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Cerebrovascular complications of sickle cell diseaseAuthor  ZoAnn Dreyer, MD Section Editors Donald H Mahoney, Jr, MD Douglas R Nordli, Jr, MD 

Deputy Editor  Jennifer S Tirnauer, MD Disclosures 

 All topics are updated as new evidence becomes available and our  peer review process iscomplete.Literature review current through: Jun 2013. | This topic last updated: Feb 6, 2013.

INTRODUCTION — Vasoocclusive phenomena and hemolysis are the clinical hallmarks of 

sickle cell disease (SCD). Vasoocclusion results in recurrent painful episodes (previously

called sickle cell crisis) and a variety of serious organ system complications that can lead to

life-long disabilities and even death.

Hemoglobin S results from the substitution of a valine for glutamic acid as the sixth aminoacid of the beta globin chain, which produces a hemoglobin tetramer (alpha2/betaS2) that is

poorly soluble when deoxygenated [1]. The polymerization of deoxy hemoglobin (Hb) S is

essential to vasoocclusive phenomena [1]. The polymer assumes the form of an elongated

rope-like fiber that usually aligns with other fibers, resulting in distortion into the classic

crescent or sickle shape and a marked decrease in red cell deformability.

However, polymerization alone does not account for the pathophysiology of SCD.

Subsequent changes in red cell membrane structure and function, disordered cell volume

control, and increased adherence to vascular endothelium also play important roles [1,2].

(See "Sickle hemoglobin polymer: Structure and functional properties" and"Vasoocclusion in

sickle cell disease".)

The cerebrovascular complications associated with SCD (cerebral infarction, intracranial

hemorrhage, and cognitive and behavioral changes) and potential strategies to prevent these

complications are reviewed here (figure 1) [3,4]. The other manifestations and overall

treatment of this disorder are discussed separately. (See "Overview of the clinical

manifestations of sickle cell disease" and "Overview of the management of sickle cell

disease".)

INCIDENCE — A cerebrovascular accident (CVA) is a leading cause of death in both children

[5] and adults [6] with SCD. The reported age-adjusted incidence is 0.61 to 0.76 per 100

patient years (ie, 0.61 to 0.76 percent per year) during the first 20 years of life [7,8]. This rate

is approximately 300 times higher than that seen in children without SCD (0.0023 per 100

patient years) [9,10].

The risk of CVA varies with the genotype. In a series of 3647 patients from the Cooperative

Study of Sickle Cell Disease, the age-adjusted incidence was 0.61 per 100 patients years in

SCD (Hb SS); the respective values for Hb SC, Hb S-beta (+) thalassemia, and Hb S beta (0)

thalassemia were substantially lower at 0.15, 0.09, and 0.08, respectively, per 100 patient

years [8]. The likelihood of having a first CVA by age 20, 30, and 45 years was 11, 15, and 24

percent, respectively, for SCD compared with 2, 4, and 10 percent, respectively, for Hb SC

(figure 2).

 Although the precise definition of a CVA varies among authors, all agree that it includes any

acute neurologic event secondary to arterial occlusion or hemorrhage that results in an

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ischemic event associated with neurologic signs and/or symptoms. Some authors also include

transient ischemic events (TIA) [8] and silent infarcts [11] in the definition.

Stroke is usually associated with narrowing or occlusion of the large cerebral arteries

[7,12,13]. The type of stroke varies with age. An ischemic infarct is most common in children

between the ages of two and nine, uncommon between the ages of 20 and 29, and has a

second peak in adults over age 29 [8]. Hemorrhagic stroke can occur in children but is most

frequent in individuals between the ages of 20 and 29. Overall data from the Cooperative

Study of Sickle Cell Disease found that among first CVAs in patients with SCD, 54 percent

were caused by cerebral infarction, 11 percent by TIA, 34 percent by intracranial hemorrhage,

and 1 percent had features of both infarction and hemorrhage [8].

In addition to the potentially devastating effect of stroke with its neurologic sequelae, subtle

injury to the brain caused by sickle cell-related vascular compromise has become better 

understood with the availability of better imaging techniques (eg, magnetic resonance imaging

[MRI], magnetic resonance angiography [MRA], and transcranial Doppler) [11,14]. These

"silent" infarcts appear to play an important role in the development of cognitive deficits.

(See 'Cognitive and behavioral dysfunction and silent infarcts' below.)

 As an example of the magnitude of changes detected by MRI and MRA, the images of all 146

children with homozygous sickle cell anemia at a single institution were reviewed [15]. At an

average age of 10 years, the estimated prevalence of infarction, ischemic damage, or atrophy

was 46 percent, while that for vasculopathy was 64 percent. Only 28 percent of children

tested negative by both modalities.

CEREBRAL INFARCTION 

Definition and pathophysiology — Cerebral infarction is defined clinically by the presence

of typical symptoms that last for at least 24 hours. Symptoms of infarctive stroke may include

hemiparesis, dysphasia, gait disturbance, and/or a change in level of consciousness. Thesefindings are associated with a corresponding radiographic lesion. (See 'Radiographic

imaging' below.)

 Although patients generally do not die acutely from infarctive stroke [8], substantial morbidity

may occur. One report evaluated 11 children who developed a first cerebral infarct and

presented with hemiparesis; 10 were hospitalized [16]. At hospital discharge, two had major 

disability, five had mild-to-moderate disability, two had symptoms but no disability, and one

was asymptomatic.

Cerebral infarction is associated largely with occlusion or stenosis of the large intracranial

arteries. The greater risk of infarction in younger children may be explained by the higher 

cerebral blood flow observed in this population. A number of other factors may contribute[17,18]:

Sludging and occlusion of small vessels by rigid red cells, which produces ischemia in

the cerebral microcirculation

Chronic anemia may reduce cerebrovascular reserve

Flow-related hemodynamic injury to the arterial endothelium, which may promote

adherence of sickle cells to the endothelium, producing further endothelial injury

Development of moyamoya vessels (see 'Moyamoya syndrome' below)

A hypercoagulable state

HLA-related susceptibility for stroke [19-23] 

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Silent cerebral ischemia is a related condition in which an infarct-like lesion is seen on MRI

without a corresponding abnormality on neurologic exam [24]. Silent ischemia produces no

overt sensorimotor deficits, but it is associated with poor cognitive performance and an

increased risk for infarction in children with SCD.

Incidence — In children and adolescents with SCD in the Cooperative Study of Sickle Cell

Disease, the incidence per 100 patient years of a first cerebral infarct in a series from the

United States was 0.70 between ages two and five years, 0.51 between ages six and nine

years, 0.24 between 10 and 19 years of age, and then fell to 0.04 between the ages of 20 and

29 [8]. Attesting to the impact of this complication, it has been estimated that 11 and 24

percent of patients with sickle cell disease have a clinically apparent stroke by the ages of 20

and 45 years, respectively [8,25].

The incidence is substantially lower in children with Hb SC, Hb S-beta (+) thalassemia, and

Hb S-beta (0) thalassemia. Saudi Arabian children with SCD have less severe anemia and a

much lower incidence of serious complications (6 to 25 percent of the rate of American or 

Jamaican black children) [26]. High levels of Hb F were thought to account for the mild clinical

course.

Recurrent stroke occurs in approximately two-thirds of patients within two years of the initial

event [7,27-29]. This risk is age-dependent: 6.4 per 100 patient years in patients with an initial

CVA before age 20 compared with 1.6 per 100 patient years in older patients [8]. Significant

and long-lasting neurologic deficits are much more likely to occur after a second stroke.

The incidence of silent ischemia appears to be greater than that of cerebral infarction and

varies depending on the sensitivity of the imaging modality.

In one MRI/MRA study of 65 neurologically intact children with SCD (age range: 1.3

to 5.9 years), 18 had silent infarcts (28 percent) [30]. Factors associated with silent

infarcts in these children included cerebral vessel stenosis on MRA, lower rates of vasoocclusive pain and acute chest syndrome, and lower hemoglobin levels.

Another study looked for the presence of silent ischemic events in children with SCD

enrolled in the Silent Cerebral Infarct Transfusion (SIT) trial, which evaluated the role

of chronic red cell transfusion in preventing clinically silent infarctions [24]. Silent

ischemic events, defined as an infarct-like lesion seen on MRI without corresponding

abnormality on neurologic exam, were found in 8 of 220 children evaluated. In

addition, acute silent events, defined as areas of restricted diffusion on diffusion-

weighted MRI in the absence of corresponding focal neurologic findings, were found

in 10 of 732 children. Repeat scans of two children showed a persistent silent lesion

in one and resolution of the lesion in the other.

Risk factors — In the Cooperative Study of Sickle Cell Disease, the following major risk

factors for completed infarctive stroke were identified on multivariate analysis [8]:

Prior TIA: Relative risk [RR] 56

Low steady state hemoglobin: RR 1.9 per 1 g/dL decrease

Rate of acute chest syndrome: RR 2.4 per event per year 

Episode of acute chest syndrome within the previous two weeks: RR 7.0

Elevated systolic blood pressure: RR 1.3 per 10 mmHg increase

In a nested case-cohort study from the Dallas Newborn Cohort, lower steady-state pulse

oximetry-derived oxygen saturation (SpO2) was associated with an increased risk of an overt

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stroke in children with SCD [31], and correlated inversely with cerebral artery blood flow

velocity as determined by transcranial Doppler ultrasonography [32].

The odds ratio for stroke was 1.32 (95% CI 1.15-1.51) for each unit (1 percent) decrease in

SpO2 when the age of the patient was controlled. In patients with strokes, SpO2 fell even

lower as the time to impending stroke decreased. Monitoring SpO2 can be used to identify

children with hemoglobin desaturation who are at increased risk of stroke. In these patients,

interventions to improve hemoglobin oxygen saturation and the underlying hemolytic anemia

[33] can be started that presumably will reduce the risk of stroke.

Multilocus genotype screening and family studies have also been employed in an attempt to

identify genetic polymorphisms or biologic differences that may increase or decrease the risk

of stroke in patients with this disease [20-22,34]. (See "Clinical variability in sickle cell

anemia", section on 'Stroke'.)

Predicting risk — Transcranial Doppler (TCD), a noninvasive procedure, has become an

important tool in predicting risk for stroke in patients with SCD. It measures the time-averaged

mean velocity of blood flow in the large intracranial vessels, which is inversely related to

arterial diameter (as documented by cerebral angiography) [35]. A focal increase in velocity

usually suggests arterial stenosis, whereas a bilateral increase may indicate bilateral arterial

disease, increased blood flow, or both [36,37].

Children — In children, a mean transcranial Doppler (TCD) velocity >170 cm/sec is

worrisome, and values >200 cm/sec in the middle cerebral or internal carotid artery are highly

associated with an increased risk of stroke, even before lesions become evident on magnetic

resonance angiograms (MRA) [38]. Patients with abnormal MRA findings and higher TCD

velocities are at even higher risk for stroke.

This association was illustrated in a study in which TCD was performed in 190 children with

sickle cell disease (age at entry: 3 to 18 years) [39]. Twenty-three patients (12 percent) hadan abnormal TCD (based upon the highest blood flow velocity in the middle cerebral artery),

and seven developed a cerebral infarction after an average follow-up of 29 months. Six of the

seven strokes occurred among the 23 patients with abnormal ultrasound results.

 A similar frequency of abnormal TCD findings (9.7 percent) was noted in the STOP I trial of 

children who had no prior history of stroke [16]. The incidence fell with age, as does the

incidence of cerebral infarction: 10.7, 9.4, and 6.3 percent between the ages of 2 to 8, 9 to 12,

and 13 to 16, respectively. (See 'Prevention of a first stroke' below.)

Significant risk factors for abnormally high cerebral velocities as determined by TCD in a

cohort of 373 stroke-free children with SCD included the following [40]:

G6PD deficiency

Lower levels of hemoglobin

Absence of alpha thalassemia

Higher levels of serum lactate dehydrogenase

These results suggest that G6PD deficiency and hemolysis independently increase the risk of 

cerebral vasculopathy in patients with SCD.

 Although TCD has been shown to be an effective screen to identify patients at high risk for 

stroke, many children with SCD in the United States are not screened because of lack of 

access to a center with TCD [41]. One study from England developed an index based upon

hemoglobin and aspartate transaminase levels and age, which correlated with the time-

averaged mean of the maximum velocity detected by TCD [42]. The authors suggest that this

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index could be used to identify patients who are more likely to have abnormal TCD and allow

them to be prioritized for more urgent TCD.

 Another major obstacle to TCD screening has been the poor compliance of patients who must

return to the medical center for the study on a day separate from their routine evaluations in

SCD clinic [43]. However, in one study from St. Jude, where TCD screening is routinely

available on the day of a clinic visit, 99 percent of patients at risk for stroke were able to be

screened, and the incidence of first stroke was reduced [44].

Other techniques for assessing the risk of stroke in children with SCD have been proposed.

A small, preliminary study suggested that conjunctival vessel velocity, as measured

by a non-invasive computer-assisted intravital microscopy, correlated with abnormal

intracranial vessel velocity, and may therefore be of use in identifying patients at high

risk of stroke [45].

A study in four children with Hb SS disease suggested that a submandibular TCD

approach may help identify obstruction in the proximal and mid portions of the internal

carotid artery, improving its sensitivity as a screening tool [46].

Further study of these approaches is warranted.

Adults — Similar data on the value of TCD in predicting strokes in adults are lacking. In one

study, the mean TCD velocity of adult patients with SCD was lower than that reported in

children with SCD [47]. In a subsequent report from the same institution, abnormalities were

detected in 35 of 60 patients who underwent magnetic resonance imaging (MRI) [48]. In these

patients, a time-averaged maximum mean velocity of 123.5 cm/sec detected all the cases of 

middle or internal carotid artery intracranial stenosis with a specificity of 100 percent. Whether 

this translates to a lower threshold of TCD velocity to predict strokes in adults with SCD

compared with that used in children with SCD (>170 cm/sec) remains unknown.Prevention of a first stroke — The ability of TCD to identify patients with SCD at high risk

for stroke provided the rationale for the multi-institutional Stroke Prevention Trial in Sickle Cell

 Anemia (STOP I trial) [16]. A total of 130 children (mean age 8.3 years) with SCD or HbS-

beta(0) thalassemia with no prior history of stroke were enrolled; all had a blood flow velocity

above 200 cm/sec on two repeated studies. The children were randomly assigned to

observation or institution of a prophylactic chronic transfusion program with a goal HbS of less

than 30 percent of total hemoglobin.

The trial was prematurely terminated at a mean follow-up of 20 months because of a marked

benefit in the prophylactic transfusion group: one infarction in the transfusion group compared

with 10 infarctions and one intracerebral hemorrhage in the control group (figure 3).

Thirty-seven percent of those enrolled in this trial had evidence of a prior silent infarct on the

initial brain MRI. Transfusion therapy significantly reduced the risk of a new silent infarct or 

stroke in this group, while patients who were not provided transfusion therapy were at a

higher risk of developing a new silent infarct or stroke during the study than those whose

initial MRI was normal.

In a subsequent follow-up report of 127 patients from the STOP I trial, six additional cases of 

stroke occurred [49]. Five of the six patients were in the trial arm of stopping blood

transfusions. Stroke occurred in two patients in the immediate post-trial period prior to

restarting transfusion therapy, in one patient who refused transfusion, and in two patients who

had restarted transfusions. The one patient who had received blood transfusion anddeveloped a stroke had discontinued transfusions at the end of the trial. All six patients had

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abnormal TCD velocities. Seventy-nine patients received transfusions during the post-trial

follow-up. In the patients who did not have a stroke, patients who received transfusions were

more likely to have normal TCD.

Further suggestive evidence supporting the effectiveness of TCD screening and subsequent

intervention in preventing stroke comes from calculation of stroke rates in California children

with SCD before and after the 1998 publication of the results of the STOP I trial [10]. Stroke

rates were relatively constant between 1991 and 1998 at 0.88 events per 100 patient-years.

In contrast, the observed rates were 0.50 and 0.17 per 100 patient years for 1999 and 2000,

respectively (p <0.005 for trend), suggesting more effective intervention following publication

of the STOP I trial results.

 As an integral part of the STOP trial, TCD measurements were taken of flow velocity in the

anterior cerebral artery (ACA) as well as the internal carotid/middle cerebral

arteries (ICA/MCA), and the following findings were reported [50]:

Among subjects at high risk of stroke due to high ICA/MCA velocity (ie,

≥200 cm/sec), the risk of stroke more than doubled with elevated, compared withnormal, ACA velocity (7.6 versus 3.2 per 100 patient-years).

Among subjects with normal ICA/MCA velocity (ie, <170 cm/sec), the risk of stroke

was more than 10-fold greater in those with elevated (ie, ≥170 cm/sec) compared

with normal ACA velocity (2.1 versus 0.20 per 100 patient-years).

Although increased ACA flow in the absence of elevated flow in the ICA/MCA was

uncommon, when present it represented a stroke risk comparable to that seen in

patients with conditionally abnormal ICA/MCA flow (ie, 170 to 199 cm/sec; stroke risk

0.9 to 1.5 per 100 patient-years). The authors suggested that such findings should

prompt early repeat studies to aid in decisions concerning interventions such as

chronic transfusion.

Recommendation — Based upon the ability of TCD to identify children at risk [39] and of a

prophylactic transfusion therapy protocol to provide benefit in such children [16], the use of 

TCD has become a routine screening tool in many centers that care for children with sickle

cell anemia. The American Academy of Neurology published an assessment of TCD in May

2004, and concluded that TCD screening of children with sickle cell disease after age two is

effective for assessing stroke risk [51].

However, the optimal frequency of TCD screening has not been established [51]. Normal flow

velocity on a single screening does not assure a continued "low risk" status. Accordingly,

intermittent screening should be performed, especially in younger children and those with

higher blood flow velocity [52]. An expert panel convened by the American Academy of Pediatrics recommends annual screening by TCD after age two years [53].

The importance of repeat screening was shown in a retrospective study of 274 patients with

sickle cell disease who had mean velocity values in the normal (ie, <170cm/sec) or 

"conditional" range (ie, 170 to 199 cm/sec) [54]. Results included:

Of the 153 subjects with normal flow velocity on initial examination, 25 (16 percent)

converted to a "conditional" velocity on a subsequent examination and 4 (3 percent)

converted directly to an abnormal flow velocity (ie, ≥200 cm/sec) over the ensuing 18

months.

The 18-month cumulative incidence of conversion from "conditional" to abnormal flow

velocity (ie, ≥200 cm/sec) was 23 percent, and was not influenced by age, initialmean velocity, blood pressure, oxygen saturation, or other laboratory values.

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We screen children with TCD study of the internal carotid artery and middle cerebral artery,

and determine the timing of repeat screening based on the highest flow velocity in either 

artery, as follows:

Flow velocity <170 cm/sec: repeat annually

Flow velocity >170 cm/sec and ≤200 cm/sec: repeat in three months  Flow velocity ≥200 cm/sec: repeat in two to four weeks

Children with abnormal flow velocity of ≥200 cm/sec in the internal carotid artery or the middle

cerebral artery on two repeated studies done by TCD are at high risk of stroke. Therefore,

patients with two abnormal TCD studies within a two- to four-week period should be entered

into a stroke prevention protocol consisting of chronic transfusion therapy [53]. This

recommendation is supported by numerous studies and randomized clinical trials

demonstrating that chronic transfusion therapy is effective primary prophylaxis for stroke in

patients with SCD, and is the treatment of choice for high-risk patients. (See 'Chronic

transfusion therapy' below.)

Chronic transfusion therapy poses certain risks, including alloimmunization and iron overload;

and although TCD has a high sensitivity for predicting stroke, the specificity is low [25]. For 

families who refuse transfusion therapy, hydroxyurea has been suggested as a second-line

option [55]. Although studies have shown that hydroxyurea may lower TCD velocities, minimal

information is available about its efficacy for primary or secondary prevention of stroke in

SCD, and there are no randomized trials to support the efficacy of hydroxyurea over chronic

transfusion therapy. Moreover, preliminary results from a randomized trial suggest that

chronic transfusion therapy is more effective than hydroxyurea to prevent recurrent stroke.

(See 'Hydroxyurea' below.)

Children entering a stroke prevention protocol should be carefully screened for neurologic

abnormalities as well as language and learning deficits. In cases with neurologic findings or dramatic differences in TCD readings, magnetic resonance imaging/magnetic resonance

angiography (MRI/MRA) exams may be appropriate for diagnosing silent infarction or other 

abnormalities. (See 'Radiographic imaging' below.)

Stopping transfusion — Whether a prophylactic transfusion program can be stopped in

patients without a prior stroke was addressed in the STOP II trial, which studied the effect of 

stopping transfusion in children thought to be at lower risk for stroke because of the following

criteria:

Treatment with periodic transfusions for a minimum of 30 months with a HbS level

<30 percent in at least 20 of the 30 months Reversion of TCD velocities to normal (ie, two normal TCD examinations at least two

weeks apart while receiving transfusions)

No prior stroke and no moderate-to-severe arterial lesions on magnetic resonance

angiography

The study was prematurely terminated by the NHLBI at which time 14 of the 41 patients

randomly assigned to stop transfusions reverted to a high risk of stroke as measured by TCD,

and two other patients had stroke recurrence. These 16 events occurred within a median time

of 3.2 months (range: 2 to 10 months) following randomization. There were no strokes or 

reversion to high stroke risk in the 38 subjects assigned to continue transfusion [56].

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 A subsequent follow-up of the 79 participants in the STOP II trial evaluated the effect of 

stopping transfusions on the development or progression of silent brain infarcts as detected

by magnetic resonance imaging. Results included [57]:

For the 21 subjects with silent brain infarcts at study entry, new lesions were seen in

3 of the 10 subjects in whom transfusions were continued and in 5 of the 11 in whomtransfusions were stopped.

For the 58 subjects with a normal MRI at study entry, new lesions were seen in none

of the 28 in whom transfusions were continued, and in 6 of the 30 in whom

transfusions were stopped.

One interpretation of the STOP II trial is that children with sickle cell disease identified as

being at high risk for stroke will likely be receiving extended, if not life-long, RBC transfusions

for prevention of stroke as well as prevention of silent brain infarcts. As such they will

resemble children with beta-thalassemia major who also require regular RBC transfusion

support and face the clinical consequences of iron overload. It is likely that these children will

either require iron chelation or earlier consideration for allogeneic hematopoietic celltransplantation [53]. (See "Iron overload syndromes other than hereditary hemochromatosis",

section on 'Transfusional iron overload'.)

The NHLBI has issued a clinical alert recommending that blood transfusions be continued in

such patients. They further concluded that the choice of clinical management, including

whether to continue periodic transfusions or to stop transfusions with TCD monitoring every

two to three months, must be made on a case-by-case basis [58].

Of importance, in the 209 patients who underwent randomization in the STOP I and STOP II

trials, there were 20 strokes. The last TCD examination before the stroke showed abnormal

velocities in all cases, confirming that abnormal TCD velocities are a good indicator of the risk

of stroke both before transfusion is initiated as well as after it is stopped [56].

Prevention of recurrent stroke — As discussed above, patients with SCD who have an

initial stroke have a high risk of recurrent stroke. Recurrent stroke occurs in approximately

two-thirds of patients within two years of the initial event, and the risk is particularly high in

patients under age 20. Significant and long-lasting neurologic deficits are much more likely to

occur after a second stroke. (See 'Cerebral infarction' above.)

Because of these high recurrence risks, we recommend intervention to reduce the risk of 

recurrence in any patient with SCD who has had a stroke. For management of an acute

stroke event, exchange transfusion is the preferred initial therapy [59]. For ongoing

prevention, chronic transfusion protocols are typically used. Treatment withhydroxyurea and

hematopoietic cell transplantation also has been considered. Although hydroxyurea has beenconsidered as an alternative to chronic transfusion therapy, the SWiTCH Trial demonstrated a

higher incidence of recurrent stroke in those receiving hydroxyurea than in those receiving

chronic transfusion. Based on this recently released safety data, hydroxyurea can no longer 

be considered adequate as the sole therapy for prevention of recurrent stroke. (See 'SWiTCH

trial' below.)

Acute therapy — We recommend urgent transfusion therapy for patients with SCD who

present with stroke. Ideally, this is accomplished by an immediate exchange transfusion to

achieve a goal HbS fraction of <30 percent and a hemoglobin level of approximately, but not

greater than, 10 g/dL.

 Although the initial optimal acute therapy following a stroke in children with sickle cell disease

remains uncertain, exchange transfusion appears to be more effective than simple transfusion

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in preventing second strokes. This was illustrated in a retrospective study of 137 children with

sickle cell disease and a history of stroke [59]. Treatment information was available in 52

patients who presented within 24 hours of onset of initial stroke symptom (ie, weakness,

paresis, seizures, dysarthria/aphasia). Second strokes were more likely in patients who

received simple transfusions (8 of 14 patients) compared with those who were treated with

exchange transfusions (8 of 38 patients; RR 5.0, 95% CI 1.3-18.6). There was no differencebetween the two treated groups in the frequency of risk factors.

Chronic transfusion therapy — After the acute episode, patients should be treated with

chronic transfusion therapy. Patients who have been stabilized with chronic transfusion

therapy should be evaluated for the option of hematopoietic stem cell transplantation.

(See "Hematopoietic cell transplantation in sickle cell disease".)

Chronic transfusion can reduce the incidence of recurrent stroke to below 10 percent when

routine monthly red blood cell transfusions are given to maintain the hemoglobin S fraction at

less than 30 percent of total hemoglobin [28,29,53,60-63]. Results of three studies evaluating

the efficacy of this approach are reported below.

In one series of 60 patients followed for a mean of approximately three years, eight (13

percent) had a recurrent stroke and 13 had at least one transient ischemic attack [62]. The

HbS fraction was higher than the desired maximum of 30 percent in almost all of the recurrent

strokes and one-half of the transient ischemic attacks. The results of one retrospective study

suggest that the presence of moyamoya vessels on angiography defines a subpopulation at

increased risk of recurrent stroke [64]. (See 'Moyamoya syndrome' below and "Moyamoya

disease: Etiology, clinical features, and diagnosis".)

 A prospective cohort study enrolled 40 children with sickle cell disease and overt stroke who

were receiving regularly scheduled blood transfusion therapy and were followed by magnetic

resonance imaging (MRI) and magnetic resonance angiography (MRA) of the brain every one

to two years. Results of this study included the following [65]:

Progressive cerebral infarcts occurred in 18 (45 percent), seven with a second overt

stroke and 11 with new silent cerebral infarcts. In four of the seven children with a

second overt stroke, HbS levels were <30 percent at the time of the second event

(10, 17, 21, and 28 percent), while HbS levels were 38 and 48 percent in two and not

measured in the third. Of the seven children with a second overt stroke, three

subsequently had a third stroke and one had a fourth stroke.

Cerebral vasculopathy was identified on the first MRA in 63 percent of the subjects.

Cerebral vasculopathy worsened in 38 percent of the subjects during the study,

including five children who had no cerebral vasculopathy identified on their initial

MRA. A strong association between worsening cerebral vasculopathy by MRA and

progressive infarcts on MRI was found (RR 12.7; 95% CI 2.6-60).

 A third program, the Creteil newborn SCA cohort, systematically assessed 217 children with

sickle cell disease by TCD starting at 12 to 18 months of age, performedMRI/MRA every two

years (or earlier for those with abnormal TCD), and offered a transfusion program, treatment

with hydroxyurea, or hematopoietic cell transplantation for selected individuals. At a median

follow-up time of 6.2 years, the following observations were made [66]:

The cumulative risks at 14 to 18 years of age were 1.9, 29.6, 22.6, and 37.1 percent

for overt stroke, abnormal TCD, stenosis, and silent stroke, respectively.

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The cumulative cerebral risk for all of these events (overt stroke, abnormal TCD,

stenoses, silent strokes) was 49.9 percent (95% CI 40-59 percent) by age 14.

Independent predictors for cerebral risk included baseline reticulocyte count and

lactate dehydrogenase level.

Results of these three studies indicate that children with sickle cell disease, even if enrolled indiagnostic and therapeutic programs early after birth, experience silent infarcts and worsening

cerebral vasculopathy at a high rate, and indicate that current treatment programs (eg,

maintaining HbS at <30 percent, hydroxyurea) are less effective than previously thought. The

French investigators noted the positive development of a reduced risk for overt stroke (1.9

percent, down from a historical high of 11 percent) but also documented an overall incidence

of cerebral events of 50 percent even when they started their program within 1.5 years of 

birth. The two latter reports raise questions regarding the traditional objective of targeting HbS

levels to less than 30 percent and indicate the need for further studies.

Given the apparent need for prolonged transfusion therapy, efforts have been made to modify

the transfusion regimen in an attempt to minimize transfusion-associated complications such

as iron overload, alloimmunization, and infection. In one study, 15 patients who had been free

of stroke or neurologic deterioration for four years and had received chronic transfusions to

maintain a hemoglobin S fraction <30 percent were placed on a modified regimen in which

the acceptable goal hemoglobin S fraction was raised to <50 percent [67]. At a median follow-

up of 84 months, no recurrent cerebrovascular events occurred and simple blood transfusion

requirements fell by 17 to 48 percent (mean 31 percent).

Whether chronic transfusion therapy can be safely stopped in a patient with a prior stroke

remains unclear. However, information is now available that suggests that for patients

receiving transfusion therapy for primary prevention there is not a clear point at which

transfusion therapy can safely be withdrawn. (See 'Prevention of a first stroke'above.)

 Attempts to discontinue this regimen at one to two years [60] or as late as 12 years [68] 

following the initial stroke event have resulted in a high rate of stroke recurrence. In one

report of 10 patients who received transfusion therapy for a mean of 9.5 years after an initial

stroke, five had a recurrent ischemic event within one year after the cessation of therapy [68].

Program costs — Investigators from Jackson Children’s Hospital and the University of Miami

Division of Pediatric Hematology Oncology performed a retrospective analysis between

January 1997 and April 1998 of the cost of chronic transfusion for stroke prevention in sickle

cell disease [69]. Sixteen patients had experienced a previous stroke and five were enrolled in

the Stroke Prevention Trial (STOP) in sickle cell disease. Charges ranged from $9828 to

$50,852 per patient per year. Outpatient charges, chelation charges, and physician-related

charges accounted for 53, 42, and 5 percent of the total charges. Charges for patients whorequired chelation therapy ranged from $31,143 to $50,852 per patient per year.

Desferoxamine accounted for 71 percent of the chelation-related charges, which ranged from

$12,719 to $24,845 per patient per year. The authors concluded that these data should be

considered in reference to cost and efficacy analyses of alternative therapies for sickle cell

disease, such as allogeneic stem cell transplantation.

Hydroxyurea — Given the risks associated with even modified chronic red cell transfusion

therapy, alternatives to transfusion have been sought [25]. One possibility is pharmacologic

manipulation of fetal hemoglobin (HbF) with hydroxyurea [70-74]. (See "Hydroxyurea and

other disease-modifying therapies in sickle cell disease", section on 'Hydroxyurea'.)

This approach was evaluated in 35 children with SCD and stroke in whom transfusion therapy

was discontinued because of the presence of alloantibodies or autoantibodies, recurrent

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stroke on transfusion therapy, iron overload, noncompliance, deferoxamine allergy, parental

request, or religious objection to blood transfusion [71]. Hydroxyureawas begun at a dose of 

15 to 20 mg/kg per day and then increased to 30 to 35 mg/kg per day based upon

hematologic toxicity. In 20 patients, transfusion therapy was continued until the full-dose of 

hydroxyurea was tolerated; in the remaining 15 there was no overlap between therapies. The

overall rate of recurrent stroke per 100-patient years was 5.7; however, the rate in the groupof patients with overlapping transfusion and hydroxyurea therapy was 3.6, which compares

favorably to the rate in patients receiving chronic transfusion therapy (2.2 to 4.2 per 100-

patient years) [62,75].

In a second study, 59 children with sickle cell anemia treated with hydroxyurea for routine

clinical management underwent serial TCD evaluation; 37 children with increased flow

velocities were then enrolled in a prospective phase II trial, with TCD velocities tested at the

maximal tolerated dose (MTD) of hydroxyurea and one year later [72]. When the MTD was

reached, there was a significant decrease in the maximal TCD flow velocities for both the

middle and anterior cerebral arteries. One year after reaching MTD, the TCD velocity was

only minimally lower. The overall incidence of new neurologic events for the entire cohort

during treatment was 0.5 events per 100 patient-years of observation.

SWiTCH trial — Based on the two above studies, a large multicenter trial was launched

(Stroke With Transfusions Changing to Hydroxyurea, or  SWiTCH trial) [76]. The trial enrolled

children and adolescents with SCD who had experienced a stroke and had received at least

18 months of transfusion therapy along with evidence of iron overload, which was often

extreme (eg, median hepatic iron levels of 13 mg/gram dry weight and median serum ferritin

levels of 3164 ng/mL) [77].

This was a noninferiority phase III trial, comparing standard

therapy (transfusion/chelation) with experimental therapy (hydroxyurea/phlebotomy), with the

primary composite endpoint allowing for an increased stroke risk

with hydroxyurea/phlebotomy (ie, estimated stroke risks of 6 and 12 percent for the standard

and experimental arms, respectively) but requiring superiority of the experimental arm for 

reducing hepatic iron concentration.

In the SWiTCH trial, subjects were randomly assigned to either continue transfusion therapy

or to receive hydroxyurea treatment. To treat the underlying iron overload, subjects receiving

transfusion therapy were given deferasirox, and those switching to hydroxyurea received

serial phlebotomy to remove the excess iron. The SWiTCH trial was terminated at the first

scheduled interim analysis for futility to reach the primary end point, as follows [78]:

  Stroke risk  ─ There were no strokes in the 66 subjects randomly assigned to

treatment with transfusion and iron chelation, while there were seven strokes (10percent) in the 67 subjects randomly assigned to treatment with hydroxyurea plus

phlebotomy. This was within the noninferiority stroke risk margin for the study.

  Removal of iron  ─ Liver iron content was not signif icantly different between the two

study arms (16.6 versus 15.7 mg/g dry weight for the standard and experimental

arms, respectively).

It was therefore concluded that transfusions plus iron chelation remain a preferable way to

manage children with sickle cell anemia, stroke, and iron overload.

INTRACRANIAL HEMORRHAGE — Intracranial hemorrhage (ICH), also called hemorrhagic

stroke in this setting, accounts for approximately one-third of cerebrovascular events inpatients with SCD [8]. The site of bleeding may be subarachnoid, intraparenchymal,

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intraventricular, or a combination of these locations. The peak incidence of ICH is between

the ages of 20 and 29 in comparison to cerebral infarction, which is much more common in

children. Approximately 3 percent of children with SCD will have a hemorrhagic stroke by 20

years of age, and 25 to 50 percent will die within two weeks of the event [7,8].

Risk factors — In the Cooperative Study of Sickle Cell Disease, two major risk factors for 

hemorrhagic stroke were identified on multivariate analysis [8]:

Low steady state hemoglobin – RR 1.6 per 1 g/dL decrease

Increased steady state leukocyte count – RR 1.9 per 5000/microL increase

In addition, a small retrospective case-cohort study from two children hospitals in the United

States suggested that a recent history of hypertension, transfusions, or corticosteroid therapy

was more likely in children with sickle cell disease who experienced hemorrhagic stroke

compared to those with ischemic strokes [79].

Clinical manifestations and evaluation — Symptoms associated with ICH are frequently

different from those seen with infarction, which typically produces focal deficits, such ashemiparesis, and are dependent upon the location of the hemorrhage. The most common

presenting features of ICH include severe headache, vomiting, stiff neck, and alterations in

consciousness. Coma and seizures in the absence of hemiparesis strongly suggest ICH.

 Angiography should be considered in all patients with ICH to identify the cause of bleeding

and to guide further therapy. Aneurysms should be repaired surgically when possible. When

large vessel vasculopathy is present without aneurysm or vascular malformation, chronic

transfusion may be recommended. However, in patients for whom the cause of hemorrhage

remains unclear, chronic transfusion will not be helpful and is not indicated [17].

(See 'Radiographic imaging' below.)

The mortality rate in patients with ICH is as high as 24 to 50 percent [8,80-82]. Deathsgenerally occur within the first two weeks of the event, many on the first day [8]. In addition,

some survivors are left with moderate to severe residual disability [80].

Subarachnoid hemorrhage — The majority of cases of ICH represent subarachnoid

hemorrhage resulting from the rupture of one or more aneurysms; multiple aneurysms are

present in approximately 45 percent of patients [80,81]. Injury to the endothelium and the high

flow conditions in sickle cell disease are thought to promote the formation of these aneurysms

[80,83]. The time required for these changes to occur may account for the peak incidence in

young adults [84].

Treatment of subarachnoid hemorrhage in children with SCD consists of nonaggressive

hydration and, as in other patients with this disorder, nimodipine to minimize the incidence of 

vasospasm, surgery (eg, clip ligation), and treatment of vasospasm should it occur after 

surgery [80,81]. Blood pressure management may present a dilemma if hypertension occurs;

lowering the pressure may reduce bleeding but also may result in ischemia or infarction

because a higher pressure may be required to maintain cerebral perfusion because of the

typical increase in intracranial pressure [85]. (See "Treatment of aneurysmal subarachnoid

hemorrhage".)

Intraventricular hemorrhage — Intraventricular hemorrhage (IVH) may be associated with

rupture of anterior cerebral artery aneurysms or direct extension of intraparenchymal

hemorrhage into the lateral or third ventricle [86]. In addition, patients who have experienced

previous cerebral infarction are at risk for intraventricular and intraparenchymal hemorrhageas a late event, months to years after the ischemic stroke [84].

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Hemorrhage into the third ventricle or cerebral aqueduct places patients at high risk for late

deterioration. Such patients may be awake and alert immediately following such a bleed and

then become comatose over the ensuing 48 hours because of obstructive hydrocephalus and

ventricular dilation. Emergent ventricular drainage may be necessary [17].

Moyamoya syndrome — In approximately 30 percent of patients with SCD who develop

intracranial hemorrhage, a moyamoya syndrome (sometimes termed "pseudo-moyamoya" or 

secondary moyamoya pattern) in the basal arteries may be demonstrated by angiography

[84,87]. These abnormalities may be the source of hemorrhage. This pattern is named for its

resemblance to findings in Moyamoya disease, a chronic cerebrovascular disease of 

uncertain etiology that occurs primarily in Japan and other Asian countries and is

characterized by severe bilateral stenosis or occlusion of the arteries around the circle of 

Willis, with prominent collateral circulation. (See"Moyamoya disease: Etiology, clinical

features, and diagnosis".)

Patients with SCD who develop moyamoya syndrome appear to be at risk for recurrence of 

strokes. This was illustrated in a retrospective study of 44 patients maintained on chronic

transfusions [64]. Nineteen of the 44 patients had evidence of moyamoya collateral circulationbased upon either magnetic resonance or conventional angiography. The risk of recurrent

stroke was greater in patients with moyamoya disease (11 of 19 patients, 58 percent) than

those without moyamoya disease (7 of 25 patients, 28 percent).

In children with SCD and moyamoya syndrome, surgical treatment has been used in an effort

to restore the circulation of the ischemic brain area, thereby reducing the risk of ischemic

stroke. In one report, indirect revascularization using encephaloduroarteriosynangiosis

(EDAS) was performed in 12 patients with SSD and documented moyamoya syndrome [88].

Ten patients had a history of stroke including four who were compliant with a transfusion

protocol at the time of their stroke. At a median follow up of 47 months after the procedure,

seven patients had postsurgical angiography, which showed revascularization of the affected

area in all cases. Two of the 12 patients experienced strokes.

 Although there are no randomized, controlled trials determining the effectiveness of surgical

treatment in patients with SCD and moyamoya disease, these results suggest that EDAS

performed by experienced neurosurgeons is a reasonable option for these patients given their 

poor outcome without intervention. (See "Moyamoya disease: Prognosis and treatment",

section on 'Secondary prevention'.)

Epidural hematoma — In addition to intracranial hemorrhage, rare case reports of epidural

hematoma developing in patients with SCD have been reported. In these cases, the

hematomas were associated with bony infarcts of the skull and required aggressive surgical

intervention [89].RADIOGRAPHIC IMAGING — Computed tomographic (CT) scanning and magnetic

resonance imaging (MRI) have become the accepted methods for confirming a clinical

diagnosis of cerebral infarction or intracranial hemorrhage in patients with SCD [90-94].

An unenhanced CT scan generally is the easiest study to obtain soon after an acute

neurologic event. It will localize an area of hemorrhage immediately, but may not

become abnormal for up to six hours after an infarct.

Compared with CT, MRI offers improved resolution and the ability to demonstrate

areas of abnormality within two to four hours following an infarct. One limitation is that

MRI requires cooperation of the patient for a prolonged period; it is also considerably

more expensive than CT.

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As noted above, transcranial Doppler can be used to identify patients at risk for stroke

[35-37,39]. It has variable sensitivity for the detection of flow abnormalities due to

prior infarction [11,95]. (See 'Predicting risk' above.)

Magnetic resonance angiography (MRA) can identify vascular disease with accuracy

similar to that of angiography and MRI [11,93,95-97].

Positron emission tomography (PET) can be used to gauge the functional activity of the cerebral tissues and, therefore, microvascular blood flow. PET scanning in

conjunction with MRI may identify a greater number of patients with silent infarcts

than does MRI alone [98].

COGNITIVE AND BEHAVIORAL DYSFUNCTION AND SILENT INFARCTS — Although

numerous studies have been performed, drawing conclusions from cognitive and behavioral

evaluations of children with SCD has been difficult. Among the major limitations are [99]:

Many reports did sibling controls and were, therefore, unable to control for 

socioeconomic, parental, and ethnic variables.

Studies performed prior to the availability of MRI could not identify children with silentinfarcts. Thus, deficits in general intelligence; in academic skills such as reading,

writing, and spelling; and in neuropsychologic functions such as attention,

visuospatial ability, and memory were ascribed to SCD itself in children who had no

history of an overt stroke [100-103].

Results have been considerably diverse among studies of behavioral and psychologic

function because of the use of highly variable assessment measures and

inconsistencies in defining the control group.

MRI has enhanced our understanding of the pathogenesis of these deficits. Although cerebral

infarction in children with SCD is usually symptomatic, 10 to 30 percent have "silent" infarcts

[30,90,91,104-106]; they are less common in Hb SC disease, occurring in 3 percent of patients in one series [90]. Silent infarcts are defined by the presence of T-2 weighted signal

changes on MRI consistent with infarction in patients with a normal neurologic examination

[107-109]. They are more common in patients with a history of seizures [105,110,111].

The importance of silent infarcts on cognitive and behavioral function can be illustrated by the

following observations:

A report from the Cooperative Study of Sickle Cell Disease evaluated 135 children

with MRI and neuropsychologic evaluation [104]. On most measures of 

neuropsychologic evaluation, children with a history of CVA performed significantly

worse than did children with silent infarcts or no MRI abnormality. On tests of 

arithmetic, vocabulary, and visual motor speed and coordination, children with silent

infarcts performed significantly worse than children with no MRI abnormality. Similar 

findings were noted in a smaller series in which children with a silent infarct had

impaired neuropsychologic performance relative to sibling controls or patients without

a stroke [112]. The location of the infarct is the primary determinant of 

neuropsychologic impairment [112-115].

Studies of children without a silent infarct on MRI have revealed cognitive functioning

similar to siblings without SCD [112]. However, measurement of cerebral blood flow

by continuous arterial spin-labeling MRI may identify children with neurocognitive

impairment before damage is evident by structural MRI or TCD [116]. This technique

is not available in many medical centers, and the reproducibility of these findings

needs to be determined.

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These findings suggest that, in the absence of cerebral disease as determined by symptoms

or MRI, no differences in cognitive ability are attributable solely to SCD. However, one study

found that behavioral and psychologic functioning in children with SCD was essentially the

same as that in other children with chronic illnesses [117]. Although the risk is somewhat

increased, only a few children develop frank psychiatric disorders or meet diagnostic criteria

for a depressive disorder [117,118].

To further understand the role of silent infarction on neurocognitive outcomes and on potential

evolution to symptomatic stroke, and to answer the question as to what is the best therapy,

the National Institutes of Health is sponsoring a large multicenter randomized trial (Silent

Infarct Transfusion Study) in children between 6 and 12 years of age. Following screening

and with detection of silent stroke, patients will be randomly assigned to transfusion therapy

or observation for a three-year period [107,119]. Analysis of study candidates at baseline

identified low hemoglobin concentration, high systolic blood pressure, and male gender as

predictors of silent cerebral infarct [108]. There is presently no high level evidence to support

the use of  hydroxyurea or hematopoietic cell transplantation for individuals with sickle cell

disease and silent cerebral infarcts [109].

SUMMARY AND RECOMMENDATIONS 

Cerebrovascular accident (CVA, stroke) is a leading cause of death in children and

adults with sickle cell disease (SCD). The risk of CVA varies by genotype (figure 2).

The risk of having a CVA by age 20 is approximately 11 percent for patients with

SCD; this incidence is more than 300 times higher than that seen in children without

SCD. (See 'Incidence' above.)

Symptoms of infarctive stroke may include hemiparesis, dysphasia, gait

disturbance, and/or a change in level of consciousness. Although patients generally

do not die acutely from infarctive stroke, substantial morbidity may occur. Recurrent

stroke occurs in approximately two-thirds of patients within two years of the initialevent, and is most common in children and adolescents. (See 'Cerebral

infarction' above.)

Transcranial Doppler (TCD) is an important tool in predicting risk for stroke in patients

with SCD, and can detect arterial stenosis at an earlier stage of disease than

magnetic resonance angiography (MRA). It measures the time-averaged mean

velocity of blood flow in the large intracranial vessels, and a focal area of higher 

velocity usually indicates arterial stenosis. In children, a mean velocity

>200 cm/sec in the middle cerebral or internal carotid artery are highly associated

with an increased risk of stroke, even before lesions become evident on magnetic

resonance angiograms (MRA). (See 'Predicting risk' above.)

Children with SCD should be routinely screened with TCD to assess risk for stroke.This is especially valuable in young children. In our practice, we screen patients

annually after age two. If the TCD velocity is between 170 and 200 cm/sec in the

internal carotid or middle cerebral artery, we re-screen in three months; if the TCD is

≥200 cm/sec, we rescreen in two to four weeks. (See 'Recommendation' above.)

We recommend that all children with a mean velocity ≥200 cm/sec on two TCD

studies within a two to four-week period be treated with a stroke prevention protocol

utilizing prophylactic transfusion, rather than no treatment (Grade 1A). Once a patient

has entered a prophylactic transfusion program, it should usually be continued

indefinitely unless other preventive measures are taken, because the risk of stroke

returns if transfusions are stopped. Complications of chronic transfusion therapy

include iron overload and alloimmunization. (See 'Recommendation' aboveand 'Chronic transfusion therapy' above and 'Stopping transfusion' above.)

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Because of high recurrence risks, we recommend intervention to reduce the risk of 

recurrence in any patient with SCD who has had a stroke. For initial treatment,

exchange transfusion is typically used with a goal of achieving a HbS fraction of <30

percent and a hemoglobin level of approximately but no greater than 10 gm/dL.After 

the acute episode, we recommend chronic transfusion therapy rather than no

treatment (Grade 1A). (See 'Chronic transfusion therapy' above.) For those with iron overload as the result of chronic transfusion therapy, we

recommend continuation of chronic transfusion along with iron chelation rather than

treatment with hydroxyurea plus phlebotomy (Grade 1B). (See 'SWiTCH trial' above.)

Intracranial hemorrhage (ICH), also called hemorrhagic stroke in this setting,

accounts for approximately one-third of cerebrovascular events in patients with SCD.

It is most common among young adults and has a high mortality rate. Presenting

features of ICH include severe headache, vomiting, stiff neck, and alterations in

consciousness. Coma and seizures in the absence of hemiparesis strongly suggest

ICH. (See 'Intracranial hemorrhage' above and 'Clinical manifestations and

evaluation' above.)

The majority of cases of ICH represent subarachnoid hemorrhage resulting from therupture of one or more aneurysms. Treatment of subarachnoid hemorrhage in

children with SCD consists of nonaggressive hydration and, as in other patients with

this disorder, nimodipine to minimize the incidence of vasospasm, surgery (eg, clip

ligation) if aneurisms are identified by angiography, and treatment of vasospasm

should it occur after surgery. (See 'Subarachnoid hemorrhage' above.)

Intraventricular hemorrhage (IVH) may be associated with rupture of anterior cerebral

artery aneurysms or direct extension of intraparenchymal hemorrhage into the lateral

or third ventricle. IVH may cause obstructive hydrocephalus and ventricular dilation,

which may present with sudden neurologic deterioration two or more days after an

initial hemorrhagic event. (See 'Intraventricular hemorrhage' above.)

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