Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease

INTRODUCTION — Stroke is a common and devastating manifestation of sickle cell disease (SCD) that can affect children and adults. This topic discusses assessment and treatment of acute stroke in children and adults with SCD.

Risk stratification and stroke prevention are presented separately. (See "Prevention of stroke (initial or recurrent) in sickle cell disease".)

PRESENTATION

Stroke subtypes

●Ischemic stroke – Central nervous system ischemia is defined as brain, spinal cord, or retinal cell death attributable to ischemia; ischemic stroke is defined as brain infarction accompanied by sudden onset of overt stroke symptoms.

●Hemorrhagic stroke – Represents one-third of acute neurologic events in patients with SCD.

•ICH – Intracerebral hemorrhage (ICH) involves bleeding directly into the brain parenchyma and formation of hematoma.

•IVH – Intraventricular hemorrhage (IVH) involves bleeding into the ventricles, excluding IVH in preterm infants.

•SAH – Subarachnoid hemorrhage (SAH) involves bleeding that occurs directly into the subarachnoid space under arterial pressure. The blood spreads quickly within the cerebrospinal fluid (CSF), leading to a rapid increase in intracranial pressure.

When to suspect — Acute ischemic stroke due to vaso-occlusion in cerebral vessels is the first consideration in a patient with SCD who presents with new neurologic findings or severe headache. However, it is important not to overlook other potential causes of neurologic deterioration. (See 'Differential diagnoses' below.)

Presenting features may suggest certain stroke subtypes or stroke mimics, though no clinical features are pathognomonic for distinguishing among types of stroke:

●Ischemic stroke – Infants may present with focal weakness but are more likely than older children to present with seizures and altered mental status. Older children usually have hemiparesis or other focal neurologic signs such as aphasia, or visual disturbance; other symptoms may include seizures, headache, and lethargy. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors" and "Overview of the evaluation of stroke".)

The most common locations for an acute ischemic stroke in patients with SCD include large vessel territories and borderzone regions (figure 1). Hemorrhagic transformation of infarcts can occur in these sites [1].

●Transient ischemic attack (TIA) – Stroke symptoms or signs lasting <24 hours have been historically defined as a TIA. However, when appropriate neuroimaging is completed, up to 33 percent of patients with stroke symptoms lasting <24 hours are found to have an infarct [2]. In a small study in children with TIA, 16 percent had infarcts on follow-up magnetic resonance imaging (MRI) [3]. This has led to a tissue-based definition of TIA as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction on neuroimaging [4]. (See "Definition, etiology, and clinical manifestations of transient ischemic attack".)

During a TIA or acute ischemic infarct, blood transfusion may hasten recovery to baseline. The traditional threshold for distinguishing stroke from TIA is therefore somewhat arbitrary.

●Cerebral venous thrombosis – Cerebral venous thrombosis (CVT; also called cerebral venous sinus thrombosis [CVST]) has a highly variable presentation, since there may be associated brain swelling, edema, venous infarction, or hemorrhagic venous infarction caused by venous occlusion. The onset can be acute, subacute, or chronic.

Headache (of gradual, acute, or thunderclap onset) is the most frequent symptom and may occur as part of an isolated intracranial hypertension syndrome, with or without vomiting, papilledema, and visual problems. In other cases, headache may be accompanied by focal neurologic deficits, focal or generalized seizures, papilledema, and encephalopathy with altered mental status or coma. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".)

●ICH – The presentation of ICH depends primarily on the size of the hematoma, anatomic location, and whether the hemorrhage extends into the ventricles. Typical findings include rapid onset of neurologic dysfunction and signs of increased intracranial pressure such as headache, vomiting, and decreased level of consciousness. For patients with large volume hemorrhage, stupor or coma is typical. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".)

●SAH – The primary symptom of aneurysmal SAH is a sudden, severe headache, which may or may not be associated with a brief loss of consciousness, nausea or vomiting, and meningismus. Restricted SAH may manifest with transient motor or sensory symptoms that suggest epileptic phenomena and/or frank seizures. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Nonaneurysmal subarachnoid hemorrhage".)

Age may be somewhat helpful for predicting the ultimate diagnosis. Ischemic stroke is more common than hemorrhagic stroke in children and adolescents with SCD. Hemorrhagic stroke is more common than ischemic stroke in adults with SCD [1]. TIA is rare in children. However, individuals of all ages with SCD may have any of these diagnoses.

The epidemiology of stroke in SCD, which may differ according to the age of the patient, is discussed separately. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Incidence'.)

Differential diagnoses — The following alternative diagnoses warrant consideration [1]:

●Infection, including acute meningitis, brain abscess, meningoencephalitis, or cerebral malaria (in endemic areas)

●Seizure, particularly when associated with prolonged postictal paralysis (Todd paralysis)

●Migraine (especially hemiplegic migraine)

●Tumors and other structural brain lesions

●Alternating hemiplegia of childhood

●Posterior reversible leukoencephalopathy syndrome (PRES)

●Metabolic derangements

●Demyelinating conditions such as acute disseminated encephalomyelitis (ADEM)

●Idiopathic intracranial hypertension

●Drug toxicity, including opioid overdose for patients on chronic opioid therapy

●Musculoskeletal conditions

●Psychogenic conditions

Distinguishing characteristics and laboratory findings are discussed separately. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Differential diagnosis' and "Differential diagnosis of transient ischemic attack and acute stroke".)

IMMEDIATE EVALUATION AND MANAGEMENT

Evaluation and treatment proceed in parallel — Initial stabilization with a rapid clinical assessment should occur simultaneously with prompt simple transfusion and neuroimaging to differentiate ischemia from hemorrhage and to exclude stroke mimics. In practice, this means that labs required for transfusion are sent while rapid neuroimaging is requested (algorithm 1).

Initial stabilization — All patients with SCD and possible stroke should have [1,5]:

●Immediate assessment by clinicians with expertise in stroke and SCD management, typically from the neurology and hematology services.

●Monitoring of oxygen saturation.

●Supplemental oxygen to maintain saturation >95 percent.

●Airway protection from aspiration.

●Baseline laboratory testing. (See 'Laboratory and other testing' below.)

●Urgent simple transfusion to reduce the percent sickle hemoglobin and to raise the hemoglobin to approximately 10 g/dL, but not higher. (See 'Simple transfusion for all patients' below and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

●Brain imaging. (See 'Neuroimaging' below.)

●Precautions to minimize crying and hyperventilation (treat pain, minimize the number of medical personnel in the room, have a parent or caregiver keep the patient calm). In some patients, crying and hyperventilation can lower the PaCO₂ and thereby induce or worsen cerebral ischemia by causing vasoconstriction.

●Avoidance of hypotension, hypovolemia, hyperthermia, hyperglycemia, and hypocarbia.

●Intravenous hydration with isotonic fluids, typically at the normal maintenance rate, holding fluids during transfusion. Volume depletion should be avoided, but fluid overload can contribute to hypertension and pulmonary edema.

●Blood pressure control. (See "Initial assessment and management of acute stroke", section on 'Blood pressure management'.)

●Identification and treatment of concurrent infection, with antipyretics if fever is present.

●Management of seizures if present.

●Intensive monitoring and care in a dedicated stroke unit when possible.

Management of acute stroke in SCD requires specialized expertise in exchange transfusion. Transfer to another facility may be required if needed to provide access to exchange transfusion. (See 'Exchange transfusion' below.)

Oxygenation and treatment of infection can reduce sickling, which could further worsen cerebral ischemia and other vaso-occlusive complications. Maximizing cerebral perfusion, ventilation, and normoglycemia is also critical. Hydration with normal saline rather than hypotonic saline will avoid the potential worsening of cerebral edema; excessive fluids should be avoided. (See "Initial assessment and management of acute stroke" and "Ischemic stroke in children: Management and prognosis", section on 'Initial management'.)

Patients with fever — Fever can occur with infection (meningitis, acute chest syndrome, sepsis) or with stroke in the absence of infection. Distinguishing between these is critical. Individuals with SCD are immunocompromised due to functional asplenia and are at high risk of sepsis from encapsulated organisms. Prompt institution of broad-spectrum antibiotics may be lifesaving. All patients with SCD who present with fever and acute neurologic findings should be treated presumptively for a bacterial infection until this possibility is eliminated, unless there is a good rationale not to do so. (See "Evaluation and management of fever in children and adults with sickle cell disease".)

Laboratory and other testing — Laboratory testing should include [1]:

●Complete blood count (CBC)

●Reticulocyte count

●Type and crossmatch for transfusion

●Percent hemoglobin S, to facilitate exchange transfusion

●Prothrombin time (PT) and activated partial thromboplastin time (aPTT)

●Basic metabolic profile with electrolytes, urea nitrogen, creatinine, and glucose

●Blood cultures if fever is present

The role of these studies is discussed in more detail separately. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis".)

Simple transfusion for all patients — Red blood cell (RBC) transfusion is the cornerstone of treatment for acute ischemic stroke because it treats anemia and lowers the percent sickle hemoglobin. The role in acute hemorrhagic stroke is less clear; however, simple transfusion is recommended for all patients. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Indications for transfusion'.)

Simple transfusion is a temporizing measure until exchange transfusion can be performed. Exchange transfusion is much more effective at lowering the percent hemoglobin S while avoiding hyperviscosity. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Risk of hyperviscosity syndrome from simple transfusion'.)

If clinical suspicion for an acute stroke is high and the patient's hemoglobin level is ≤8.5 g/dL, a simple transfusion should be given rapidly, within two hours of clinical presentation. Raising the hemoglobin to 10 g/dL also facilitates sedation for neuroimaging and central venous catheter placement if necessary. Overtransfusion (to hemoglobin >10 g/dL) is avoided since it may cause hyperviscosity, which decreases oxygen delivery.

If the hemoglobin level is <5 g/dL, it can be raised to 10 g/dL with sequential simple transfusions of 5 to 10 mL/kg, and the hemoglobin S concentration can then be determined to assess the need for exchange transfusion.

Neuroimaging — Neuroimaging (brain and neurovascular) is critical for all patients with suspected stroke in order to:

●Differentiate ischemia from hemorrhage

●Exclude stroke mimics, such as tumor

●Assess the status of large cervical and intracranial arteries

The major management implication of the distinction between ischemia and hemorrhage is in helping to decide whether urgent exchange transfusion is appropriate. Urgent exchange transfusion is indicated for patients with acute ischemic stroke, TIA, and/or hemorrhagic transformation of an acute ischemic stroke. The role of exchange transfusion in the management of hemorrhagic stroke is less clear.

Imaging methods are reviewed here briefly and presented separately. (See "Neuroimaging of acute stroke".)

●MRI versus CT – Brain magnetic resonance imaging (MRI) is preferred if it can be obtained rapidly. Brain MRI is more sensitive for acute ischemia than computed tomography (CT), particularly with diffusion-weighted imaging (DWI) in the hyperacute time period. Brain MRI provides better visualization of the posterior fossa and detects intracerebral hemorrhage (ICH) with good sensitivity using high susceptibility sequences.

Limitations of MRI include availability and cost. Young children and other individuals who cannot cooperate with lying still may require sedation for MRI, which carries additional risks and costs. Head CT typically takes <5 minutes and thus is easier to obtain, and unenhanced CT has a high sensitivity for hemorrhage. However, CT is a source of radiation exposure.

•Children – Head CT is generally not considered adequate to diagnose ischemic stroke; MRI may be required to reliably exclude stroke mimics. CT should be used if MRI is not rapidly available or if a child is not stable for (or cannot tolerate) MRI. If CT is unrevealing, MRI can be obtained once the patient is stabilized [1].

•Adults – Either CT or MRI may be used as the initial study. Brain MRI with DWI is typically preferred if available because it is more sensitive for acute ischemic stroke. For older adults with risk factors for embolic stroke such as atrial fibrillation, head CT with CT angiography (CTA) of the head and neck will rapidly diagnose large vessel occlusion. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Brain imaging' and "Neuroimaging of acute stroke".)

Given these considerations, the imaging approach and local institutional practices may vary.

●MRA and CTA – Magnetic resonance angiography (MRA) or CTA should be obtained in all adults and children with acute stroke to evaluate large vessel arteriopathy (large vessel stenosis, dissection, moyamoya, atherosclerosis) and to exclude aneurysm. In a patient whose clinical picture is not concerning for arterial dissection or aneurysm, vascular imaging can be deferred until after the patient has been stabilized.

●MRV – Brain MRI with magnetic resonance venography (MRV) is the most sensitive technique for demonstrating cerebral venous sinus thrombosis (CVST). Some experts recommend obtaining MRV with the initial MRI to reduce the likelihood of missing a cerebral venous thrombosis (CVT), particularly those with altered mental status and headache [1].

Clinical features and evaluation for CVST are presented separately. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Neuroimaging'.)

●Lack of access to imaging – A large portion of the world's SCD population may not have immediate access to neuroimaging. For these individuals, it is necessary to make a presumptive diagnosis of stroke based on clinical features alone, as discussed separately. (See "Sickle cell disease in sub-Saharan Africa", section on 'Stroke'.)

Supportive care

●Venous thromboembolism (VTE) prophylaxis – Prophylaxis for deep venous thrombosis and pulmonary embolism is indicated for patients with acute stroke who have restricted mobility or other risk factors for VTE, such as an indwelling central venous catheter, significant inflammation, or high body mass index. VTE prophylaxis in younger children is determined on a case-by-case basis; sequential compression devices may be preferred to anticoagulation in some children. (See "Prevention and treatment of venous thromboembolism in patients with acute stroke".)

●Swallowing assessment – Dysphagia is common after stroke and is a major risk factor for developing aspiration pneumonia. Swallowing function should be assessed prior to administering oral medications or food. Nothing should be administered orally until swallowing function is evaluated. (See "Complications of stroke: An overview", section on 'Dysphagia'.)

TIA AND ISCHEMIC STROKE MANAGEMENT

Transfusion — For patients with SCD who have a clinically and/or radiologically confirmed acute ischemic stroke or TIA, we suggest exchange transfusion (algorithm 1).

Goals — The goals of transfusion in ischemic stroke are:

●Lower the percentage of sickle hemoglobin to <30 percent of total hemoglobin (typically 15 to 20 percent).

●Aim for a total hemoglobin of approximately 10 g/dL.

This is best achieved using exchange transfusion. However, it takes time to mobilize resources and possibly transfer to another facility for exchange transfusion. When exchange transfusion is not available within two hours of presentation and the hemoglobin is ≤8.5 g/dL, simple transfusion can be performed, with careful estimation of the transfusion volume so as not to raise the post-transfusion hemoglobin above 10 g/dL, often while awaiting the results of the clinical assessment and neuroimaging and possibly the placement of an apheresis catheter. (See 'Immediate evaluation and management' above.)

Exchange transfusion

●Rationale – We use exchange transfusion rather than simple transfusion alone or other interventions for children and adults with SCD who have confirmed ischemic stroke or TIA. The rationale is that reducing the percentage of hemoglobin S decreases vaso-occlusion and further ischemia, and that children who have early exchange transfusion have a lower rate of recurrent stroke compared with those who receive only simple transfusion [6].

A high percentage of adults with TIA have an ischemic stroke within seven days, and exchange transfusion is protective [7].

Simple transfusion cannot provide a sufficient volume of allogeneic red blood cells (RBCs) to lower the percentage of hemoglobin S sufficiently without causing hyperviscosity or transfusion-associated circulatory overload.

●Procedure – Exchange transfusion involves a type of apheresis (erythrocytapheresis) in which blood removed from the patient is depleted of RBCs, reconstituted with donor RBCs, and retransfused in a continuous circuit. This procedure typically requires placement of a double-lumen apheresis catheter. If equipment for automated exchange is not available, manual exchange can be performed. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Exchange blood transfusion'.)

A single exchange transfusion is usually sufficient to lower the hemoglobin S concentration to the desired level. The apheresis catheter can be removed after the exchange transfusion is completed unless it is absolutely required for venous access.

Total hemoglobin and percent hemoglobin S are monitored during the exchange. The usual post-transfusion targets are:

•Total hemoglobin approximately 10 g/dL (not higher)

•Hemoglobin S <30 percent of total hemoglobin (target, 15 to 20 percent)

This should maintain the hemoglobin S concentration <30 percent of total hemoglobin for two to four weeks until another transfusion is needed. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Exchange blood transfusion'.)

●Supporting evidence – There are no randomized trials comparing exchange transfusion with simple transfusion or other interventions for acute stroke in SCD.

Evidence for the benefit of transfusion in patients with SCD and acute stroke includes our clinical experience and studies revealing improved cerebral perfusion with transfusion [8,9]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Mechanisms'.)

Evidence for the superiority of exchange transfusion in secondary prevention (reducing the risk of stroke recurrence) includes a 2006 retrospective study of 137 children with SCD and acute stroke [6]. For the 52 patients who presented within 24 hours of onset of initial stroke symptom for whom treatment information was available, second strokes were more likely in those who received simple transfusions (8 of 14 patients [57 percent]) compared with those who were treated with exchange transfusions (8 of 38 patients [21 percent]; RR 5.0, 95% CI 1.3-18.6), despite similar baseline risk factors.

Our approach is consistent with a 2014 consensus report on SCD management from the National Heart, Lung, and Blood Institute (NHLBI) in the United States [10,11], and with 2020 guidelines from the American Society of Hematology [5].

Additional information on risks and benefits of simple versus exchange transfusion are presented separately. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

Reperfusion therapy — Reperfusion therapy (intravenous thrombolysis with tissue plasminogen activator [tPA] and/or mechanical thrombectomy) for acute ischemic stroke associated with SCD is controversial, and data are sparse.

For adults with a high likelihood of a non-SCD-related cause of ischemic stroke, such as embolism in the setting of atrial fibrillation or large artery stenosis or occlusion, it is logical to consider reperfusion therapies unless there is a strong reason not to do so (algorithm 1). Patients most likely to benefit are older adults with conventional stroke risk factors such as hypertension, diabetes, hyperlipidemia, and/or atrial fibrillation [12].

●Intravenous thrombolysis – Adults with SCD presenting with symptoms of acute ischemic stroke should be considered for intravenous tPA (algorithm 2) [5]. They should meet typical criteria:

•Age ≥ 18 years

•No hemorrhage on brain imaging

•Within 4.5 hours of stroke symptom onset

•No contraindications for thrombolysis

Full inclusion and exclusion criteria are listed in the table (table 1).

For children <18 years with SCD, intravenous tPA is not recommended [5].

There is a concern that the use of thrombolytic agents could precipitate intracranial hemorrhage (ICH) at a higher rate in individuals with SCD. However, the risk of ICH in SCD appears to be due to an increased prevalence of aneurysm rather than increased bleeding tendency specific to SCD. Thus, SCD is not an exclusion criterion for tPA treatment of adults with ischemic stroke. An observational study using administrative data to compare 832 adults with stroke and SCD versus 3328 adults with stroke who did not have SCD found no difference in the percentage treated with thrombolytic therapy (8.2 versus 9.4 percent) or in the incidence of symptomatic ICH complicating thrombolysis (4.9 versus 3.2 percent) [13]. Thrombolysis was felt to be safe; however, the effect on functional outcomes was not reported.

Administration of tPA should not replace or delay typical SCD-related acute stroke care, specifically simple blood transfusion [5]. Since tPA guidelines require the placement of two intravenous lines, tPA infusion and transfusion could be concurrent. Importantly, the apheresis catheter for exchange transfusion must be placed before tPA is administered. Older adults with typical stroke risk factors such as atrial fibrillation, diabetes, hypertension, or hyperlipidemia may be viewed as more likely to benefit from tPA than younger adults without these risk factors [5,12]. Moyamoya disease is a relative contraindication to tPA. (See 'Moyamoya syndrome' below.)

●Mechanical thrombectomy (MT) – MT is not well-studied for the treatment of stroke in patients with SCD [5]. In the general population, mechanical thrombectomy is indicated for patients with acute ischemic stroke due to a large artery occlusion in the anterior circulation who meet eligibility criteria and can be treated within 24 hours of the time last known to be at their neurologic baseline (last time known well), regardless of whether they receive intravenous thrombolysis for the same ischemic stroke event. (See "Mechanical thrombectomy for acute ischemic stroke".)

Patient selection for MT is reviewed in the figure (algorithm 3) and discussed separately. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.)

Patients and their families/caregivers must be counseled about the limited evidence for reperfusion therapies in SCD [5,12,14]. These therapies should only be used in centers with significant experience and in consultation with the appropriate specialists from neurology, hematology, and interventional radiology. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".)

Evaluation for the cause — Additional evaluation for causes of ischemic stroke and TIA other than vaso-occlusive vasculopathy may be appropriate in select cases, particularly in adults with typical stroke risk factors. (See "Overview of the evaluation of stroke".)

These may include:

●Cardioembolic sources such as atrial fibrillation or patent foramen ovale (PFO)

●Vasospasm in association with drug use (eg, from cocaine or amphetamines)

●Vascular disease associated with hypercholesterolemia or diabetes

Appropriate history, brain and blood vessel imaging, cardiac monitoring, echocardiography, and laboratory testing (fasting lipids, hemoglobin A1c) are essential for the evaluation for these risk factors

In principle, any of these conditions could affect patients of any age. However, their likelihood is age-dependent. Additional information on possible etiologies and evaluation in children is presented separately.

●Newborns (see "Stroke in the newborn: Classification, manifestations, and diagnosis" and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis")

●Children (see "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors" and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis")

Other rare stroke mimics must be considered if the initial evaluation and imaging do not reveal a cause. (See 'Differential diagnoses' above and "Differential diagnosis of transient ischemic attack and acute stroke".)

Treatment for specific causes

Moyamoya syndrome — For patients with moyamoya syndrome (bilateral or unilateral internal carotid artery stenosis with prominent collateral vessels) and acute stroke, acute treatment is mainly symptomatic and directed towards improving cerebral blood flow with fluids and transfusion and controlling seizures. In moyamoya disease, tPA should not be used due to the increased risk of bleeding.

Some clinicians start antiplatelet therapy for children and adults with moyamoya syndrome; however, evidence is lacking for prevention of infarct recurrence. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis".)

Cerebral venous thrombosis — The main treatment for symptomatic cerebral venous thrombosis (CVT, also called central venous sinus thrombosis [CVST]) is anticoagulation with heparin (unfractionated or low molecular weight [LMW] heparin).

Hemorrhagic venous infarction, intracerebral hemorrhage (ICH), or isolated subarachnoid hemorrhage (SAH) are not contraindications to anticoagulation in CVT, including in patients with SCD [1]. (See "Cerebral venous thrombosis: Treatment and prognosis".)

Testing for hypercoagulable conditions and COVID-19 is appropriate when CVT is found. (See "Overview of the causes of venous thrombosis" and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

Other causes — Other defined traditional stroke mechanisms may be present in patients with SCD. Management is reviewed separately:

●Small vessel disease – (see "Lacunar infarcts")

●Large vessel atherosclerosis – (see "Management of symptomatic carotid atherosclerotic disease" and "Intracranial large artery atherosclerosis: Treatment and prognosis")

●Cardiogenic embolism – (see "Stroke in patients with atrial fibrillation")

Role of antiplatelet agents and anticoagulation

●Antiplatelet agents – The efficacy of antiplatelet agents has not been studied for acute treatment or secondary prevention of SCD-associated TIA or ischemic stroke in children or adults [15].

In the general population, aspirin or short-term dual antiplatelet therapy (DAPT) are indicated for most adults with acute TIA or acute ischemic stroke, and antiplatelet therapy may be appropriate for adults with SCD who have an acute TIA or ischemic stroke, particularly if they have traditional stroke risk factors, especially intracranial atherosclerosis. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".)

Antiplatelet therapy may also be appropriate for secondary stroke prevention in adults with SCD who have traditional stroke risk factors, similar to the general population [16]. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".)

●Anticoagulation – We generally do not use anticoagulation for ischemic stroke in patients with SCD. However, SCD is a hypercoagulable state, and prophylactic dose anticoagulation may be appropriate for venous thromboembolism (VTE) prophylaxis in those admitted with an acute medical illness, especially adults and those with decreased mobility. (See 'Supportive care' above and "Prevention and treatment of venous thromboembolism in patients with acute stroke".)

Anticoagulation may be appropriate for:

•CVT (see "Cerebral venous thrombosis: Treatment and prognosis")

•Increased probability of thromboembolic disease, after the immediate risk of hemorrhagic conversion has receded (see "Stroke in patients with atrial fibrillation" and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome")

Administration and adverse events are discussed separately. (See "Venous thromboembolism: Initiation of anticoagulation" and "Venous thromboembolism: Anticoagulation after initial management".)

INTRACRANIAL HEMORRHAGE MANAGEMENT — Intracranial hemorrhage (ICH), also called hemorrhagic stroke, accounts for approximately one-third of cerebrovascular events in patients with SCD and is more common in older individuals [17]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Incidence' and "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Risk factors: Hemorrhagic stroke'.)

Urgent interventions — In addition to acute stabilization of the patient as described above (see 'Immediate evaluation and management' above), the following should be done immediately (algorithm 1):

●Discontinue all anticoagulants and antiplatelet agents, unless the benefits of continuing are thought to outweigh their risks for that patient, such as in the setting of CVST and hemorrhagic venous infarction or a prosthetic heart valve where anticoagulation might be held briefly for stabilization and then restarted.

●For patients receiving an anticoagulant, decide whether a reversal agent is needed. For those who have received a short-acting anticoagulant for which several half-lives have passed, reversal may not be required.

●For patients with thrombocytopenia, administer platelet transfusions as necessary to maintain the platelet count ≥100,000/microL.

●Obtain neurosurgical consultation if a procedure may be required to reduce intracranial pressure or to treat a bleeding aneurysm.

●Obtain imaging such as CT- or MR-angiography to guide further therapy in most cases.

Management of ICH and subarachnoid hemorrhage (SAH) in the general population is discussed separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Nonaneurysmal subarachnoid hemorrhage".)

Additional therapy according to type of bleed

●Hemorrhagic transformation of arterial ischemic stroke– Hemorrhagic transformation of an ischemic stroke should be managed as with other causes of hemorrhagic stroke, including stopping and reversing any anticoagulation, correcting any coagulopathy, and transfusing platelets as needed. Transfusion is appropriate. (See 'Transfusion' above.)

●Cerebral venous sinus thrombosis (CVST) – Management is similar to individuals without SCD. (See "Cerebral venous thrombosis: Treatment and prognosis".)

●SAH from aneurysmal bleeding – Initial treatment of SAH includes intensive care monitoring, analgesia, and close attention to blood pressure control; as well as ventriculostomy for those with increased intracranial pressure. Aneurysm repair should be attempted if possible. Details are presented separately. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Treatment of cerebral aneurysms" and "Nonaneurysmal subarachnoid hemorrhage".)

Patients with SAH who are undergoing surgery should have exchange transfusion if possible prior to surgery, to reduce sickle hemoglobin to <30 percent of total hemoglobin; ideally surgery is performed within a week of exchange transfusion. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Prophylactic preoperative transfusion'.)

●Intraventricular hemorrhage (IVH) – IVH may occur when subarachnoid or intraparenchymal hemorrhage extends into the ventricles [18]. Patients with prior ischemic stroke may be at risk for IVH and intraparenchymal hemorrhage, even months to years later [19].

Hemorrhage into the third ventricle or cerebral aqueduct confers a high risk for late deterioration. Patients may be awake and alert immediately following the bleed and become comatose over the ensuing 48 hours because of obstructive hydrocephalus and ventricular dilation. Emergency ventricular drainage may be necessary [20]. Management is discussed separately. (See "Intraventricular hemorrhage".)

Despite these interventions, mortality from ICH in SCD is as high as 24 to 30 percent [14,17]. Deaths generally occur within the first two weeks, many on the first day [17]. Some individuals have moderate to severe residual disability [21].

FOLLOW-UP AFTER THE ACUTE EVENT

●Repeat imaging – If the initial magnetic resonance imaging (MRI) study does not show ischemic injury and clinically the patient seemed to have a stroke or transient ischemic attack (TIA), we perform a repeat MRI of the brain two to four weeks after the initial presentation, since diffusion weighted images of the brain may rarely be negative upon presentation and may still demonstrate very small areas of ischemic injury upon subsequent imaging [22].

●Secondary stroke prevention – Secondary stroke prevention is critical, typically involving chronic transfusions. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of recurrent ischemic stroke (secondary stroke prophylaxis)' and "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of hemorrhagic strokes'.)

●Cognitive or behavioral dysfunction – (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Management of cognitive and behavioral dysfunction'.)

●Motor deficits – (See "Overview of geriatric rehabilitation: Patient assessment and common indications for rehabilitation", section on 'Stroke' and "Overview of ischemic stroke prognosis in adults", section on 'Interventions that improve outcomes'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias" and "Society guideline links: Stroke in children".)

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY AND RECOMMENDATIONS

●Presentation – Acute ischemic stroke due to cerebral vaso-occlusion is the first consideration in patients with sickle cell disease (SCD) who present with new neurologic findings or severe headache. Hemorrhagic stroke accounts for one-third of events. It is important not to overlook other potential causes of neurologic deterioration, including transient ischemic attack (TIA), cerebral venous thrombosis (CVT), seizure, infection, and other stroke mimics. (See 'Presentation' above.)

●Immediate measures – Management involves initial stabilization by clinicians with expertise in stroke and SCD, supplemental oxygen to maintain saturation >95 percent, rapid clinical assessment and baseline laboratory testing, and simple transfusion, followed by neuroimaging (algorithm 1). Patients with fever should receive empiric broad-spectrum antibiotics and antipyretics. (See 'Immediate evaluation and management' above.)

•Neuroimaging – Brain and neurovascular imaging is essential to differentiate ischemia from hemorrhage, exclude stroke mimics, and assess large cervical and intracranial arteries. Magnetic resonance imaging (MRI) is generally preferred. (See 'Neuroimaging' above.)

•Transfusion – For patients with SCD who have a suspected or confirmed stroke (ischemic or hemorrhagic) or TIA, we suggest exchange transfusion (Grade 2C). The goal is to lower the percentage of sickle hemoglobin to <30 percent of total hemoglobin (typically to 15 to 20 percent) without raising the total hemoglobin >10 g/dL and causing hyperviscosity. Simple transfusion is used as a temporizing measure until exchange transfusion can be instituted. (See 'Transfusion' above.)

•Reperfusion – Adults with SCD and acute ischemic stroke should be evaluated for intravenous thrombolysis and mechanical thrombectomy. (See 'Reperfusion therapy' above.)

●Mechanism-specific treatment – The following is appropriate in addition to immediate assessment, stabilization, and other standard acute stroke management (algorithm 1):

•Ischemic stroke or TIA – Antiplatelet therapy may be appropriate for adults with SCD who have an acute TIA or ischemic stroke, particularly if they have traditional stroke risk factors. (See 'Role of antiplatelet agents and anticoagulation' above.)

•Intracranial hemorrhage – Neurosurgical evaluation and angiography to guide therapy. Additional interventions for specific types of hemorrhagic stroke are discussed above. (See 'Intracranial hemorrhage management' above.)

•Moyamoya syndrome – Some clinicians start antiplatelet therapy. (See 'Moyamoya syndrome' above.)

•CVT – Heparin anticoagulation, even if hemorrhagic transformation occurs. (See 'Cerebral venous thrombosis' above.)

●Follow-up – Secondary stroke prevention is critical. Repeat imaging, cognitive assistance, and rehabilitation services may be appropriate. (See 'Follow-up after the acute event' above.)

ACKNOWLEDGMENTS

UpToDate acknowledges ZoAnn Dreyer, MD, who contributed to earlier versions of this topic review.

The UpToDate editorial staff also acknowledge the extensive contributions of Donald H Mahoney, Jr, MD, to earlier versions of this topic review.