain) and presence of fever on the eighth day of admission.[376] So-called "angiogram-negative subarachnoid haemorrhage", SAH that does not show an aneurysm with four-vessel angiography, carries a better prognosis than SAH with aneurysm; however, it is still associated with a risk of ischemia, rebleeding and hydrocephalus.[377] Perimesencephalic SAH (bleeding around the mesencephalon in the brain), however, has a very low rate of rebleeding or delayed ischemia, and the prognosis of this subtype is excellent.[378] The prognosis of head trauma is thought to be influenced in part by the location and amount of subarachnoid bleeding.[379] it is difficult to isolate the effects of SAH from those of other aspects of traumatic brain injury; it is unknown whether the presence of subarachnoid blood actually worsens the prognosis or whether it is merely a sign that a significant trauma has occurred.[379] People with moderate and severe traumatic brain injury that have SAH when admitted to a hospital have as much as twice the risk of dying as those who do not. They also have a higher risk of severe disability and persistent vegetative state, and traumatic SAH has been correlated with other markers of poor outcome such as post traumatic epilepsy, hydrocephalus, and longer stays in the intensive care unit. However,

more than 90% of people with traumatic subarachnoid bleeding and a Glasgow Coma Score over 12 have a good outcome.[379] There is also modest evidence that genetic factors influence the prognosis in SAH. For example, having two copies of ApoE4 (a variant of the gene encoding apolipoprotein E that also plays a role in Alzheimer's disease) seems to increase risk for delayed ischemia and a worse outcome.[380] the occurrence of hyperglycemia (high blood sugars) after an episode of SAH confers a higher risk of poor outcome.[381]

Long-term outcomes Neurocognitive symptoms, such as fatigue, mood disturbances, and other related symptoms are common sequelae. Even in those who have made good neurological recovery, anxiety, depression, posttraumatic stress disorder and cognitive impairment are common; 46% of people who have suffered a subarachnoid haemorrhage have cognitive impairment that affects their quality of life. [3] Over 60% report frequent headaches. [382] Aneurysmal subarachnoid haemorrhage may lead to damage of the hypothalamus and the pituitary gland, two areas of the brain that play a central role in hormonal regulation and production. More than a quarter of people with a previous SAH may develop hypopituitarism (deficiencies in one or more of the hypothalamic-pituitary hormones such as growth hormone, luteinizing hormone or follicle-stimulating hormone).[383]

Prevention of SAH Because no randomized controlled trials have specifically examined whether treatment of medical risk factors reduces the occurrence of SAH, available evidence is derived from observational cohort studies. It has been suggested that control of these major risk factors may have a greater impact on SAH in younger than in older patients.[384] 62

Hypertension is a common risk factor for hemorrhagic stroke. In a review by Collins et al, [385] an average reduction in diastolic blood pressure of 6 mm Hg by antihypertensive medication produced an aggregate 42% reduction in stroke incidence. However, there are few data on aneurysmal SAH in these studies because of limited sample size for SAH events. Although there has been a marked improvement in blood pressure control in the general population, there has been little change in the incidence of SAH during that time.[386-388] Regardless of whether hypertension control reduces the incidence of SAH, it may reduce the severity; untreated hypertension appears to be an independent risk factor for poor outcome after SAH.[389] Similarly, only indirect evidence exists to indicate that smoking cessation reduces risk for SAH. In a case-control study, [390] former smokers had a lower relative risk than light or moderate smokers, and there was an inverse relationship between time since the last cigarette and risk of SAH. In a prospective study of 117 006 women, it was observed that former smokers also had a lower relative risk of SAH than current smokers and that duration since quitting was associated with a decreased risk.[391]

Prevention of SAH: Summary and Recommendations: [95] 1. The relationship between hypertension and aneurysmal SAH is uncertain. However, treatment of high blood pressure with antihypertensive medication is recommended to prevent ischemic stroke, intracerebral haemorrhage, and cardiac, renal, and other end-organ injury (Class I, Level of Evidence A). 2. Cessation of smoking is reasonable to reduce the risk of SAH, although evidence for this association is indirect (Class IIa, Level of Evidence B). 3. Screening of certain high-risk populations for unruptured aneurysms is of uncertain value (Class IIb, Level of Evidence B); advances in noninvasive imaging may be used

for screening, but catheter angiography remains the gold standard when it is clinically imperative to know if an aneurysm exists.

Comparative study So, if we go through the comparative studies of different aspects of subarachnoid haemorrhage, we will see that SAH is a form of stroke and comprises 1â&#x20AC;&#x201C;7% of all strokes Incidence is approximately 9 per 100â&#x20AC;&#x2030;000 person-years which has remained stable over the last 30 years with a higher rates in Japan and Finland. Age for SAH is younger than the population usually affected by stroke, the risk still increases with age. Modifiable risk factors are smoking, hypertension and drinking 150 g or more of alcohol; genetic factors operate in only a minority. Repeated reviews do not reveal any major change in epidemiological aspects and risk factors in the recent years. In majority cases, cause is ruptured saccular aneurysm (around 85%); Perimesencephalic haemorrhage constitutes ~10% of all episodes of SAH. If patients presents with classic picture like sudden onset of severe headache (frequently described as the "worst ever"), with nausea, vomiting, neck pain, photophobia, seizures (1 in 14) and loss of consciousness and examination reveals meningismus, a diminished level of consciousness, and localizing neurologic signs, it is straightforward that they should be referred for further investigation. But about one-third of cases, acute severe headache are the only symptoms and study reveals about one in ten people with sudden severe headache diagnosed with a subarachnoid haemorrhage . So there is a considerable room for missed or delayed diagnosis. CT scanning is mandatory in all, to be followed by (delayed) lumbar puncture if CT is negative.


After diagnosis, stabilizing the patient is the first priority and patients should be transferred to centers with neurovascular expertise. General measures include force bed rest with nutritional support, pain control, care for bowel and bladder. Catheter angiography for detecting aneurysms is gradually being replaced by CT angiography. A poor clinical condition on admission may be caused by a remediable complication of the initial bleed or a recurrent haemorrhage in the form of intracranial haematoma, acute hydrocephalus or global brain ischaemia. Blood pressure should be monitored and controlled to balance the risk of stroke, hypertension-related rebleeding, and maintenance of cerebral perfusion pressure. A short course of antifibrinolytic agents combined with a program of early aneurysm treatment may be used. Rebleeding risk remains around 40% over the subsequent four weeks, suggesting that interventions should be aimed at reducing this risk as soon as possible.Recent studies reveals more favourable outcome for endovascular treatment. Measures of proven value in decreasing the risk of delayed cerebral ischaemia are a liberal supply of fluids, avoidance of antihypertensive drugs and administration of nimodipine. Administration of prophylactic anticonvulsants may be considered in the immediate posthemorrhagic period once ischaemia has occurred, treatment regimens such as a combination of induced hypertension and hypervolaemia, or transluminal angioplasty, are plausible, but of unproven benefit. Up to half of all cases of SAH are fatal and 10â&#x20AC;&#x201C;15% dies before reaching a hospital and those who survive often have neurological or cognitive impairment. Outcome of SAH depends upon various factors like higher age, poorer neurological grade, hypertension, associated cardiac and liver disease, location of aneurysms and development of complications during hospital stay and also on institutional factors.

There may be a limited role for investigation of high risk subgroups but mass screening is not cost effective. As subarachnoid haemorrhage is a fatal situation, disease prevention is important. Though the pathogenesis of development of SAH is unclear, cessation of smoking, alcohol ingestion and blood pressure control reduces risk for SAH, though the incidence of subarachnoid haemorrhage had remained stable over the last 30 years.

Future Research Further epidemiologic studies and new treatments are needed to improve the outcome of patients with subarachnoid haemorrhage. Determinants of the growth and rupture of aneurysms need to be studied. Improved prevention and diagnosis of cerebral vasospasm require more study. Promising areas of research that warrant further testing in well-designed clinical trials include, among others, the use of human albumin for neuroprotection,[392] intracisternal application of thrombolytic therapy and washing to decrease the blood burden,[393] and new radiologic and endovascular techniques (e.g., biologically active coils and stents) to improve the treatment of aneurysm and vasospasm. [394,395]

Other areas to be addressed are the need for prophylactic anticonvulsants and the

implementation of aggressive preventive measures, such as hypertension control and smoking cessation. Conclusion Considerable progress is being made in the management of SAH. Medical and surgical therapies that effectively prevent rebleeding and vasospasm are reflected by declines in mortality and morbidity. The current standard of practice calls for microsurgical clipping or endovascular coiling of the aneurysm neck whenever possible. Treatment


morbidity is determined by numerous factors, including patient, aneurysm, and institutional factors. Favorable outcomes are more likely in institutions that treat high volumes of patients with SAH, in institutions that offer endovascular services, and in selected patients whose aneurysms are coiled rather than clipped. Optimal treatment requires availability of both experienced cerebrovascular surgeons and endovascular surgeons working in a collaborative effort to evaluate each case of SAH.

Still, there is considerable room for improvement. Several promising therapies are being tested; one or more of these interventions likely will be shown to further improve outcomes after SAH. However, most successful therapies are based on early treatment. Thus, the medical community must give greater attention to the early diagnosis of SAH and the acute care of patients with SAH who are critically ill.

New revised adting