Table of Contents
Patients, Families and Friends
Health Care Providers
|TREATMENT OF ACUTE AND CHRONIC COMPLICATIONS - Chapter 13. Stroke and Central Nervous System Disease|
|Health Care Providers - The Management of Sickle Cell Disease, 4th ed.|
NIH Publication No. 02-2117. Revised May28, 2002 (Forth Edition) National Institutes of Health, National Heart, Lung, and Blood Institute. Download the entire PDF file for Adobe
STROKE AND CENTRAL NERVOUS SYSTEM DISEASE
Stroke is one of the major complications of sickle cell disease (SCD). The Cooperative Study of Sickle Cell Disease (CSSCD) showed that the prevalence and incidence of stroke in patients with SCD-SS was four times that of those with SCD-SC (1). Because of this difference in risk, and because most of the available data are from patients with SCD-SS, screening of neurologically asymptomatic patients and primary stroke prevention recommendations pertain to those with SCD-SS, not SCD-SC. (See figures1,2 and 3)
Recommendations for treatment of symptomatic patients and secondary prevention pertain to all SCD patients. Children with SCD may have a variety of anatomic and physiologic abnormalities involving the central nervous system (CNS) even if they appear to be neurologically "normal" (2). The abnormalities may be associated with deterioration in cognitive function with effects on learning and behavior and may increase the risk for clinical and subclinical damage to the CNS in the future.
The approach to management depends on the specific brain manifestation of interest and the age of the patient. Therefore, this chapter is divided into sections based on the major CNS concerns of children and adults.
STROKE AND CENTRAL NERVOUS SYSTEM DISEASE IN CHILDREN
TRANSIENT ISCHEMIC ATTACK (TIA) AND BRAIN INFARCTION
Brain dysfunction occurs when oxygen supply to the brain falls below a critical level based on need. Symptoms of brain ischemia include hemiparesis; visual and language disturbances; seizures (especially focal seizures); and altered sensation, mentation, and alertness. There is evidence that oxygen demands are higher in children than in adults, making the child with SCD who also has significant anemia at particular risk.
As soon as brain ischemia is suspected, a prompt and thorough evaluation and consideration for therapy is recommended (figure 1). After initial stabilization and evaluation, patients should receive urgent noncontrast computed tomography (CT) scan of the brain to rule out hemorrhage or other nonischemic etiologies. Consideration should be given to the possibility that the symptoms are due to CNS infection, trauma (e.g., subdural hematoma), or intoxication—particularly if focal signs arenot prominent.
In the acute stage of ischemic stroke for the general non-SCD adult population, the only approved therapy is recombinant tissue plasminogen activator (t-PA) if given within 3 hours (3), but there are no data establishing its use in children with SCD where the pathophysiology may differ completely. Therefore, it is not recommended.
The usual treatment for pediatric patients in the acute stage of ischemic stroke is hydration with transfusion, although there are no controlled treatment studies. Exchange transfusion is preferred, as it avoids the theoretical risk of increasing blood viscosity that may accompany rapid elevations in hematocrit, but care must be taken to avoid hypotension that may worsen cerebral ischemia (4). Because fever increases cerebral metabolism, any degree of hyperthermia should be treated. Hypothermia to treat stroke is promising but not supported by data adequate to form a recommendation.
Acute treatment in an intensive care unit (ICU) or stroke unit will facilitate close observation and treatment. Seizures should be treated, but prophylactic therapy or corticosteroids are not recommended. Hypoxemia and hypotension should be treated and normoglycemia maintained. There are no proven neuroprotective therapies as yet to lessen damage or promote recovery.
In early ischemia (less than 3 hours), the cranial CT may be negative or show only subtle signs. Magnetic resonance imaging (MRI) provides better detail of the areas of ischemia, and diffusion weighted imaging (DWI) shows hyperintense areas of brain ischemia within minutes after onset of severe ischemia. Unless the diagnosis is in doubt, MRI should be deferred until treatment has been initiated. Evaluation within the first hours to days with MRI is recommended, because MRI-based studies provide significant additional information, such as the ability to detect very early and sometimes clinically silent acute lesions with DWI, prior infarction that may not be seen on CT, and imaging of the arteries by magnetic resonance angiography (MRA), which may show large vessel occlusive disease (5) or aneurysms. EEG is recommended only if there is a clinical suspicion of seizure.
In the subacute phase, evaluations should be undertaken to make a final determination of the cause. In many cases, evaluation of the intracranial vessels will show occlusive vasculopathy characteristic of SCD. Even though intracranial arterial vasculopathy is the most likely cause of stroke in this setting, consideration should be given to other etiologies that cause stroke in young persons (6). If there is a history of head or neck trauma, and arterial dissection is suspected, the radiologist should be notified so that appropriate changes in the magnetic resonance (MR) acquisition protocol can be made prior to study.
Other causes of stroke in children—such as infection, cardiac embolism, and clotting disorders including anticardiolipin antibodies— should be considered (7). While hemiparesis typically improves, cognitive deficits are often significant and long lasting; formal testing should be carried out to identify rehabilitation and educational needs.
TIAs have been defined as ischemic events in which the symptoms resolve in less than 24 hours. Because TIAs are a strong predictor of stroke in other settings and in SCD as well, there is a general recommendation that all patients with TIA receive appropriate therapy for stroke prevention. In this particular setting there are few data. The diagnosis of TIA is difficult in children, especially those who are very young, and painful episodes can mimic hemiparesis or paraparesis. In cases where the history is weak for the event actually being a TIA, caution is advised, especially if longterm transfusion is being considered.
In the case of a child in which a TIA is observed or strongly suspected, a prior recommendation is reiterated as a reasonable approach (2): if the patient has significant large vessel disease on imaging, transfusion should be undertaken.
If the patient has not been screened for stroke risk by transcranial Doppler (TCD) ultrasound (8), this should be done and treatment initiated according to the discussion under "Prevention of Brain Infarction," below, and figure 2. Alternatively, other tests, if available, such as positron emission tomography (PET) (9) or MR spectroscopy, could be employed.
If these indicate significant "brain at risk," prophylactic treatment with transfusion can be undertaken on the basis that the child’s brain blood supply has already failed once, even if transiently, and is at significant risk for subsequent deterioration.
Antiplatelet agents are usually recommended for TIAs in cases without SCD, but there are very few data on efficacy in SCD. Agents such as aspirin, clopidogrel, and combination dyprimadole/aspirin are used in adults andin cases where transfusion is not undertaken.
The clinical presentation of intracranial hemorrhage is dramatic and may include severe headache, vomiting, stupor, or coma. However, hemiparesis may be present, especially with intraparenchymal bleeding. A child with such a presentation requires rapid but careful evaluation to rule out meningitis, sepsis, hypoxemia, drug intoxication, or other metabolic derangements. A noncontrast cranial CT should be performed as soon as possible. Intracranial hemorrhage should be approached based on the location of the blood on the CT scan, as described below.
Subarachnoid hemorrhage (SAH)
The usual cause of subarachnoid hemorrhage (SAH) is rupture of a berry aneurysm. The aneurysm may not be seen on CT, but can sometimes be inferred by the location of blood. Minor subarachnoid hemorrhages may have no identifiable cause even when angiography is performed, but an angiogram is recommended to identify aneurysms or arteriovenous malformations (AVM) if surgery is being considered. This is clinically relevant because aneurysms may rebleed, and SCD patients may have multiple aneurysms that require management. Surgical clipping, as well as AVM removal, has been successfully performed in many patients with SCD. Although aneurysms can be identified using MR, MRA is not a definitive test for aneurysms unless special techniques are used (20). However, MRI/MRA can reliably detect AVM. The initial treatment of subarachnoid hemorrhage is stabilization in a neurological intensive care unit or pediatric ICU, depending on local expertise and the age of the child. Initial care includes intravenous normotonic fluids to avoid dehydration. The effect of transfusion on the course and outcome of hemorrhage is not known; however, reduction of sickle hemoglobin (Hb S) to less than 30 percent of total hemoglobin is recommended.
Nimodopine, a calcium antagonist that improves outcome after SAH by counteracting delayed arterial vasospasm, is indicated in adults with SAH (10). Use in this setting with young children is not approved but is reasonable on an empiric basis. The adult dosage of 60 mg orally every 4 hours for 21 days should be adjusted by weight.
If the CT shows blood primarily confined to the parenchyma, the cause may still be an AVM, but an aneurysm is not likely unless there is also subarachnoid bleeding. Intraparenchymal bleeding may be associated with large vessel vasculopathy, especially if a moyamoya formation is present. In some patients, no vessel pathology can be seen on angiography. Evaluation of these patients with MRA may be sufficient if there is no subarachnoid blood, because an aneurysm is not likely as the source of bleeding. Better definition of the vasculature can be obtained with conventional angiography. Initial management depends on the size and location of the bleeding. A rapid search for coagulopathy should be made with a determination of the activated partial thromboplastin time (aPTT) and prothrombin time (PT) and correction of any coagulopathy. Management of the hematoma includes medical control of intracranial pressure and consideration for surgical removal in selected cases, particularly if there is a large (>3 cm) cerebellar hematoma.
Rebleeding in this setting in the short term is rare. Normotonic fluids and avoidance of hypotension are important (11).
Intraventricular hemorrhage is unusual but may be seen in the case where fragile moyamoya vessels near the ventricular wall rupture into the ventricular space. In such cases the pediatric patient is at risk for acute hydrocephalus and death if ventricular flow is obstructed. The child should receive prompt neurosurgical evaluation for intraventricular catheter placement for drainage. After acute stabilization, evaluation of the cerebral vessels (best done by conventional angiography) should be undertaken to try to identify the underlying cause.
PREVENTION OF BRAIN INFARCTION
Several uncontrolled studies have documented a reduction in recurrent cerebral infarction using chronic blood transfusion with the target of reducing Hb S to less than 30 percent of total hemoglobin (12,13). The reduction in recurrent stroke risk is significant, but patients may still have a stroke despite adequate transfusion and low Hb S levels. If a patient on transfusion has a "breakthrough" cerebral infarction or TIA, the Hb S level should be checked to ensure that it is being maintained at 30 percent or below, and the etiology of ischemia should be evaluated. Consideration should be given to risk factors beyond SCD related vasculopathy, including elevated homocysteine or a hypercoagulable state. Elevated homocysteine can be reduced with folate and treatment recommended for patients without SCD (14). Data suggest that some SCD patients have elevated antiphospholipid antibodies (15) and protein C and S deficiencies (16). If the abnormalities are severe enough, anticoagulation with warfarin should be considered. Treatment of these conditions has not been tested in randomized clinical trials but is reasonable based on pathophysiology.
After several years of transfusion therapy, it may be reasonable to allow Hb S levels to rise up to 50 percent by reducing the intensity of transfusions; this has not been formally tested, however. Moreover, attempts to identify a duration after which transfusion can be safely stopped have not been defined. Some studies have reported high rates of recurrent stroke (17), although others have suggested that transfusion may be safely withdrawn in older patients who have been extensively treated (18). Current recommendations are that transfusion should be continued for at least 5 years or at least until the child reaches the age of 18. Chronic transfusion induces iron overload, which must be managed along with the transfusions (see chapter 25, Transfusion, Iron Overload, and Chelation).
Patients with stroke have received bone marrow transplantation (19). The current indications, efficacy, and outcome of this therapy are discussed in chapter 27, Hematopoietic Cell Transplantation. Hydroxyurea is used for reduction of painful episodes in adults with SCD, but the trial establishing its use provides no guidance on whether hydroxyurea is a suitable alternative to transfusion for prevention of stroke. Clinical studies in children have reported short-term safety, but these studies have not established hydroxyurea as an alternative to transfusion for stroke prevention in this setting (20). Anticoagulants and antiplatelet agents have not been studied in this indication.
PRIMARY STROKE PREVENTION
The CSSCD established that patients with SDC-SS have rates of stroke in childhood in the range of 0.5-1 percent per year (1). In the Stroke Prevention Trial in Sickle Cell Anemia (STOP) study, children between 2 and 16 years of age who were at risk for first-time stroke, as determined by having TCD velocity greater than 200 cm/sec, were randomized to receive either periodic transfusions to maintain the Hb S level below 30 percent or standard supporting care (21). An interim analysis demonstrated that periodic transfusions were efficacious in preventing first-time stroke, in the children randomized to the transfusion arm. At the end of the trial, all participants were offered periodic transfusion therapy. The main side effects of the transfusion therapy were iron accumulation and alloimmunization, through the rate of occurrence was low. A new trial, known as STOP II, is now in place to determine whether transfusions need to be continued indefinitely of if they can be stopped after some period of time when risk of stroke has diminished.
TCD can be performed with either the dedicated 2-MHz pulsed Doppler device used in STOP or with TCD attachments to ultrasound imaging machines (transcranial Doppler imaging, or TCDI) that have also been used in this setting (22).
IDENTIFICATION OF PATIENTS AT RISK
In addition to TCD, a number of other approaches have been used to identify children at risk for stroke (figure 2). The CSSCD identified five significant risk factors in a long-term prospective study: prior TIA, low steady-state hemoglobin, rate and recency of acute chest syndrome (ACS), and elevated systolic blood pressure. The newborn cohort of the CSSCD identified three early life (first 2 years) predictors of severe outcomes such as stroke (23). These included dactylitis, severe anemia, and leukocytosis.
Other clinical and laboratory indicators of stroke risk that have been reported include stroke in a sibling, subtle neurological abnormalities, severe anemia, high leukocyte count, certain s-gene haplotypes, and no a-gene deletion (2).
SUBCLINICAL BRAIN DISEASE
The CSSCD confirmed that about 13 percent of children with SCD have "silent" brain lesions on MRI, in predominantly frontal and parietal cortical, subcortical, and border-zone locations (24,25). These lesions are associated with poor performance on neuropsychological testing. Recent evidence from the CSSCD confirms an earlier smaller study indicating that the risk of clinical stroke is increased if MRI is abnormal. The presence of these lesions should prompt evaluation of the child for learning and cognitive problems, and evaluation of cerebral vessels for primary stroke prevention (see above). Silent lesions are evidence of brain injury and should also lead to reevaluation of the patient’s history, which may reveal symptoms that were not previously recognized, as well as reexamination of the patient’s clinical and laboratory risks for stroke.
The rate of stroke in children with positive MRI and with TCD that do not reach current treatment guidelines is not clear, and the risks and benefits of prophylactic transfusion based on silent MRI lesions have not been determined. Intervention in patients with silent lesions and additional indicators of cerebral dysfunction or abnormality have been suggested, but no recommendation for treatment can be made at this time.
STROKE AND BRAIN DISEASE IN ADULTS WITH SCD
The CSSCD confirmed the relatively high rates of stroke in adults with SCD and the predominance of hemorrhage compared with infarction in adults with SCD. There is less information on treatment and prevention in adults with SCD. The clinician must decide whether to approach a patient with TIA or stroke who has SCD in a manner similar to that used in children with SCD, or along guidelines established for adults without SCD (26,27). The interaction of SCD-specific risk factors with risks factors for stroke seen in adults without SCD has not been determined, although high blood pressure was identified as a stroke risk in the CSSCD. Specifically, the role of chronic transfusion is unclear. The recommendations that follow are based primarily on current recommendations for treatment and prevention in patients without SCD (figure 3).
Treatment of hyperacute ischemic stroke in adults is accomplished using recombinant tissue plasminogen activator (t-PA). It is not clear whether t-PA, which has a significant risk of bleeding, is appropriate for patients with SCD; no experience with its use has been reported. However, there is no clear justification to exclude SCD patients from t-PA therapy, and it remains the only therapy approved by the U.S. Food and Drug Administration for treatment of ischemic stroke.
According to established guidelines, use of t-PA is indicated when:
Thrombolytic therapy cannot be recommended if:
In addition, t-PA should not be given unless emergent care and appropriate facilities are available. Caution is advised before giving t-PA to patients with severe stroke, and careful explanation of the risk of bleeding to patient and family is advised. There is a 6.4 percent risk of symptomatic brain hemorrhage, and about half of these are fatal. If a hemorrhage occurs, the guidelines suggest red cell transfusions as needed (for extracranial bleeds) and urgent administration of 4 to 6 units of cryoprecipitate or fresh frozen plasma and 1 unit of single donor platelets. Surgical drainage of intracranial hemorrhage should be considered. Although t-PA can be given to patients on antiplatelet agents, these drugs, as well as any dose of heparin, should not be given for the first 24 hours after using t-PA. There is evidence that aspirin (325 mg one-time dose) within the first 48 hours after stroke onset has a small beneficial effect and is recommended if t-PA is not used.
The acute evaluation of the patient requires a noncontrast CT scan to rule out hemorrhage. After the decision is made regarding t-PA, an MR study of the brain is recommended to better delineate the area of ischemia/infarction. Prevention of stroke in patients with TIA or stroke is accomplished with either antiplatelet agents or warfarin, based on the likely cause of the symptoms.
The following workup is recommended for adults presenting with TIA or ischemic stroke:
Health care providers also should consider etiologies seen in young patients with stroke without SCD, including CNS infection, illicit drug use, and arterial dissection.
There are currently three options for antiplatelet therapy for secondary stroke prevention. Table 1 summarizes the American Stroke Association’s recommendations regarding these agents. These guidelines are similar to those for prevention of stroke after completed brain infarction (26,28).
Alternative therapy is chronic blood transfusion as used in children with SCD. Recently, surgical bypass has been reported in a patient with SCD. Surgical procedures that have been developed to treat moyamoya syndrome may be considered, due to the similarity in anatomic location of the arterial disease in moyamoya and SCD (29). These procedures may be last-resort options for patients who cannot be otherwise treated or who continue to have brain infarction despite medical therapy. However, risk and benefit in this setting have not been established and no recommendation can be made.
Adults with intracerebral hemorrhage should be approached in the manner outlined above for children, with the exception that nimodopine is recommended without qualification for patients with subarachnoid hemorrhage (11).
SUMMARY OF RECOMMENDATIONS
|Last Updated on Thursday, 10 June 2010 13:54|