Sickle Cell Disease

A 4-year-old boy with known homozygous sickle cell disease (SCD) presented for the first time at our neurosonology laboratory for a screening examination of his basal cerebral arteries. At that time, he was free of neurologic symptoms and his medical history was unremarkable.

• Was there any abnormality in the flow parameters of the basal cerebral arteries suggestive of intracranial vessel narrowing, especially in the anterior circulation: terminal internal carotid artery (ICA), M1 segment of the middle cerebral artery (MCA), and A1 segment of the anterior cerebral artery (ACA)?

Extracranial Duplex Sonography

No vessel wall pathology was identified. High flow velocities were detected in both ICA (left: 224/82 cm/s, time-averaged maximum velocity = V_mean 128 cm/s; right: 201/79 cm/s, V_mean 117 cm/s). Flow parameters in the vertebral arteries (VAs) were normal (not shown).

Transcranial Duplex Sonography

Regular extracranial and transcranial duplex examinations during the following 4 years showed constant findings.

The patient suffered from recurrent SCD crises with bouts of thoracic and multifocal osseous pain and pulmonary infections with respiratory insufficiency. Also, severe anemia with low hematocrit (0.19–0.25 L/L) and hemoglobin (6–8 g/dL) values and sickle cell hemoglobin (HbS) of ~90% was finally observed. Because hydroxyurea treatment proved ineffective, repeated transfusion therapy was performed and, later, a bone marrow transplant was conducted. No neurologic symptoms developed during the entire observational period.

Extracranial and Transcranial Duplex Sonography

Normal flow velocities were observed in all extracranial and intracranial arteries and no signs of cerebral hyperperfusion were found (not shown).

Conclusion

Unremarkable ultrasound findings in the brain-supplying arteries comparable to healthy children without anemia after bone marrow transplantation.

Clinical Aspects

SCD is a hereditary disorder in the spectrum of hemoglobinopathies of hemolytic anemias. The heredity is auto-somal recessive with a point mutation on chromosome 11 leading to an abnormal hemoglobin, sickle cell hemoglobin (HbS), in erythrocytes. HbS tends to form pathologic aggregates in the deoxygenated state with hemolysis. SCD is a common hematologic disorder in countries in which malaria is a relevant infectious disorder. The highest prevalence of SCD is found in up to 40% of the population in countries close to the equator, especially in Africa and Asia. These patients have a relative resistance against malaria, explaining the relevant selection advantage.

Patients, especially children, with SCD are at high risk of stroke. Stroke occurs in ~10% of patients with SCD under 20 years of age and is most common between the ages of 4 and 15 years (Platt 2005). The annual stroke rate in unselected children is 0.5–1% (Ohene-Frempong et al 1998), which increases up to 3% if silent ischemia is detected on MRI (Miller et al 2001). About 12% of asymptomatic SCD children reveal pathologic flow velocities suggestive of significant arterial stenosis (Adams et al 1992a). Children with time-averaged maximum velocities = mean flow velocities (V_mean) >200 cm/s in the anterior circulation have an annual stroke risk of ~10% which decreases to <1% under regular transfusion therapy (Adams et al 1998).

The pathophysiologic mechanisms of stroke in SCD are still not completely understood but two different lesion patterns affecting (1) small intracranial vessels and (2) large intracranial vessels can be distinguished. Considering the microcirculation, deoxygenation of the HbS leads to its polymerization and distortion of the erythrocytes. The disfiguration of the red blood cells is initially reversible but tends to become permanent (Bunn 1997). The adherence of sickle erythrocytes to the endothelium is enhanced by von Willebrand protein and procoagulant characteristics of their membranes (Kaul et al 1993). These mechanisms reduce the ability of erythrocytes to traverse the microcirculation and may result in intracerebral microvascular occlusions and ischemia. Large-vessel occlusive vasculopathy predominantly involves the anterior circulation, in particular the supraophthalmic ICA, proximal MCA, and ACA near the carotid-T (Stockman et al 1972). Again, the pathomechanism is not completely understood. One reasonable hypothesis is that sickle cells are “sticky” and particularly tend to attach to the vessel endothelial cells, leading to activation and damage of the endothelium. This damage and activation is thought to then induce a vicious cycle, whereby inflammatory mediators, adhesion molecules, procoagulants, oxidants, and growth factors are continuously produced which further activates endothelial and white cells, creating more damage and activation. Furthermore, a fibrous intima proliferation as well as migration and proliferation of smooth muscle cells occurs, causing hyperplastic lesions with increasing vessel narrowing (Brass et al 1988, Platt 2005, Rothman et al 1986, Seibert et al 1998). Finally, acute thrombotic vessel occlusion leading to ischemic stroke might occur. Postmortem analysis often reveals arteries occluded by a thrombus containing sickle red cells, platelets, white blood cells, thrombin, and fibrin (Balkaran et al 1992).

The progression of large intracranial artery stenosis leads to an increasing stroke risk in children with SCD. Patients developing a high stroke risk can be identified in time by ultrasound with transcranial Doppler (TCD) or TCCS blood flow velocity analysis. Both methods allow diagnosis and monitoring of intracranial flow velocities to determine the individual stroke risk and select patients for prophylactic treatment like regular transfusion therapy (Adams et al 1998). Transfusion therapy suppresses the patient’s erythropoiesis and consecutive HbS fraction. This is thought to interrupt the cascade of intima proliferation and large arterial vessel narrowing. Remission of arterial stenosis with normalization of flow velocities has been reported. Conversely, discontinuation of periodic transfusions may cause a relapse with increased flow velocities and stroke risk (Adams and Brambilla 2005). It remains unclear whether the dynamic of flow velocity changes during transfusion therapy might predict the safety of switching to hydroxyurea therapy (Kwiatkowski et al 2011).

Hydroxyurea stimulates HbF production, and HbF reduces the polymerization of deoxyhemoglobin S and inhibits the sickling of the red cells (Bunn 1997). This leads to a reduction of hemolysis and an increase of the hemoglobin concentration. A further effect of hydroxyurea is the reduction of HbS, reduction of the aforementioned SCD-related complications, and reduction of blood flow velocities in the intracranial arteries but not a decreased stroke recurrence (Kratovil et al 2006, Wang et al 2000, Zimmerman et al 2007). However, our own data failed to show differences across intracranial flow parameters between patients with and without hydroxyurea treatment (Doepp et al 2012). Stem-cell transplantation is an alternative treatment option in patients, to avoid long-term transfusion therapy and its associated problems (Adams and Brambilla 2005). In our patient, hemolytic anemia and intracranial arterial flow velocities normalized completely after stem-cell transplantation, indicating remission of anemia-related hyperperfusion.

Angiologic and Anatomic Aspects

In general, normal children have a higher CBF and therefore concomitantly higher intracranial blood flow velocities than adults (Schöning and Hartig 1996, Schöning et al 1996). Even higher velocities are seen in children with anemia and reduced hemoglobin or hematocrit. SCD patients with anemia were shown to have 40–50% higher flow velocities than healthy children (Adams 2007). Therefore, cut-off values for mild, moderate, and severe intracranial stenosis have been exclusively established for SCD. A normal V_mean in the MCA in SCD without stenosis ranges between 100 and 130 cm/s (Adams et al 1989). Compared with catheter angiography, a V_mean exceeding 190 cm/s was reported as a cut-off value for stenosis of the M1-MCA, A1-ACA and P1-PCA with a sensitivity and specificity of 90% and 100%. This cut-off also takes into consideration additional criteria, such as poststenotic or absent flow pattern in the MCA and signs of collateral flow. The same group established a slightly lower threshold (V_mean MCA ≥170 cm/s) using TCD as the best cut-off value for predicting stroke risk in children with SCD with a sensitivity and specificity of 86% and 91% (Adams et al 1992b). These findings were further supported by a large prospective randomized trial, the Primary Stroke Prevention in Sickle Cell Anemia Trial (STOP trial). Analyzing the effectiveness of transfusion therapy in SCD, the trial defined a V_mean MCA of 170–200 cm/s as conditional and >200 cm/s as abnormal (Adams et al 1998). Based on the STOP criteria, abnormal findings were seen using TCCS in 8% of cases and in 9.4% of cases analyzed by TCD in 125 asymptomatic patients (Malouf et al 2001).

Two points regarding the comparison between TCD and TCCS deserve mention. First, velocity measurements without angle correction showed a better accuracy than measurements using angle correction. Second, when compared with TCCS, a slightly higher efficiency was seen for the use of TCD (92% versus 90%) (Arkuszewski et al 2012). Conversely, another study with 110 patients showed that TCCS peak systolic flow measurements were superior to TCD-determined V_mean values (Naffaa et al 2015). Potential differences of flow velocities between TCD and TCCS without and with angle correction are important for clinical practice (not only in SCD), and were systematically analyzed by several authors. Values of V_mean ~10–20% higher were found in all basal cerebral arteries using TCD compared with non-angle-corrected TCCS (Jones et al 2001, Krejza et al 2007a, Seibert et al 1998). The differences were negligible, however, when the angle-corrected TCCS was used (Krejza et al 2007a). Other authors described method-dependent differences of flow velocities in some but not in all intracranial arteries (Neish et al 2002). Low flow velocities (<70 cm V_mean in MCA, ACA, or ICA) were also reported as a risk factor for stroke, which needs further clarification as low flow may indicate severe compromise of the microcirculation or reflect severe stenoses in the distal MCA and/or ACA segments (Buchanan et al 2013).