The age and characteristics of the patient should guide the acute treatment of ischemic stroke in adults with SCD given the very limited published experience [32
]. In young adults with HbSS, the use of exchange transfusion is supported by a large retrospective cohort study that demonstrated a much lower risk of recurrent stroke in children treated with exchange transfusion versus those treated with simple transfusion, and that cerebral blood flow normalized in one child 1 week after exchange transfusion [33
]. Treatment with thrombolytic agents should be considered in adults that meet accepted criteria based on the increased proportion of favorable outcomes seen in ischemic stroke overall [35
], but there are no published reports of thrombolysis for acute ischemic stroke in children or adults with SCD, and the increased rate of intracranial hemorrhage in people with SCD may result in an increased risk of this complication with thrombolysis. For these reasons it should be clear that the use of thrombolytic agents in adults with SCD should be considered an off-label use of an US FDA (tissue plasminogen activator) approved drug, and this should be discussed with the patient and family in these terms. There is a need for studies of tissue plasminogen activator for the treatment of acute ischemic stroke in patients with SCD.
The goals of acute treatment for ischemic stroke are to limit primary and secondary injury from the stroke, limit early recurrence, and establish effective secondary prevention. Management of stroke patients in certified stroke centers and dedicated stroke units has been demonstrated to improve outcomes [36
]. Interventions to limit injury include supportive measures to optimize cerebral perfusion, oxygenation, ventilation and maintain normoglycemia; also, treatment of hyperthermia, and cardiac monitoring for the first 24 h.
The role in adults with SCD of interventions proven to be effective for the acute management and secondary prevention of ischemic stroke in the general population is unclear. In the absence of specific data, we recommend considering the interventions described for stroke in adults in general. The identified risk factors and pathophysiology of the stroke should guide the approach to secondary prevention. For example, anticoagulation in patients with a strong indication (i.e., atrial fibrillation, mechanical heart valve, intracardiac thrombus or concurrent pulmonary embolus); risk factor modification in those with hypertension, obesity, diabetes, tobacco and hypercholesterolemia; and carotid endarterectomy in symptomatic carotid stenosis, to name a few. Antiplatelet therapy should be considered in all adults with acute ischemic stroke – the first choice should be aspirin 325 mg daily. Other antiplatelet agents such as aspirin/dipyridamole, clopidrogel and ticlopidine have not been studied in acute stroke, although they do have a role for secondary prevention [31
]. In the specific case of adults with SCD, aspirin, aspirin combined with dipyridamole and ticlopidine have all been evaluated in small studies for the prevention or treatment of pain from SCD without increased bleeding [39
], but these agents increase the risk of hemorrhagic stroke in the general population [40
]. This may be of additional concern in adults with SCD given limited data that hemorrhagic stroke occurs even more frequently in those with a history of ischemic stroke as children [41
]. Statins can also be considered for use in this setting for adults with SCD, and started during hospitalization for the acute event, as these agents may improve outcomes and decrease recurrence of ischemic stroke and TIA when used in patients with ischemic stroke [42
]. Based on a small prospective study, the short-term use of statins appears safe in adults with SCD despite the low baseline levels of cholesterol in this population [43
]. The long-term safety of statins in patients with SCD is unknown.
The cornerstone of secondary prevention of ischemic stroke in children with SCD is regular transfusion to maintain Hb S less than some threshold (initially 20%, now typically 30–50%) before the next transfusion based on observational studies. This approach has been found to reduce the risk of recurrent stroke from 67% at 4 years to 2.1 episodes per 100 person-years [4
]. However, when transfusions were stopped in this population most subjects had recurrent stroke within 12 months (70% after 1–2 years of transfusion and 50% after 12 years of transfusion) [45
]. One group of investigators reported a greatly reduced rate of recurrent stroke (1.2 per 100 person-years) after stopping regular transfusions in nine people; seven were at least 18 years of age and six were treated with hydroxyurea [47
]. Regular transfusions to maintain Hb S < 30% is our preferred first-line treatment for young adults with SCD and first ischemic stroke as children or adults, but there are only published data to support this approach in those with first stroke during childhood. In addition, transfusion alone is inadequate therapy for many patients as progressive cerebral injury occurred in 45% (18/40) of well-transfused children (mean pretransfusion Hb S of 29%) with median follow-up of 5.5 years [48
Alternative approaches to secondary prevention include hydroxyurea, hematopoietic stem cell transplantation and revascularization. Hydroxyurea, after at least 6 months of transfusions, reduced the rate of recurrent stroke in children and young adults (median age at last follow-up of 19 years, range 13–29 years) to 4.6 per 100 person-years of follow-up [49
]. This is significantly lower than seen in untransfused patients. However, the randomized Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) Trial demonstrated an increased number of recurrent strokes in children treated with hydroxyurea (7/67) compared with children treated with transfusions (0/66) [50
]. Thus, hydroxyurea may reduce the risk of recurrent stroke compared with no therapy, as demonstrated in a large retrospective case series of Jamaican children, but is probably inferior to regular transfusions to maintain Hb S <30% [51
Hematopoietic stem cell transplantation (HSCT) is a promising therapy for secondary stroke prevention in SCD. After myelo-ablative HSCT for stroke with an HLA-matched sibling donor, 90% (26/29) of children were stroke free at a median of 3.2 years, with one transplant-related death, and both recurrent strokes occurred after the stem cell therapy had failed. There was no silent progression of cerebral injury in the 28 patients with follow-up MRIs [52
]. However, a study of children treated with a similar preparative regimen with the MRIs performed and interpreted at a single center identified progressive or new persistent cerebral injury in five out of nine children, but no overt strokes [53
]. The greatest barriers to HSCT for adults with SCD and stroke remains the small proportion of adults (approximately 20% of referred patients) that have an HLA-matched sibling donor and the limited adult experience with HSCT [54
]. HSCT using alternative donors (matched un related or haploidentical donors) is currently being evaluated in adults [55
The addition of cerebral revascularization procedures may decrease the risk of recurrent stroke in people with SCD and moyamoya. Small case series of children and young adults treated by encephaloduroarteriosynangiosis, an external bypass procedure, have shown a reduction in the rates of recurrent stroke from as high as 61 per 100 person-years before to 2.1–6.1 per 100 person-years after the procedure [56
]. However, the potential biases inherent to case series with a comparison of rates before and after the intervention limit the confidence in these findings.