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Original filename: HSA NEJM.pdf
Title: 010600 Avoiding Pitfalls in the Diagnosis of Subarachnoid
Author: Edlow

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Review Article

Primary Care



“For it happens in this, as the physicians say it happens in hectic
fever, that in the beginning of the malady it is easy to cure but
difficult to detect, but in the course of time, not having been either detected or treated in the beginning, it becomes easy to detect but difficult to cure.”
— Niccolò Machiavelli, The Prince


ATIENTS with headache account for 1 to
2 percent of visits to the emergency department1-4 and up to 4 percent of visits to physicians’ offices.5 Most have primary headache disorders,
such as migraine and tension-type headaches. Only
a few patients have treatable secondary causes that
threaten life, limb, brain, or vision,1,3-5 such as subarachnoid hemorrhage (Table 1). Roughly 80 percent of patients with nontraumatic subarachnoid hemorrhage have ruptured saccular aneurysms, which
occur in 30,000 patients annually in the United
States.6 Among the remaining 20 percent, about half
have nonaneurysmal perimesencephalic hemorrhages.7,8 The initial diagnostic approach is the same for
both groups.
Among all patients with headache who presented
to emergency departments, retrospective studies1,3,4
have found that approximately 1 percent had subarachnoid hemorrhage. One prospective study 9 put that
figure at 4 percent. Two prospective studies found that
if only patients with “the worst headache” of their
lives and a normal neurologic examination were considered, 12 percent of such patients had subarachnoid
hemorrhage.9,10 This proportion increased to 25 percent when patients whose examinations were abnormal were included.10
The initial hemorrhage may be fatal, may result in
devastating neurologic outcomes, or may produce relatively minor symptoms. Because early definitive sur-

From the Departments of Emergency Medicine (J.A.E.) and Neurology
(L.R.C.), Beth Israel Deaconess Medical Center and Harvard Medical School,
Boston. Address reprint requests to Dr. Edlow at the Department of Emergency Medicine, Finard 202, 330 Brookline Ave., Boston, MA 02215, or
at jonathan_edlow@hms.harvard.edu.
©2000, Massachusetts Medical Society.

gery to repair aneurysms reduces short-term complications (primarily recurrent bleeding and vasospasm) and improves outcomes,11 accurate early diagnosis is critical. Despite the widespread availability of
neuroimaging equipment, misdiagnosis of subarachnoid hemorrhage remains common,12,13 and it is an
important cause of litigation related to emergency
medicine.14 This review is intended to provide primary
care and emergency physicians with a strategy for identifying patients who should be evaluated for subarachnoid hemorrhage and establishing the diagnosis.

The typical patient with subarachnoid hemorrhage
has a sudden onset of severe headache (frequently described as being the worst headache of his or her life)
that develops during exertion. Transient loss of consciousness or buckling of the legs often accompanies
the headache. Vomiting soon follows. The physical
examination may show retinal hemorrhages (Fig. 1),
nuchal rigidity, restlessness, a diminished level of consciousness, and focal neurologic signs (Table 2). Patients with these classic findings present little diagnostic difficulty. However, in the absence of such
symptoms and signs, clinicians often miss the diagnosis, as several studies have demonstrated.
During the 1980s, 23 to 37 percent of all patients
referred to the University of Iowa with subarachnoid
hemorrhage were given an incorrect diagnosis on their
first visit to a physician.15,16 These patients tended to
be less ill than those given a correct diagnosis and to
have normal neurologic examinations.
Among patients treated at four Connecticut neurosurgical units in the 1990s, 25 percent of patients
with subarachnoid hemorrhage initially received an
incorrect diagnosis; most of them were in good clinical condition at presentation.13 The condition of half
the 54 patients with an incorrect diagnosis worsened, usually as a result of recurrent bleeding, before
definitive treatment was begun. Of the 163 patients
given a correct diagnosis, the condition of only 2.5
percent worsened. Among patients who were in good
clinical condition when first seen, 91 percent of patients with a correct diagnosis had good or excellent
outcomes at six weeks, as compared with 53 percent
of patients with an incorrect diagnosis. British investigators also found that half of a series of patients with
subarachnoid hemorrhage initially received an incorrect diagnosis; 65 percent had recurrent bleeding before a correct diagnosis was given.12
Table 3 shows the results of these four studies in
which a substantial proportion of patients were givVol ume 342

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Subarachnoid hemorrhage
Cervicocranial-artery dissection
Temporal arteritis
Acute angle-closure glaucoma
Hypertensive emergency
Carbon monoxide poisoning
Pseudotumor cerebri
Cerebral venous and dural sinus thrombosis
Acute stroke (hemorrhagic or ischemic)
Mass lesion
Intracranial hematoma (parenchymal,
subdural, or epidural)
Parameningeal infection
*These causes are diseases or conditions that are
treatable and that, if untreated, threaten life, limb,
brain, or vision.



Nuchal rigidity
Diminished level of consciousness

Any (could result from possible
complications of aneurysmal rupture: hydrocephalus, hematoma,
or ischemia)
Posterior communicating artery
Posterior fossa*
Anterior communicating artery
Posterior fossa
Middle cerebral artery

Retinal and subhyaloid hemorrhage
Third-nerve palsy
Sixth-nerve palsy
Bilateral weakness in legs or abulia
Nystagmus or ataxia
Aphasia, hemiparesis, or left-sided
visual neglect



*Sixth-nerve palsy may also be associated with nonspecific changes related
to increased intracranial pressure.

rhage were excluded because of a delay of more than
three days before referral.20
Three facts are clear. First, physicians consistently
misdiagnose subarachnoid hemorrhage. Second, the
patients with the greatest likelihood of benefiting
from surgery are the ones who most often receive an
incorrect diagnosis. Third, early complications develop in patients with an incorrect diagnosis, resulting in
worse outcomes more often in these patients than in
those initially given a correct diagnosis. Misdiagnosis
stems from three recurring, correctable patterns of
diagnostic error: failure to appreciate the spectrum of
clinical presentation, failure to understand the limitations of computed tomography (CT), and failure
to perform and correctly interpret the results of lumbar puncture (Table 4).

Figure 1. Subhyaloid Hemorrhage.
The retina of the right eye of a patient with aneurysmal subarachnoid hemorrhage has small, flame-shaped hemorrhages
(arrowheads) and a large subhyaloid hemorrhage (arrow) temporal to the optic disk. At the inferior margin of the subhyaloid
hemorrhage, the blood forms layers in a gravity-dependent fashion. Ocular hemorrhages in patients with subarachnoid hemorrhage can be flame-shaped, subhyaloid, or vitreous and are
thought to result from an acute increase in intracranial pressure
that causes obstruction of venous outflow from the eye. These
hemorrhages may be the only clue to the underlying cause in
unconscious patients with subarachnoid hemorrhage. (Provided by Dr. John J. Weiter.)

en an incorrect diagnosis. Frequent misdiagnosis has
also been documented in the Netherlands,17 Portugal,18 and Australia.19 In the International Cooperative
Study on the Timing of Aneurysm Surgery, involving 68 centers in 14 countries, nearly half the eligible patients with aneurysmal subarachnoid hemor30 ·

Warning Headache

Between 20 and 50 percent of patients with documented subarachnoid hemorrhage report a distinct,
unusually severe headache in the days or weeks before the index episode of bleeding, referred to as a
warning headache.21-28 These so-called thunderclap
headaches develop in seconds, achieve maximal intensity in minutes, and last hours to days. The differential diagnosis includes subarachnoid hemorrhage29-31;
acute expansion, dissection, or thrombosis of unruptured aneurysms32; cerebral venous sinus thrombosis33; brief headaches during exertion and sexual intercourse34; and benign thunderclap headache.31 All
patients with thunderclap headache should be evaluated for subarachnoid hemorrhage.
Deviations from the Classic Presentation

Roughly half of all patients with subarachnoid
hemorrhage have episodes of minor bleeding, often

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Patients with incorrect diagnosis — no./total no. (%)
Delay in diagnosis — days

ET AL.13

ET AL.15

ET AL.16


69/136 (51) 54/217 (25) 56/150 (37) 41/182 (23) 220/685 (32)




no. of patients

Specific misdiagnoses
No diagnosis or headache of unknown cause
Migraine, cluster, or tension headache
Meningitis or encephalitis
Systemic infection (influenza, gastroenteritis, or viral syndrome)
Stroke or cerebral ischemia
Hypertensive crisis
Cardiac causes (myocardial infarction, arrhythmia, and syncope)
Sinus-related condition
Neck problem (disk-related or arthritis)
Psychiatric diagnosis (including malingering and alcohol
Trauma-related condition
Back pain

no. (%)





52 (24)
47 (21)
23 (10)
23 (10)
17 (8)
16 (7)
14 (6)
13 (6)
11 (5)
10 (5)





3 (1)
1 (<1)
32 (15)

*Some patients had more than one diagnosis.
†The numbers in parentheses denote the percentages of patients with the particular misdiagnoses among all patients with an incorrect

with atypical features.35,36 Among 500 patients with
subarachnoid hemorrhage in one series, the condition
developed in 34 percent during nonstrenuous activities and in 12 percent during sleep.37 The headache
may be in any location, may be localized or generalized, may be mild,38 may resolve spontaneously, or
may be relieved by nonnarcotic analgesics.39 Patients
with such less severe headaches are incorrectly given
a diagnosis of a more common condition — possibly migraine, tension-type, or sinus-related headaches.12,13,15-17 Even these less severe types of headache tend to develop abruptly and have a distinctive
quality. When vomiting is prominent, especially if accompanied by low-grade fever, viral syndrome, viral
meningitis, influenza, or gastroenteritis is often diagnosed.12,13,15-17 Patients with prominent neck pain
may be given a diagnosis of cervical sprain or arthritis,12,15,16,40 and those with blood irritating the lumbar theca may be given a diagnosis of sciatica.15,38 Patients who are confused, agitated, or restless and who
are unable to give cogent histories may receive primary psychiatric diagnoses.12,13,15-17,38
According to the International Headache Society,
a first episode of severe headache cannot be classified
as migraine or tension-type headache; diagnostic criteria require multiple episodes with specific characteristics (more than 9 episodes for tension-type headache
and more than 4 episodes for migraine without aura).41 Although patients with primary headache dis-

orders must have their first headache at some point,
the diagnosis cannot be made definitively at that time.
The first or worst headache requires evaluation, as do
qualitatively different headaches in patients with established headache patterns, even if the headache is
not the “worst ever.”
In patients with unruptured aneurysms, seizures,
mass effect, cranial neuropathy, or brain ischemia from
passage of a clot into the territory distal to the aneurysm may also develop.32 Typically, aneurysmal thirdnerve palsy dilates the pupil, whereas microvascular
infarction does not, although there are exceptions.42
Patients with partial lesions that spare the pupil must
be evaluated for the presence of aneurysms.
Secondary Head Injury, High Blood Pressure,
and Abnormal Electrocardiographic Findings

Diagnostic ambiguity arises in patients with subarachnoid hemorrhage who lose consciousness, fall,
and sustain head injuries.13,16,43 Blood seen on CT
scanning may be incorrectly attributed to trauma,
the most common cause of blood in the subarachnoid space. Some patients may have high blood pressure, with or without alterations in consciousness.20
Excessive focus on blood pressure may lead to the
incorrect diagnosis of primary hypertensive emergency.13,15,16 Up to 91 percent of patients with subarachnoid hemorrhage have cardiac arrhythmias,44 and
electrocardiographic patterns mimicking myocardial
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Failure to appreciate the spectrum of presentations of subarachnoid
Failure to evaluate patients with “warning headaches” (severe, abrupt, unusual headaches)
Failure to recognize that headache can improve spontaneously or with nonnarcotic analgesic drugs
Overreliance on the classic presentation, leading to the following incorrect
Viral syndrome, viral meningitis, or gastroenteritis
Migraine or tension-type headache
Sinus-related headache
Neck pain (rarely, back pain)
Psychiatric disorders
Focus on secondary head injury (resulting from syncope)
Focus on electrocardiographic abnormalities
Focus on high blood pressure
Lack of knowledge of presentations of unruptured aneurysm
Failure to understand the limitations of computed tomography
Loss of sensitivity with increasing time between onset of headache and
False negative results in cases of small-volume bleeding (spectrum bias)
Interpretation factors (e.g., variations in expertise of physician reading the
Technical factors (e.g., variations in thickness of slices taken at the base of
the brain, motion artifact)
False negative results for blood with a hematocrit of less than 30 percent


Failure to perform lumbar puncture and correctly interpret cerebrospinal fluid findings
Failure to perform lumbar puncture in patients with negative, equivocal, or
suboptimal results on computed tomography
Failure to recognize that xanthochromia may be absent very early (<12
hours after hemorrhage) and very late (>2 weeks after hemorrhage)
Failure to realize that visual inspection for the presence of xanthochromia
is less sensitive than spectrophotometry
Failure to distinguish properly between “traumatic tap” and true subarachnoid hemorrhage

ischemia or infarction are seen, resulting in the erroneous diagnosis of a primary cardiac disorder.15-17
Despite these caveats, most patients with subarachnoid hemorrhage have abrupt onset of severe, unique
headache or neck pain. Many will have abnormal findings on neurologic examination, if only subtle meningismus or ocular findings. An understanding of this
wide spectrum of clinical presentation, coupled with
a careful history taking and physical examination that
actively targets these diagnostic clues, is the best
strategy for identifying patients who should be evaluated for subarachnoid hemorrhage.

The first diagnostic study should be noncontrast CT
(Fig. 2).6-8,11,45 Technique is important. Very thin cuts
(3 mm in thickness) through the base of the brain
are recommended, because thicker cuts (10 mm) miss
small collections of blood.46 The plane of scanning
should be parallel to the hard palate.46 Blood and adjacent bone, which both appear white, can be difficult to distinguish from one another, especially in
small hemorrhages. Because the increased density of
blood on CT is a function of the hemoglobin con32 ·

Figure 2. Subarachnoid Hemorrhage on CT Scan.
A 34-year-old woman presented to the emergency department
with headache. While sitting at her desk three hours earlier, she
had had a syncopal episode, followed immediately by a moderate-intensity, unusual, localized headache in the left frontal and
temporal areas. She was awake and alert and had no meningeal,
ophthalmologic, or neurologic signs. The CT scan without contrast material showed blood in the subarachnoid space. In Panel A, blood fills the basal cisterns and extends into the sylvian
fissures bilaterally and the interhemispheric fissure anteriorly.
In Panel B, the blood in the more rostral sylvian fissures is more
difficult to see. Both images show enlarged lateral, third, and
fourth ventricles, indicating the presence of communicating hydrocephalus.

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centration,46 blood with a hemoglobin concentration below 10 g per deciliter may appear isodense.47
Artifacts of motion in the scans of restless patients can
render such scans technically suboptimal and obscure
the diagnosis.
The sensitivity of CT decreases over time from
the onset of symptoms; the dynamics of cerebrospinal
fluid and spontaneous lysis can result in the rapid
clearing of subarachnoid blood.48 In the International
Cooperative Study of the Timing of Aneurysm Surgery, over 3500 patients with aneurysmal subarachnoid hemorrhage underwent scanning with the type
of CT equipment in use between 1980 and 1983.
Ninety-two percent of the scans were positive on the
day of rupture, but this percentage declined to 86 percent one day later, 76 percent two days later, and 58
percent five days later.20 In another study, 85 percent
of scans were positive five days after rupture and 50
percent at one week.49
Four studies have evaluated modern, third-generation CT scanners.9,48,50,51 Retrospective studies of
patients admitted to the hospital with subarachnoid
hemorrhage indicate that 100 percent of patients who
underwent scanning in the first 12 hours (80 of 80)50
and 93 percent of patients studied within the first 24
hours (134 of 144)51 after the onset of headache had
positive findings on CT scanning. Prospective studies of outpatients found a sensitivity of 98 percent
(117 of 119) for scanning performed in the first 12
hours48 and 93 percent (14 of 15) for scanning performed in the first 24 hours.9
In three of these studies,9,48,50 expert neuroradiologists interpreted the CT scans, but in many hospitals
such experts are not available. The fourth study,51 in
which the readings of the initial radiologist were used,
found a sensitivity of 93 percent for scanning performed within 24 hours after the onset of symptoms.
Skill in correctly identifying hemorrhage on CT varies
widely among emergency physicians, neurologists, and
general radiologists.52 Less experienced physicians
undoubtedly miss subtle abnormalities.
Spectrum bias is another issue; alert patients are
more likely to seek care later and have normal CT
scans than those with diminished mental status.20 In
the International Cooperative Study, 15 percent of
638 alert patients had normal scans.53 Patients with
small hemorrhages, who are the most likely to receive
an incorrect clinical diagnosis, are also more likely to
have negative results on CT.48 Although magnetic resonance technology is continually advancing and can
detect aneurysms, standard magnetic resonance imaging is inferior to CT for the detection of acute subarachnoid hemorrhage.54 Magnetic resonance imaging with fluid-attenuated inversion recovery shows
promise,55 but CT remains the imaging method of
choice because of its wider availability, lower cost, and
greater convenience for ill patients and because there
is wider experience with its interpretation.56


Lumbar puncture should be performed in a patient whose clinical presentation suggests subarachnoid
hemorrhage and whose CT scan is negative, equivocal, or technically inadequate.6-8,45,48 This recommendation, however, is often not followed in practice.9
Lumbar puncture as a first strategy, postulated to be
cost effective in carefully selected patients who have
completely normal physical examinations,57 may be
safe but has not been studied clinically.
Duffy reported that of 55 patients who underwent
lumbar puncture as the initial means of diagnosing
subarachnoid hemorrhage, the condition of 7 deteriorated immediately thereafter.58 Hillman described
four alert patients with subarachnoid hemorrhage
whose neurologic condition deteriorated after lumbar
puncture.59 In both studies, all the patients whose condition deteriorated had either clots on CT or a dilated pupil. Patients with possible bacterial meningitis should be treated with antibiotics while awaiting
Even when lumbar punctures are performed, errors are sometimes made in interpreting cerebrospinal fluid findings. The cerebrospinal fluid pressure
should always be measured. High intracranial pressure is an important clue in the occasional patient
with cerebral venous sinus thrombosis33 or pseudotumor cerebri and may help distinguish bleeding due
to traumatic lumbar puncture from true subarachnoid hemorrhage.60
“Traumatic taps” occur in up to 20 percent of lumbar punctures61 and must be distinguished from true
hemorrhage. Depending on the method of detection,
between 0.5 and 6.0 percent of the population has
incidental intracranial aneurysms.11 Misinterpretation
of a traumatic tap in a patient with an incidental aneurysm can precipitate potentially risky diagnostic and
therapeutic interventions, so distinguishing traumatic
taps from true hemorrhages is critical. Neither the impression of the operator nor the time-honored “threetube method,” in which one looks for a diminishing
erythrocyte count in three successive tubes of cerebrospinal fluid, is entirely reliable in identifying a traumatic tap.7,62 A finding of crenated erythrocytes is
also without value.7 Erythrophages are found inconsistently in the cerebrospinal fluid62,63 and may take
days to develop.7 The use of D-dimer levels in cerebrospinal fluid to differentiate true hemorrhage from
traumatic tap has proved inconsistent.9,63,64 If clear fluid is obtained on a second puncture one interspace
higher than the initial tap, then it is likely that the
first puncture was traumatic.60
After aneurysmal hemorrhage, erythrocytes rapidly disseminate throughout the subarachnoid space,
where they persist for days or weeks and then are gradually lysed.56,60 Released hemoglobin is metabolized
to the pigmented molecules oxyhemoglobin (reddish
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pink) and bilirubin (yellow), resulting in xanthochromia. Oxyhemoglobin can be detected within hours.
The formation of bilirubin, an enzyme-dependent
process, is diagnostically more reliable but requires up
to 12 hours to occur.60,65 Timing is therefore important in interpreting the results of a lumbar puncture;
cerebrospinal fluid should be centrifuged and examined promptly so that erythrocytes resulting from
bleeding during lumbar puncture do not undergo lysis
in vitro, producing xanthochromia from oxyhemoglobin.
Most authorities agree that the presence of xanthochromia is the primary criterion for a diagnosis of subarachnoid hemorrhage in patients with negative CT
scans.7,8,61 Others contend that the presence of erythrocytes, even in the absence of xanthochromia, is more
accurate.66 These divergent opinions may be explained
by the various methods of detecting xanthochromia.
Those who believed that xanthochromia is most important used spectrophotometry, whereas those who
believed that erythrocytes are most important used
visual inspection, which can miss discoloration in up
to 50 percent of specimens.67
In a study by Vermeulen et al., all 111 patients with
subarachnoid hemorrhage who underwent lumbar
puncture between 12 hours and 2 weeks after the onset of symptoms had xanthochromic cerebrospinal
fluid, as determined by spectrophotometry.68 Vermeulen et al., along with others, recommend waiting 12
hours after the onset of headache, so that a traumatic
first attempt undertaken earlier does not lead to xanthochromia and diagnostic confusion when a subsequent puncture is performed.7,8,57,68,69 The disadvantages of delaying lumbar puncture for 12 hours are
primarily logistic (e.g., the prolongation of a patient’s
emergency department stay). In addition, there is the
potential for “ultra-early” rebleeding — that is, within the first 12 hours after hemorrhage.70
We do not advocate delayed lumbar puncture in
patients with negative CT scans. Patients with persistently bloody cerebrospinal fluid without xanthochromia (as determined by any method in patients
presenting in the first 12 hours after the onset of headache and as determined visually in patients presenting after 12 hours) should undergo vascular imaging
when the level of clinical suspicion of subarachnoid
hemorrhage is high. This approach also applies to patients with xanthochromic cerebrospinal fluid.
If CT or lumbar puncture indicates the presence of
subarachnoid hemorrhage, consultation with a specialist and vascular imaging are indicated. What if the
evaluation is negative? Is vascular imaging indicated in
such patients? Day and Raskin reported on a patient
with “explosive” headache and negative results on CT
and lumbar puncture who, on angiography, had an
unruptured internal-carotid-artery aneurysm and vasospasm.71 The aneurysm was clipped, and the patient
recovered. Raps et al. described seven other patients
34 ·



Clinical history
Onset of headache: abrupt, maximal at onset, “thunderclap”
Severity of headache: usually “worst of life” or very severe
Qualitative characteristics: first headache ever of this intensity, unique or different in patients with prior headaches
Associated signs and symptoms
Loss of consciousness*
Focal neurologic signs*
Epidemiologic factors
Cigarette smoking
Alcohol consumption (especially after a recent binge)
Personal or family history of subarachnoid hemorrhage*
Polycystic kidney disease*
Heritable connective-tissue diseases
Ehlers–Danlos syndrome (type IV)
Pseudoxanthoma elasticum
Fibromuscular dysplasia*
Sickle cell anemia
Alpha1-antitrypsin deficiency
Physical findings
Retinal or subhyaloid hemorrhage*
Nuchal rigidity*
Any unequivocal neurologic finding (focal or generalized)*
*Patients with this risk factor are at very high risk for aneurysm; clinicians should consider a consultation with a specialist and noninvasive vascular imaging for such patients, even
when the results of computed tomography and lumbar puncture are negative.

with unruptured aneurysms and thunderclap headaches.32
On the other hand, in a retrospective evaluation
of 71 patients with thunderclap headaches whose results on CT and lumbar puncture were negative, none
of the patients had subarachnoid hemorrhage during
an average follow-up period of 3.3 years.72 Nearly half
were later given a diagnosis of migraine or tension
headache. Furthermore, in three prospective studies
in which a total of 117 patients with thunderclap headaches and negative findings on CT and lumbar puncture were followed for over one year, none of the
patients had hemorrhage or died suddenly.10,30,73

The data described above strongly support two
conclusions. First, most warning headaches are, in reality, indications of unrecognized subarachnoid hemorrhages that can be diagnosed by appropriate methods. Second, properly performed and interpreted CT
and lumbar puncture in patients with acute, severe
headache will identify the vast majority of patients
with subarachnoid hemorrhage. Symptomatic treatment of the headache, discharge, and outpatient follow-up are a safe practice in patients whose results

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are normal. Important exceptions are patients presenting more than two weeks after the onset of symptoms,
who often have negative CT findings and may have
normal cerebrospinal fluid. Also, some patients whose
diagnostic-test results are ambiguous or who are at
unusually high risk for aneurysm (Table 5) should undergo neurologic or neurosurgical consultation and
vascular imaging by magnetic resonance, CT, or conventional catheter angiography.
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