Prevention and management of stroke in sickle cell disease

Sickle Cell Disease(SCD) is one of the most common hemoglobinopathies in the world which causes stroke. The management of stroke depends on the manifestations and the age of the patient. Especially in childhood, anatomic and physiological abnormalities of CNS may be a predisposing factors. Stroke mostly affects the distal segments of the Internal Carotid Artery, but also middle and anterior segments of the cerebral arteries are involved. The most important predisposing factors are the arterial malformations, stenosis and obstructions in cranial arteries, generally involving Internal Carotid Artery, frequently Proximal Middle Cerebral or Anterior Cerebral Arteries. After infarcts at brain vessels, most frequent clinical findings are hemiparesis or hemiplegia, impaired speech, focal seizures, gait disturbances. Risk factors for predisposing stroke are prior transient ischemia, baseline Hb decrease, acute chest sydrome within previous two weeks, systolic blood pressure rises, leucocyte increases. The patient with silent stroke or transient ischemic attacks may be asymptomatic or without neurological symptoms. Neuroimaging abnormalities may be seen without significant clinical findings in children with SCD. We talk about silent stroke if there are neuroradiological abnormalities without clinical findings. Children with silent strokes are more prone to new strokes. If there is a significant stroke a ischemic stroke often present with focal neurological signs and symptoms. If patient is asymptomatic or have suspected stroke, first step may be performance of Transcranial Doppler Ultrasonography (TCD). Children with time-averaged mean velocity (TAMV), measured in Middle Carotid Artery or in distal internal carotid Artery abnormally elevated, defined as TAMV≥200cm/sec, have sixfold increase for stroke than those with normal TAMV≤170cm/sec. For these patients under the risk of stroke, chronic blood transfusion is recommended for prevention of primary stroke events. Because of high oxygene demand in children, the child with SCD who also has anemia is at particular risk. The management of acute stroke includes to rule out hemorrhage, stabilize vital signs, careful use of hydration and RBCs transfusion. Exchange blood with normal RBCs is mandatory; it will improve tissue perfusion and oxygenation. Long-term management of stroke is directed to prevent recurrences with fluids supplementation, a chronic transfusion programme at least for 6 months with exchange transfusion or erythrocytapheresis for reducing the HbS under 30%. After 3 years of HbS levels to be maintained <30%, the HbS leveles can be raised safely to less than 50% if the patient has remained neurologically stable. Indefinite chronic transfusion programme was advised for the patients with abnormal TCD values. Hydroxyurea (HU) is an alternative therapy in reducing TCD values and to try to increase HbF improving the clinical outcome. Periodical cranial Doppler ultrasound examination and selective red blood cell transfusions ‘d be useful for stroke prevention. 镰状细胞病(SCD)是世上最常见的血红蛋白病，可致中风 中风防治受症状表现和病人的年龄所左右。 尤其对于患儿，中枢神经系统的组织异常和生理异常可能是诱病因素。 中风通常影响颈内动脉的末端，但也会牵连到脑动脉的中段和前段。 中风最重要的诱病因素有动脉畸形、器官狭窄和大脑动脉阻塞，一般和到颈内动脉有关，但牵连到大脑中动脉或大脑前动脉更为常见。 脑血管梗塞后，通常临床发现轻偏瘫或偏瘫、语言障碍、病灶性颠痫和步态障碍等。 诱病性中风具有的风险包括：前两周内引起短暂性局部缺血、血红蛋白含量减少和急性胸痛综合症，然后导致收缩压升高和白血球增加。 轻度中风或短暂性脑缺血发作的患者可能无症候或无神經症狀。 在没重大临床发现的情况下，镰状细胞病患儿可做脑神经成像检查，异常亦会发现。 下边我们将讨论无临床表现情况下神经放射性异常。 轻度中风的患儿再次中风的可能性很大。 如果中风严重，脑缺血的出现经常伴随着局部性神經系統症候和症状 如果患者无症候或疑似中风，首先应进行经颅多普勒超声（TCD）检查。 在异常抬升的中动脉或内动脉末端测量时间平均血流速度(TAMV)，结果为TAMV≥200cm/sec，该患者中风的可能性是正常情况（TAMV≤170cm/sec）的六倍。建议对有中风危险的患者采取慢速输血的方法，以防止主要中风事件。 由于儿童对氧的需求量高，患镰状细胞病同时伴有贫血的儿童危险系数尤其高。 急性中风防治的措施包括：排除溢血的可能性、稳定生命体征、谨慎利用水和作用和（血红细胞）RBCs输血 必须使用正常的RBCs交换血液；提高组织灌注和氧化作用。 中风的长期防治旨在阻止再次补充液体，用交换输血或红细胞除去法慢速输血至少6个月，以便把血红蛋白含量减少到30%以下。 血红蛋白含量<30% 保持3年后，如果患者神经稳定，可将其升高到50%以下。 TCD值不正常的患者，建议采取不定期慢速输血程序。 作为降低TCU值的备用疗法，羟基脲（HU）尝试提高HbF的含量，达到改善临床结果的目的。 防止中风有效的措施包括定期对大脑进行多普勒超声检查和有选择性的进行血红细胞输血。


Introduction
Sickle cell disease is one of the causes of major morbidities for brain disease called stroke.7] In Turkey, especially in the southern parts, HbS syndromes are more frequent than in the other parts of the country.In the Çukurova Region which is called for the cities of Içel, Antiochus, Adana, Maraş the frequency of HbS differs from 0.5% to 37%.The patients mostly have haplotype 19%. 5 They are white, have mild and severe courses and also suffers from cerebrovascular accidents about 5%. 8he sickled red blood cells forces the shear pressure of the vessel endothelium , damages the surface and causes to the predisposes occlusion of the vessel.By means of leukocytes and cytokines of cellular adhesion, occlusion, ischemia or infarcts, sometimes life threatening events, superpose. 9In accordance with a population statistics, death from SCD is 12% and SCD is the forth cause in all deaths. 10The predisposing factors of stroke in SCD are pneumonia, aplastic crises, viral disease, painfull crises, priapism and dehydratation.Higher leucocyte counts accounts as a risk factor for stroke in SCD patients.Because leukocytes are large, porly deformable , and tend to adhere to endothelium, all characteristics may influence rheological features and blood flow. 11More than 50% of the cases live beyond 50 years.Most of the deaths are not due to the result of chronic organ failure but as a result of acute painfull crisis, chest syndrome or from the stroke (Figure 1).
Sickle Cell Disease(SCD) is one of the most common hemoglobinopathies in the world which causes stroke by the physiopathologi- cal events beginning with vasculopathy in circulating blood.It is seen as homozygous status as sickle cell anemia or in double heterozygosity with β o -thalassemia(S/ β o ); with HbE(S/E), etc.The stroke is the most troublesome complication of sickle cell anemia.The management of stroke depends on the manifestations and age of the patient.When the oxygene supply to the brain is insufficient, brain dysfunction occurs, this is called as stroke.As a result, ischemia, infarct and tissue necrosis superposes.The Cooperative Study of Sickle Cell Disease showed that stroke is four times prevalent in homozygous SS (SCD) patients than the other SCD syndromes and it is about 0.5% to 1.0% in children. 12Especially in childhood, anatomic and physiological abnormalities of CNS may be a predisposing factor even if they seem to be normal neurologically. 13Although, mostly, it affects the distal segments of the Internal Carotid Artery, also middle and anterior segments of the cerebral arteries are involved.The presence of cerebral infarction with transcranial Doppler ultrasound is seen as a high risk factor for stroke.
In childhood, about 7% of the acute brain infarcts result with bad outcome.In first 20 years of life, the incidence of stroke is about 0.7%, but it reaches to peak values between 5-10 years of life because of high flow rate in brain and vulnerability of changes of endothelium in this age group. 14.In Çukurova Region, the incidence for 25 years follow-up of 320 patients is 5.0%. 6Stroke may be the only event or coincides with pneumoniae, aplastic crises, viral diseases, painfull crises, priapism and dehydratation. 15The most important predisposing factors are the arterial malformations, stenosis and obstructions in cranial arteries generally involving Internal Carotid Artery, frequently Proximal Middle Cerebral or Anterior Cerebral Arteries.The damaged endotel shows intimal thickening and smooth muscles poliferate.][18][19] Most SCD patiients who develop focal motor symptoms of stroke recover with no obvious motor deficits.Overall, cerebrovascular disorders and stroke are major complications in SCd which deteriorate the clinical course, quality of life , and mortality rate in people with SCD.The phenotypic variations in SCD children is dependent to the functions of regulatory genes.In addition to this, the presence of the story with stroke in the past history of the family means genetic factors play some roles in occurence of stroke.

The Clinical findings
After infarcts at brain vessels most frequent clinical findings are hemiparesis or hemiplegia, impaired speech, focal seizures, gait disturbances.At the same time behavioral and cognitive disturbances may be seen.If stroke is with bleeding, sudden severe headache, sometimes neck pain, vertigo, syncope, nistagmus, ptosis, meningismus and photofobia may be seen. 7Risk factors for predisposing stroke are prior transient ischemia, baseline Hb decrease, acute chest sydrome within previous two weeks, systolic blood pressure rises, leucocyte increases. 20

Diagnosis
The patient with silent stroke or transient ischemic attack may be asymptomatic or without neurological symptoms.Neuroimaging abnormalities may be seen without significant clinical findings in children with SCD.If there are neuroradiological abnormalities without clinical findings, it is recognized as silent stroke.The children with silent strokes are more prone to new strokes than the children with physiologically normal.The silent strokes are located mostly in Frontal lobe (border zone strokes).The cognitive processes are more disordered in the children with silent stroke. 21f there is a significant stroke, neurological findings may be associated with clinical outcome.Ischemic stroke often presents with focal signs and symptoms especially hemiparesis, hemisensory deficits and complaints, focal seizures or visual disturbances.Severe headache and altered level of consciousness are more typical for intracranial hemorrhage.Bilateral hemiparesis is uncommon in SCD because of the blood supply in brainstem which is less affected by occlusive vasculopathy than carotid systems. 22The death may be the result of hemorrhagic stroke, but is is very rare after ischemic stroke.
If patient is asymptomatic or have a suspected stroke, first step may be performance of Transcranial Doppler Ultrasonography (TCD).Children with time-averaged mean velocity (TAMV), measured in Middle Carotid Artery or in distal internal carotid Artery, elevated, o n l y defined as TAMV≥200cm/sec, have a sixfold increase for stroke than those with normal TAMV≤170cm/sec. 23,24For these patients under the risk of stroke, chronic blood transfusion is recommended for prevention of primary stroke events. 25Therapy should be considered also for the prevention of conversion to abnormal TCD velocities.] The rates of primary stroke have been decreased since the implementation of comprehensive TCD screening. 28,29Because of high oxygene demand in children, the child with SCD who also has anemia is at particular risk.CBC, ISCs, retic.count, HbF level and peripheral blood smear must be performed.The diagnostic approach is done with TCD (trans cranial doppler), CT(computerized tomography), MRI (magnetic resonance imaging), MRA (magmetic resonance angiography) and cerebral arteriography.The indication for surgical intervention is based upon MRA (Figure 2).

Treatment
The management of acute stroke includes rule out hemorrhage, stabilization of vital signs, careful use of hydration and RBCs transfusion.SCD stroke patients are generally anemic, correction of anemia.Exchange blood with normal RBCs is mandatory;it will improve tissue perfusion and oxygenation, reversing tissue damage is the goal of early therapy for stroke.Long-term management of stroke is directed to prevent recurrences of strokes in SCD patiets.In treatment, fluid supplementation, chronic transfusion programme at least for 6 months with exchange transfusion or erythrocytapheresis for reducing the HbS under 30%. 26Both chronic transfusion and Hydroxurea (Hydrea) should be considered after stroke. 222][33] Transfusions were effective in the original STOP trial, 26 but because of discontinuation of chronic transfusion in patients with abnormal TCD velocities resulted in returning of velocities into the abnormal range of stroke. 27Indefinite chronic transfusion programme was advised for the patients with abnormal TCD values.Hydroxyurea(HU) therapy is an alternative therapy in reducing TCD values form abnormal to normal values.HU should be given to increase HbF. 30,34HU enhances the HbF production and may improve clinical outcome.HYDREA(Hydroxyurea) increases fetal hemoglobin synthesis but limits the synthesis ability of bone marrow.
Because of the decrease especially of the granulopoiesis, the granulocyte and platelet counts must be performed in 2 weeks intervals.The effect of HYDREA will appear after months, so the patients must be followed carefully. 35n selected cases , stem cell transplantation (SCT) will be lifesaving. 36,37Stroke could be prevented by periodical cranial Doppler ultrasound examination and selective red blood cell transfusions are the first steps for the prevention of stroke. 10n the last several decades, teharapeutic approach for acute vasoocclusion episodes in SCD narcotic analgesics, i,e, morphine, as well as oxygene supplementation and fluid as neeeded.As is involved small or large arteries or veins , endothelial dysfunction leads to endotheliopathy and stroke, ending with ischemia, infarct or bleeding.
The gene replacement or gene addition therapies are tried in transgenic Mouse models but not in human objects.Hox-B4 idrected differentiation of mesodermal progenitors into hematopoietic stem cells is not efective as human cells;therefore additional factors will be required for efficient HSC differentiation. 38or perevntion of SCD, the goals of management should be to motivate the pairs to prenatal diagnosis if both are trait, to educate the people in productive ages and screening programmes, to educate the population, screening before marriages, to educate teenagers in schools.

Figure 2 .
Figure 2. Transcranial doppler ultrasonography.Normal blood velocity at left side, and increased blood velocity at right side.