Sickle Cell

SICKLE CELL AND STROKES

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Stroke is a common and potentially devastating manifestation of sickle cell disease (SCD) that can affect children and adults. Challenges in management include distinguishing acute stroke from other cerebrovascular manifestations of the disease such as meningitis, cerebral malaria, or seizure disorder, and distinguishing acute ischemic stroke from hemorrhagic stroke. Care of the patient with an acute stroke requires specialized expertise in exchange transfusion practices.

This topic discusses an approach to the acute assessment and treatment of stroke in children and adults with SCD.

Risk stratification and primary stroke prevention, as well as secondary prevention for individuals with SCD who have had an acute stroke or transient ischemic attack (TIA) are presented in detail separately.

Introduction

Stroke is a devastating and potentially fatal complication to sickle cell disease. Strokes are difficult to explain on the basis of the central pathological process in sickle cell disease, namely the occlusion of small vessels by deformed sickled cells. The key event in this process is polymerization of the deoxygenated form of the molecule with consequent red cell deformation. Hemoglobin deoxygenation and polymerization occurs in the microcirculation and venous system.

Stroke in patients with sickle cell disease involves large vessels in the arterial circulation. The internal carotid artery and the middle cerebral arteries are affected with particular frequency, with devastating consequences. Other vessels commonly compromised are the anterior cerebral and basilar arteries. Blockade of these large arteries by deformed red cells is implausible.

Transcranial doppler studies of children show that high blood flow velocity through these vessels is associated with higher probabilities of arterial occlusive stroke. Children with flow rates of >190 cm/minute through the internal carotid artery are at great risk of stroke. The Stroke Prevention (STOP) Trial was designed to determine whether prophylactic transfusions could prevent arterial-occlusive stroke in children in whom the flow rate through the assessed arteries equaled or exceeded 200 cm/sec. Those randomized to receive chronic transfusion had significantly fewer strokes than did those observed without transfusion during the study. The results were so convincing that the trial was terminated prematurely and a clinical alert was issued by the National Heart, Lung, and Blood Institute.

Treatment of Stroke

Stroke is a life-threatening event for patients with sickle cell disease. Exchange transfusion followed by chronic blood transfusion to maintain the level of HbS at <30% is mandatory. Patients with stroke run a risk of recurrence of about 50% in the absence of chronic transfusion.

The duration of chronic transfusion needed to prevent recurrent stroke is undefined. Cessation of chronic transfusion after as long as five years was associated with a high incidence of recurrent stroke in some studies. Clearly, most children do not continue indefinitely with chronic transfusion after a stroke. Many adults with sickle cell disease have a history of stroke in childhood. Very few of these adults continue receive chronic transfusions, however. At some point, often during the transition between pediatric and adult care facilities, chronic transfusions are terminated. One report highlights an experience in which chronic transfusions were stopped in several adults without deleterious consequences (17). Clearly, more data are needed to address this critical question.

http://sickle.bwh.harvard.edu/stroke

Why do I need to know about stroke? Children with SCD are more likely to have strokes than those without the disease. Of all people with SCD, the risk of stroke is highest in the most commonly detected type of sickle cell disease – sickle cell anaemia (HbSS).
The risk of stroke in children with SCD is greatest between the ages of 2and16. About10% of all children with SCD will have a stroke by the time they are 20 years old. Stroke recurrence is also a major concern for children and their families. Stroke recurs in over 60% of children with SCD.
If you have a child with SCD, make sure you speak to their doctor about the risk of stroke.

What is a stroke? A stroke is a brain attack. It happens when the blood supply to the brain is cut off due to:

• a clot blocking the flow of blood to the brain (also known as an ischaemic stroke)

• or a bleed in or around the brain from a burst blood vessel (also known as a haemorrhagic stroke).

When the blood supply is disrupted, parts of the brain become damaged or destroyed. Some strokes are fatal whilst others can cause permanent or temporary paralysis to one side of the body and the loss of the ability to speak, read or write. Recovery is possible but may be slow and can vary from person to person. Children with sickle cell are at risk of having both ischaemic (a blockage; created by the build up of deformed sickle cells) and haemorrhagic (bleed) strokes, although ischaemic strokes are more common.

If you suspect a stroke, it is important to call an ambulance so that your child can be taken to hospital and have a brain scan as quickly as possible. This will determine what type of stroke it is, and will help with any possible treatment.’
‘Silent’ stroke About17% of children with SCD also have ‘silent infarcts’ – strokes with no obvious symptoms at the time but which can lead to cognitive impairment (such as diminished memory, attention, emotion, concentration or reason) in the long term.
In the case of ‘silent’ strokes, because there are no obvious signs it is important to look out for possible long term changes in children with SCD. These could include changes in behaviour, concentration, memory, fatigue levels or handwriting.
Many parents and teachers do not know the potential risk of ‘silent’ stroke and can overlook or misinterpret changes in behaviour or concentration, putting it down to children playing up. In the case of children with SCD, it is important to investigate these changes just in case they are a result of ‘silent’ stroke.
www.scyss.org/sickle_cell_and_stroke_booklet_yellow

Treatments used for stroke

Transfusion

There have been few studies of stroke in patients with SCD, and such patients are not often included in clinical trials, such as trials of antiplatelet drugs, that investigate stroke prevention and treatment. In the 1970s and 1980s, clinical series from several centers indicated that children with SCD and stroke had a very high early (3 years) recurrent stroke risk11 and that if they were given transfusion therapy this risk was drastically reduced.12,13 In most cases, the transfusion programs were sufficient to reduce total sickle cell hemoglobin values to less than 30% of the total hemoglobin values. Although not tested in a clinical trial, long-term transfusion therapy was associated with a reduced recurrence to as low as 10% and has become routine after stroke in children.

It has not been established when it is safe to discontinue long-term transfusion therapy after stroke. In practice, many adult hematologists discontinue this therapy in young adults when they take over their care owing to the maturation of children with stroke; alternatively, some patients tire of the program and fail to continue with regular transfusions, but the rate of stroke after discontinuation in these cases has not been systematically reported. One group found that discontinuation of transfusion therapy only 1 to 2 years after stroke led to recurrence within 1 year in 7 of 10 patients; however, another group observed no recurrences in 7 children who had received transfusions an average of 2 years before cessation. 

The only randomized clinical trial using any therapy in SCD-related stroke was performed as part of primary prevention strategy. The Stroke Prevention Trial in Sickle Cell Anemia tested whether long-term transfusion therapy can reduce the risk of first stroke by 92% in high-risk children aged 2 to 16 years selected by screening with transcranial Doppler ultrasonography (TCD). The children randomized in this study, none of whom had a history of stroke at entry, were identified by TCD showing time-averaged mean (as opposed to peak systolic) velocities of 200 cm/s or more in the internal or middle carotid artery (normal mean ± SD adult velocities, 62 ± 12 cm/s). Children with SCD generally have TCD velocities in the range of 130 to 140 cm/s, and the 200-cm/s cutoff is about 2 SDs above normal for children of this age and degree of anemia. Children in the untreated arm had a stroke risk of 10% per year, which is about 10 to 20 times the baseline risk in children with SCD in this age group who are not selected by TCD. 

Exchange transfusions or simple transfusions are options; exchange transfusions have the advantage of causing less iron accumulation at the price of exposure to more units of blood and greater expense. In the acute setting, exchange transfusions avoid the potential adverse effect of bringing hemoglobin toward a more normal level and thus raising viscosity. In the long term iron loading is reduced but exchange transfusion requires more blood and exposes the patient to more units of blood.

Transfusion is also used in the acute setting of stroke in children immediately after stabilization, but there are no controlled data on the effect of transfusion on acute stroke itself. There are also no data supporting its use in adults, either for prevention or for treatment of stroke. In addition, it is unclear whether transfusion is helpful in preventing recurrent intracranial brain hemorrhage, although it is frequently administered in this setting in preparation for cerebral angiography. It may be able to reduce hemodynamic stress on a continuing basis, which may lower the risk of aneurysm rupture, but studies are needed to test the impact of transfusion on hemorrhage.

Transfusion has many drawbacks, including alloimmunization with long-term transfusion and iron overload, which becomes a problem after only a few years of therapy and has to be treated with chelation. Chelation therapy with the only available agent, desferoxamine, is usually recommended when serum ferritin levels reach 5618 pmol/L. The initial dose is 50 mg/kg administered by subcutaneous infusion over an 8-hour period daily for several days a week. Long-term compliance with chelation therapy is a problem as there is no oral chelator.

Hydroxyurea

Hydroxyurea therapy emerged from decades of unsuccessful efforts to find agents capable of elevating the percentage of fetal hemoglobin, since observations of populations and a study of natural history have shown that increased percentages of fetal hemoglobin correlate with reduced disease severity. Hydroxyurea is the only chemotherapeutic agent approved for the treatment of SCD. The double-blind, placebo-controlled study of hydroxyurea therapy in 299 adults with SCD for the reduction of painful episodes was terminated early when significant reductions in pain episode frequency, acute chest syndrome, need for hospitalization, and blood transfusions became evident. There were too few strokes in this study, however, to determine any effect of the drug on the risk of stroke. No study has addressed the issue of whether hydroxyurea therapy has efficacy in stroke prevention in a controlled fashion. 

How hydroxyurea therapy works in SCD is debatable, but it elevates the percentage of fetal hemoglobin, improves red blood cell deformability, reduces the irreversibly sickled cell fraction, and is associated with improvements in rheology and red blood cell survival. Abnormal adhesion of blood cells may also be modified.  Hydroxyurea therapy has been shown to reduce granulocytes, reticulocytes, and platelets, but it is not clear if it has a beneficial effect on pain crises. Hydroxyurea therapy is initiated at a dosage of 15 mg/kg per day, and the dosage is typically escalated by 5 mg/kg per day every 8 to 12 weeks, with monitoring of the levels of platelets, reticulocytes, and neutrophils and interruption of treatment temporarily or permanently if toxic effects are evident. Few patients can tolerate a dosage higher than 30 mg/kg. It is not clear how important it is to increase the dosage to the maximal tolerated dose as opposed to lower doses for the control of pain crises. In any case, the role of hydroxyurea therapy in stroke prevention needs to be established.

Bone Marrow Transplantion (BMT)

Bone marrow transplantation may be curative in SCD and is potentially an option for stroke prevention. Data are available on 120 patients that show that HLA-identical sibling stem cell allografts can successfully replace sickle cells with normal donor-derived red blood cells and that stable mixed chimerism, even with a relatively low proportion of donor cells, can ameliorate the symptoms and complications of SCD, although an effect on stroke specifically is noclear. Survival has been in the 90% range, and event-free survival about 85%. The cumulative incidence of graft rejection or return of SCD is 11%. Although most patients who have undergone BMT have survived without developing SCD, approximately 8% have died, and about half of these deaths occurred in the setting of graft-vs-host disease. In addition to acute and chronic graft-vs-host disease, seizures and intracerebral hemorrhage have been reported in patients with stroke who undergo BMT, and there are other transient but benign complications of the procedure.

The impact of BMT on central nervous system disease in 22 patients with stable donor engraftment who were followed up for at least 2 years was reported by Walters et al. Ten patients had history of stroke, 4 had silent infarcts on MRI scans, one had a transient ischemic attack, and 1 had positive results on TCD screening prior to BMT. Conclusions based on clinical and MRI follow-up were that no significant central nervous system events had occurred and that most of the patients had shown “stabilization” of underlying cerebral vasculopathy. 

Other Treatments

Intravenous tissue plasminogen activator therapy should be considered in adults with acute ischemic stroke, if the therapy can be delivered within 3 hours of symptom onset and there are no contraindications according to existing guidelines. There is no clear justification to exclude the adult patient with SCD from thrombolytic therapy. Adequate hydration, normothermia, and euglycemia should be maintained, and hypotension should be avoided in the setting of acute stroke.

In terms of stroke prevention, in adults with stroke, or in children who cannot undergo long-term transfusion therapy, warfarin therapy is an unproven alternative and may be reasonable if there is evidence of intracranial arterial stenosis. There is no systematic experience with either anticoagulation or antiplatelet agents in this setting, but given the support for use of these agents in adults generally, it is reasonable to use them in adults with SCD when no other specific stroke prevention strategy is available on the basis of existing guidelines for their use.  In cases of treatment failure and recurrent strokes despite medical therapy, and in the setting of severe vascular disease, surgery is an option. There have been a few reports of the successful establishment of a collateral supply using a procedure called encephaloduroarteriosyangiosis, in which a superficial scalp artery with galea is mobilized and passed through the dura to lie on the arachnoid surface of the brain.

Modification of other factors unrelated to SCD may contribute to stroke prevention, and patients with SCD should receive a workup for the cause of stroke. Although the prevalence of SCD-related vasculopathy is high, other mechanisms and risk factors for stroke should be considered, especially in adults with SCD and stroke. Drug abuse, the presence of anticardiolipin antibodies and other hypercoagulable states, vasculitides, arterial dissection, cardioembolic or paradoxical emboli, and elevated homocysteine levels should all be considered. Also, other modifiable stroke risks, such as smoking, diabetes, hypertension, and obesity, should be addressed in cases of SCD.

http://jamanetwork.com/journals/jamaneurology