Keywords

1 Introduction

Sickle cell disease (SCD) is an inherited hematologic disorder characterized by the formation of misshapen red blood cells (RBCs) when sickle hemoglobin becomes deoxygenated and polymerizes. SCD causes a broad spectrum of clinical manifestations in various organ systems and is associated with significant morbidity and mortality in children and adults. Imaging plays a crucial role in the detection and description of the extent of involvement of SCD in the brain, head and neck, and spine.

Neurovascular complications, such as cerebrovascular ischemia/infarcts, hemorrhage, various intra- and extracranial vasculopathy, and cognitive impairment, are among the most significant complications in SCD. SCD also affects the osseous structures of the head and neck, including the inner ears. Neuroimaging plays an important role in diagnosing neurological complications of SCD as well as in monitoring the effects of medical and surgical treatments. Currently, neuroimaging of SCD largely relies on various conventional imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), Doppler ultrasound, and catheter angiogram. Recently, quantitative MRI (qMRI) and functional MRI techniques, such as diffusion tensor imaging (DTI), perfusion imaging, and MR spectroscopy, have been introduced to assess and monitor patients with SCD. In this chapter, the pathophysiology, epidemiology, clinical features, and characteristic neuroimaging manifestations of SCD with conventional as well as advanced imaging techniques are reviewed. Current therapeutic approaches and management of SCD and the potential role of imaging in management will also be discussed.

1.1 Etiology, Classification, and Pathophysiology

The term SCD refers to a variety of β-globin (HBB) genotypes that all result in abnormally shaped RBCs. The mutation underlying SCD is an A-to-T transversion in the codon for amino acid position 6 in the β-globin gene. Because of this mutation, a valine residue replaces the normal glutamic acid residue (glu6val) and HbS β-globin chains are substituted for normal β-globin chains [1, 2]. Each hemoglobin molecule contains two β-globin and two α-globin subunits. Hemoglobin with two normal β-globin chains is referred to as hemoglobin A (HbA) and is the major hemoglobin of adults. Fetal hemoglobin (HbF), a molecule of two γ-globin and two α-globin chains, is most prevalent in the fetus and newborns up to about three months of age. Other variant hemoglobin that can be present as compound heterozygotes with HbS are hemoglobin C (HbC), hemoglobin E (HbE), and hemoglobin D (HbD) [1, 2]. SCD is a recessive trait, which means that patients must carry two abnormal alleles of HBB in order for the disease to fully manifest. Homozygosity for the HbS gene or sickle cell anemia is the most common genotype of SCD [1, 2]. HbSC disease is the second most common genotype. SCD can also be caused by compound heterozygosity for HbS and one of the many forms of β-thalassemia. Deoxygenation causes HbS molecules to polymerize, causing RBCs to assume various abnormal shapes, some of which resemble a sickle. The change in shape causes RBC membrane damage and is associated with a decrease in RBC elasticity, rendering them unable to pass through small capillaries. Hemolytic anemia or a shortened lifespan of the RBC is also a feature of this cellular damage [1, 2]. Sickled cells can become irreversibly fixed in the “sickle” shape because of permanent membrane damage and fail to resume normal shape after oxygen tension is restored. These sickled cells and other RBCs can be sequestered in the spleen and other reticuloendothelial cell-containing organs and also lyse in the circulation, leading to anemia.

Patients who carry one abnormal HBB allele and a normal β-globin gene are said to have sickle cell trait (HbAS) and have 60 % HbA and 40 % HbS. HbAS is considered a benign entity with only rare complications. In carriers of HbAS, because each RBC contains 40 % HbS, polymerization of HbS occurs only under special conditions, like in the hypoxic, acidotic, and hyperosmolar conditions of the renal medulla and in the spleen of some people who are hypoxic. One prospective study in patients with HbAS showed that even otherwise asymptomatic patients had a high percentage of vasculopathy, such as arterial tortuosity, but the pathophysiologic consequences remain unclear [3]. Patients with HbAS may develop hyposthenuria and occasional hematuria and have a higher incidence of thromboembolic disease.

The two major pathophysiological processes in SCD are vaso-occlusion and hemolytic anemia that is both intra- and extravascular [1, 2, 4]. 3Vaso-occlusion can occur at both the micro- and macrovascular levels. At the microvascular level, the abnormal adherence of sickled RBCs to the capillary and venule endothelium can lead to intravascular stasis of blood flow. Stasis attracts leukocytes and fosters platelet adherence and degranulation, as well as fibrin deposition. This microvascular occlusion can lead to tissue ischemia and infarct. Inflammation can enhance the expression of adhesion molecules, further increasing the tendency of sickled erythrocytes to adhere to the vascular endothelium, worsening vaso-occlusion [1, 2, 4]. At the macrovascular level, abnormal adhesion of sickled RBCs and white blood cells (WBCs) to vessel sites of high flow turbulence may damage the vascular wall, resulting in intimal hyperplasia of large vessels, stenosis, and progressive occlusion of the large cerebral arteries [5]. Chronic hemolytic anemia from the accelerated breakdown of sickled RBCs may also result in macrovascular occlusion from intimal hyperplasia secondary to an inflammatory cascade triggered by increased free hemoglobin levels [1, 2, 4]. In addition, sickled RBCs may adhere to damaged vessel walls, which can result in secondary thrombosis and distal branch emboli [5–7]. In the past, small vessel occlusion by intravascular sickling and slugging of RBCs was considered to be the primary cause of strokes in SCD. It is now understood, however, that occlusion of small vessels accounts for about 25 % of cerebral infarct in SCD while macrovascular complications account for 75 % [8].

1.2 Epidemiology

SCD is most common in people from sub-Saharan Africa, South and Central America, the Caribbean islands, the Mediterranean countries, India, Saudi Arabia, and their descendants worldwide [1, 2]. It is now estimated that 200,000 children affected with SCD are born every year, approximately 2,000 children in the USA. The estimated US prevalence ranges from 70,000 to 140,000 [4]. About 8 % of African Americans have HbAS. In some regions of Africa, more than a quarter of the populations are carriers; very high gene frequencies are also found in some parts of Saudi Arabia and Greece, in tribal populations of India, and in Brazil [1, 2, 4]. HbAS confers some protection from Plasmodium falciparum malaria; the underlying protective mechanism is still subject of scientific investigation [9].

Mortality in patients with SCD has significantly improved in high-resource countries. The universal newborn screening for hemoglobinopathies has become standard practice in such countries, enabling early diagnosis and patient management [1, 4]. In 2000, the universal administration of the pneumococcal vaccine has further decreased the mortality and morbidity of childhood invasive pneumococcal disease, including in children with SCD. As a result of these programs, SCD-related death fell by 42 % from 1999 through 2002 [10]. It is estimated that 94 % of children with SCD now live to adulthood, and more than 98 % of children with SCD in high-resource countries are living into adulthood [11]. This has caused a mortality shift toward older ages and SCD is considered a chronic condition requiring comprehensive, lifelong management [4]. However, in low-resource countries, more than 50 % of children younger than five years of age die due to complication of SCD [4].

2 Clinical Manifestations

2.1 Painful Episodes

Pain, both acute and chronic, is a hallmark of SCD. Acute painful episodes are the most common vaso-occlusive events with inflammatory and ischemic consequences in patients with SCD of all ages, although they are more common in teenagers and young adults [1, 2, 4]. In young children, one of the first manifestations of SCD is the so-called hand-foot syndrome (i.e., sickle cell dactylitis), a painful swelling of the hands and feet due to inflammation of the metacarpal and metatarsal periosteum. Painful episodes may involve any bones, muscles, mesentery, and other organs. Although acute vaso-occlusive pain is generally self-limiting and does not result in permanent organ damage, increased frequency of pain is associated with early death in patients with SCD who are older than 20 years [12]. The cause of chronic pain is poorly understood, but it can be debilitating and may result from leg ulcers, avascular necrosis of bone, and neuropathic complications [4]. An important consideration for the neuroradiologist is that the skull and maxillofacial bones may be affected by acute pain. Typical symptoms are headaches or localized pain and swelling. Frequently, these are caused by bone infarcts with subperiosteal hemorrhage [13].

2.2 Sickle Cell Acute Events

Besides the painful episodes described above, patients with SCD may also experience splenic and hepatic sequestration crisis, aplastic crisis, acute chest syndrome (ACS), and stroke. In addition, SCD patients are more susceptible to infection and its complications, such as sepsis, pulmonary embolism, pulmonary hypertension, cardiomyopathy, and hepatic disease [1, 2, 4].

Infection with B19 parvovirus can suppress the production of RBCs in patients with SCD for 2 to 3 days, causing an acute, life-threatening aplastic anemia with pallor, tachycardia, and fatigue. Severe anemia can also result acutely from sequestration of blood in the spleen or liver [2]. ACS is the second most common cause of hospitalization among patients with SCD and a leading cause of mortality [14]. ACS is an acute lung injury that causes development of a new alveolar pulmonary infiltrate involving at least one lung segment. ACS is caused by a combination of pulmonary infection, fat embolism, and intravascular pulmonary sequestration of sickled erythrocytes, resulting in lung injury and infarct. Recurrent ACS can lead to chronic respiratory insufficiency. Occasionally, ACS culminates with multi-organ failure [2].

2.3 Infarcts

Infarcts are the consequences of vaso-occlusive crises. Infarcts may involve the brain, liver, spleen, kidney, and bones. Infections often precede vaso-occlusive episodes in children, suggesting that fever, dehydration, and acidosis may be contributing factors [6]. Bone infarction can occur anywhere in the skeleton. It results directly from the sickling of RBCs in the bone marrow, which causes stasis of blood and sequestration of cells [13, 15].

Stroke is one of the most severe complications of SCD because it may result in permanent neurological deficits or death. The incidence of stroke varies depending on the SCD genotype. The prevalence of cerebral vascular accident (CVA) was 11 % in patients under 20 years of age with homozygous HBSS [16]. Ischemic strokes are more common in the children, adolescent, and old adult SCD patients, while the incidence of hemorrhagic strokes peaks between the ages of 20–29 years [16]. Silent cerebral infarcts (SCIs) occur more commonly than overt strokes, with a prevalence of 21.8 % in children with HbSS ages 6–19 years [17]. SCIs are defined as a lesion on MRI, without corresponding neurological deficits lasting longer than 24 h. SCIs are clinically significant because they indicate a higher likelihood of subsequent overt stroke [18]. Although SCD is recognized as a hypercoagulable state, the incidence of venous infarction due to thrombosis is unknown [19].

2.4 Cognitive Deficits

As more SCD patients survive to adulthood, the neurocognitive dysfunction caused by SCD is becoming an emerging problem in young adults [20]. Studies correlating MRI evidence of brain damage have come to controversial conclusions, with some stating that neurocognitive deficits in SCD patients are associated with focal brain injury and silent strokes in children while others state that these deficits are associated more with anemia and age. A recent study suggests that volume reduction of the basal ganglia and thalamus may correlate with cognitive deficits in adult with SCD [21]. These reports suggest that the cause of the neurocognitive impairment is multifactorial and that further correlating studies using functional imaging for cerebral blood flow and hypoxia may be needed [20].

3 Treatment

3.1 Hydroxyurea (HU)

Hydroxyurea (HU) is a drug that promotes the production of HbF, the normal hemoglobin which is more prevalent in newborns. HU is currently the only established preventive pharmacologic treatment for both children and adults with SCD. The presence of HbF inhibits HbS polymerization and higher levels of HbF are associated with reduced mortality in SCD patients [2]. In a randomized controlled trial, HU was shown to decrease the frequency of painful episodes and acute chest syndrome and the need for blood transfusion and hospital admissions in SCD patients [22].

3.2 Blood Transfusion

Chronic blood transfusions have been demonstrated to reduce the risk of both primary and secondary strokes and SCIs [23] and prevent repeated ACS [2, 4]. There is currently no specific treatment for acute stroke in SCD. However, blood transfusion within 48 hours after acute stroke may decrease the incidence of subsequent strokes [24]. The aim of transfusion therapy is to reduce HbS to below 30 %, which effectively prevents overt stroke and SCIs [25]. However, it can result in morbidity related to iron overload and iron deposition in multiple organs, including the liver, heart, and endocrine systems, and often necessitates iron chelation therapy [2, 4].

3.3 Hematopoietic Cell Transplantation

Hematopoietic cell transplantation is the only curative treatment for SCD thus far. However, there is a lack of suitable allogeneic marrow donors (usually HLA-matched siblings) for about 90 % of eligible patients [2]. There is a 5–10 % mortality rate associated with this treatment, mostly due to graft failure, lack of response to first-line immunosuppressive therapy, graft-versus-host disease (GVHD), relapse after the initial successful treatment, and secondary clonal and malignant disease [26]. There are especially poor outcomes in patients over the age of 16 years who are subjected to myeloablative conditioning regimens, making the use of non-myeloablative regimens standard in older patients [2].

4 Neurovascular Complications Concept and Imaging Features

4.1 Stroke

Stroke or CVA is defined as a sudden-onset neurological deficit that persists for more than 24 hours. SCD is one of the most common causes of stroke in children and young adults. The Cooperative Study of Sickle Cell Disease (CSSCD) classified stroke in SCD patients as ischemic, hemorrhagic, or transient ischemic attack [16]. The special forms of ischemic stroke in SCD patients are the so-called silent cerebral infarcts (SCIs) and stroke caused by cerebral fat embolism [27].

Imaging approaches for stroke in SCD patients are the same as for non-SCD patients. The purpose of acute stroke imaging in SCD is to determine the extent of brain damage, to differentiate ischemic stroke from hemorrhagic stroke, and to help identify and delineate underlying vasculopathy.

CT of the brain without contrast is usually the first imaging modality used in the acute setting, which allows for quick assessment of hemorrhagic versus ischemic stroke, for detection of other causes to explain new neurological deficits, and for evaluation of the extent of damage and complications. Other benefits of CT include its easier accessibility and 24/7 availability at most institutions, as well as short exam times [28]. Disadvantages of CT include ionizing radiation exposure, low sensitivity for detection of small infarcts, and low sensitivity for stroke detection in the first several hours [29].

MRI with diffusion-weighted imaging (DWI) is very useful in detecting acute infarcts as well as determining the exact location and extent of ischemic lesions [30, 31]. Apparent diffusion coefficient (ADC) maps in conjunction with DWI help to pinpoint regions of early ischemia and infarct [32]. T2-weighted (T2-WI) imaging and fluid-attenuated inversion recovery (FLAIR) imaging are used for detecting T2 high signal intensity lesions [33], such as acute stroke and silent infarcts. Gradient echo T2*-weighted (T2*WI) images and susceptibility-weighted images (SWI) are used to detect hemorrhagic lesions [34]. While MRI offers the benefits of increased sensitivity for pathology compared to CT and avoidance of radiation exposure, it requires considerable patient cooperation and in many pediatric patients, may require sedation. The other disadvantages of MRI are limited access for acutely ill patients at many institutions and relatively long duration of imaging studies.

Vascular imaging studies in the head and neck may be considered in all patients with SCD, irrespective of whether they had previous episodes of stroke [30, 35]. CTA and MRA can be used to detect intracranial arterial occlusion or stenosis and aneurysms. CTA exposes patients to high levels of ionizing radiations and contrast media; therefore, MRA is preferred in children [30]. MR venography can be useful when venous thrombosis is suspected. Conventional catheter angiogram is an invasive procedure but yields higher anatomical detail of vascular anatomy and pathology than other imaging modalities, including information on hemodynamic function. Catheter angiogram is usually indicated prior to surgery or endovascular interventions [31]. A careful risk–benefit evaluation should be performed prior to subjecting an SCD patient to catheter angiogram. If anesthesia is necessary, special care should be taken in the perioperative care of patients with SCD [36].

4.1.1 Ischemic Stroke

The majority of stroke in SCD is caused by large vessel disease, which may involve the proximal cerebral arteries and the neck arteries [8, 27]. Macrovascular stroke in SCD has imaging features of cortical involvement and is more commonly unilateral [8]. DWI with ADC map is essential for diagnosing acute ischemic infarct and for differentiating it from chronic ischemic changes. Both acute and chronic changes can have high intensity on T2-WI images. With FLAIR imaging, abnormal T2 high signal may be more easily detected than conventional T2-WI imaging, particularly in the periventricular and subcortical regions (Figs.1, 2, 3, 4, and 5).

Fig. 1
figure 1figure 1

A 38-year-old woman with SCD, presenting with altered mental status. (a) Axial FLAIR image shows multiple high signal intensity lesions of the bilateral periventricular white matter (arrows). (b, c) Corresponding axial DWI (b = 1,000) (b) with ADC map (c) shows multiple foci of restricted diffusion in the left periventricular white matter consistent with acute infarcts (arrows). Right periventricular lesions suggest chronic ischemia or prior infarcts

Full size image
Fig. 2
figure 2figure 2

A 6-year-old girl presenting with right-sided weakness. (a, b) Axial FLAIR images show multiple high-signal-intensity lesions at the left frontal border zone (watershed) areas (arrows). (c, d) Corresponding axial DWI (b = 1,000) shows restricted diffusion in the left MCA territory and border zone larger than that shown on FLAIR images consistent with acute infarct (arrows). (e) Axial T2-WI image shows loss of flow voids in the left proximal MCA (arrow). (f) MRA shows obvious stenosis of left MCA (arrow) and decrease of flow-related signal distally

Full size image
Fig. 3
figure 3figure 3

A 16-year-old woman presenting with headache and syncope. (a) Axial FLAIR image demonstrates encephalomalacia (asterisks) with surrounding gliosis (arrows) in the right frontoparietal ACA-MCA border zone (watershed) distribution indicating old ischemic changes. (b) MRA shows decreased caliber and flow-related signal with wall irregularity of the visualized right extracranial ICA (arrows)

Full size image
Fig. 4
figure 4figure 4

A 22-year-old woman presenting with seizure. Axial T2-WI image shows bilateral frontal high signal intensity, indicating chronic ischemic changes and encephalomalacia (asterisks), predominantly in ACA-MCA border zone (watershed) distribution

Full size image
Fig. 5
figure 5figure 5

A 14-year-old girl presenting with past episode of right hemiplegia. Axial FLAIR image shows high signal (arrows) and prominent sulci (asterisks), indicating volume loss and gliosis with cortical involvement in the left cerebral hemisphere

Full size image

Arterial stenosis or occlusion is often seen in conjunction with infarcts of the cerebral gray matter (the cortex, basal ganglia, and thalamus) (Fig. 2). However, white matter infarcts can be seen in the setting of arterial stenosis or occlusion as well, particularly in border (watershed) zones [8] (Fig. 3). The anterior circulation is more often involved than the posterior circulation. The radiologist should screen for loss of vascular flow voids on T2-WI images, which may indicate vasculopathy (Fig. 2e). FLAIR imaging can show high signal in cortical vessels in the setting of altered flow velocities, such as slow distal flow of a stenotic arterial branch or leptomeningeal collaterals [37] (Fig. 6). In these cases, the radiologist may decide to add brain MRA or recommend other angiographic imaging such as CTA or catheter angiogram for further evaluations regarding diagnosis, treatment, and management.

Fig. 6
figure 6figure 6

A 10-year-old girl presenting with left facial droop, drooling, and hand tingling. (a) (b) Axial FLAIR images show multiple high signal intensity vessels in the Sylvian fissure and frontoparietal sulci (arrows), indicating slow flow or thrombosis. (c) MRA shows loss of flow-related signal in the right MCA distribution (asterisks) and bilateral proximal ACAs (arrows)

Full size image

4.1.2 Hemorrhagic Stroke

Hemorrhagic stroke in SCD is relatively more common in adults than in children. Although it is rare, primary hemorrhagic stroke, such as subarachnoid and parenchymal hemorrhage, is frequently fatal in SCD patients. Aneurysms are the most common identified cause of subarachnoid hemorrhage in adult patients with SCD [27], although their exact prevalence is unknown. Compared with patients without SCD, aneurysms in SCD patients are often multiple, have an increased propensity for the posterior cerebral circulation, and may be prone to rupture at smaller sizes [38]. Moyamoya syndrome is a common cause of parenchymal hemorrhage in SCD in children [8], which will be discussed later in more detail.

Non-contrast CT is the first imaging modality of choice in the diagnosis of acute hemorrhagic stroke (Figs. 7 and 8). In the current clinical practice, MRI may occasionally be obtained prior to CT when there is high suspicion for acute stroke based on clinical symptoms. Radiologists should be familiar with the MR imaging features of acute hemorrhage that are the same as non-SCD patients, to avoid delayed diagnosis of hemorrhagic strokes. The accuracy of MRI in detecting acute parenchymal hemorrhage is similar to CT, especially when gradient echo sequences, such as T2*-WI imaging and SWI, are used [39]. Catheter angiogram using three-dimensional (3D) digital subtraction angiography is still the gold standard for the diagnosis and preoperative delineation of intracranial aneurysms. Noninvasive techniques such as MRA and CTA are more commonly used, and recently their accuracy is considered satisfactory [40, 41]. CTA is often the first-line modality to search for underlying aneurysms in the setting of acute subarachnoid hemorrhage, while MRA is commonly used in the non-acute setting (Figs. 9 and 10).

Fig. 7
figure 7figure 7

A 20-year-old man presenting with altered mental status. Axial non-contrast CT shows a high density area in the right frontal lobe white matter with surrounding low density indicating edema (arrow), compatible with acute hemorrhage

Full size image
Fig. 8
figure 8figure 8

A 14-year-old boy presenting with severe headache. Axial non-contrast CT shows high density in the right Sylvian fissure consistent with acute subarachnoid hemorrhage (arrows)

Full size image
Fig. 9
figure 9figure 9

A 34-year-old man presenting with headache. (a) MRA shows an ovoid focus of flow-related signal arising from the junction of the cavernous–clinoid segments of the left ICA extending inferiorly, consistent with an aneurysm (arrow). (b) Catheter angiogram of the left ICA lateral view confirmed the aneurysm (arrow)

Full size image
Fig. 10
figure 10figure 10

A 22-year-old man presenting with headache and vertigo. (a) Axial FLAIR image shows multiple high signal foci (arrows) in the left frontal white matter without abnormal diffusion restriction (not shown) consistent with silent cerebral infarcts. (b) MRA shows a 3 mm aneurysm at the medial portion of the left IC-ophthalmic segment (arrow). Tortuous extracranial right internal carotid artery and bilateral vertebral arteries are also noted (open arrows)

Full size image

4.1.3 Silent Cerebral Infarct (SCI)

SCI is the most common neurovascular complication in both pediatric and adult patients with SCD. SCIs have been seen in children under the age of 6 years [42]. They may represent a different pathogenesis from either ischemic or hemorrhagic strokes as they involve small vessels in watershed distributions instead of the larger cerebral vessels [43]. Measurement of arterial velocities with transcranial Doppler (TCD) ultrasound are not predictive of SCI risk, unlike with overt ischemic stroke, which supports a different pathophysiology between overt stroke and SCI [44]. Several studies showed that SCIs are more frequent in patients with arterial stenosis and intracranial arterial tortuosity, suggesting that large vessel disease may play a role in the pathophysiology of these lesions [42, 45, 46]. Children with arterial stenosis are at higher risk of brain parenchymal injury as they have more SCIs [47] (Fig. 10).

The presence of SCI is considered a predictor of future strokes [17, 48, 49]. SCIs have been shown to progress in both number and size over time [49]. Associated neurocognitive abnormalities also may be progressive [50]. Small foci of acute SCI may be found in asymptomatic children with SCD [42]. SCIs may continue to progress in spite of initiation of chronic transfusion therapy after a stroke [51]; however, a recent study showed that in patients without a stroke and not at high risk of a stroke, chronic transfusions reduced the occurrence of new SCIs by 56 % over a median observation period of 3 years [23].

SCIs are defined as T2 high signal intensity lesions of at least 3 mm in the greatest linear dimension in children and 5 mm in adults, visible on at least two planes of T2-WI images [20, 52] (Figs. 11 and 12). Because of their small size, detection of SCI depends largely on the MR imaging technique, such as the use of FLAIR, slice thickness, multiplanar acquisitions, and the magnetic field strength [53]. With further advances in imaging and more utilization of 3.0-T or higher magnet field units, it is likely that more cases of SCI will be detected in individuals with SCD [49].

Fig. 11
figure 11figure 11

A 6-year-old girl presenting with SCD for screening MRI. Coronal FLAIR image shows high signal foci in the right frontal subcortical white matter (arrow), compatible with silent cerebral infarct

Full size image
Fig. 12
figure 12figure 12

A 42-year-old woman presenting with left facial numbness. (a) Axial FLAIR image shows multiple high signal intensity lesions in the right frontoparietal white matter (arrows). (b) DWI (b = 1,000) shows corresponding restricted diffusion in the postcentral gyrus consistent with acute infarct (arrow)

Full size image

4.1.4 Cerebral Fat Embolism

Fat embolism syndrome is a very rare but potentially lethal complication of SCD that is not widely recognized [54]. In non-SCD patients, fat embolism syndrome is usually a complication of long bone fractures. The pathogenesis of fat embolism syndrome in SCD remains controversial. It is thought to be caused by bone marrow infarcts and necrosis, with subsequent embolization through osseous venous channels into the venous circulation. Neurologic dysfunction in the setting of fat embolism syndrome may result directly from vessel occlusion by fat emboli, from disruption of the blood–brain barrier by toxic free fatty acids, or both [54, 55].

Typical MR imaging findings of cerebral fat embolism include tiny foci of restricted diffusion and corresponding T2 high signal intensities representing microinfarcts. Lesions can involve the cerebral white matter, basal ganglia, thalamus, brain stem, and cerebellum. This MR imaging pattern, sometimes called a “starfield” pattern, is not very specific and can also be seen in cardiogenic or septic emboli, vasculitis, and tiny hemorrhagic metastases [54]. T2*-WI images and SWI frequently demonstrate microhemorrhages in cerebral fat embolism [55].

4.2 Moyamoya Syndrome

Vascular pathology in SCD includes arterial tortuosity, stenosis, occlusion, and aneurysm formation. A special form of cerebrovascular manifestation in SCD patients is “moyamoya syndrome,” a progressive stenosis of major intracranial arteries with formation of numerous collateral circulations, typically via lenticulostriate and thalamoperforating arteries (Fig. 13). Moyamoya syndrome typically involves the distal ICA (internal carotid artery) and proximal ACA (anterior cerebral artery) and MCA, with relative sparing of the posterior circulation. The name moyamoya syndrome is derived from moyamoya disease, a rare, presumed genetic, progressive cerebrovascular disorder. The term “moyamoya” means “puff of smoke” in Japanese and refers to the appearance of collateral vessels on cerebral angiogram [56]. The pathophysiology of moyamoya syndrome in SCD is poorly understood. It is hypothesized that sickle-shaped RBCs occlude the vasa vasorum of the carotid arteries [31], leading to intimal hyperplasia [57]. The prevalence of moyamoya syndrome in SCD patients has been reported for 35 % of conventional catheter angiogram studies [7] and in 20–40 % of MRA studies [8, 58]. It was shown that 75 % of patients with moyamoya syndrome demonstrated radiographic progression of arteriopathy and 65 % of patients showed clinical progression during follow-up [59] (Fig. 14).

Fig. 13
figure 13figure 13

A 24-year-old man presenting with multiple episodes of ischemic infarct. (a) Axial FLAIR image shows bilateral periventricular high signal intensity with cystic foci compatible with old ischemic change (arrows). (b) MRA shows occlusion of the right ICA terminus (asterisk) and severe stenosis of the left ACA (arrow) and distal MCA (open arrow). (c) Catheter angiogram of the right ICA shows occlusion of the supraclinoid ICA (arrow). Posterior communicating artery (PComm) is markedly prominent (asterisk) and diffuse moyamoya-like collateral vessels are noted (open arrows). (d) Subsequent image of the ICA catheter angiogram shows more apparent “moyamoya” (puff-of-smoke) appearance of the collateral vessels (open arrows)

Full size image
Fig. 14
figure 14figure 14

A 15-year-old man presenting with recurrent headache. (a, b) In 2005, Axial FLAIR image (a) shows normal brain and MRA (b) shows possible stenosis of the right proximal ACA and bilateral proximal MCA (asterisk). (c, d) In 2006, axial FLAIR image (c) still shows normal brain, but MRA (d) shows obvious occlusion of the right terminal ICA (asterisk). The patient received bilateral pial synangiosis for cerebral revascularization in 2007. (e, f) In 2013, axial FLAIR image (e) shows bilateral frontal old infarcts with encephalomalacia and gliosis (arrows). MRA (f) shows bilateral occlusion of the terminal ICAs (asterisks) and bilateral prominent superficial temporal arteries (arrowheads) after revascularization. Serial FLAIR images and MRA images over 8 years demonstrate progression of arterial stenosis, bilateral frontal lobe infarcts, and atrophy in spite of revascularization

Full size image

Moyamoya syndrome can be detected on MRA as progressive large vessel occlusions and major collateral flow patterns, the so-called moyamoya vessels. On T2-WI images, moyamoya syndrome presents with loss of flow voids in the circle of Willis (Fig. 15) and on time-of-flight MRA as a loss of flow-related signal (Fig. 16). Collaterals typically present as multiple flow voids on T2-WI and T1-WI images in the thalamoperforate and lenticulostriate territories. High signal intensity vessels within the cortical sulci on FLAIR images can indicate a decreased flow of cortical arteries [37] (Fig. 6).

Fig. 15
figure 15figure 15

A 22-year-old woman presenting with seizure. Axial T2-WI image shows loss of normal flow voids of the bilateral MCA and ACA (arrows). In contrast, prominent posterior circulation flow voids are noted (arrowheads)

Full size image
Fig. 16
figure 16figure 16

A 38-year-old woman with SCD presenting with altered mental status. MRA shows multiple stenoses and occlusions of the right ICA terminus, bilateral ACAs, bilateral PCAs (posterior cerebral artery), and left MCA (arrows)

Full size image

Incidentally discovered asymptomatic moyamoya syndrome in children has the potential to progress, both radiographically and clinically. Monitoring and screening with imaging in high-risk patients facilitates early referral to neurosurgery and allows for timely revascularization therapy [59]. Patients with moyamoya syndrome may have a particularly poor prognosis and may benefit from revascularization of ischemic brain parenchyma by establishing collaterals from the external carotid artery (ECA) branches to the ICA territories [60]. Superficial temporal artery (STA) to middle cerebral artery (MCA) bypass is a direct revascularization procedure, which is technically difficult. Indirect revascularization procedures such as encephaloduroarteriosynangiosis (EDAS) and pial synangiosis are becoming popular for the surgical treatment of moyamoya syndrome [61]. Pial synangiosis is a technique in which the dura and the arachnoid are opened and the STA adventitia is sutured directly to the pia [62], and it has a relatively low risk of complications [63]. Pial synangiosis typically results in an increase in collaterals from the STA or middle meningeal artery (MMA) to the brain [62]. MRA or CTA can be used to monitor the patency of synangiosis between STA branches and pial arterial branches after cerebral revascularization (Fig. 14) .

4.3 Extracranial Vasculopathy

Extracranial ICA stenosis is rare, but it has been reported that there is an association between the presence of extracranial internal carotid arteriopathy and stroke risk in SCD [64–66]. Doppler ultrasound screening studies found stenosis or occlusion of the cervical ICA in 3–6 % of the children, and the majority of these also had strokes [65]. One MRA study reported that patients with an acute neurologic event, TCD abnormalities, and previous history of stroke also showed cervical ICA stenosis and/or occlusion. The most commonly involved artery is the proximal ICA, within 1 cm from its origin from the CCA [66] (Fig. 17). In addition, a recent study showed that the high velocity of extracranial ICA detected with submandibular Doppler ultrasound is highly predictive of intracranial arterial stenosis seen on MRA [67]. The differential diagnosis of extracranial ICA stenosis and/or occlusion includes atherosclerosis, arteritis, and fibromuscular dysplasia. Age, location, and lack of systemic inflammation or hypercoagulability help differentiate SCD-related extracranial internal carotid arteriopathy from other conditions [68].

Fig. 17
figure 17figure 17

A 30-year-old woman with SCD, evaluation for revascularization. (a) Catheter angiogram of the right CCA (lateral view) shows complete occlusion of the extracranial ICA near its origin (arrow). (b) Catheter angiogram of the left CCA (lateral view) shows stenosis of the ICA at the ophthalmic segment (arrow). (c) Catheter angiogram of the left subclavian artery shows tortuosity of the left VA (arrows)

Full size image

Arterial tortuosity is considered to be an adaptive response to chronic anemia in patients with SCD. Chronic anemia is associated with increased cardiac output and high blood flow velocity due to the increased need for blood supply, which can lead to arterial tortuosity and can occur in all cervical arteries [68]. Cerebrovascular tortuosity may serve as a predictor of chronic brain hypoxia [53]. On imaging, tortuosity can be diagnosed when the following features are present: dilatation or ectasia of an artery segment, abnormal increase in length of an arterial segment, and obvious bowing of an artery [53, 69] (Figs. 17, 18, and 19) .

Fig. 18
figure 18figure 18

A 34-year-old woman with SCD, presenting for annual MRI follow-up. MRA shows no significant stenosis or occlusion of the intracranial arteries; however, dilatation and elongation of the extracranial left ICA are seen (arrows)

Full size image
Fig. 19
figure 19figure 19

A 20-year-old man with SCD. MRA shows tortuous left extracranial ICA (arrows) and aneurysmal dilatation of the extracranial segment of the left VA (open arrow)

Full size image

5 Posterior Reversible Encephalopathy Syndrome (PRES)

There have been several case reports of posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (RPLS), in patients with SCD [70–74]. The vast majority of the patients are in the pediatric population [71]. It is believed that there are two major pathomechanisms in PRES: a cytotoxic event after an increase in blood pressure that causes vasoconstriction and cerebral ischemia or a vasogenic etiology where hypertension in combination with endothelial dysfunction and failure of cerebral autoregulation causes vasodilation [70]. Studies have identified PRES as a common neurological complication of SCD, and this entity needs to be considered when evaluating a child with acute neurological deterioration, especially if the patient is hypertensive, has history of ACS, and has received systemic steroid therapy or blood transfusion [72–74]. A diagnosis of PRES may predict a high risk for morbidity and mortality [73]. On MR imaging, PRES usually presents as symmetrical areas of high signal intensities on T2-WI and FLAIR images without associated restricted diffusion, suggesting vasogenic edema, which is the same as non-SCD patients [73] (Fig. 20) .

Fig. 20
figure 20figure 20

A 5-year-old girl with SCD, presenting with headache and hypertensive status. Axial FLAIR image shows high signal intensity lesions in the bilateral occipital lobes (arrows). Given the distribution, clinical course, and documented hypertension, the findings are compatible with PRES

Full size image

6 Other Sickle Cell Disease Imaging Manifestations

There are several osseous complications related to SCD. These include chronic bone marrow changes in response to long-standing anemia and acute bone infarcts as well as osteomyelitis. Osteoporosis and iron deposition in the bone marrow due to repeated transfusions can also be seen [13, 15, 68, 75, 76].

6.1 Craniofacial Bone

6.1.1 Bone Marrow Hyperplasia

As a result of chronic anemia in SCD patients, the red marrow in bony erythrocyte production never undergoes the conversion to fatty yellow marrow [68, 75]. Furthermore, as the anemia becomes more severe and long-standing, the bone marrow spaces expand secondary to increased RBC production [68, 75]. This marrow expansion is most frequently noted clinically in the skull and facial bones. The non-conversion of the bone marrow is demonstrated by diffuse low signal intensity on T1-WI images relative to the signal in the intervertebral disks [15] (Figs. 21 and 22).

Fig. 21
figure 21figure 21

An 18-year-old man with SCD. Sagittal T1-WI image shows the diffuse expansion of the marrow space of the skull (arrows)

Full size image
Fig. 22
figure 22figure 22

A 10-year-old boy with SCD, presenting with back pain. Sagittal T1-WI image of the lumbar spine shows low signal in the vertebral bodies (asterisks) relative to the intervertebral disk, compatible with an activated bone marrow triggered by chronic anemia. Note also the “H”-shaped deformity of vertebral bodies, compatible with end-plate infarcts and subsequent height loss

Full size image

6.1.2 Bone Infarct

Bone infarcts are more common than osteomyelitis among children with SCD. Ischemia causes pain, even before infarct occurs. For SCD patients presenting with headache or localizing facial pain, acute craniofacial bone infarct should be a major diagnostic consideration [13, 15]. The orbital walls, mandible, cranial vault, and skull base are commonly affected by bone infarcts in SCD patients [13, 15] (Fig. 23). In the spine, it is hypothesized that bone infarcts contribute to the characteristic “letter H” deformity of vertebral bodies that is typical of patients with SCD [77] (Fig. 22).

Fig. 23
figure 23figure 23

A 6-year-old boy presenting with temporomandibular joint pain and headache. Axial fat-suppressed T2-WI image demonstrates high signal intensity in the left mandibular ramus (arrow), compatible with bone infarct

Full size image

MR imaging is more sensitive than CT in detecting bone infarcts. MR imaging findings of acute bone infarcts include increased signal on T2-WI images, particularly with fat-suppression techniques such as STIR, and associated high signal intensity on DWI with corresponding low signal intensity on ADC map (Fig. 24). There may also be subperiosteal hemorrhage. The high signal intensity of the affected bones on fat-suppressed T1-WI images, which may represent the sequestered RBCs in the infarcted marrow [13, 78], can be very helpful in the differentiation of bone infarcts from osteomyelitis (Fig. 25).

Fig. 24
figure 24figure 24

A 15-year-old boy with SCD, presenting with headache. (a) Coronal T2-WI image shows high signal intensity in the skull consistent with bone marrow edema (arrows), as well as mixed abnormal signal intensity in the subgaleal fluid collection consistent with hemorrhage (open arrow). (b) Axial DWI (b = 1,000) shows an area of increased signal in the skull, compatible with bone infarct (arrows)

Full size image
Fig. 25
figure 25figure 25

A 17-year-old man presenting with headache. Sagittal T1-WI image shows high signal intensity of the bone marrow in the parietal bone consistent with bone infarct with hemorrhage (arrow) (Adapted with permission from Lippincott Williams and Wilkins/Wolters Kluwer Health: Journal of Computer Assisted Tomography [13], copyright (2013))

Full size image

6.1.3 Osteomyelitis

Osteomyelitis is less common than bone infarcts and typically affects long bones. However, osteomyelitis may also occur in craniofacial bones, particularly the mandible, because of its relatively poor blood supply [13, 68] (Fig. 26). Differentiation between infarct and osteomyelitis in early presentation with imaging alone can be quite challenging. The typical MR imaging findings, including bone marrow edema, heterogeneous bone marrow enhancement, and soft tissue swelling, can be seen in osteomyelitis as well as bone infarcts. In the presence of fluid collections, MR susceptibility artifact is suggestive of blood products from subperiosteal hematoma, which is more commonly seen with bone infarcts. Infectious fluid collections may exhibit restricted diffusion [13].

Fig. 26
figure 26figure 26

A 25-year-old man presenting with left jaw swelling and pain. Coronal contrast-enhanced CT shows peripherally enhancing low density fluid collections medial and lateral to the left mandibular ramus (arrows), consistent with subperiosteal abscess formation

Full size image

6.2 Temporal Bone

Sensorineural hearing loss (SNHL) is a well-recognized inner ear complication of SCD [68, 79]. The most accepted pathogenesis of SNHL is the recurrent vaso-occlusion of the labyrinthine blood vessels, either in the distribution of the anteroinferior cerebellar artery or a branch of the basilar artery, which can result in labyrinthine hemorrhage (LH) and labyrinthitis ossificans (LO) [79]. In the past, LH was considered relatively rare in patients of SCD with sudden-onset SNHL and vertigo, but it was recently shown that abnormalities can be detected by MR imaging in approximately one-third of SCD patients with inner ear symptoms, with males preferentially affected [79].

High signal intensity on non-contrast high-resolution T1-WI images is a characteristic finding for LH. Contrast-enhanced T1-WI images can exclude tumors such as schwannomas and hemangiomas that would show intense and localized enhancement, and fat-suppressed MR imaging or high-resolution temporal bone CT may be used to exclude lipoma and fat-containing tumors (Fig. 27).

Fig. 27
figure 27figure 27

A 14-year-old man presenting with sudden onset of right-sided hearing loss. Axial T1-WI image shows high signal intensity in the right cochlea (arrow) compared to left, suggesting labyrinthine hemorrhage

Full size image

The characteristic imaging finding of LO is the high density of the membranous labyrinth on CT. On high-resolution T2-WI images, the normal T2 high signal from the fluid in the membranous labyrinth is lost. LO is the end stage of labyrinthitis, characterized pathologically by proliferation of fibroblasts and finally osteoblasts. In patients with SCD presenting with inner ear complaints, dedicated temporal bone imaging should be performed, preferably by MR imaging (Fig. 28).

Fig. 28
figure 28figure 28

A 12-year-old boy presenting with hearing loss. (a) Axial high-resolution T2-WI image (DRIVE sequence) shows signal loss of the right cochlea (asterisk). (b) Axial CT shows ossification of the cochlea corresponding to signal loss on MRI (a), consistent with labyrinthitis ossificans (arrow)

Full size image

7 Advanced Imaging

7.1 Diffusion Tensor Imaging (DTI)

Diffusion tensor imaging (DTI), which measures the directional tendencies of Brownian water molecule motion in biologic tissues, has a potential to detect and quantify microstructural brain changes earlier than conventional MRI [80]. This advanced MRI technique can show the orientation and integrity of white matter fibers in vivo. The apparent diffusion coefficient (ADC), which is comparable to mean diffusivity as a measure of the degree of restriction to water diffusion, and fractional anisotropy (FA), a measure of the preponderant directionality of water diffusion, are two of the most frequently used DTI metrics for measuring microstructural tissue damage in patients with brain disease [80]. DTI directionality information is used for fiber tractography, which is the only way to obtain 3D fiber architecture of white matter tracts in vivo [80].

Using region of interest (ROI) based analysis in a study comparing SCD patients with controls, FA values in the prefrontal segment of the corpus callosum (which covers the first sixth of the corpus callosum), upper frontal white matter area, centrum semiovale, anterior periventricular white matter area, posterior periventricular white matter area, and brain stem were significantly lower in SCD patients than controls. ADC values were significantly higher in SCD patients compared to controls in the prefrontal segment of the corpus callosum and sensory segment of the corpus callosum (which covers the posterior one-third but not including the posterior one-fourth), caudate nucleus, thalamus, and pons [81]. The increase in ADC along the fibers may indicate extracellular water content increase secondary to axonal loss and fiber density reduction, both of which could be attributed to chronic ischemia. One study found a significant reduction in DTI fiber counts in the corpus callosum of SCD patients compared to controls. A significant reduction in DTI fiber counts was also observed in the corticospinal tracts bilaterally. These results can be explained by axonal damage due to vasculopathy [81].

7.2 Perfusion Imaging

Perfusion imaging can be achieved with contrast-enhanced CT, contrast-enhanced MRI, non-contrast MRI with arterial spin labeling (ASL) technique, and positron emission tomography (PET) imaging [82]. Perfusion imaging does not affect treatment decisions in SCD patients. However, there is value in studying brain perfusion in SCD to better understand the pathophysiology of the disease. Perfusion imaging allows the calculation of relative cerebral blood flow (CBF) and blood volume in the brain. Because of the very high radiation dose compared to conventional head CT, CT perfusion and PET imaging should be cautiously used in children [82]. Perfusion MRI techniques commonly used include dynamic susceptibility contrast (DSC) MRI and ASL. Compared with ASL, DSC MRI perfusion provides higher spatial resolution, requires shorter scanning time, and can measure other hemodynamic parameters such as cerebral blood volume (CBV) and mean transit time (MTT) simultaneously [83]. ASL using either continuous or pulsed ASL sequence is a noninvasive MR perfusion imaging technique that uses arterial blood water protons as an endogenous tracer of perfusion [84–86] (Fig. 29). Perfusion imaging studies can show changes of cerebral blood flow immediately after the event [87]. ASL studies of whole brain CBF in SCD patient compared to controls have been controversial [84–86]. ASL has been used to correlate CBF with both full-scale and performance IQ [85]. Using ASL, studies have identified right-left CBF asymmetries that could be early indicators of subclinical pathological changes in microvasculature and/or hemodynamics in SCD patients. The described perfusion asymmetries, however, could not always be associated with the presence of ischemic lesions [84–86].

Fig. 29
figure 29figure 29

A 10-year-old boy with SCD presenting with acute visual symptoms. (a) Axial DWI (b = 1,000) shows mildly increased signal in the bilateral parietal lobes. (b) Arterial spin labeling perfusion image shows decreased blood flow in the bilateral parieto-occipital lobes (arrows). (c) Axial DWI (b = 1,000) 2 days after the initial MRI shows discrete areas of diffusion restriction in the bilateral parietal lobes (arrows) and in the left frontal periventricular watershed distribution (open arrows)

Full size image

7.3 MR Spectroscopy (MRS)

MR spectroscopy (MRS) is an advanced MR imaging method for quantitative and qualitative assessment of the metabolic state of brain tissue. Reports of MRS in SCD are limited. In 1992, one study showed that normally appearing brain tissues on conventional MRI did not show abnormal MRS findings [88], meaning there was no additional increase in sensitivity in disease detection with MRS. The same group reported a reversible temporary decrease of N-acetylaspartate (NAA), which is considered a marker of neuronal tissue, at the time of a stroke episode [89]. Another study showed that NAA was increased in the basal ganglia and generally in the brain of SCD patients [90]. These results suggest that brain NAA appears not to be a reliable marker of viable neurons in SCD patients at this moment.

7.4 Quantitative MRI (qMRI)

Remarkable advances in MR imaging have led to the development of a variety of quantitative MR imaging (qMRI) techniques, including diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), relaxometry, magnetization transfer imaging, perfusion imaging, MR spectroscopy, and volumetry [91].

qMRI studies of T1 spin–lattice relaxation times have shown reduced gray matter relaxivity in pediatric patients with SCD compared to healthy controls [92, 93], especially in the caudate nucleus and in cortical gray matter. In addition, volumetric deficits of gray matter in patients with SCD were reported in the absence of volumetric deficits in the white matter [94]. These observations support the idea that gray matter is selectively vulnerable to injury in pediatric SCD patients. In the future, the use of qMRI techniques, such as T1 values and volumetry, may serve as early markers of brain damage in young SCD patients [92–94].

qMRI studies examined with mixed TSE pulse sequence showed T1 lengthening, T2 and secular-T2 shortening, and an increase in bone marrow volume in patients with SCD [75, 76]. The T1 lengthening supports the fact that there is less yellow marrow volume and more red marrow volume in patients with SCD, which suggests the failure of red-to-yellow marrow conversion. T2 and secular-T2 shortening also supports the failure of red-to-yellow marrow conversion. Increased iron deposition as a result of hemolysis in subjects with severe disease and repeated blood transfusions can account for the shortening of T2 and secular-T2 times. By using the specific changes seen in T1, T2, and secular-T2 relaxation times, qMRI can be a useful tool in the assessment and monitoring of disease severity in patients with SCD [75, 76]. In addition, qMRI has been used to evaluate the extracranial structures, such as salivary glands [95] and lacrimal glands [96].

7.5 Nuclear Medicine

Brain perfusion single-photon emission computed tomography (SPECT) is a functional neuroimaging technique that allows for noninvasive evaluation of the physiological and pathophysiological status of the brain. SPECT imaging may demonstrate cerebral perfusion deficits in SCD patients with normal brain MR images. One study found that neurologically intact adult SCD patients exhibit brain perfusion decreases in areas such as the basal ganglia, thalamus, watershed areas of the anterior circulation, and cerebellar and occipital cortex [97]. These findings may contribute to the understanding of the mechanisms underlying the evolution of cerebral vasculopathy in SCD patients. Calculation of cerebrovascular reserve with acetazolamide (Diamox)-induced cerebrovascular vasodilatation in conjunction with SPECT imaging has a role in identifying SCD patients who are at a high risk for stroke [98].

S ince the late 1990s, perfusion and metabolic imaging techniques, such as positron emission tomography (PET), have been increasingly used to investigate the microvascular blood flow in patients with SCD. One study showed that PET may detect abnormalities missed by structural MRI in patients with SCD and a history of stroke [99]. Another study found that metabolic compromise in SCD patients exceeded the corresponding anatomic abnormality demonstrated on MRI [100].

8 Management

8.1 Prevention of Primary Stroke

Early screening of SCD patients with TCD ultrasound is the gold standard for assessing stroke risk [25]. In the absence of early TCD screening, stroke occurs in 7.4 % and 11 % of patients with SCD by 14 and 20 years of age, respectively, [16, 101] and by age 30 and 45 years, 15 % and 24 % will experience overt stroke, respectively [16, 102]. In a newborn cohort, an early TCD screening and transfusion program employed in patients at risk decreased the overt stroke risk to 1.9 % by 18 years of age [103]. It has been recommended to obtain serial TCD and brain MRI/MRA studies to monitor the effectiveness of transfusion in children with abnormal TCD velocities [104] (Fig. 30).

Fig. 30
figure 30figure 30

An 8-year-old boy with SCD presenting with annual follow-up with transcranial Doppler screening. Peak systolic velocity (PSV) in the left MCA was 258.7 cm/s (<200, normal; 200–249, conditional; ≥250 abnormal). Follow-up MRA showed left MCA stenosis (not shown)

Full size image

The time-averaged mean of the maximal velocity (TAMMV) in large intracranial arteries is a powerful, noninvasive tool that can be utilized to classify an individual patient’s risk of stroke [25]. According to the TCD criteria for SCD, TAMMV < 170 cm/s in any intracranial artery is considered normal, and TAMMV of 170–199 cm/s is conditional. TAMMV > 200 cm/s is considered abnormal and indicates the need for transfusion. TAMMV > 200 cm/s is associated with a 40 % risk of stroke within the next 3 years [105]. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) documented that chronic transfusion therapy in patients with a mean blood flow velocity of >200 cm/s with TCD prevented the initial occurrence of stroke, decreasing the annual incidence of stroke from 10 % to <1 % [25]. TCD is repeated every 12 months after a normal scan and every 3 months with a conditional scan. Although TAMMV is the gold standard TCD measurement in the setting of SCD, in clinical practice, peak systolic velocity (PSV) measurements are more commonly used in vascular ultrasound practice and have been shown to be highly correlated with TAMMV in the prediction of future stroke [106] (Fig. 30). However, a recent abstract has demonstrated that PSV alone may overestimate the risk of stroke in children, demonstrating the importance of TAMMV as the primary initial measurement for stroke-risk stratification [107].

8.2 Prevention of Secondary Stroke

SCIs that may be found in approximately 20–37 % of children with SCD are associated with increased risk of subsequent overt stroke [42, 44, 53]. Transfusion therapy has been shown to reduce overt strokes in patients with SCIs. Despite transfusion treatment, there remains a 20 % secondary stroke rate [108] and a 25 % likelihood of additional SCIs [51]. Hydroxyurea (HU) has also been shown to reduce TCD velocities and has shown some benefit in reducing the risk of secondary stroke [109]. A randomized clinical trial, Stroke With Transfusions Changing to Hydroxyurea (SWiTCH), evaluated HU with phlebotomy as an alternative to the ongoing transfusion therapy, but the study was closed early after an interim analysis revealed equivalent liver iron between the two groups, failing to meet the primary end point [110]. MRI can monitor the progression and extent of the ischemic change, and MRA can monitor the stenosis and/or occlusion of the intra- and extracranial arteries (Fig. 14).

9 Summary

Sickle cell disease (SCD) is one of the most important hereditary hematologic disorders which may result in severe neurovascular complications due to vaso-occlusion. Radiological evaluation is extremely important in daily practice, such as TCD in stroke-risk screening with velocity measurements of the cerebral arteries, CT in detecting hemorrhagic strokes, MRI in diagnosing acute infarct, white matter changes and cerebral vasculopathy, and catheter angiogram in evaluating precise vascular features and in treatment planning. Radiologic imaging features may also support the current understanding of the pathophysiology underlying neurovascular complications of SCD. Advanced MR imaging and nuclear imaging have the potential to provide additional findings that may improve the management of the neurovascular complications of SCD, but further investigations are still necessary. Finally, radiologists and clinicians should be familiar with the pathophysiology and imaging findings of the neurovascular complications of SCD as well as various complications in the craniofacial region and spine, which may be crucial for timely diagnosis and appropriate treatment.