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Neuroimaging in Sickle Cell Disease: A Review

Sickle cell disease is the most common hereditary hemoglobinopathy, which results in abnormally shaped and rigid red blood cells. These sickle‐shaped red blood cells cause vaso‐occlusion and ischemic phenomena that can affect any organ in the body. As a common cause of disability, the neurological manifestations of sickle cell disease are particularly important. Neuroimaging has a crucial role in the diagnosis, management, and prevention of the complications of sickle cell disease. These complications can affect the brain parenchyma, vasculature, and skull and can be ascribed directly or indirectly to a vasculopathy of small and large vessels. Vaso‐occlusion can cause ischemic stroke. Ischemic damage in the absence of an acute neurological deficit, and therefore only apparent on neuroimaging, is termed silent cerebral ischemia. Weakening of the arterial walls can cause aneurysms. In its most severe form, a vasculopathy of the terminal internal carotid arteries can progress to moyamoya syndrome, characterized by steno‐occlusive disease and the formation of friable collateral arteries. Rupture of aneurysms or friable collateral arteries is a potential cause of intracranial hemorrhage. The skull and vertebrae may be affected by extra‐medullary hematopoiesis, due to severe anemia, or iron deposition, due to chronic red blood cell transfusion. Impaired blood supply to bone is associated with osteomyelitis and osteonecrosis. Fat embolization syndrome is a rare complication of osteonecrosis, which may cause devastating neurological impairment. Awareness and early recognition of the diverse manifestations of sickle cell disease on neuroimaging is crucial to ensure optimal treatment in a complex patient cohort.


Introduction
Sickle cell disease (SCD) is the most common genetic hemoglobinopathy and is characterized by a chronic anemia and vasculopathy that causes vaso-occlusion and multiorgan ischemic damage.
The cerebral complications of sickle disease are particularly important as they are a common cause of disability, often at a young age. Imaging is central in the screening, diagnosis, and treatment optimization of patients with SCD. Awareness of the varied neurological complications of SCD, which have significant overlap in their clinical presentation, is vital.
In this review, the manifestations of SCD seen on imaging of the brain are discussed.

Pathophysiology of SCD
SCD is an autosomal recessive disorder caused by a mutation within the β-globin chain of the sickle hemoglobin molecule, HbS. Deoxygenated HbS is prone to polymerization resulting in insoluble crystals. HbS crystals deform the red blood cell (RBC) into a sickle shape, which are relatively rigid and adherent to vascular endothelium. Rigid RBCs are less able to flow through terminal arterioles and capillaries, causing congestion, intravascular sludging, and hemolysis. 1 Adherence of RBCs to endothelium and circulating extracellular hemoglobin This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. causes a vasculopathy due to a cascade of endothelial activation, vasoconstriction, intimal hyperplasia, and smooth muscle proliferation. RBC stasis in a proinflammatory and prothrombotic milieu brings about tissue ischemia and reperfusion injury. 2 Vaso-occlusion, the lower oxygen affinity of HbS, and physiological stress, such as sepsis, act together to promote further sickling. Consequently, a vicious cycle is instigated that culminates in an acute sickle crisis and ischemic damage that can affect any organ of the body.
Depending on various clinical, genetic, and rheologic factors, the endothelial damage may give rise to vascular stenosis, ectasia, or aneurysm formation. 3,4 The clinical course of SCD is notoriously variable. 5,6 This variability underlines the importance of neuroimaging to diagnose, or identify those at elevated risk, of suffering from the neurological complications of SCD. 24% of SCD patients will have an ischemic stroke by the age of 14, 24, and 45 years, respectively. 8-10 Identification of stroke is important because, without secondary prevention, two-thirds of children will suffer a repeat stroke. 11 Ischemic stroke may occur due to poor microvascular flow (due to endothelial damage and RBC sludging and congestion) or macrovascular occlusion (due to, for example, emboli caused by stenoses within proximal large vessels). Notably, there is also an association between SCD and cardiac anomalies, such as atrial septal defects, which may cause paradoxical embolism. 12 The clinical syndrome depends on the infarct location as well as the speed and completeness of the occlusion. Importantly, the often presumed better prognosis in younger patients afforded by greater neural plasticity does not translate to an improved prognosis. 13,14 In SCD, acute infarcts have a predilection for the high cortical convexity and within arterial border zones. 15,16 Acute infarction appears as progressive low attenuation on Computed Tomography (CT). The greater ease of access to CT over MRI should be balanced against its lower sensitivity, particularly in hyperacute phase, and poor specificity in the context of background chronic ischemic damage. Diffusion weighted imaging (DWI) is the gold standard for detection of acute ischemia (Fig 1). The absence of hyperintensity on fluid-attenuated inversion recovery (FLAIR) images indicates an infarct onset of less than a few hours. Within approximately 7 days of the onset of ischemia, the infarct will exhibit DWI hyperintensity with low values on apparent diffusion coefficient (ADC) map. 17 Evidence of a large vessel vasculopathy has been observed in 64% of patients with SCD presenting with an acute infarct. 18 Importantly, the presence of a progressive intracranial large vessel vasculopathy has been associated with a more than tenfold increase in the risk of recurrent stroke. 19 Examining the flow-related signal voids on T2-weighted imaging may indicate stenosed or irregular vessels. However, a dedicated angiogram, either contrast-enhanced CT angiogram (CTA) or time-of-flight MR angiogram (TOF MRA), is usually indicated. Extra-cranial stenosis is rare and an intracranial vasculopathy is usually present. 20,21 Transcranial Doppler (TCD) is used to identify elevated arterial blood velocity within the anterior circulation, which indicates a significant stenosing vasculopathy. Patients with a time averaged mean maximal velocity (TAMM) of >200 cm/s had a 17-fold increase in the risk of ischemic stroke when compared to patients with a normal TAMM (<170 cm/s). 22 Patients with a TAMM >200 cm/s had a 40% risk of stroke in the subsequent 3year period. While less commonly studied, a TAMM below 70 cm/s is also abnormal and associated with an increased risk of stroke. 23 Presumably, low velocities are due to measurements within poststenotic vessels. Annual screening with TCD has been recommended for asymptomatic patients between the age of 2 and 16 years with HbSS genotype. 24 In adults, TCD is not routinely performed as the association between TAMM and stroke risk is less well established. 18,25,26 Abnormal velocities usually require dedicated intracranial angiography, most commonly a TOF MRA, to better evaluate the degree of intracranial vasculopathy. 27 In those with elevated TAMM, the mainstay of stroke prevention is chronic RBC transfusion to reduce HbS to less than 30% of total hemoglobin. Chronic transfusions reduce TCD peak velocity and reduce the risk of stroke by approximately 90%. 28 Where RBC transfusion is not possible, hydroxyurea can reduce the HbS percentage by increasing the fetal variant of hemoglobin, HbF. In a cohort of patients without severe intracranial vasculopathy, hydroxyurea was equally effective at reducing stroke when compared to chronic transfusions. 29

Silent Cerebral Ischemia
Silent cerebral ischemia (SCI) refers to ischemic damage identified on imaging that does not have a clinical correlate. The lesion should be apparent in two planes and measure at least 3 mm in diameter on FLAIR imaging. 30 SCI is associated with cognitive impairment 31-33 and a 14-fold elevated risk of overt ischemic stroke. 34 SCI is more common than overt strokes 35 and is seen in approximately 25% and 39% of patients by the age of 6 and 18 years, respectively. 36,37 RBC transfusions more than halved the risk of new SCI lesions and overt stroke over a 3-year period. 30 This effect was observed in patients with a normal TCD, suggesting that SCI could be a more sensitive method of identifying children at elevated risk of stroke.
By virtue of being asymptomatic, silent ischemic lesions are not usually imaged in the acute phase and therefore appear as hyperintensities on T2-weighted imaging without diffusion restriction. 35 In a study of asymptomatic patients with SCD, the presence of an incidental acute ischemic event, based on low ADC values, was present in 1.3% of children. Interestingly, a particular lesion was only demonstrated in half of cases on subsequent imaging, which implies that at least some silent ischemic events are reversible. 35 Infarct size and location will determine whether it will be silent or symptomatic. In 90% of children, silent ischemic lesions were confined to a relatively small volume of brain tissue within the frontal and parietal watershed areas (Fig 2). 38 The predilection for these areas is explained by the inherently lower blood supply from end arterioles between vascular territories. SCI corresponded to areas of lowest cerebral blood flow (CBF) based on arterial spin labeling (ASL), an advanced MRI technique for measuring parenchymal perfusion without the requirement for intravenous contrast. 38 While SCI and perfusion defects are more common in the presence of proximal stenosis or significant vessel tortuosity, they are also seen in the absence of large vessel vasculopathy, 37 suggesting a contribution to tissue-level hypoperfusion from microvascular pathology. Multiple studies have shown a correlation between ASLderived CBF and hemoglobin concentration, 39 and between ASL-derived CBF and cognitive function. 40 However, there have been no robust studies showing an association between perfusion parameters and the risk of future stroke. Therefore, MR perfusion is not routinely used in clinical practice to guide the management of SCD patients.

Parenchymal Volume Loss
Even in the absence of focal brain lesions, automated segmentation of volumetric MRI studies of patients with SCD has shown volume loss within the cortex, 41 deep gray structures, 42,43 and white matter, 42,44 all of which correlate with reduced cognitive function. Diffusion tensor imaging has also shown reduced white matter tract density and integrity. [45][46][47] Notably, the accelerated parenchymal volume loss observed in children with SCI when compared to healthy controls was not ameliorated by chronic RBC transfusion, 46 unlike the risk of acute ischemic stroke. This suggests differences in the pathophysiology of ischemic stroke and atrophy.
As changes in volume, white matter tract integrity, as well as findings on quantitative MRI, such as gray matter T1 shortening, 48 are observed in otherwise normal brains, focal lesions seen on conventional MRI may represent the "tip of the iceberg." As such, future studies evaluating the association between these findings and the development of clinically significant disease, such as ischemic stroke, will be of great interest.

Moyamoya Syndrome
Endothelial damage and subsequent vasculopathy is a defining feature of SCD. The apex of the internal carotid artery (ICA) and middle cerebral artery (MCA) are particularly susceptible to a progressive steno-occlusive vasculopathy with the development of fragile collaterals. 49 Collaterals arise from the thalamoperforate arteries, lenticulostriate arteries, as well as branches of the external carotid artery that supply the dura and skull base. On catheter angiogram, these collateral vessels appear as a "puff of smoke"--which translates to "moyamoya" in Japanese.
Among patients with SCD who had suffered at least one ischemic stroke, the prevalence of moyamoya syndrome was 43%, 50 although 10.4% of asymptomatic children with SCD also had evidence of a large vessel vasculopathy on MRA. 51 The presence of moyamoya collaterals was associated with 2.4-fold elevated risk of recurrent ischemic stroke. 50 Serpiginous collateral vessels should be sought on T2weighted imaging, where they appear as thready flow-related signal voids. Dedicated angiography is required, such as CTA (Fig 3), to accurately evaluate the degree of stenosis and the extent of collateral vessels. The "ivy sign" is indirect evidence of a proximal stenosis and can be seen as hyperintensity on FLAIR 52 and postgadolinium enhancement 53 caused by slow flow and compensatory dilatation of pial vessels (Fig 4).
Treatment of moyamoya syndrome relies upon optimizing the treatment of underlying SCD. Surgical management can be considered in cases of recurrent stroke. There is a wide variety of surgical approaches to revascularization, which can be categorized as either direct or indirect. Both approaches have different advantages and the choice of procedure depends on the surgical risk and the patient's vascular anatomy. 54 A direct bypass is possible if there is a suitably large branch of the MCA onto which a branch of the superior temporal artery can be anastomosed (Fig 4). The procedure provides immediate revascularization, which also brings the risk of hyperperfusion syndrome, characterized by headache, focal neurological deficits, and seizures. Indirect methods, such as an encephaloduroarteriosynangiosis (EDAS), involves suturing of the galea associated with the posterior branch of the superficial temporal artery into a linear durotomy from which collateral supply to the cortex may develop (Fig 5). While this procedure is technically less demanding than a direct procedure, reperfusion only occurs when collaterals develop. Optionally, a pial synangiosis may be performed whereby the adventitia is sutured to the pia mater, hastening collateral vessel formation.
The MRA of the EDAS shown in Figure 5 highlights a pitfall in time-of-flight MRA. There are short segments where there is no flow-related vessel enhancement despite the presence of efferent flow indicating bypass patency. This loss of signal is usually a consequence of either slow (increasing saturation effects) or turbulent flow (increasing intravoxel dephasing). 55 These artifacts can be reduced by minimizing the MRA echo time, ideally between 3 and 7 milliseconds, and performing 3D rather than 2D image acquisition. 55 With the tendency of TOF MRA to overestimate stenosis sever-ity, a CTA can be considered if more accurate assessment is required.

Intracranial Aneurysms
Aneurysm rupture is the most common cause of intracranial hemorrhage in SCD patients. Sustained endothelial injury causing vessel wall weakening is the presumed reason for increased prevalence of aneurysms in patients with SCD. While a similar pathophysiology is suggested for moyamoya vasculopathy, one study found little correlation between the two entities, 56 which would suggest some differences in the underlying mechanisms. Saccular aneurysms are found on routine imaging in approximately 6% of adults 56 and 4% of children. 4 Compared to the general population, SCD patients are more likely to have multiple aneurysms, 4,56,57 which are more likely to be within the posterior circulation (5-14% vs. 30%). 58,59 The ICA is the most commonly involved artery followed by the posterior cerebral artery. 60 Similar to the general population, the vast majority of aneurysms are saccular. 60 Catheter angiography is the gold-standard for the detection of intracranial aneurysms; however, due to the practical advantages of noninvasive imaging techniques, TOF MRA and CTA are generally preferred (Fig 6). The accuracy of TOF MRA and CTA for unruptured intracranial aneurysms is comparable and generally reported at above 95%. 61  Close follow-up to identify large or enlarging aneurysms is particularly important in the context of SCD where aneurysms are more likely to rupture at smaller sizes when compared to the general population. 62 Among patients with SCD, women between 30 and 39 years of age are at greatest risk of subarachnoid hemorrhage from a ruptured aneurysm. 56 Aside from discrete saccular aneurysm formation, dilatation of the vertebrobasilar system is often seen in the context of SCD and the degree of dilatation was shown to be inversely proportional to hematocrit. 63 Vessel dilatation and tortuosity is potentially a response to a hyperdynamic circulation due to chronic anemia. Intra or extracranial vessel tortuosity, but an otherwise normal brain on MR imaging, was associated with an increased risk of stroke. 64 Given the greater propensity to rupture at smaller sizes, aneurysm treatment has been suggested for aneurysms greater than 5 mm. 65 Clipping after craniotomy has been the standard of care although endovascular coiling and stenting are becoming increasingly common. 66 Treatment of aneurysms is complicated by their multiplicity, the risk of intraoperative sickling, and hypercoagulability increasing the risk of embolization after endovascular insertion of a permanent device. General measures, such as maintaining preoperative HbS below 30%, avoidance of hypoxia, and the use of nonionic contrast medium, are used to mitigate the risk of periprocedural complications. 57

Intracranial Hemorrhage
SCD patients are at risk of hemorrhage within the parenchymal, subarachnoid, subdural, and extradural compartments. Intracranial hemorrhage is less common than ischemic stroke; 4 however, when it does occur, it is more likely to be fatal. 8 While the incidence of ischemic stroke is highest in early childhood, the risk of hemorrhage is greatest in early adulthood, 8,56 where a ruptured aneurysm is the most common cause. 4,6 Parenchymal hemorrhage may be caused by shearing of friable and maximally dilated collateral vessels. Intra-axial hemorrhage is also seen following hemorrhagic transformation of an acute infarct. Subdural and extradural hemorrhages may complicate bone infarction, which is discussed in more detail in the Bone section.
Irrespective of the compartment, acute blood is hyperattenuating on CT, which decreases over time. MRI, specifically FLAIR, gradient echo imaging, and susceptibility weighted imaging (SWI), is at least as sensitive as CT in detecting acute blood. [67][68][69] However, MRI is significantly more sensitive than CT at detecting subacute and chronic blood products. 70 Local susceptibility-induced dephasing causes T2-weighted hypointensity within a parenchymal hematoma, except during the late subacute period when hemoglobin is extracellular. Development of methemoglobin, which causes T1 shortening, occurs in subacute blood. Interpretation of DWI is made difficult by the confounding effects of T2-shine through and T2blackout, but true diffusion restriction may be expected in acute hematoma where RBCs are tightly packed. 71 In the absence of significant mass effect, treatment of hematomas is generally supportive and does not significantly differ from the management of intracranial hemorrhage in the general population. 72 Notably, microhemorrhages are not thought to be common in SCD based on multiple studies using SWI. [73][74][75] This finding underlines differences in the pathophysiology of SCD and other diseases of the microvasculature, such as atherosclerosis and amyloid angiopathy.

Posterior Reversible Encephalopathic Syndrome
Posterior reversible encephalopathy syndrome (PRES) is a radioclinical syndrome characterized by subcortical vasogenic edema that presents with headache, visual disturbance, seizures, and altered mental status. PRES is associated with many conditions, including SCD, where the majority of cases have been described in children in the context of acute chest syndrome, 76 sepsis, 77 and overtransfusion. 78,79 The pathophysiology is multifaceted and not fully understood. Vasogenic edema may be due to increased perfusion pressure from systemic hypertension overwhelming cerebral autoregulation. 80 This causes blood-brain barrier disruption and fluid extravasation. The posterior circulation is more commonly affected due to the reduced sympathetic innervation compared to the anterior circulation, which is important in CBF autoregulation. Much less frequently, cytotoxic edema can occur in PRES, perhaps due to mass effect from the vasogenic edema causing microcirculation compression, 81 or due to severe reduced regional perfusion due to vasoconstriction or vasospasm, which may be partly immune mediated. 82,83 PRES is seen on CT as cortical swelling with mainly subcortical hypoattenuation. While there is a predilection for the parietal and occipital lobes, the watershed regions in the frontal lobes are also commonly involved. Rarely, there is involvement of the basal ganglia or the cerebellum. 84 On MRI, vasogenic edema may give rise to T2-shine through, which is reversible. DWI hyperintensity with corresponding high values on the ADC map implies vasogenic edema. On the other hand, low ADC values imply cytotoxic edema, which implies irreversibility 81 (Fig 7). Intracranial hemorrhage has been reported in between 9% and 33% of cases of PRES, 85,86 while microhemorrhages have been observed on SWI in approximately half of patients. 87 Between 21% and 44% of cases demonstrate patchy postgadolinium enhancement presumably due to endothelial damage causing blood-brain barrier disruption. 85,88 Treatment for PRES is generally supportive with the avoidance of any precipitating factors. Clinical outcome was poorer with increasing severity of edema on T2-weighted imaging and the presence of diffusion restriction. 81,88,89 Like PRES, endothelial dysfunction has been implicated in reversible cerebral vasoconstriction syndrome (RCVS). Two cases of RCVS in SCD patients have been reported in the literature. In one case report, RCVS occurred in an SCD patient immediately following RBC transfusion-a common precipitant of RCVS. 90 In a second case, RCVS was diagnosed alongside PRES and large intracranial hemorrhage. 91 Therefore, despite an overlap in the pathophysiology of PRES and RCVS, a clear association between RCVS and SCD has not been established.

Fat Embolization Syndrome
Fat embolization syndrome (FES) is typically a complication of long-bone fractures caused by fat globules entering the blood. In SCD, bone marrow infarction causes mobilization of fat globules into the systemic circulation via venous sinusoids within trabecular bone, which can cause microvascular occlusion in any organ. Furthermore, a high concentration of circulating  free fatty acids, among other proinflammatory cytokines, causes endothelial damage, disruption of the blood-brain barrier, and ultimately microhemorrhages. [92][93][94] Clinical presentation is usually with respiratory distress, focal neurological deficits, altered mental status and, most specifically, a petechial rash.
While FES remains a very rare complication of SCD, it is becoming more commonly recognized due to the wider availability of more sensitive imaging techniques. A "starfield" pattern of diffuse hyperintensities on DWI may be observed due to small amounts of blood products or focal ischemic damage. Randomly scattered microhemorrhages are best appreciated as punctate hypointensities on T2* images or, ideally, dedicated SWI (Fig 8). 92 In early studies, mortality has been reported to be as high as 64%. 95,96 However, this is likely to be an overestimation due to recent improvements in FES diagnosis and medical management of acute sickling crises. In more recent reports, mortality with and without red cell transfusion were starkly different at 24% versus 92%. 94 With improved survival, there has been an increase in the number of patients with ongoing neurological deficit; only one-fifth of patients return to baseline neurological function. 94 Contrary to all other manifestations of SCD, the majority of FES occur in patients with milder forms of the disease, such as sickle cell trait and sickle cell β-thalassemia. 97 Moreover, patients with sickle cell trait are only half as likely as patients with SCD to make a full recovery. 94 The reason for this is unclear, but immune dysregulation in patients who have not undergone autosplenectomy (which is the most common in patients bearing the HbSS genotype) has been proposed. 96

Bone
The skull and the vertebrae are commonly affected by SCD through vaso-occlusive crises, chronic anemia, and infection. When these entities affect the skull or vertebrae, they are potential causes of headache or back pain. 98,99 The physiological stress caused by increased red cell turnover, low oxygen saturation, and chronic anemia in SCD may cause bone marrow hyperplasia. Impaired blood flow caused by marrow hyperplasia predisposes to sickling, which causes loss of trabecular bone and cortical thinning, bone ischemia, and ultimately osteonecrosis. On radiography, marrow hyperplasia may manifest as widening of diploic space and hairon-end appearance on skull radiograph. Osteonecrosis in the vertebral bodies may cause ill-defined radiolucency and eventually vertebral endplate collapse giving rise to H-shaped vertebra. MRI is significantly more sensitive than plain radiography and is able to detect marrow changes well before endplate collapse. 99 On MRI, bone marrow hyperplasia is seen as vertebral body T1-weighted hypointensity relative to muscle. 100 In more severe anemia, extramedullary hematopoiesis may occur, which is seen as soft tissue surrounding the bones and herniation of avidly enhancing medullary tissue into the paranasal sinuses. 101 Identifying osteonecrosis may be made difficult by persistent T1-weighted and T2-weighed hypointensity caused by persistent red marrow or iron overload from chronic RBC transfusion (Fig 9). 102 Areas of bone marrow infarction cause edema and, potentially, fluid collections appearing as T2-weighted and DWI hyperintensity (Fig 8). 103 Vertebral body osteonecrosis is also associated with intravertebral air, appearing as hypointensity on all MRI sequences. 104 Chronically, areas of infarcted bone become hypointense on both T1-weighted and T2-weighted imaging due to sclerosis and fibrosis. 105 An important complication of bone infarction is the development of subperiosteal hematomas, which can cause raised intracranial or intraorbital pressure. 101,106 A subperiosteal hematoma within the orbit can cause pain, loss of vision, and proptosis. Large hematomas may require surgical decompression or evacuation due to the risk of orbital compartment syndrome.
The loss of normal blood supply to the bone marrow that can cause osteonecrosis also confers an elevated risk of osteomyeli-

Fig 9.
A midline sagittal T2-weighted image of a 12-year-old male with sickle cell disease who had been receiving chronic red blood cell transfusions shows calvarial bone marrow expansion. Furthermore, the low signal in the vertebral bodies was due to iron overload, which was confirmed on MRI of the liver. tis, where Salmonella species are the most likely causative organism. 107 The mandible is more susceptible to osteomyelitis than the skull due to a relatively poor blood supply. 108 Distinguishing osteomyelitis from osteonecrosis on imaging can be challenging, particularly in the early stages of disease where both processes can cause bone marrow edema and subperiosteal fluid collections. Acute vaso-occlusive crises are significantly more common than osteomyelitis. The presence of T1 shortening, due to the presence of sequestered RBCs, may favor bone marrow infarction. 98,109 Second, a fluid collection associated with a bone infarct is more likely to cause susceptibility artifact due to the presence of blood products, while a fluid collection associated with osteomyelitis is more likely to cause diffusion restriction. 110 Vertebral body infarction typically causes is a thin rim of enhancement, while osteomyelitis is more likely to display an irregular, geographic, enhancement pattern. 110 Within the spine, involvement of the disk is more suggestive of infection than osteonecrosis. Chronically, osteomyelitis is more likely than osteonecrosis to cause cortical destruction. 100

Conclusion
There are wide-ranging neuroimaging manifestations of SCD in the early and late stages of disease affecting the vessels, parenchyma, and bone. The cerebral complications are associated with significant neurological and cognitive deficit.
Particularly, as the life expectancy of patients with SCD continues to increase, it is hoped that this review will remind the radiologist of the importance of the early identification of the complications of SCD to enable treatment optimization and minimization of the risk of further neurological impairment in this complex multiorgan disease.