Among the most debilitating and poorly understood complications of sickle cell disease (SCD) are the conditions affecting the central nervous system (CNS), including cerebrovascular disease and diffuse structural abnormalities associated with clinical and silent stroke, seizures, headache, and cognitive impairment (Figure 9-1).1 Neurologic complications affect at least 25% of SCD patients2 and are often, but not always, associated with underlying large-vessel vasculopathy.3 There is a broad spectrum of acute and chronic complications1; some of the risk factors are universal, but others appear to be specific and, in some cases, paradoxical.4 Ischemic and hemorrhagic stroke may occur in the context of acute illness, including chest and vaso-occlusive crises, or “out of the blue.”5 In addition, seizures, headache, and coma are common in patients with SCD.1,6-8 Advances in neuroimaging have demonstrated evidence for large-vessel and, potentially, small-vessel involvement, along with hemodynamic stress, both in symptomatic clinical stroke and apparently asymptomatic patients with covert or silent cerebral infarction.1 Screening for large-vessel vasculopathy with transcranial Doppler ultrasound (TCD; Cases 1 and 2) and magnetic resonance angiography (MRA; Cases 1, 2) and for parenchymal damage (ischemic and hemorrhagic; Cases 2-11) with magnetic resonance imaging (MRI) is now established.1 Computed tomography (CT) may be essential for acute diagnosis and emergency management of ischemia (Case 3) or hemorrhage (Cases 9 and 11), and arterial or venous occlusion (Cases 3 and 4), although because the radiation dose is high, magnetic resonance, including magnetic resonance venography (MRV; Case 7), should be organized, if possible. Management strategies currently focus on blood transfusion and hydroxyurea.1 Follow-up from the Stroke Prevention in Sickle Cell Anemia (STOP) trials has demonstrated that if children aged 2 to 16 years with abnormal TCD cerebral blood flow velocities (time-averaged mean maximum velocity >200 cm/s; Case 1) are regularly transfused indefinitely, the majority of pediatric strokes are preventable.9,10 The Transfusions Switching to Hydroxyurea (TWiTCH) trial showed noninferiority for continuing with hydroxyurea at maximum-tolerated dose in those with abnormal time-averaged mean maximum velocities, but normal MRA, transfused on the STOP protocol for 1 year.11 Chronic transfusion for children aged 5 to 14 years with silent cerebral infarction was shown to prevent further infarction, particularly clinical stroke, in the Silent Infarct Transfusion (SIT) trial.12 Bone marrow transplantation has been used for secondary stroke prevention in some, and revascularization is an option if there is intracranial vessel occlusion with collateral formation (moyamoya).10
Neurologic complications in sickle cell disease (SCD). Time of flight angiography image overlaid on 3-dimensional rendered fluid-attenuated inversion recovery (FLAIR) image, edited to depict common neurologic complications in SCD. Adapted from Stotesbury H, Kawadler JM, Hales PW, Saunders DE, Clark CA, Kirkham FJ. Vascular instability and neurological morbidity in sickle cell disease: an integrative framework. Front Neurol. 2019;10:871.