Ibrahim Alghaithi Pediatric Hematology/Oncology Fellow June 30 th,2011

Transcription

1 Ibrahim Alghaithi Pediatric Hematology/Oncology Fellow June 30 th,2011

2 Objectives Overview of 1. Cerebrovascular disease and its incidence in SCD 2. Methods of predicting risk of stroke 3. Primary stoke prevention and prevention of recurrent stroke 4. Hemorrhagic stroke 5. Cognitive and behavioral dysfunction related to silent infarcts

3 Introduction Vasoocclusive phenomena and hemolysis are the clinical hallmarks SCD The cerebrovascular complications associated with SCD Cerebral infarction Intracranial hemorrhage Cognitive and behavioral changes The definition of cerebrovascular accidente (CVA) Although varies among authors, all agree that it includes any acute neurologic event secondary to arterial occlusion or hemorrhage that results in an ischemic event associated with neurologic signs and/or symptoms Some authors also include transient ischemic events (TIA) and silent infarcts in the definition

4 Incidence CVA is a leading cause of death in both children and adults with SCD The reported age-adjusted incidence: / 100 patient years (ie, 0.61 to 0.76 % per yr) during first 20 yrs of life ~ 300 times > children without SCD ( per 100 patient yrs)

5 Incidence The risk of CVA varies with the genotype In a series of 3647 patients from the Cooperative Study of Sickle Cell Disease Age-adjusted incidence per 100 patients years in Hb SS = 0.61 Hb SC = 0.15 Hb S-beta (+) thal = 0.09 Hb S beta (0) thal = 0.08 The likelihood of having a first CVA Blood 1998; 91:288.

6 Incidence The type of stroke varies with age Ischemic infarct Most common in children 2-9 yrs Uncommon yrs Second peak in adults > 29 yrs Hemorrhagic stroke Can occur in children but is most frequent yrs Overall data from the Cooperative Study of Sickle Cell Disease, among first CVAs in patients with SCD: 54 % caused by cerebral infarction 11 % by TIA 34 % by intracranial hemorrhage 1 % had features of both infarction and hemorrhage

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8 Cerebral Infarction Clinical stroke generally is defined by the presence of typical symptoms that last for at least 24 hours Symptoms of infarctive stroke may include hemiparesis, dysphasia, gait disturbance and/or a change in level of consciousness Although patients generally do not die acutely from infarctive stroke, substantial morbidity may occur Recurrent stroke Occurs in approximately 2/3 of patients within 2 yrs of initial event This risk is age-dependent: per 100 patient years in patients with an initial CVA before age 20 - Compared to 1.6 per 100 patient years in older patients Significant and long-lasting neurologic deficits are much more likely to occur after a second stroke

9 Risk factors In the Cooperative Study of Sickle Cell Disease, the following major risk factors for completed infarctive stroke were identified on multivariate analysis : Prior TIA, Relative risk (RR) 56 Low steady state hemoglobin, RR 1.9 per 1 g/dl decrease Rate of acute chest syndrome, RR 2.4 per event per year Episode of acute chest syndrome within the previous 2 weeks, RR 7.0 Elevated systolic blood pressure: RR 1.3 per 10 mmhg increase

10 Transcranial Doppler Noninvasive procedure, has become an important tool in predicting risk for stroke in patients with SCD It measures the time-averaged mean velocity of blood flow in the large intracranial vessels, which is inversely related to arterial diameter (as documented by cerebral angiography) A focal increase in velocity usually suggests arterial stenosis Bilateral increase may indicate bilateral arterial disease, increased blood flow, or both In children, mean velocity (in the middle cerebral or internal carotid artery ) >170 cm/sec is worrisome values >200 cm/sec highly associated with an increased risk of stroke, even before lesions become evident on MRA Patients with abnormal MRA findings and higher TCD velocities are at even higher risk for stroke

11 Transcranial Doppler This association was illustrated in a study in which TCD was performed in 190 children with sickle cell disease (age at entry: 3 to 18 years) 23 patients (12 %) had an abnormal TCD (based upon the highest blood flow velocity in the middle cerebral artery) 7 developed cerebral infarction after an average follow-up of 29 months 6 of the 7 strokes occurred among the 23 patients with abnormal ultrasound results N Engl J Med Feb 27;326(9):

12 Transcranial Doppler Significant risk factors for abnormally high cerebral velocities as determined by TCD in a cohort of 373 strokefree children with SCD included the following: G6PD deficiency Lower levels of hemoglobin Absence of alpha thalassemia Higher levels of serum lactate dehydrogenase These results suggest that G6PD deficiency and hemolysis independently increase the risk of cerebral vasculopathy in patients with SCD Blood Nov 15;112(10):

13 Adults Similar data on the value of TCD in predicting strokes in adults are lacking In one study, the mean TCD velocity of adult patients with SCD was lower than that reported in children with SCD Neurology. 2006;67(4):572.

14 Adults In a subsequent report from the same institution, abnormalities were detected in 35 of 60 patients who underwent magnetic resonance imaging (MRI) In these patients, a timeaveraged maximum mean velocity of cm/sec detected all the cases of middle or internal carotid artery intracranial stenosis with specificity of 100 % Whether this translates to a lower threshold of TCD velocity to predict strokes in adults with SCD compared to that used in children with SCD (>170 cm/sec) remains unknown Stroke. 2009;40(7):2408.

15 Prevention of First Stroke The multi-institutional Stroke Prevention Trial in Sickle Cell Anemia (STOP I trial) Rationale: ability of TCD to identify patients with SCD at high risk for stroke Total of 130 children (mean age 8.3 yrs) with SCD or HbS-beta(0) with no prior history of of stroke All had blood flow velocity >200 cm/sec on two repeated studies Randomized to observation or prophylactic chronic transfusion (goal HbS <30 %) Prematurely terminated at mean followup of 20 months because of marked benefit in the prophylactic transfusion group: one infarction in the transfusion group compared to 10 infarctions and one intracerebral hemorrhage in the control group (STOP trial)

16 Prevention of First Stroke (STOP trial) 37% had evidence of a prior silent infarct on the initial brain MRI Transfusion therapy significantly reduced the risk of new silent infarct or stroke in this group while patients who were not provided transfusion therapy were at higher risk of developing new silent infarct or stroke during the study than those whose initial MRI was normal Stroke rates in California children with SCD : 0.88 events per 100 patient-years : 0.50 and 0.17 per 100 patient years, respectively Suggesting more effective intervention following publication of the STOP I trial results Further suggestive evidence supporting the effectiveness of TCD screening and subsequent intervention in preventing stroke

17 Prevention of First Stroke (STOP trial) TCD measurements were taken of flow velocity in the anterior cerebral artery (ACA) as well as the internal carotid/middle cerebral arteries (ICA/MCA), and the following findings were reported: Among subjects at high risk of stroke due to high ICA/MCA velocity (ie, 200 cm/sec), the risk of stroke more than doubled with elevated, compared with normal, ACA velocity (7.6 vs 3.2 per 100 patient-years) Among subjects with normal ICA/MCA velocity (ie, <170 cm/sec), the risk of stroke was >10-fold greater in those with elevated (ie, 170 cm/sec) compared with normal ACA velocity (2.1 vs 0.20 per 100 patient-years) Although increased ACA flow in the absence of elevated flow in the ICA/MCA was uncommon, when present it represented a stroke risk comparable to that seen in patients with conditionally abnormal ICA/MCA flow (ie, cm/sec; stroke risk 0.9 to 1.5 per 100 patient-years) Such findings should prompt early repeat studies to aid in decisions concerning interventions such as chronic transfusion

18 Prevention of First Stroke Recommendation TCD become routine screening tool in many centers Based upon ability of TCD to identify children at risk ability of prophylactic transfusion to provide benefit in such children Optimal frequency of TCD screening Has not been established Normal flow velocity on a single screening does not assure a continued "low risk" status Accordingly, intermittent screening should be performed, especially in younger children and those with higher blood flow velocity

19 Prevention of First Stroke Recommendation The importance of repeat screening was shown in a retrospective study 274 patients with sickle cell disease who had mean velocity values in the normal (ie, <170 cm/sec) or "conditional" range (ie, cm/sec) Of the 153 subjects with normal flow velocity on initial examination 25 (16 %) converted to a "conditional" velocity on a subsequent examination 4 (3 %) converted directly to an abnormal flow velocity (ie, 200 cm/sec) over the ensuing 18 months The 18-month cumulative incidence of conversion from "conditional" to abnormal flow velocity (ie, 200 cm/sec) was 23 % was not influenced by age, initial mean velocity, blood pressure, oxygen saturation, or other laboratory values Br J Haematol. 2008;142(1):94

20 Prevention of First Stroke Recommendation Children with abnormal flow velocity of 200 cm/sec in the internal carotid artery and the middle cerebral artery on two repeated studies done by TCD are at high risk of stroke Patients with two abnormal TCD studies within two to four week period should be entered into a stroke prevention protocol, consisting of chronic transfusion therapy Chronic transfusion therapy is supported by numerous studies and randomized clinical trials as effective primary prophylaxis for stroke in patients with SCD, and is the treatment of choice for high-risk patients This recommendation recognizes that TCD has high sensitivity and low specificity for predicting stroke Chronic transfusion therapy poses certain risks, including alloimmunization and iron overload

21 Prevention of First Stroke Recommendation For families who refuse transfusion therapy, hydroxyurea has been suggested as second line option Although studies have shown that hydroxyurea may lower TCD velocities Minimal information is available about its efficacy for primary or secondary prevention of stroke in SCD There are no randomized trials to support the efficacy of hydroxyurea over chronic transfusion therapy

22 Stopping Transfusion STOP II trial Address whether a prophylactic transfusion program can be stopped in patients without prior stroke Children thought to be at lower risk for stroke because of the following criteria: Treatment with periodic transfusions for minimum of 30 months with a HbS level <30 %in at least 20 of the 30 months Reversion of TCD velocities to normal (ie, 2 normal TCD examinations at least two weeks apart while receiving transfusions) No prior stroke and no moderate-to-severe arterial lesions on magnetic resonance angiography The study was prematurely terminated by the NHLBI 14 of the 41 patients randomly assigned to stop transfusions reverted to a high risk of stroke as measured by TCD 2 other patients had stroke recurrence These 16 events occurred within median time of 3.2 months following randomization There were no strokes or reversion to high stroke risk in the 38 subjects assigned to continue transfusion N Engl J Med. 2005;353(26):2769.

23 Stopping Transfusion The NHLBI has issued a clinical alert recommending Blood transfusions be continued in such patients The choice of clinical management, including whether to continue periodic transfusions or to stop transfusions with TCD monitoring every two to three months, must be made on a case-by-case basis One interpretation of the STOP II trial Children with sickle cell disease identified as being at high risk for stroke will likely be receiving extended, if not life-long, RBC transfusions As such they will resemble children with beta-thalassemia major who also require regular RBC transfusion support and face the clinical consequences of iron overload It is likely that these children will either require iron chelation or earlier consideration for allogeneic hematopoietic cell transplantation

24 Prevention of Recurrent Stroke Recurrent stroke Occurs in approximately 2/3 of patients within 2 yrs of the initial event Risk is particularly high in patients < age 20 Significant and long-lasting neurologic deficits are much more likely to occur after second stroke

25 Prevention of Recurrent Stroke Because of these high recurrence risks, intervention is recommended to reduce the risk of recurrence in any patient with SCD who has had a stroke For management of an acute stroke event, exchange transfusion is the preferred initial therapy For ongoing prevention, chronic transfusion protocols are typically used Treatment with hydroxyurea and hematopoietic cell transplantation also has been considered Although hydroxyurea has been considered as alternative to chronic transfusion therapy, the SWiTCH Trial demonstrated a higher incidence of recurrent stroke in those receiving hydroxyurea than in those receiving chronic transfusion Based on this recently released safety data, hydroxyurea can no longer be considered adequate as the sole therapy for prevention of recurrent stroke

26 Acute Therapy Urgent transfusion Ideally, immediate exchange transfusion Goal HbS <30 % and Hb of approximately, but not >, 10 gm/dl Although initial optimal acute therapy following a stroke in children with sickle cell disease remains uncertain, exchange transfusion appears to be more effective than simple transfusion in preventing second strokes This was illustrated in retrospective study of 137 children with sickle cell disease and history of stroke Treatment information was available in 52 patients who presented within 24 hours of onset of initial stroke symptom (ie, weakness, paresis, seizures, dysarthria/aphasia) Second strokes were more likely in patients who received simple transfusions (8 of 14 patients) compared to those who were treated with exchange transfusions (8 of 38 patients), (RR 5.0, 95% CI 1.3 to 18.6). There was no difference between the two treated groups in the frequency of risk factors Pediatr. 2006;149(5):710

27 Chronic Therapy After the acute episode, patients should be treated with chronic transfusion therapy Chronic transfusion can reduce the incidence of recurrent stroke to below 10 % when routine monthly red blood cell transfusions are given to maintain HbS at <30%

28 Chronic Therapy Whether chronic transfusion therapy can be safely stopped in a patient with a prior stroke remains unclear Attempts to discontinue this regimen at 1-2 yrs or as late as 12 yrs following the initial stroke event have resulted in high rate of stroke recurrence In one report: 10 patients who received transfusion therapy for mean of 9.5 yrs after an initial stroke 5 had a recurrent ischemic event within one year after the cessation of therapy J Pediatr. 1991;118(3):377

29 SWiTCH trial Large multicenter trial (Stroke With Transfusions Changing to Hydroxyurea, orswitch trial) Enrolled children and adolescents with SCD who had experienced a stroke had already received at least 18 months of transfusion therapy already had evidence of iron overload Randomly assigned to either continue transfusion therapy or to receive hydroxyurea treatment Trial was terminated early by the National Heart, Lung, and Blood Institute (NHLBI) higher incidence of stroke in the experimental arm (Hydroxyurea plus serial phlebotomy) as compared with the control arm (transfusion therapy plus deferasirox) J Pediatr. 2004;145(3):287

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31 Intracranial Hemorrhage (ICH) Also called hemorrhagic stroke in this setting Accounts for approximately 1/3 of cerebrovascular events in patients with SCD The site of bleeding may be Subarachnoid intraparenchymal Intraventricular or a combination of these locations The peak incidence: yrs; in comparison to cerebral infarction, which is much more common in children Approximately 3%of children with SCD will have a hemorrhagic stroke by 20 years of age, and %will die within 2 weeks of the event

32 Risk Factors In the Cooperative Study of Sickle Cell Disease, two major risk factors for hemorrhagic stroke were identified on multivariate analysis [7]: Low steady state hemoglobin RR 1.6 per 1 g/dl decrease Increased steady state leukocyte count RR 1.9 per 5000/microL increase Small retrospective case-cohort study from two children hospitals in the United States suggested that a recent history of hypertension, transfusions, or corticosteroid therapy was more likely in children with sickle cell disease who experienced hemorrhagic stroke compared to those with ischemic strokes Blood. 1998;91(1):288

33 Clinical Manifestations and Evaluation Symptoms associated with ICH Are different from those seen with infarction, which typically produces focal deficits such as hemiparesis Are dependent upon the location of the hemorrhage The most common presenting features include severe headache vomiting stiff neck alterations in consciousness Coma and seizures in the absence of hemiparesis strongly suggest ICH

34 Clinical Manifestations and Evaluation Angiography should be considered in all patients with ICH to identify the cause of bleeding and to guide further therapy The mortality rate: 24-50% Deaths generally occur within the first two weeks of the event, many on the first day In addition, some survivors are left with moderate to severe residual disability

35 Subarachnoid Hemorrhage The majority of cases of ICH Resulting from the rupture of one or more aneurysms Multiple aneurysms are present in approximately 45 %of patients Injury to the endothelium and the high flow conditions in sickle cell disease are thought to promote the formation of these aneurysms The time required for these changes to occur may account for the peak incidence in young adults Treatment consists of Nonaggressive hydration As in other patients with this disorder, Nimodipine (Ca channel blocker) to minimize the incidence of vasospasm Surgery (eg, clip ligation) Blood pressure management may present a dilemma if hypertension occurs Lowering the pressure may reduce bleeding but also may result in ischemia or infarction because a higher pressure may be required to maintain cerebral perfusion because of the typical increase in intracranial pressure

36 Intraventricular Hemorrhage (IVH) May be associated with rupture of anterior cerebral artery aneurysms or direct extension of intraparenchymal hemorrhage into the lateral or third ventricle Patients who have experienced previous cerebral infarction are at risk for intraventricular and intraparenchymal hemorrhage as a late event, months to years after the ischemic stroke Such patients may be awake and alert immediately following such a bleed and then become comatose over the ensuing 48 hours because of obstructive hydrocephalus and ventricular dilation Emergent ventricular drainage may be necessary

37 Moyamoya Syndrome ~30 % of patients with SCD who develop intracranial hemorrhage These abnormalities may be the source of hemorrhage This pattern is named for its resemblance to findings in Moyamoya disease Chronic cerebrovascular disease of uncertain etiology Occurs primarily in Japan and other Asian countries Characterized by severe bilateral stenosis or occlusion of the arteries around the circle of Willis, with prominent collateral circulation

38 Moyamoya Syndrome Patients with SCD who develop moyamoya syndrome appear to be at risk for recurrence of strokes This was illustrated in a retrospective study of 44 patients maintained on chronic transfusions 19 of the 44 patients had evidence of moyamoya collateral circulation based upon either magnetic resonance or conventional angiography The risk of recurrent stroke was greater in patients with moyamoya disease (11 of 19 patients, 58 %) than those without moyamoya disease (7 of 25 patients, 28 %) Blood. 2002;99(9):3144

39 Moyamoya Syndrome In children with SCD and moyamoya syndrome, surgical treatment has been used in an effort to restore the circulation of the ischemic brain area reducing the risk of ischemic stroke In one report: Indirect revascularization using encephalo-duroarterio-synangiosis (EDAS) Performed in 12 patients with SCD and documented moyamoya syndrome 10 patients had history of stroke including 4 who were compliant with transfusion protocol at the time of their stroke At median follow up of 47 months after the procedure - 7 patients had postsurgical angiography, which showed revascularization of the affected area in all cases - 2 of the twelve patients experienced strokes Although no randomized, controlled trials, these results suggest that EDAS performed by experienced neurosurgeons is a reasonable option for these patients given their poor outcome without intervention J Neurosurg Pediatr. 2008;1(3):211

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41 Radiographic Imaging CT scanning and MRI have become the accepted methods for confirming a clinical diagnosis of cerebral infarction or intracranial hemorrhage in patients with SCD Unenhanced CT scan Generally is the easiest study to obtain soon after acute neurologic event It will localize area of hemorrhage immediately but may not become abnormal for up to six hours after infarct MRI Compared with CT, offers improved resolution and ability to demonstrate areas of abnormality within 2-4 hours following infarct Limitation: requires cooperation of the and more expensive Transcranial Doppler Can be used to identify patients at risk for stroke It has variable sensitivity for the detection of flow abnormalities due to prior infarction Magnetic resonance angiography (MRA) Can identify vascular disease with accuracy similar to that of angiography and MRI

42 Radiographic Imaging Positron emission tomography (PET) can be used to gauge the functional activity of the cerebral tissues and, therefore, microvascular blood flow PET scanning in conjunction with MRI may identify a greater number of patients with silent infarcts than does MRI alone

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44 Cognitive and Behavioral Dysfunction and Silent Infarcts "silent" infarcts % of SCD Less common in Hb SC disease, occurring in 3 % of They are more common in patients with a history of seizures Silent infarcts are defined by the presence of T-2 weighted signal changes on MRI consistent with infarction in patients with a normal neurologic examination

45 Cognitive and Behavioral Dysfunction and Silent Infarcts The importance of silent infarcts on cognitive and behavioral function: A report from the Cooperative Study of Sickle Cell Disease - Evaluated 135 children with MRI and neuropsychologic evaluation - On most measures of neuropsychologic evaluation, children with a history of CVA performed significantly worse than did children with silent infarcts or no MRI abnormality - On tests of arithmetic, vocabulary, and visual motor speed and coordination, children with silent infarcts performed significantly worse than children with no MRI abnormality Pediatrics. 1996;97(6 Pt 1):864

46 Cognitive and Behavioral Dysfunction and Silent Infarcts Studies of children without a silent infarct on MRI have revealed cognitive functioning similar to siblings without SCD These findings suggest that: In the absence of cerebral disease as determined by symptoms or MRI, no differences in cognitive ability are attributable solely to SCD However, one study found that behavioral and psychologic functioning in children with SCD was essentially the same as that in other children with chronic illnesses Although the risk is somewhat increased, only a few children develop frank psychiatric disorders or meet diagnostic criteria for a depressive disorder

47 Cognitive and Behavioral Dysfunction and Silent Infarcts Silent Infarct Transfusion Study Large multicenter randomized trial Sponsored by the National Institutes of Health To further understand the role of silent infarction on neurocognitive outcomes and on potential evolution to symptomatic stroke answer the question as to what is the best therapy Children between 6-12 years of age Following screening and with detection of silent stroke, patients will be offered transfusion therapy or observation for a three year period

48 Summary Cerebrovascular accident is a leading cause of death in children and adults with SCD The risk of CVA varies by genotype Children with SCD should be routinely screened with TCD to assess risk for stroke All children with increased risk for stroke as determined by TCD should be treated with a stroke prevention protocol utilizing prophylactic transfusion Once a patient has entered a prophylactic transfusion program it should usually be continued indefinitely unless other preventive measures are taken

49 Summary To reduce the risk of recurrence in any patient with SCD who has had a stroke: exchange transfusion is typically used as initial treatment After the acute episode, patients should be treated with chronic transfusion therapy Alternative strategies, such as the use of hydroxyurea, have not been established as an effective therapy, especially after an acute event Hemorrhagic stroke is most common among young adults and has a high mortality rate Children with silent infarct have impaired neuropsychologic performance relative patients without a stroke

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