on 18-Jul-2022 (Mon)

In the Ancient Near East the Copper Age covered about the same period, beginning in the late 5th millennium BC and lasting for about a millennium before it gave rise to the Early Bronze Age.

In the year 1000, the county of Anjou (in west-central France) was ruled by Fulk Nerra (987–1040), a brutal and rapacious warlord.

Roman imperial rule had provided stability and affluence in the West until the late fourth century CE (Common Era). In the East the Roman Empire lived on until 1453, ruled from the great city of Constantinople, founded in 324 by Constantine the Great–the first emperor to convert to Christianity.

In the West between the fifth and the seventh centuries power devolved on to a bewildering array of ‘barbarian’ tribes, but around the year 500 one of these groups, the Franks, established control over north-eastern Gaul, giving rise to a kingdom known as Francia

By 800, a descendant of these Franks, Charlemagne (768–

814), had united such a huge swathe of territory–encompassing much of modern France, Germany, Italy and the Low Countries–that he could lay claim to the long-dormant title of emperor of the West.

Charlemagne and his successors, the Carolingians, presided over a short-lived period of renewed security, but their empire crumbled under the weight of succession disputes and repeated invasions by Scandinavian Vikings and eastern European Magyars.

Although Gregory went too far, too fast and ended his pontificate in ignominious exile in southern Italy, his bold strides did much to advance the twinned causes of reform and papal empowerment, establishing a platform from which one of his successors (and former adviser), Pope Urban II (1088–99), could instigate the First Crusade.

The most influential early Christian thinker to wrestle with these issues was the North African bishop St Augustine of Hippo (354–430 CE).

His work laid the foundation upon which the papacy eventually built the notion of crusading. St Augustine argued that a war could be both lawful and justifiable if fought under strict conditions. His complex theories were later simplified to produce just three prerequisites of a Just War: proclamation by a ‘legitimate authority’, such as a king or bishop; a ‘just cause’, like defence against enemy attack or the recovery of lost territory; and prosecution with

‘right intention’, that is, with the least possible violence.

During the second half of the eleventh century, Latin Christianity began to edge ever closer towards the acceptance of holy war. In the early stages of the Reform movement, the papacy began to perceive the need for a military arm with which to reinforce its agenda and manifest its will. This prompted a succession of popes to experiment with the sponsoring of warfare, calling upon Christian supporters to defend the Church in return for vaguely expressed forms of spiritual reward. It was under the forceful guidance of Pope Gregory VII that the doctrine and application of sacred violence jumped ahead. Intent upon recruiting a papal army that owed its allegiance to Rome, he set about reinterpreting Christian tradition. For centuries theologians had characterised the internal, spiritual battle that devoted Christians waged against sin as the ‘warfare of Christ’, and monks were sometimes described as the ‘soldiers of Christ’. Gregory twisted this idea to suit his purpose, proclaiming that all lay society had one overriding obligation: to defend the Latin Church as ‘soldiers of Christ’ through actual physical warfare.

Early in his pontificate, Gregory laid plans for a grand military enterprise that can be regarded as the first real prototype for a crusade. In 1074 he tried to launch a holy war in the eastern Mediterranean in aid of the Greek Orthodox Christians of Byzantium, who were, he claimed, ‘daily being butchered like cattle’ by the Muslims of Asia Minor.

But in the early 1080s, with the conflict with the German emperor in full flow, Gregory took a critical step towards clarification. He wrote that his supporters should fight the emperor and face ‘the danger of the coming battle for the remission of all their sins’.

Nonetheless, Gregory cannot be regarded as the prime architect of the crusades because he manifestly failed to construct a compelling and convincing notion of holy war that resonated with the Christians of Europe. That would be the work of Pope Urban II.

According to Muslim tradition, Islam was born in c. 610 CE when Muhammad–an illiterate, forty-year-old Arab native of Mecca (in modern Saudi Arabia)–began to experience a series of ‘revelations’ from Allah (God), relayed by the Archangel Gabriel.

In 622 the Prophet was forced to flee to the nearby city of Medina, a journey which served as the starting date for the Muslim calendar, and he then waged a bloody and prolonged war of religion against Mecca, finally conquering the city shortly before his death in 632.

In the mid-630s ferocious armies of highly mobile, mounted Arab tribesmen began to pour out of the Arabian Peninsula. By 650 they had achieved startling success. With mercurial speed, Palestine, Syria, Iraq, Iran and Egypt were absorbed into the new Arab-Islamic state. Over the next century the pace of expansion slowed from this breakneck pace, but inexorable gains continued, such that in the mid-eighth century the Muslim world stretched from the Indus River and the borders of China in the east, across North Africa to Spain and southern France in the west.

In the context of crusading history, a critical stage in this whole process was the capture of Jerusalem in 638 from the Greek Christians of Byzantium. This ancient city came to be revered as Islam’s third-holiest site, after Mecca and Medina.

It was once popular to suggest that the Islamic world might have swept across all Europe, had not the Muslims been twice thwarted in their attempts to capture Constantinople (in 673 and 718) and then defeated in 732 at Poitiers by Charlemagne’s Frankish grandfather Charles the Hammer.

Problems were apparent as early as 661, when the established line of

‘Rightly Guided Caliphs’ ended with the death of ‘Ali (the Prophet’s cousin and son-in-law) and the rise of a rival Arab clan–the Umayyad dynasty.

The Umayyads moved the capital of the Muslim world beyond the confines of Arabia for the first time, settling in the great Syrian metropolis of Damascus, and they held sway over Islam until the mid-eighth century.

However, this same period witnessed the emergence of the Shi‘a (literally the ‘party’ or ‘faction’), a Muslim sect who argued that only descendants of

‘Ali and his wife Fatima (Muhammad’s daughter) could lawfully hold the title of caliph.

In 750 a bloody coup brought Umayyad rule to an end, propelling another Arab dynasty–the Abbasids–to power.

Communities of Shi‘ite Muslims continued to live, largely in peace, alongside and among Sunnis across the Near and Middle East. But in 969 a particularly assertive Shi‘ite faction seized control of North Africa.

Championed by a dynasty known as the Fatimids (because they claimed descent from Fatima, Muhammad’s daughter), they set up their own rival Shi‘ite caliph, rejecting Sunni Baghdad’s authority.

A further, dramatic change transformed the world of Islam in the eleventh century–the coming of the Turks. From around 1040, these nomadic tribesmen from Central Asia–noted for their warlike character and agile skill as mounted archers–began to seep into the Middle East. One particular clan, the Seljuqs (from the steppes of Russia, beyond the Aral Sea), spearheaded the Turkish migration.

Having adopted the religion of Sunni Islam, these fearsome Seljuqs declared their unswerving allegiance to the Abbasid caliph and readily supplanted the now sedentary Arab and Persian aristocracy of Iran and Iraq.

By 1055, the Seljuq warlord Tughrul Beg had been appointed as sultan of Baghdad and could claim effective overlordship of Sunni Islam; a role which members of his dynasty would hold as a hereditary right for more than a century. The advent of the Seljuq Turks brought a new, vital lease of life and unity to the Abbasid world.

Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical radiographic syndrome of heterogeneous etiologies that are grouped together because of similar findings on neuroimaging studies. It is also often referred to as:

● Posterior reversible encephalopathy syndrome (PRES)

● Reversible posterior cerebral edema syndrome

● Posterior leukoencephalopathy syndrome

● Hyperperfusion encephalopathy

● Brain capillary leak syndrome

None of these names are completely satisfactory; the syndrome is not always reversible, and it is often not confined to either the white matter or the posterior regions of the brain.

CLINICAL MANIFESTATIONS — The symptoms of RPLS evolve rapidly over hours to days. Hypertension is frequent but not invariable. The hypertensive crisis may precede the neurologic syndrome by 24 hours or longer [2,10].

The clinical syndrome of RPLS is characterized by [38]:

● Headaches – The headache is typically constant, nonlocalized, moderate to severe, and unresponsive to analgesia [10].

● Altered consciousness – Altered consciousness ranges from mild somnolence to confusion and agitation, progressing to stupor or coma in extreme cases [1,10,59,70].

● Visual disturbances – Visual perception abnormalities are often detectable. Hemianopia, visual neglect, auras, visual hallucinations, and cortical blindness may occur [1,71]. Cortical blindness may be accompanied by denial of blindness (Anton syndrome).

● Seizures – Seizures are often the presenting manifestation [1,7,52,72]. Seizures are usually generalized tonic-clonic; they may begin focally and often recur. Status epilepticus has been reported [60,73]. Preceding visual loss or visual hallucinations suggest occipital lobe origin in some patients. Only a minority of patients, usually those with milder disease, are seizure free [2].

The funduscopic examination is often normal, particularly in eclamptic and chronically hypertensive patients, but papilledema may be present with accompanying flame-shaped retinal hemorrhages and exudates.

The deep tendon reflexes may be brisk, and Babinski signs may be present [ 10]. A few patients may have weakness and incoordination of the limbs [1,8,74]. Other focal neurologic deficits are rare.

Relatively unusual patients with symptoms referable to the upper cervical spinal cord (limb weakness, bladder dysfunction), along with one or more of the symptoms above have also been described [75].

Neuroradiographic abnormalities of RPLS are often apparent on CT scans (image 1) [76] but are best depicted by MRI (image 2) [22].

Typical findings are bilateral areas of white matter edema in the posterior cerebral hemispheres, particularly the parieto-occipital regions, but variations do occur [37,38,77]. Extensive vasogenic edema has been associated with worse clinical outcomes in some series [2,78], but not with the severity of clinical presentation [38,66]

Other testing — The clinical and radiologic features of RPLS are not specific; other conditions such as toxic-metabolic encephalopathy should be evaluated thoroughly. Thus, laboratory studies should include a blood count, electrolytes, creatinine, blood urea nitrogen (BUN), and liver function tests. Comorbid medical conditions (eg, sepsis, hyponatremia, renal failure, ischemic bowel disease) can exacerbate neurologic deterioration and are important to identify for that reason as well [8]. (See "Acute toxic-metabolic encephalopathy in adults" and "Acute toxic-metabolic encephalopathy in children".)

A lumbar puncture is not required for the evaluation of most patients with suspected RPLS but may be obtained if there is a specific concern for meningitis, encephalitis, or malignancy. In RPLS, cerebrospinal fluid (CSF) typically shows a modestly elevated protein level (mean 58 mg/dL in one study) but no pleocytosis [103]. An elevated white blood cell count in the CSF should prompt consideration of other diagnoses. (See 'Differential diagnosis' below.)

DIAGNOSIS — While there are no specific diagnostic criteria for RPLS, it is becoming an increasingly recognized disorder. In the appropriate clinical setting (in particular hypertension, immunosuppressive or cytotoxic therapy, kidney disease), clinicians should recognize the neurologic syndrome of headache, visual symptoms, confusion, and seizures, and order brain MRI, which typically supports the diagnosis. Diffusion-weighted imaging (DWI), if available, adds considerable diagnostic and prognostic information. (See 'Neuroimaging' above.)

Because the neuroradiographic findings are not specific, repeat neuroimaging may be necessary. With treatment, resolution of findings on neuroimaging within days to weeks is expected.

Most case series and case reports suggest that RPLS is usually benign. In many cases, RPLS seems to be fully reversible within a period of days to weeks, after removal of the inciting factor and control of the blood pressure [1,7,46,47,70,133]. Radiologic improvement lags behind clinical recovery.

Clinical setting and risk factors – RPLS most often occurs in the setting of hypertensive crisis, preeclampsia, or with cytotoxic immunosuppressive therapy; however, it can also occur in many other clinical settings (table 1).

Blood pressure – Treatment of hypertension is the mainstay of treatment in patients with RPLS.

In addition, we suggest cautious blood pressure lowering in patients with blood pressure that is only borderline hypertensive (eg, 120 to 140 mmHg systolic), particularly if such measurements exceed the patient's baseline values (Grade 2C).

We target an approximate 10 to 25 percent reduction of blood pressure initially and use an easily titratable parenteral agent such as clevidipine, nicardipine, or labetalol. Overaggressive blood pressure lowering can lead to complications; comorbid medical conditions should be considered in management. (See 'Blood pressure management' above.)

Discontinuation of causative agent – We suggest stopping or lowering the dose of the offending immunosuppressant or cytotoxic agent, permanently if possible (Grade 2C). When another agent is substituted, or if the original agent is restarted, patients should be followed closely for recurrence of RPLS. (See 'Discontinuation of immunosuppressive therapy' above.)

Treatment of other acute medical conditions (eg, sepsis, renal failure) may also hasten patient's recovery. (See 'Other' above.)

We suggest that antiseizure medications be discontinued after symptoms and neuroimaging findings resolve (Grade 2C). The risk of late recurrence or epilepsy after uncomplicated RPLS appears to be low. (See 'Seizure management' above.)

Common conditions associated with intracerebral hemorrhage (ICH) include hypertension, cerebral amyloid angiopathy, and ruptured vascular malformation. Other etiologies include cerebral venous thrombosis, vasculopathies, primary or metastatic tumors, and coagulopathies.

Major risk factors for spontaneous ICH include older age, hypertension, and the use of antithrombotic (antiplatelet and anticoagulant) therapy.

Predictors of hemorrhage growth associated with neurologic deterioration include a shorter time from symptom onset to initial imaging, initial ICH volume, antithrombotic medication use, and imaging signs of ICH heterogeneity on noncontrast CT or focal contrast extravasation on CT angiography (image 17 and image 18).

The signs and symptoms of ICH vary according to the location and size of the hemorrhage (table 1).

In most circumstances, ICH onset occurs during routine activity. However, some hypertensive hemorrhages occur with exertion or intense emotional activity [111].

The neurologic symptoms and signs may be progressive over minutes or a few hours (figure 1), in contrast with brain embolism and subarachnoid hemorrhage, where the neurologic symptoms and signs are often maximal at onset. However, some patients with large ICH are obtunded or comatose when first discovered or at first evaluation upon arrival to the emergency department.

Headache, vomiting, and a decreased level of consciousness may develop if the hemorrhage is large. This symptom complex is typically absent with small hemorrhages. However, headache and vomiting occur in approximately one-half of patients with ICH (figure 2). Headache may be due to traction on meningeal pain fibers, increased intracranial pressure (ICP), or blood in the cerebrospinal fluid; it is most common with cerebellar and lobar hemorrhages. Patients may complain of a stiff neck and have meningismus on physical examination if there is intraventricular blood.

Stupor or coma attributed to the ICH is often an ominous sign. Exceptions include patients with thalamic hemorrhage with involvement of the reticular activating system who may recover after acute blood is resorbed and those with acute hydrocephalus who might improve if treated with an external ventricular drain. Patients may also present with stupor or coma due to reversible causes such as acute metabolic derangements or seizure.

Neurologic signs and ICH location — Neurologic signs vary depending upon the location of the hemorrhage (image 1). In one study, bleeding involved the putamen in approximately 35 percent of cases, cerebral lobes in 30 percent, cerebellum in 16 percent, thalamus in 15 percent, and pons in 5 to 12 percent [112].

In the subsequent Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) of over 2000 subjects with imaging-confirmed ICH and hypertension, the frequency of affected brain structures was as follows [ 113]:

● Putamen/globus pallidus – 56 percent

● Posterior limb of internal capsule – 46 percent

● Anterior limb of internal capsule – 5 percent

● Thalamus – 31 percent

● External capsule – 27 percent

● Lobar – 14 percent

● Cerebellum or brainstem – 7 percent

● Caudate head – 2 percent

Intraventricular extension of the ICH was identified in 29 percent in this study.

Neurologic exam deficits typically correspond to the location of the hemorrhage and associated edema. Patients with deficits not attributable to the hemorrhage should be evaluated for other causes, such as expansion of the hemorrhage, post-ictal symptoms after a seizure, or increased intracranial pressure.

Putaminal hemorrhage – Spread of hemorrhage into the putamen most commonly occurs along white matter fiber tracts, causing hemiplegia, hemisensory loss, homonymous hemianopsia, and gaze palsy. Stupor and coma may develop if the hemorrhage is large.

Caudate hemorrhage – Hemorrhage typically originating within the head of the caudate nucleus may cause acute-onset confusion, personality changes, or memory impairment as well as transient contralateral weakness or numbness [114]. Headache and drowsiness may also occur, especially if bleeding extends into the adjacent intraventricular space

Internal capsule hemorrhage – Small hemorrhages restricted to the internal capsule may cause mild dysarthria, contralateral hemiparesis, and sensory deficit [115].

Cerebellar hemorrhage – Cerebellar hemorrhage usually originates in the dentate nucleus and may extend into the hemisphere and fourth ventricle and possibly into the pontine tegmentum. These bleeds typically cause an inability to walk due to imbalance, vomiting, and occipital headache. Some patients have referred pain to the neck or shoulder, neck stiffness, gaze palsy, and/or facial weakness. Notably, there is often no hemiparesis. The patient may become stuporous due to obstructive hydrocephalus or brainstem compression.

Patients with acute cerebellar hemorrhage may frequently deteriorate and require surgery.

Thalamic hemorrhage – Thalamic hemorrhages may extend in a transverse direction to the posterior limb of the internal capsule, downward to put pressure on the tectum of the midbrain, or medially to rupture into the third ventricle. Symptoms include hemiparesis, hemisensory loss, and occasionally transient homonymous hemianopsia. Pupils may be miotic and unreactive along with a gaze palsy (eg, peering at the tip of the nose, skewed, or "wrong-way eyes" toward the weak side [in contrast with hemispheric cortical injury in which the eyes are deviated away from the hemiparesis]). Aphasia may occur if the bleed affects the dominant hemisphere, while neglect may develop if the bleed affects the nondominant hemisphere. Patients with small anterior thalamic hemorrhages may present with drowsiness, acute confusion, or neuropsychiatric symptoms.

Lobar hemorrhage – Lobar hemorrhages vary in their neurologic signs depending upon location. They most often affect the parietal and occipital lobes. These bleeds are associated with a higher incidence of seizures. Occipital hemorrhages frequently present with a very dense contralateral homonymous hemianopsia. Hemorrhages in the frontoparietal region will produce a contralateral plegia or paresis of the leg with relative sparing of the arm

Pontine hemorrhage – Pontine hemorrhages typically originate in brainstem nuclei and may extend into the base of the pons. These often lead to deep coma over the first few minutes following the hemorrhage, probably due to disruption of the reticular activating system. The motor examination may be marked by bilateral paralysis. The pupils are pinpoint and react to a strong light source. Horizontal eye movements are often absent, and there may be ocular bobbing, facial palsy, deafness, and dysarthria if the patient is awake

Seizures — Seizures may accompany acute ICH. Seizures in the first days after ICH occur approximately 15 percent of patients [116,117]; they are more common in lobar hemorrhages (affecting cortical tissue) than in deep or cerebellar ICH [118-121].

Cardiac abnormalities — Cardiac abnormalities are commonly associated with spontaneous ICH [122]. The most frequently associated electrocardiographic (ECG) changes are prolonged QT interval and ST-T wave changes. These changes may reflect catecholamine-induced cardiac injury, which is most likely due to a centrally mediated release of excess catecholamines caused by increased intracranial pressure or autonomic disturbance [123].

Mild elevations in serum myocardial enzymes often accompany the ECG changes, including cardiac troponin and beta natriuretic peptide [122]. Echocardiographic abnormalities may involve global or regional wall motion abnormalities and reduced ejection fraction. Ventricular arrhythmias may occur with brainstem compression [124].

Head CT — Noncontrast head computed tomography (CT) accurately identifies the presence of acute ICH, distinguishing it from ischemic stroke. Hyperacute blood will appear hyperdense except in rare cases of severe anemia when it might appear isodense.

Clinical suspicion for ICH is based upon features such as acute onset of gradually worsening symptoms and increasing neurologic deficit, particularly if accompanied by severe headache, vomiting, severe hypertension, and decreased level of consciousness or coma. However, the distinction between brain hemorrhage and ischemia cannot be made on the basis of clinical characteristics alone [158]. Importantly, headache may be absent in some cases of ICH.

Neuroimaging with brain computed tomography (CT) or magnetic resonance imaging (MRI) is mandatory to confirm the diagnosis of ICH and to exclude ischemic stroke and stroke mimics as possible causes [158].

We obtain follow-up imaging when an underlying cause is suspected by clinical features or initial imaging findings (table 3) [158]. Initial imaging findings that may suggest a specific underlying cause include:

• Early perihematomal edema out of proportion to the underlying ICH (image 9) [161]

• ICH within arterial vascular territory suggesting primary ischemic infarction (image 7)

• Multifocal hemorrhage (image 19)

• Isolated intraventricular hemorrhage (image 20)

Clinical presentation – The overwhelming majority of patients with aneurysmal subarachnoid hemorrhage (SAH) present with a sudden-onset severe headache, which may be associated with brief loss of consciousness, seizures, nausea or vomiting, or meningismus.

Imaging – Noncontrast head computed tomography (CT) reveals the diagnosis in more than 90 percent of cases if performed within 24 hours of bleeding onset

Lumbar puncture – Lumbar puncture is mandatory if there is a strong suspicion of SAH despite a normal head CT, with the disputed exception of select patients with isolated headache and normal examination presenting early and scanned within six hours of headache onset.

The classic findings are an elevated opening pressure, an elevated red blood cell count that does not diminish from cerebrospinal fluid (CSF) tube 1 to tube 4, and xanthochromia. Immediate centrifugation of the CSF can help differentiate bleeding in SAH from that due to a traumatic spinal tap

Identifying the source of bleeding – Once a diagnosis of SAH has been made, the etiology of the hemorrhage must be determined with vascular imaging. Of the available tests, digital subtraction angiography (DSA) has the highest resolution to detect intracranial aneurysms and define their anatomic features and remains the gold standard test for this, but CT angiography is being increasingly used as a first-line vascular test.

Repeat angiography is necessary if the initial study is negative, unless the pattern of hemorrhage is perimesencephalic, in which a repeat angiography may be considered optional. Additional testing is required for SAH that is nonaneurysmal.

Headache characteristics – The classic presentation of patients with aneurysmal SAH is a sudden-onset, severe headache typically described as the "worst headache of my life" [1]. Every patient with this kind of headache, often referred to as a "thunderclap headache" (see "Overview of thunderclap headache"), should be evaluated for SAH. Headache is often an isolated finding. In neurologically intact patients with a severe-onset headache peaking within one hour, three large sequential studies with a total of 5283 patients found that 329 patients (6 percent) had SAH [2-5].

Importantly, the headache onset in SAH is not always noted as instantaneous, either because the patient does not perceive it that way or because the physician does not elicit that information. In a study that included 132 patients with SAH, the time to peak intensity was one hour in six (5 percent), and the physician interobserver agreement for sudden onset was only moderate (kappa = 0.49) [2].

Location is not useful since the headache can be localized or generalized.

In addition to headache, common associated symptoms of SAH include a brief loss of consciousness, vomiting, and neck pain or stiffness. In one series, these occurred in 9, 61, and 75 percent of patients, respectively, and each of these symptoms was more common in patients with SAH compared with patients without SAH [3].

Meningismus, often accompanied by lower back pain, may develop several hours after the bleed, since they are caused by the breakdown of blood products within the cerebrospinal fluid (CSF), which lead to an aseptic meningitis [ 6].

While many patients have an altered level of consciousness, coma is unusual. Seizures occur during the first 24 hours in less than 10 percent of patients but are a predictor of poor outcome [ 7]. SAH may also present as sudden death; as many as 22 percent of patients die before reaching the hospital [8]

Clinical settings – While the onset of symptoms in the setting of physical exertion, activities associated with a Valsalva maneuver, or emotional stress suggest SAH, aneurysmal SAH occurs most often during nonstrenuous activity, rest, or sleep [10,11].

Examination findings – Physical examination often shows hypertension and may show meningismus.

Terson syndrome (preretinal hemorrhages) may be seen and implies a poorer prognosis. In a systematic review, patients with Terson syndrome had higher Hunt and Hess grades ( table 1) and significantly higher mortality than those without [12]. The preretinal hemorrhages of Terson syndrome may indicate a more abrupt increase in intracranial pressure and must be distinguished from the more benign retinal hemorrhages sometimes associated with SAH [13].

Nearly any neurologic sign may be present (table 2) and will depend on the location of the hemorrhage, presence or absence of hydrocephalus, elevated intracranial pressure, ischemia, infarction, or hematoma [14].

Although a pupil-involving third nerve palsy is often cited as a finding of SAH, it is more common with an expanding but unruptured aneurysm of the posterior communicating artery or superior cerebellar artery, which is located close to where the third nerve exits the brainstem [15,16]. If present, this finding mandates a work-up for an aneurysm including some form of cerebral angiography, but its absence does not decrease the likelihood of SAH in patients with acute headache.

However, clinical grade assessment at the time of nadir, or after neurologic resuscitation, appears to be more predictive of outcome [17,18]. The grading system proposed by Hunt and Hess (table 1) and that of the World Federation of Neurological Surgeons (WFNS) (table 3) are among the most widely used. The WFNS system incorporates the Glasgow Coma Scale (table 4) combined with the presence of motor deficit.

The Fisher scale is an index of vasospasm risk based upon a computed tomography (CT)-defined hemorrhage pattern (table 5), and the modified Fisher scale (also known as the Claassen scale) is a similar index of the risk of delayed cerebral ischemia due to vasospasm (table 6).

The complaint of the sudden or rapid onset of severe headache is sufficiently characteristic that SAH should always be considered in the evaluation. All patients with this complaint should undergo immediate evaluation for SAH beginning with head computed tomography (CT), even those who are alert and neurologically intact at the time of initial presentation [2,19].

Additional clues to the diagnosis of SAH, such as preretinal hemorrhages, neck pain, or meningismus, may or may not be present. In a systematic review and meta-analysis that included 22 diagnostic studies of emergency department patients evaluated for spontaneous SAH, the presence of meningismus on physical examination had a positive likelihood ratio of 6.6 [ 20]

Ottawa Subarachnoid Hemorrhage Rule – In neurologically intact patients presenting with acute nontraumatic headache that reached maximal intensity within one hour, a clinical decision rule (the Ottawa Subarachnoid Hemorrhage Rule) that included any of the following features had a sensitivity of 100 percent and a specificity of 15 percent for the diagnosis of SAH [2]:

• Age ≥40 years

• Neck pain or stiffness

• Limited neck flexion on examination

• Witnessed loss of consciousness

• Onset during exertion

• Thunderclap headache (instantly peaking pain)

Misdiagnosis and delayed diagnosis – Misdiagnosis and delayed diagnosis of SAH are common and can lead to delays in treatment and worse outcomes [24,25]. Missed or delayed diagnosis of SAH usually results from three errors (table 8) [16]:

• Failure to appreciate the spectrum of clinical presentation associated with SAH

• Failure to obtain a head CT scan or to understand its limitations in diagnosing SAH

• Failure to perform a lumbar puncture or correctly interpret the results

Perhaps the most important source of misdiagnosis results from the misconception that patients with aneurysmal SAH always appear "sick" or have neurologic findings or altered mental status when in fact nearly 40 percent of patients are awake, alert, and neurologically intact [16].

From a practice perspective, the vast majority of patients will be correctly diagnosed if all patients with thunderclap headache undergo head CT (and lumbar puncture if the CT is done after six hours from headache onset).

In contrast, a 2017 systematic review identified three studies published from 1996 to 2007 in emergency department populations with a pooled misdiagnosis rate of 7 percent [29].

Failure to obtain a head CT scan at initial contact was the most common error, occurring in 73 percent of misdiagnosed patients. Among patients with SAH and normal mental status at first contact (45 percent), the misdiagnosis rate rose to 20 percent and was associated with a nearly fourfold increase in mortality at 12 months as well as increased morbidity among survivors.

Standard diagnostic approach — The first step in the diagnosis of SAH is noncontrast head CT [19]. A lumbar puncture should be done if the head CT is negative [19]. If both tests are negative, they effectively eliminate the diagnosis of SAH as long as both tests are performed within two weeks of the event [26,30].

The sensitivity of all diagnostic tests for SAH is time-dependent, measuring time from onset of the bleed. This is due to the physiologic brisk flow of cerebrospinal fluid (CSF). Normally, there is approximately 150 mL of CSF in a person's subarachnoid space at any point in time, but 450 to 500 mL are manufactured per 24 hours. This is why CT scans and red blood cell (RBC) counts are very sensitive early after bleeding onset but lose sensitivity with the passage of time.

RBCs present in the CSF undergo lysis, resulting in breakdown products such as bilirubin and oxyhemoglobin, a process that takes time, accounting for the fact that xanthochromia is not sensitive early but becomes increasingly sensitive after a few hours.

Anemia with hematocrits of 30 percent or less and poor scan quality due to patient movement are other causes of ambiguous or false-negative CT results. However, the most important factor that affects CT sensitivity is time from onset.

The distribution of blood on CT (performed within 72 hours after the bleed) is a poor predictor of the site of an aneurysm except in patients with ruptured anterior cerebral artery or anterior communicating artery aneurysms and in patients with a parenchymal hematoma [39]. However, the distribution of blood does have implications about whether or not the cause of the SAH is aneurysmal (image 1).

Blood restricted to the subarachnoid space in front of the brainstem suggests a nonaneurysmal perimesencephalic (also called pretruncal) SAH. Convexal SAH suggests reversible cerebral vasoconstriction syndrome (RCVS) in younger patients or cerebral amyloid angiopathy in older patients, whereas blood adjacent to bone in the anterior or middle cranial fossae suggests traumatic SAH.

Lumbar puncture is mandatory if there is a strong suspicion of SAH despite a normal head CT [31,40]. Although controversial, one possible exception involves select patients with isolated headache, a normal examination, and a negative CT scan performed within six hours from onset of headache and interpreted by an expert reviewer, as discussed below. (

Lumbar puncture should include measurement of opening pressure, routine CSF analyses including RBC and white blood cell (WBC) counts, and visual inspection for xanthochromia. The classic lumbar puncture findings of SAH are an elevated opening pressure, an elevated RBC count that does not diminish from CSF tube 1 to tube 4, and xanthochromia. Accidental trauma to a capillary or venule may occur during performance of a lumbar puncture, increasing the number of both RBCs and WBCs in the CSF.

Clearing of blood (a declining RBC count with successive collection tubes) is purported to be a useful way of distinguishing a traumatic lumbar puncture from SAH. However, this is an unreliable sign of a traumatic tap, since a decrease in the number of RBCs in later tubes can also occur in SAH [41]. This method can reliably exclude SAH only if there is substantial RBC count in the first tube, and the late or final collection tube is normal.

Given the brisk flow of CSF (approximately 20 to 25 mL is produced every hour), even discarding 10 mL will take only 30 minutes for the body to replace [43].

The greater the RBC count in the last tube, the more likely SAH is the cause. In one study examining CSF results in 1739 patients with acute nontraumatic headache, fewer than 2000 RBCs/microL in addition to no xanthochromia excluded aneurysmal SAH with a sensitivity of 100 percent [44].

Xanthochromia may be visually detected by comparing a vial of CSF with a vial of plain water held side by side against a white background in bright light [45].

The presence of xanthochromia indicates that blood has been in the CSF for at least two hours. Therefore, if the CSF is analyzed quickly after a traumatic lumbar puncture or SAH, there will not be xanthochromia; the absence of xanthochromia cannot be used as evidence of a traumatic tap if a lumbar puncture is performed in a SAH of less than two hours duration. Over the course of the ensuing hours, more patients will have xanthochromia, and by 12 hours post SAH, 100 percent of patients will have xanthochromia, even when measured visually [ 46]. Xanthochromia lasts for two weeks or more [47,48].

In this series, xanthochromia for the detection of cerebral aneurysms had a sensitivity and specificity of 93 and 95 percent.

Other conditions that can produce xanthochromia include increased CSF concentrations of protein (150 mg/dL), systemic hyperbilirubinemia (serum bilirubin >10 to 15 mg/dL), and traumatic lumbar puncture with more than 100,000 RBCs/microL.