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1 TRANSCRANIAL DOPPLER ULTRASONOGRAPHY (TCD) FOR ASSESSMENT OF STROKE RISK IN SICKLE CELL DISEASE NOTE: These slides are for use in educational oral presentations only. If any published figures/tables from these slides areto be used for another purpose (e.g. in printed materials), it is the individual’s responsibility to apply for the relevant permission. Specific local use requires local approval.
2 Outline Sickle cell disease (SCD) Transcranial Doppler (TCD) TCD in SCDTCD EquipmentGuidelines for TCD in SCDSummaryLIC = liver iron concentration; MRI = magnetic resonance imaging;SF = serum ferritin; SIR = signal intensity ratio;SQUID = superconducting quantum interface device.
4 What is SCD?An inherited disorder affecting haemoglobin (Hb) synthesisSickle cell erythrocytes have a mutant form of Hb and HbSresulting from Glu→Val mutation in 6th codon of β-globin chainHbS turns normally pliable erythrocytes into rigid, sickle-shaped cellsThe irregular erythrocyte morphology leads toepisodes of vascular occlusion and acute painprogressive organ damageChildren have increased risk of infection and strokeLife expectancy may be shortenedSickle cell disease (SCD) comprises a group of inherited disorders affecting hemoglobin (Hb) synthesis and is characterized by chronic hemolytic anemia.1A single point sickle mutation in the gene encoding the β-globin chain of hemoglobin leads to an amino acid substitution, resulting in the formation of sickle hemoglobin: HbS (α2βs2).1Erythrocytes with HbS have irregular morphology. Under low oxygen conditions these polymerize and have a tendency to become distorted and lose their elasticity, making them less able to pass through narrow capillaries. This leads to vascular occlusion and associated symptoms – severe pain and progressive organ damage.1SCD is inherited in an autologous recessive manner:Homozygous individuals (2 mutant β-globin chains) have full disease phenotype.Heterozygous individuals (1 mutant β-globin chain) are normally asymptomatic but may exhibit symptoms under some conditions (eg at low oxygen levels such as high altitudes, or when severely dehydrated).2Signs and symptoms of SCD usually present around 6–12 months after birth and life expectancy may be reduced.1ReferencesSchnog JB et al. Neth J Med 2004;62:364–374.Sickle Cell Anemia and Genetics: Background Information. From Genetics: Classroom activities and instructional material.http://chroma.gs.washington. edu/outreach/genetics/sickle/sickle-back.html.Image from: www2.med.umich.edu/prmc/media/newsroom/downloadImages. cfm?ID=656.HbS = sickle cell haemoglobin.Schnog JB, et al. Neth J Med. 2004;62: Image from www2.med.umich.edu/prmc/media/newsroom/downloadImages.cfm?ID=656.
5 Clinical manifestations of SCD AnaemiaRed cell survival ~ 17 days (120 days in healthy people)1PainAcute and chronic1Central nervous systemOvert stroke, silent stroke, and neurocognitive impairment1–3PulmonaryRecurrent acute chest syndrome, pulmonary hypertension, and chronic sickle lung disease1,2SkinChronic ulcers, typically around the ankles1JointsOsteonecrosis (avascular necrosis) of femoral and humeral heads1,2EyesRetinal ischaemia, detachments – “sickle retinopathy”1,2KidneysInability to concentrate urine; proteinuria progressing to nephrotic syndrome; end-stage renal failure4CardiovascularCardiac decompensation and cardiomyopathy1SCD has a wide range of clinical manifestations, primarily due to red blood cell hemolysis and vascular occlusion.Recurrent episodes of acute pain due to ischemia are a key characteristic of the disease.Brain infarction, which causes overt stroke, particularly affects younger patients and can lead to permanent disability.1,2,3 This is usually a result of the occlusion of certain brain arteries (known as large Circle of Willis).4 The origin of this vasculopathy is unknown in SCD, but it can be predicted by transcranial Doppler ultrasonography, as discussed later.4‘Silent infarctions’, which result in neurocognitive impairment,1,3 arise due to disease of the brain’s microvasculature.5 It is unclear as to whether this is associated with occlusion of the large arteries; children with silent infarcts have a higher risk of overt stroke, but the independent risk factors for silent and overt stroke differ.6Older patients are more likely to experience intracranial hemorrhage (due to aneurysmal or moyamoya vessel rupture), which may be fatal.2,3,7Acute chest syndrome and related chronic sickle lung disease are characterized by dyspnea, pleuritic pain, cough or fever, restrictive and obstructive lung disease and pulmonary hypertension.1Both vaso-occlusion and severe anemia are thought to contribute to recurrent chronic leg ulceration, particularly on the ankles.1The hip and shoulder joints are especially prone to infarction. Avascular necrosis of the femoral head may lead to total disability and requirement for a hip prosthesis.1,2Sickle retinopathy results from vaso-occlusion in the peripheral retina. Several complications associated with retinal ischemia can lead to blindness.1,2Most patients will have some form of renal impairment as the kidney microenvironment is particularly favorable for HbS polymerization. Patients have a reduced ability to concentrate urine leading to dehydration and progressive proteinuria.1Due to hemolytic anemia, patients with SCD will often have a hyperdynamic circulation to compensate for reduced oxygen carrying capacity and consequently develop cardiomyopathy.1ReferencesSchnog JB et al. Neth J Med 2004;62:364–374.Claster S & Vichinsky EP. Br Med J 2003;327:1151–1155.Prengler M et al. Ann Neurol 2002;51:543–552.Adams RJ. Arch Neurol 2007;64:1567–1574.Hillery CA and Panepinto JA. Microcirculation 2004;11:195–208.Switzer JA et al. Lancet Neurol 2006;5:501–512.Ohene-Frempong K et al. Blood 1998;91:288–2941Schnog JB, et al. Neth J Med. 2004;62: Claster S, Vichinsky EP. Br Med J. 2003;327: Prengler M, et al. Ann Neurol. 2002;51: Ataga KI, Orringer EP. Am J Hematol. 2000;63:
6 Prevalence of SCDThe frequency of the HbS gene is highest in populations in which malaria is (or was) endemic1,2Approximately 200,000 new cases of SCD occur in Africa every year1Recent population migrations have led to an increase in disease frequency in other areasin the USA, SCD affects over 50,000 African-American individuals and occurs in 1 out of 375 newborns3annually, more than 6,000 conceptions in the Caribbean and Central and South America are affected by SCD2> 1 out of 2,400 live births (all ethnic groups) are affected in England, where 12,500 individuals live with the disease4The allele encoding HbS provides a genetic advantage against malaria. Highest frequencies are therefore observed in locations where malaria is, or was, endemic, most notably in Africa but also in parts of the Middle East and the Mediterranean.1,2Heterozygous individuals have too few sickle cell erythrocytes in the blood stream to cause symptoms, but have enough to provide resistance against the malarial parasite. Hence, this genotype provides a selective advantage in regions where the often fatal cerebral malaria (Plasmodium falciparum) occurs.2Homozygous HbS individuals show a diseased phenotype and many die in infancy. Approximately 200,000 homozygous HbS babies with SCD are born in Africa each year.1Migration from tropical regions has increased the frequency of SCD to other parts of the world, including the Americas and Northern Europe.3–5ReferencesWeatherall DJ and Clegg JB. World Health Organization Bulletin 2001;79:704–712.Serjeant GR. Lancet 1997;350:725–730.Modell B and Darlison M. World Health Organization Bulletin 2008;86:480–487.Sickle Cell Disease: screening, diagnosis, management, and counselling in newborns and infants – Clinical practice guideline number 6 AHCPR 1993;PublicationSickle Cell Society. Sickle Cell Society Publication SC4 2005:Image from: Christianson A et al. March of Dimes Global Report on Birth Defects: The Hidden Toll of Dying and Disabled Children (http://www.marchofdimes.com/MOD-Report-PF.pdf).<0.11-4.95-9.91—18.9≥19<0.11-4.95-9.91—18.9≥19Births with a pathological Hb disorder per 1,000 live births1Weatherall DJ, Clegg JB. Bull World Health Organ. 2001;79: Modell B, Darlison M. Bull World Health Organ. 2008;86: Sickle cell disease: screening, diagnosis, management, and counseling in newborns and infants – clinical practice guideline number 6 AHCPR 1993;Publication Sickle Cell Society. Sickle Cell Society Publication SC4 2005: Image from Christianson A, et al. March of Dimes Global Report on Birth Defects: the hidden toll of dying and disabled children (www.marchofdimes.com/MOD-Report-PF.pdf).Global distribution of pathological Hb disorders, 1996 (WHO)
7 Management and treatment of SCD BMT is the only curative treatment for SCD that is currently available1,2introduces stem cells that express normal Hbavailability of suitable matched donors is a major limitationOther current treatments aim at preventing and managing SCD complicationsHU promotes the production of HbF-expressing RBCsHU treatment reduces the occurrence of painful crises and hospital admissions,3 and may reduce the risk of stroke4,5Transfusion therapy to increase Hb and decrease sickle cell proportions in the blood is a major therapeutic approachtransfusion can reduce the risk of stroke and other SCD complications6,7The only curative treatment for SCD that is currently available is bone marrow transplantation, introducing stem cells with the capacity to produce normal Hb instead of HbS.1,2 However, the treatment depends on the availability of suitable matched donors, which are in short supply.The remaining therapies in current use seek to prevent and treat the extensive clinical manifestations of SCD.Hydroxyurea (HU) promotes rapid erythrocyte regeneration, increasing the likelihood of erythroblasts expressing HbF (fetal hemoglobin) developing.3 As HbF inhibits HbS polymerization and sickle cell formation3, increased proportions of HbF are associated with reductions in clinical symptoms, including stroke risk, as observed in clinical trials with HU.4–6Transfusion therapy is currently the major therapeutic approach to managing SCD complications. By reducing the proportion of sickle cells in the blood, transfusion therapy appears to reduce the impact of many SCD symptoms, including stroke.7,8Transfusion therapy may lead to iron overload, which can result in damage to organs such as the heart and liver. Iron chelation therapy can effectively reduce iron overload in SCD patients.9ReferencesHoppe CC and Walters MC. Curr Opin Oncol 2001;13:85–90.Walters MC et al. Blood 2000;95:1918–1924.Coleman EC and Inusa B. Clin Paediatr 2007;46:386–391.Charache S et al. N Engl J Med 1995;332:1317–1322.Ware RE et al. J Pediatr 2004;145:346–352.Zimmerman SA et al. Blood 2007;110:1043–1047.Styles LA and Vichinsky E. J Paediatr 1994;125:909–911.Adams RJ et al. N Engl J Med 1998;339:5–11.Vichinsky E et al. Br J Haematol 2007;136:501–508.BMT = bone marrow transplantation; HbF = fetal haemoglobin; HU = hydroxyurea.1Hoppe CC, Walters MC. Curr Opin Oncol. 2001;13: Walters MC, et al. Blood. 2000;95: Charache S, et al. N Engl J Med. 1995;332: Ware RE, et al. J Pediatr. 2004;145: Zimmerman SA, et al. Blood. 2007;110: Styles LA, Vichinsky E. J Pediatr. 1994;125: Adams RJ, et al. N Engl J Med. 1998;339:5-11.
9 TCD – a non-invasive diagnostic tool TCD – a safe, non-invasive diagnostic tool1,2allows indirect real-time evaluation of intracranial cerebral circulation via ultrasonography1,2Ultrasonic beam bounces off erythrocytes within an artery2—reflected signal is processed to obtain a waveform that allowsaccurate determination of blood flow velocities1,2accurate determination of flow direction2addition of calculated parameters (e.g. PI)2Blood flow velocities are used to predict stroke risk3Typical TCD sonographic recording from MCA(velocity scale on left)4cm/s22020018016014012010080604020–20–40–60–80–100–12048DEPTH118MEAN0.72PI163SYS6SAMPLEPOWERTCD is a safe, inexpensive, non-invasive diagnostic tool that allows indirect real-time evaluation of intracranial arteries via ultrasonic beam (2 MHz frequency) produced from piezo-electric crystals that have been stimulated electrically.1,2The ultrasonic beam bounces off erythrocytes within an artery. The reflected signal is received by a transducer and converted to an electric signal. This information is subtracted from the transmitted signal and processed to obtain a waveform that allows:2Accurate determination of blood flow velocitiesAccurate determination of flow directionAddition of calculated parameters, such as pulsatility index (PI). PI is a reliable marker of resistance distal to the site being evaluated – usually calculated by the Gosling equation: (peak systolic velocity – end-diastolic velocity)/mean velocity.The calculated blood flow velocities can be used to predict stroke risk.3ReferencesAaslid R et al. J Neurosurg 1982;57:769–774.Kassab MY et al. J Am Board Fam Med 2007;20:65–71.Adams RJ et al. N Engl J Med 1992;326:605–610.1Aaslid R, et al. J Neurosurg. 1982;57: Kassab MY, et al. J Am Board Fam Med. 2007;20: Adams RJ, et al. N Engl J Med. 1992;326: McCarville MB, et al. Am J Roentgenol. 2004;183:MCA = middle cerebral artery; PI = pulsatility index.
10 TCD blood flow velocities vary with age Blood flow velocity in the MCA is low after birth, but rises rapidly during the first few days of lifePeak velocities approaching 100 cm/s are observed between the age of 4 and 6 years, after which blood flow velocity declines steadily throughout life1201008060402010305070Age (years)MCA MV (cm/s)Normal blood flow velocities, as measured by TCD, vary with age.Blood flow in the middle cerebral artery (MCA) is low immediately after birth (24 cm/sec) but rapidly rises in the first few days of life.Velocity continues to rise more slowly to a peak approaching 100 cm/sec between the age of 4 and 6 years.Velocity then decreases steadily throughout life to about 40 cm/sec in the seventh decade. This decrease is slower during adulthood compared with late childhood and adolescence.The figure represents the mean MCA velocities from 16 TCD studies of healthy children and adults. The bars represent ± 2 SD above and below the mean.Where possible, data were extracted in age groups of 3–5 years for children and 10 years for adults.ReferenceAdams RJ et al. Normal Values and Physiological Variables. In:Transcranial Doppler, Newell D and Aaslid R, eds, Raven Press, NewYork, 1992;41–48.MV = mean velocity.Adams RJ, et al. Normal values and physiological variables. In: Newell D, Aaslid R, editors. Transcranial Doppler. New York: Raven Press;
11 Direction in relation to probe Mean ± SD flow velocity (cm/s) Accepted guidelines for normal TCD study: blood flow velocities in an adultArteryWindowDepth (mm)Direction in relation to probeMean ± SD flow velocity (cm/s)Middle cerebralTemporal30–60Toward55 ± 12Anterior cerebral60–85Away50 ± 11Posterior cerebral60–70Bidirectional40 ± 10Terminal internal carotid55–6539 ± 09Internal carotid (siphon)Orbital60–8045 ± 15Ophthalmic40–6020 ± 10VertebralOccipital38 ± 10Basilar80–11041 ± 10This table illustrates the accepted guidelines for adult normal blood flow velocities in a TCD study.ReferenceKassab MY et al. J Am Board Fam Med 2007;20:65–71.(adapted from Ringelstein EB et al. Ultrasound Med Biol 1990;16:745–761).Kassab MY, et al. J Am Board Fam Med. 2007;20:65-71.Ringelstein EB, et al. Ultrasound Med Biol. 1990;16:
12 TCD acoustic windows – arteries insonated Examination of an artery by TCD is called “insonation”TCD probe is placed over different “acoustic windows”— specific areas of skull where cranial bone is thinA. Transtemporal window insonatesMCAanterior cerebral arteryposterior cerebral arteryterminal portion of ICA before its bifurcationB. Transorbital window insonatesophthalmic arteryICA at siphon levelC. Transforaminal (occipital) window insonatesdistal vertebral arteriesbasilar arteryD. Submandibular window insonatesmore distal portions of the extracranial ICABACDExamination of an artery by TCD is called ‘insonation’.The TCD probe is placed over different ‘acoustic windows’, which are specific areas of the skull where the cranial bone is thin.The arteries insonated via each of the four windows are listed here.ReferenceKassab MY et al. J Am Board Fam Med 2007;20:65–71.ICA = internal carotid artery.Kassab MY, et al. J Am Board Fam Med. 2007;20: Image from products/cmetcd.html. Accessed Nov 2010.
14 Rationale for TCD in SCD 102030405060Approximately 11% of patients with SCD have a stroke by 20 years of age, with a peak incidence in the first decade of life1Stroke accounts for ~ 10% of all mortality in SCD (Figure)2Silent infarct identified by MRI is a significant predictor of overt stroke in children333–48%Patients (%)9.8%7.0%6.6%InfectionStrokeTherapy complicationsSplenic sequestrationCauses of death in SCD2There is a high risk of stroke in patients with SCD, especially in young children and teenagers.1In a US study, morphological evidence of the cause of death was studied in 306 autopsies of SCD, which were accrued between 1929 andThe most common cause of death for all sickle variants and for all age groups was infection (33–48%). Other causes of death included stroke 9.8%, therapy complications 7.0%, splenic sequestration 6.6%, pulmonary emboli/thrombi 4.9%, renal failure 4.1%, pulmonary hypertension 2.9%, hepatic failure 0.8%, massive hemolysis/red cell aplasia 0.4% and left ventricular failure 0.4%.Death was frequently sudden and unexpected (40.8%) or occurred within 24 hours after presentation (28.4%), and was usually associated with acute events (63.3%).Investigation of 248 patients enrolled in the Cooperative Study of Sickle Cell Disease before the age of 6 months showed that silent infarct (identified on MRI) was a significant predictor of subsequent stroke: 5 (8.1%) of 62 patients with silent infarct had strokes compared with 1 (0.5%) of 186 patients without prior infarct; incidence per 100 patient-years of follow-up was increased 14-fold (1.45 vs 0.11 per 100 patient-years, P=0.006).3ReferencesOhene-Frempong K et al. Blood 1998;91:288–294.Manci EA et al. Br J Haematol 2003;123:359–365.Miller ST et al. J Pediatr 2001;139:385–390.MRI = magnetic resonance imaging.1Ohene-Frempong K, et al. Blood. 1998;91: Manci EA, et al. Br J Haematol. 2003;123: Miller ST, et al. J Pediatr. 2001;139:
15 Flow velocity as predictor of stroke in SCD SCD – associated with progressive occlusion of large intracranial arteries1Arteries most frequently affected1MCAintracranial ICAAbnormal TAMMV (≥ 200 cm/s) in MCA or ICA isstrongly associated with increased stroke risk in children2indication for blood transfusion3TAMMV, cm/sPredictive category≤ 170Normal171–199Borderline≥ 200AbnormalCorrelation between blood flow velocity and category used to predict stroke risk2,4SCD is associated with progressive occlusion of the large intracranial arteries.1The arteries most frequently affected in SCD are the middle cerebral and intracranial internal carotid arteries.1The table illustrates the association between blood flow velocity and the category used to predict stroke risk, as defined by Adams and colleagues.2An abnormal time averaged mean maximum velocity is strongly associated with increased stroke risk in children2, and is now accepted as being an indication for blood transfusion.3ReferencesKassab MY et al. J Am Board Fam Med 2007;20:65–71.Adams RJ et al. Ann Neurol 1997;42:699–704.Adams RJ et al. N Engl J Med 1998;339:5–11.TAMMV = time-averaged mean of the maximum velocity.1Kassab MY, et al. J Am Board Fam Med. 2007;20: Adams RJ, et al. Ann Neurol. 1997;42: Adams RJ, et al. N Engl J Med. 1998;339: Abboud MR, et al. Blood. 2004;103:
16 Abboud MR, et al. Blood. 2004;103:2822-6. Correlation between abnormal TCD velocities and stenoses on MRA in children with SCDStudy rationaleMRA is frequently used to study blood flow in the brains of children with SCDdo MRA results correlate with TCD velocities used to predict stroke risk?Children with higher TCD velocities and abnormal MRA findings are at a higher risk of strokeTCD can identify flow abnormalities indicative of stroke risk before MRA lesions become evidentPatients with abnormal MRA had significantly higher TCD velocities (p < 0.001)Overall, 100 patients with TCD velocities in the abnormal category underwent MRA examinationOverall, 4/13 patients with abnormal MRA had strokes compared with 5/40 patients with normal MRA (p < 0.03)This was a study of 100 children who had abnormal TCD velocities indicating a high risk of stroke.The study aimed to correlate observations using MR angiography, an imaging technique frequently used to detect vascular lesions in the brains of SCD patients, with blood velocities measured by TCD.Patients with abnormal MR angiography results had significantly higher TCD velocities (P<0.001).Patients with abnormal MR angiography results were significantly more likely to have strokes. However, as 5/40 patients with abnormal TCD velocities but normal MR angiography results had strokes, this suggests that TCD may be able to indicate stroke risk before lesions become visible on MR angiography.ReferenceAbboud MR et al. Blood 2004;103:2822–2826.Abboud MR, et al. Blood. 2004;103:
17 Correlation between TAMMV on TCD and stenoses on MRA in SCD Study rationalerelationship between neuroimaging abnormalities and TCD is unclear in adult patients with SCDimaging abnormalities reported in up to 44% of children with SCD; prevalence in adults unknownDifferences: adults vs childrenfrequency of imaging abnormalities in adults—higher than in childrenTCD velocities in adults with intracranial stenoses—lower than in childrenPatients with intracranial stenoses on MRA had significantly higher TAMMV than those without (p = 0.01)Overall, 50 adults (> 16 years) with SCD were examined with MRI, MRA, and TCDTAMMV cm/s allowed diagnosis of MCA or ICA intracranial stenoses with 100% sensitivity and 73% specificityThis Brazilian study was carried out because, while neuroimaging abnormalities are reported in up to 44% of children with SCD, their prevalence in adults with TCD was unknown, as was their relationship to TCD findings.In 50 adults with SCD, they found a strong correlation between higher TCD velocity and intracranial stenoses on MR angiography.TAMMV cm/s was 100% sensitive in allowing diagnosis of intracranial stenoses in the middle cerebral or internal carotid artery.While adults were found to have a greater frequency of abnormalities detected on MRI/MR angiography compared to those described in children, the TCD velocities in adults with stenoses were lower than those described for children.ReferenceSilva GS et al. Stroke 2009;40:2408–2412.Silva GS, et al. Stroke. 2009;40:
18 Middle cerebral artery Consistency of TCD velocities in SCD patients with different ethnic backgroundsMiddle cerebral arteryABC406080100120140160180Mean velocity (cm/s)TCD and TCCS performed in12 African children with SCD (Group A)12 age-matched healthy Africans (Group B)12 age-matched healthy Caucasians (Group C)ResultsPI and depth values in MCA and BA were similar with TCD and TCCS in all 3 groupsTAMMV, PSV, and EDV in MCA and BA were higher in Group A with both TCD and TCCS evaluationsimilar lower values in African and Caucasian healthy controlsConclusionsethnic background does not seem to influence TCD velocityinternationally accepted reference values for blood velocities can be usedPatient groupThis study was performed in Italy in order to verify the feasibility of TCD and transcranial color coded sonography screening, and the applicability of international reference values of blood velocities in a population of African immigrants with HbSS SCD.Both TCD and transcranial color-coded sonography (TCCS) were performed in 12 African children with SCD (HbSS; Group A), 12 age-matched healthy Caucasians (Group B), and 12 age-matched healthy Africans (Group C).The results showed that pulsatility index and depth values in the middle cerebral and basilar arteries were similar with TCD and TCCS in all 3 groups.TAMMV, peak systolic velocity and end diastolic velocity in the middle cerebral and basilar arteries were higher in the children with SCD on both TCD and TCCS, while there were similar lower values in the African and Caucasian healthy controls.In conclusion, ethnic background does not appear to influence TCD velocity. Therefore, internationally accepted reference values for blood velocities can be used in different ethnic groups.ReferenceColombatti R et al. Ital J Pediatr 2009;35:15.Mean of PSV (●), TAMMV (■), and EDV (▲) on TCD (open) and TCCS (solid) in the 3 groups of patientsBA = basilar artery; EDV = end-diastolic velocity; PSV = peak systolic velocity; TCCS = transcranial colour-coded sonography.Colombatti R, et al. Ital J Pediatr. 2009;35:15.
19 TCD, neurological exam, and MRI—association with overall morbidity and mortality in SCD Increasing morbidity/ mortalityIncreasing neuropsychological deficitsTCD normal; exam normal; MRI normalTCD normal; exam normal; silent infarctTCD high; exam normal; silent infarctTCD high; exam normal; MRI normalStrokeHaemorrhageNeuro exam: normal abnormalThis diagram illustrates estimates of morbidity and mortality, and association with neurological test performance and TCD findings, in patients with sickle cell anemia (HbSS).The different clinical subgroups are represented by circles that approximate their relative numbers in a typical HbSS population in care at US institutions.There is a wide spectrum of brain injury, and a wide spectrum of impact of that injury on overall morbidity and mortality in patients with HbSS.The most catastrophic injury is the classical acute stroke.Hemorrhagic stroke is associated with the highest neurologic morbidity and mortality.ReferencePlatt OS. Hematology Am Soc Hematol Educ Program 2006;54–57.Platt OS. Hematology Am Soc Hematol Educ Program. 2006:54-7.
20 TCD testing and transfusion therapy—STOP Overall, 1,934 children aged 2–16 years with SCDscreened with TCD (identical equipment in all cases)Overall, 130 with abnormal TCD (mean flow velocity in MCA or ICA ≥ 200 cm/s) + no earlier history of strokeRANDOMIZEDOngoing transfusions to reduce HbS concentration to < 30% total Hb(n = 63)This landmark stroke prevention trial (STOP) was the first trial designed by Adams to test whether reducing sickled Hb to <30% with blood transfusion would decrease the likelihood of the first stroke by 70%. This was a prospective, randomized, controlled, multicenter treatment trial in which 1934 children with SCD (sickle cell anemia [HbSS] or sickle β-thalassemia [HbSβ]) were screened with TCD to detect those at highest risk for development of occlusive cerebral vasculopathy.All patients also underwent baseline MRI, neurologic exam, physical exam, CBC, and Hb analysis.Those who were TCD-positive (mean blood flow velocity in middle cerebral artery or internal carotid artery ≥200 cm/sec) with no previous history of stroke (130 children) were randomized to receive either transfusion aimed at keeping HbS <30% or standard care.Standard care included penicillin prophylaxis, pneumococcal vaccination, folic acid supplementation, surgery, and treatment of acute illness, including transfusion when needed for transient episodes but excluding the use of HU or anti-sickling agents. Vaccination against hepatitis B was required if appropriate.ReferenceAdams RJ et al. N Engl J Med 1998;339:5–11.Standard care(n = 67)STOP = Stroke Prevention Trial in Sickle Cell Anemia.Adams RJ, et al. N Engl J Med. 1998;339:5-11.
21 TCD testing and transfusion therapy in SCD—STOP findings Regular transfusions (every 3–4 weeks) reduced stroke risk in children identified by TCD as high riskAfter a mean follow-up of 19.6 months, there was a 92% reduction in stroke risk in the transfusion group compared with the standard- care group (p < 0.001)510152025303540Transfusion(n = 63)Standard care(n = 67)Percentage92% difference (p < 0.001)1/63 (1.6%)11/67 (16.42%)Children with strokeThe STOP results showed that children identified as high risk on TCD, and who were given regular transfusion therapy, had a significantly reduced risk of stroke compared with high-risk children randomized to receive only standard care.ReferenceAdams RJ et al. N Engl J Med 1998;339:5–11.Adams RJ, et al. N Engl J Med. 1998;339:5-11.
22 TCD findings as stroke predictors in SCD—STOP findings TCD findings as predictors of strokebaseline results of TCD studiesabnormal on the side on which stroke occurred: all casesabnormal on the opposite side: 6 patientsTCD and MRI findings were significant predictors of stroke when considered separately (p = and p = 0.038, respectively)only the TCD finding was a significant predictor of stroke when both MRI and TCD studies were considered together (p = 0.08 and p = 0.03, respectively)TCD was found to be a significant predictor of stroke, both as a separate factor and when considered with MRI results.ReferenceAdams RJ et al. N Engl J Med 1998;339:5–11.Adams RJ, et al. N Engl J Med. 1998;339:5-11.
23 TCD testing and transfusion therapy in SCD— consequences of STOP findings STOP trial outcome led toearly termination of the study1widespread implementation of TCD screening and transfusion therapy as the standard of care in paediatric patients at high risk of strokeinitiation of the STOP II trial to determine when transfusion can be safely terminated2The observation that transfusion greatly reduced the risk of a first stroke in these children led to early termination of the study1 and the widespread implementation of transfusion therapy as a standard approach to the management of high-risk pediatric SCD patients.The STOP II trial2 was initiated to try and determine the optimum time to discontinue transfusions in these children.ReferencesAdams RJ et al. N Engl J Med 1998;339:5–11.Adams RJ et al. N Engl J Med 2005;353:2769–2778.STOP II = Optimizing Primary Stroke Prevention in Sickle Cell Anemia.1Adams RJ, et al. N Engl J Med. 1998;339: Adams RJ, et al. N Engl J Med. 2005;353:
24 TCD testing and transfusion therapy in SCD—STOP II Prospective, randomized, controlled, multicentre treatment trialOverall, 79 children with SCD aged2–16 yearswere at high risk of stroke based on TCD findings and had received transfusions for ≥ 30 monthsTCD had normalized, and patients had no severe MRA lesions at the start of STOP IIOverall, 38 continued chronic transfusion therapyOverall, 41 discontinued chronic transfusion therapyOverall, 14 (34%) reverted to high-risk TCD; 2 developed strokeNo neurological eventThis prospective, randomized trial included 79 high-risk (TCD) children who had received transfusion therapy for ≥30 months, resulting in TCD normalization by the start of the trial. The composite primary end point was stroke or reversion to high risk TCD. Among the 41 children in the transfusion-halted group, high-risk TCD results developed in 14 and stroke in 2 others within a mean (SD) of 4.5 2.6 months (range, 2.1 to 10.1) of the last transfusion. Neither of these events of the composite end point occurred in the 38 children who continued to receive transfusions.The study was stopped after 79 children of a planned enrollment of 100 underwent randomization.Discontinuation of transfusion for the prevention of stroke in children with SCD results in a high rate of reversion to abnormal blood-flow velocities on Doppler studies and stroke.ReferenceAdams RJ et al. N Engl J Med 2005;353:2769–2778.STOP II trial terminated 2 years early. It is not recommended to stop blood transfusions in patients with SCD at high risk of stroke based on TCD findingsAdams RJ, et al. N Engl J Med. 2005;353:
25 TCD screening in SCD—impact on annualized stroke rate 0.5Retrospective cohort of all children with SCD within a large managed-care planStroke incidence rates were estimated before (pre-TCD) and after (post-TCD) first TCD screeningSince STOP, TCD use increased 6-foldAnnualized stroke rate decreased from 0.44 to 0.19 per 100 person-years from pre- to post-TCD0.440.40.3Annualized stroke rate per 100 patient-years0.190.20.1The impact of TCD screening in SCD on annualized stroke rate was investigated in a retrospective cohort of all children with SCD within a large managed care plan in the US.Stroke incidence rates were estimated pre-TCD screening (from January 1993 to the end of 1997) and after the first TCD (from January 1998 to the end of 2005).Data from the 157 children in the cohort showed that TCD screening increased 6-fold after the STOP results were published.Importantly, they found that the annualized stroke rate decreased from 0.44 to 0.19 per 100 person-years from pre- to post- TCD screening.ReferenceArmstrong-Wells J et al. Neurology 2009;72:1316–1321.Pre-TCDPost-TCDArmstrong-Wells J, et al. Neurology. 2009;72:
26 High conversion rate from ‘‘borderline’’ to ‘‘abnormal’’ TCD findings if untreated Review of TCD examinations in 274 untreated children with SCD (HbSS and HbSβ0-thalassaemia; excluding those receiving HU or transfusions)Overall, 54 patients had borderline TCD velocities(TAMMV 170–199 cm/s)Overall, 18-month cumulative conversion to abnormal TCD(TAMMV ≥ 200 cm/s) = 23%There is also evidence that children with ‘conditional’ TCD findings may become high risk if untreated.This retrospective study of TCD examinations in 274 untreated children with HbSS (excluding those receiving HU or transfusions) showed that nearly a quarter of those with ‘marginal’ TCD findings converted to ‘abnormal’ (ie high risk) within 18 months.The investigators concluded that therapy should be considered in such patients in order to prevent conversion to abnormal TCD velocities.1Follow-up TCD examinations of children enrolled in the STOP trial suggested that conversion to abnormal velocities was most likely in younger patients with higher baseline TCD velocities2ReferencesHankins JS et al. Br J Haematol 2008;142:94–99.Adams RJ et al. Blood 2004;103:3689–3694.Conclusion—therapy should be considered for the prevention of conversion to abnormal TCD velocities1During the STOP trial, such conversion to abnormal velocities most likely occurred in younger patients and in those with higher initial flow velocities2HbSS = sickle cell anaemia.1Hankins JS, et al. Br J Haematol. 2008;142: Adams RJ, et al. Blood. 2004;103:
27 TCD and stroke risk in children with HbSC disease—study rationale Rationale for studymost studies of TCD and stroke risk are centred on patients with HbSSHbSC disease—caused by co-inheritance of HbS and HbCclinical features of HbSC and HbSS overlap, but with HbSCcerebrovascular disease and stroke are less commonlifetime risk of stroke is 2–3%50–100 times greater risk than that of general paediatric populationvalue of TCD for stroke prevention in HbSC is unknownSince most studies of TCD and stroke risk have been focussed on patients with sickle cell anemia (HbSS), Deane and colleagues undertook a retrospective audit of patients with HbSC disease, which is caused by co-inheritance of HbS and HbC – the second most common form of SCD after sickle cell anemia (25–30% of cases).While the clinical features of HbSC and HbSS overlap, patients with HbSC have longer preservation of splenic function, an apparently lower risk of infection, a far greater risk of proliferative retinopathy, but a lower risk of cerebrovascular disease and stroke. Nevertheless, their lifetime stroke risk is still up to 100 times greater than that of the general pediatric population.Thus far, the value of TCD for stroke prevention in HBSC was unknown.ReferenceDeane CR et al. Arch Dis Child 2008;93:138–141.HbC = haemoglobin C; HbS = haemoglobin S; HbSC = haemoglobin SC.Deane CR, et al. Arch Dis Child. 2008;93:
28 TCD and stroke risk in children with HbSC disease—design and results Retrospective audit of routine TCD scans and clinical data from 46 children (mean age 8.1 years) with HbSC diseaseMean TAMMV = 94 cm/s(98th centile of 128 cm/s)Significantly less than published ranges for HbSS1 child had stroke at age 5 years, when TAMMV = 146 cm/sConclusionsTAMMV > 128 cm/s could indicate the possibility of significant cerebrovascular disease in HbSCNo evidence on which to base a programme of primary stroke prevention in HbSCTCD measurement is likely to function as a screen for those requiring further investigationThis was a retrospective audit of routinely performed TCD scans and clinical data from 46 children, mean age 8.1 years, with HbSC disease.They found that mean TAMMV was 94 cm/s (98th centile 128 cm/s), which is significantly less than published ranges for HbSS.1 child had a stroke at age 5, when TAMMV was 146 cm/s.The authors concluded that TAMMV >128 cm/s in HbSC patients could indicate the possibility of significant cerebrovascular disease.However, there is currently no evidence on which to base a program of primary stroke prevention in HbSC.ReferenceDeane RC et al. Arch Dis Child 2008;93:138–141.Deane RC, et al. Arch Dis Child. 2008;93:
30 TCD equipment Wide range of TCD equipment is available from small and portable to large and stationary machinesPortable machines can be used at bedside for reliable evaluation of cerebral vasculatureThere is a wide range of equipment for performing TCD, including portable and larger machines.Portable machines may be particularly convenient for reliable bedside evaluation of the cerebral circulation.Image from:config=ps_prodDtl&prodID=158.Image from Accessed Nov 2010.
31 Transcranial Doppler devices TCD = non-duplex (non-imaging TCD)TCDI = duplex (imaging TCD)Higher cost1Buying a dedicated TCD doppler is expensive: app EuroMany hospitals have sonography equipment1Buying separate imaging transducer for already existing doppler machine costs app EuroUsed Stroke Prevention Trial in Sickle Cell Anemia Study (STOP) trial1Effectively identifies major intracranial arteries2Risk of inaccurate velocity is lower than with TCD2May reveal unexpected vascular findings (e.g. aneurysm, vascular malformation) 1Important: measurements obtained with TCDI are significantly lower than those obtained with TCD sonography1–4should be considered when predicting the risk of stroke in children with SCDSince most studies of TCD and stroke risk have been focussed on patients with sickle cell anemia (HbSS), Deane and colleagues undertook a retrospective audit of patients with HbSC disease, which is caused by co-inheritance of HbS and HbC – the second most common form of SCD after sickle cell anemia (25–30% of cases).While the clinical features of HbSC and HbSS overlap, patients with HbSC have longer preservation of splenic function, an apparently lower risk of infection, a far greater risk of proliferative retinopathy, but a lower risk of cerebrovascular disease and stroke. Nevertheless, their lifetime stroke risk is still up to 100 times greater than that of the general pediatric population.Thus far, the value of TCD for stroke prevention in HBSC was unknown.ReferenceDeane CR et al. Arch Dis Child 2008;93:138–141.1McCarville MB, et al. AJR Am J Roentgenol. 2004;183: Krejza J, et al. Am J Neuroradiol. 2007;28: Jones AM, et al. Pediatr Radiol. 2001;31: Jones A, et al. Pediatr Radiol. 2005;35:66-72.
32 Transcranial Doppler devices (cont.) TCD = non-duplex (non-imaging TCD)TCDI = duplex (imaging TCD)Since most studies of TCD and stroke risk have been focussed on patients with sickle cell anemia (HbSS), Deane and colleagues undertook a retrospective audit of patients with HbSC disease, which is caused by co-inheritance of HbS and HbC – the second most common form of SCD after sickle cell anemia (25–30% of cases).While the clinical features of HbSC and HbSS overlap, patients with HbSC have longer preservation of splenic function, an apparently lower risk of infection, a far greater risk of proliferative retinopathy, but a lower risk of cerebrovascular disease and stroke. Nevertheless, their lifetime stroke risk is still up to 100 times greater than that of the general pediatric population.Thus far, the value of TCD for stroke prevention in HBSC was unknown.ReferenceDeane CR et al. Arch Dis Child 2008;93:138–141.McCarville MB, et al. AJR Am J Roentgenol. 2004;183:
33 TCD machines and manufacturers Nicolet BiomedicalSONARA, SONARA/tek1Compumedics Germany GmbH2analog: Smart-/EZ-Dop®, Multi-Dop® Prodigital: Doppler-Box™, Multi-Dop® Tdigital, Multi-Dop® XdigitalDoppler-Box™Multi-Dop®Tdigital1http://www.akumed.no/1862/158_SONARA_Family_Brochure.pdf. Accessed Nov Image from Accessed Nov 2010.
34 TCD machines (non-duplex) Rimed Ltd.1Digi-Lite™Spencer Technologies2ST3 DIGITALDigi-LiteTMRimed’s probe holderST3 DIGITAL1Image from Accessed Nov Image from Accessed Nov 2010.
35 TCDI allows artery visualization Advances in TCD result in the imaging of intracranial arteriesConventional colour orientation for TCDI examinationsBlood flow towards the transducerBlood flow away from the transducerAdvances in TCD have allowed imaging of intracranial arteries as well as determination of blood flow, shown as the waveform.According to convention, shades of red indicate blood flow towards the transducer, and shades of blue indicate blood flow away from the transducer.It should be noted that the appearance of intracranial arterial blood flow is dependent on many instrument controls – estimations of arterial size are not accurate from the color Doppler display.ReferenceTCDI = imaging TCD.Image from products/cmetcd.html. Accessed Nov 2010.
36 TCDI versus non-imaging TCD Study comparing TCDI (with image of artery) with non-imaging TCD (waveform only)Overall, 37 children with SCD and without intracranial arterial narrowing on MRA were studied1TCDI identified the major intracranial arteries more effectively than did TCD1Difference between TCDI and TCD velocities similar to that found in previous studies2 and should be considered when used for stroke risk prediction3Risk of inaccurate velocity sampling is lower with TCDI than with TCD1TCDTCDIFound arteries (%)94.9%99.3%Mean depth of insonation (all arteries)No significant differenceVelocities (right and left sides)Significantly lower (~ 20%) with TCDI vs TCDSimilar with angle-corrected* TCDI vs TCD*TCDI enables an operator to determine an angle between the course of an artery and the ultrasound beam and to correct measurements for cosine of the angle.In this study, the accuracy of imaging TCD (ie with an image of the artery) was compared with that of non-imaging TCD (ie waveform only, illustrating blood flow velocity).37 children with SCD and without intracranial narrowing on MR angiography were studied with both techniques, including both angle-corrected and uncorrected TCDI.As illustrated in the table, TCDI identified the major intracranial arteries more effectively than TCD.The risk of inaccurate velocity sampling was also lower with TCDI versus TCD.1The difference between TCD and TCDI velocities was similar to that observed in a previous study, where velocities were 10–15% lower using TCDI compared with TCD in 29 children with SCD.2The TCD velocity thresholds used to predict stroke risk may require modification when using TCDI.3ReferencesKrejza J et al. Am J Neuroradiol 2007;28:1613–1618.Jones AM et al. Pediatr Radiol 2001;31:461–469.Jones A et al. Pediatr Radiol 2005;35:66–72.MRA = magnetic resonance angiography 1Krejza J, et al. Am J Neuroradiol. 2007;28: Jones AM, et al. Pediatr Radiol. 2001;31: Jones A, et al. Pediatr Radiol. 2005;35:66-72.
37 TCDI machines and manufacturers Acuson Sequoia 512Vivid E9Siemens medical1e.g. Acuson Sequoia 5122GE Healthcare3e.g. LOGIQ linee.g. Vivid linePhilips Healthcare4e.g. HD lineHD15LOGIQ 91www.medical.siemens.com/webapp/wcs/stores/servlet/StoreCatalogDisplay~q_catalogId~e_-1~a_langId~e_-1~a_storeId~e_10001.htm. Accessed Nov www.sequoiaultrasound.com/pdf/sequoiaultrasound.com/Sequoia_512_Brochure.pdf. Accessed Nov 2010.3www2.gehealthcare.com/portal/site/usen/gehchome. Accessed Nov www.healthcare.philips.com/main/products/ultrasound/index.wpd. Accessed Nov 2010.
39 Adams RJ, et al. Ann Neurol. 2003;54:559-63. STOP strategy for primary stroke prevention: opinions of leading neurologistsAdoption of the STOP trial primary prevention strategy could lead toprevention of 100–200 strokes/yearmore children reaching adulthood with normal arterial vesselsreduced prevalence of severe arterial disease and moyamoya syndromeTransfusion in the short term is manageable with a number of beneficial effects beyond stroke preventionRequiring definite evidence of arterial disease (e.g. MRI evidence of stroke) would identify a more specific higher-risk population, but opportunity for those children to reach adulthood with relatively intact neurological function will be lostFull quote from editorial:“If the STOP primary prevention strategy were widely adopted, it is reasonable to argue that 100–200 strokes per year would be prevented, and many more children would reach adulthood with arterial vessels that are normal and less prone to have infarction or hemorrhage later in life.”“The prevalence of severe arterial disease…due to SCD would probably go down with systematic application of the STOP approach which calls for first screening at age 2 years. Transfusion in the short term is manageable and has…beneficial effects beyond stoke prevention.”“Requiring definite evidence of arterial disease or overt clinical or even MRI evidence of stroke would certainly identify a higher risk population, but the opportunity for those children to reach adulthood with relatively intact neurological function will be lost.”ReferenceAdams RJ et al. Ann Neurol 2003;54:559–563.Adams RJ, et al. Ann Neurol. 2003;54:
40 US and UK guidance for TCD screening in SCD— based on STOP findings 1998 – National Heart, Lung, and Blood Institute clinical alert12004 – Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology—TCD assessment22009 – National Health Service Antenatal and Newborn Screening Programmes3“Since the greatest risk of stroke occurs in early childhood, it is recommended that children ages 2–16 receive TCD screening”“TCD is of established value in the screening of children aged 2 to 16 years with sickle cell disease for stroke risk (Type A [established as a useful predictive for suspected condition], class I [evidence provided by prospective studies in broad spectrum of persons with suspected condition])”Based primarily on data from the landmark STOP trial,1 US and UK guidelines now recommend regular TCD screening in children with SCD aged 2–16 years.2-4ReferencesAdams RJ et al. N Engl J Med 1998;339:5–11.NIH. Clinical alert from the NHLBI, Sept 18, 1997:http://www.nhlbi. nih.gov/ new/press/nhlb-18a.htm.Sloan MA et al. Neurology 2004;62:1468–1481.NHS. Transcranial Doppler Scanning for Children with Sickle Cell Disease, March 2009: FINDER/ViewResource.aspx?resID=“All children and young adults with sickle cell anaemia (HbSS) and HbSβ zero thalassaemia, should be offered annual TCD scans from age 2 years until at least age 16 years”1NIH. Clinical alert from the NHLBI Sept Sloan MA, et al. Neurology. 2004;62: NHS. Transcranial Doppler scanning for children with sickle cell disease Mar. FINDER/ViewResource.aspx?resID=
41 Identification and management of stroke risk in children with SCD—NIH guidelines Child with HbSS, aged > 2 years, with no symptomsEvaluate educational needs based on resultsNeuropsychological testingTCD unavailableTCDHigh risk based on other information†Abnormal ( 200 cm/s)Normal (< 200 cm/s)Low riskProtocol treatment or clinical trialConfirm abnormalRepeat TCD every 3–12 months*ObservationOr treatment optionsobservation for progressionHUtransfusionother (e.g. antiplatelet agents)MRI/MRANIH guidelines recommend that transfusions are continued indefinitely in children with sickle cell anemia (HbSS) aged 2 years or over at high risk of stroke, based on TCD findings when possible.ReferenceNIH Publication No The Management of Sickle Cell Disease.Revised 2002 (4th edition). NIH, Bethesda, MD, USA,gov/health/prof/blood/sickle/sc_mngt.pdf.Abnormal examChronic transfusion*Optimal frequency of re-screening not established; younger children with velocity closer to 200 cm/s should be re-screened more frequently.†Prior transient ischaemic attack, low steady-state Hb, rate and recency of acute chest syndrome, elevated systolic blood pressureAccessed Nov 2010.
42 TCD scanning decision tree: NHS guidelines Children aged 2–16Initial TCD scanInadequate scan/low velocitiesNormal< 170 cm/sBorderline170–199 cm/sAbnormal 200 cm/sIf child is uncooperative, consider rescanning when appropriate. If due to a poor scanning window, consider an alternative techniqueRepeat TCD scan in 1 year. In older children who have already had several normal scans, the time interval might be extended to 2 yearsRe-scan between 1 and 4 months depending on the age of the child and the blood velocity. Children younger than 10 years and those with higher velocities are considered to be at higher risk and should be scanned earlierDiscuss stroke risk and consider chronic transfusion. A re-scan might be considered appropriate depending on the blood velocity and individual clinical circumstancesNHS guidelines recommend routine TCD scanning of children with SCD aged 2–16 years.Scan results should be divided into five categories, namely, Inadequate image; Unusual low velocity; Normal velocity – ‘low risk’; Borderline velocity – ‘marginal’; and High velocity – ‘high risk’.Classification should be based on maximal velocity recorded during the scan of the distal intracranial internal carotid artery (ICA) and the middle cerebral artery (MCA).Specific action taken following categorization of the results should depend on the age of the child, and clinical history should be considered when determining timescales of repeat scans.Due to the long-term implications of chronic transfusion, as recommended for high-risk patients, NHS guidelines suggest that all available data, including a comprehensive neurological assessment and the results of other imaging studies such as MRI/MRA (although these are not used for risk classification), should be considered prior to commencing treatment.ReferenceNHS. Transcranial Doppler Scanning for Children with Sickle cell disease,March 2009:Resource. aspx?resID=Velocities are non-imaging TCD and TAMMV.Decisions apply to TAMMVs in the distal ICA, bifurcation, and/or MCA only.For bilateral or multifocal TAMMVs > 170 cm/s, choose the highest single value for the decision tree.Recurrent inadequate scans or low velocities may indicate severe stenosis. Consider using other imaging techniques.For any particular child, detailed clinical knowledge and judgement might override this guidance.Accessed Nov 2010.
44 Summary—SCDSCD is an inherited Hb disorder. Symptoms include episodes of acute pain and ischaemic stroke due to vascular occlusion by sickle-shaped erythrocytesBMT is the only curative therapy1,2Current therapies are aimed at the prevention and treatment of complicationstreatment with HU has been shown to reduce the occurrence of painful crises3 and to lower TCD velocities in patients with SCD4Intermittent or chronic transfusion therapy is a major therapeutic approach that is becoming increasingly utilized to reduce the risk of stroke and other SCD clinical manifestations5,6Bone marrow transplantation, which introduces stem cells that are able to express normal Hb, is currently the only curative therapy for SCD.1,2Other therapies currently in use aim to prevent and treat the complications of SCD.In clinical trials, HU has been shown to reduce the median occurrence of painful crises by 44% compared with placebo3 and lowers TCD velocities in children with SCD,4 although whether this reduces risk of stroke is yet to be established.Intermittent or chronic transfusion therapy is used to increase Hb content and oxygen carrying capacity of the blood and decrease the proportion of circulating sickle cells. It is becoming increasingly utilized to significantly reduce the risk of stroke and other SCD complications.5,6Iron overload is a major complication arising from the increased use of transfusion therapy. However, evidence is growing that iron burden in SCD can be effectively managed with iron chelation therapy.7ReferencesHoppe CC and Walters MC. Curr Opin Oncol 2001;13:85–90.Walters MC et al. Blood 2000;95:1918–1924.Carache S et al. New Engl J Med 1995;332:1317–1322.Zimmerman SA et al. Blood 2007;110:1043–1047.Styles LA and Vichinsky E. J Pediatr 1994;125:909–911.Adams RJ et al. N Engl J Med 1998;339:5–11.Vichinsky E et al. Br J Haematol 2007;136:501–508.1Hoppe CC, Walters MC. Curr Opin Oncol. 2001;13: Walters MC, et al. Blood. 2000;95: Carache S, et al. N Engl J Med. 1995;332: Zimmerman SA, et al. Blood. 2007;110: Styles LA, Vichinsky E. J Pediatr. 1994;125: Adams RJ, et al. N Engl J Med. 1998;339:5-11.
45 Summary—TCDTCD is a safe, inexpensive, and non-invasive diagnostic tool1intracranial arterial blood flow velocities are presented as wave-form recordingblood flow velocities predict stroke riskIntracranial arteries are examined (insonated) via 4 acoustic windows in the skull1Imaging TCD adds further information2visualization of arteriesenables angle-corrected blood velocity measurementReferencesKassab MY et al. J Am Board Fam Med 2007;20:65–71.Krejza J et al. AJR Am J Roentgenol 2000;174:1297–1303.1Kassab MY, et al. J Am Board Fam Med. 2007;20: Krejza J, et al. AJR Am J Roentgenol. 2000;174:
46 Summary—TCD in SCDChildren and teenagers with SCD: very high risk of stroke and stroke-related morbidity and mortality1–3TAMMV ≥ 200 cm/s in MCA or intracranial ICA indicates high stroke risk in children4Landmark STOP trial: TCD screening can identify patients with high-risk SCD5TCD screening, accompanied by transfusion therapy in high-risk patients, has reduced the annualized stroke rate in SCD6High proportion of untreated children with SCD and ‘‘borderline’’ TCD velocities converts to high risk over time7US and UK guidelines recommend TCD screening for children with SCD aged 2–16 years8,9ReferencesOhene-Frempong K et al. Blood 1998;91:288–294.Manci EA et al. Br J Haematol 2003;123:359–365.Miller ST et al. J Pediatr 2001;139:385–390.Adams RJ et al. Ann Neurol 1997;42:699–704.Adams RJ et al. N Engl J Med 1998;339:5–11.Armstrong-Wells J et al. Neurology 2009;72:1316–1321.Hankins JS et al. Br J Haematol 2008;142:94–99.NIH. Clinical alerts from the NHLBI, Sept 18, 1997:NHS. Transcranial Doppler Scanning for Children with Sickle Cell Disease, March 2009: FINDER/ViewResource.aspx?resID=1Ohene-Frempong K, et al. Blood. 1998;91: Manci EA, et al. Br J Haematol. 2003;123: Miller ST, et al. J Pediatr. 2001;139: Adams RJ, et al. Ann Neurol. 1997;42: Adams RJ, et al. N Engl J Med. 1998;339: Armstrong-Wells J, et al. Neurology. 2009;72: Hankins JS, et al. Br J Haematol. 2008;142: NIH. Clinical alerts from the NHLBI Sept 18. 9www.library.nhs.uk/GUIDELINESFINDER/ViewResource.aspx?resID= Accessed Nov 2010.
51 GLOSSARY LIC = liver iron concentration LVEF = left-ventricular ejection fractionMCA = middle cerebral arteryMDS = Myelodysplastic syndromesMDS-U = myelodysplastic syndrome, unclassifiedMRA = magnetic resonance angiographyMRI = magnetic resonance imagingMV = mean velocity.N = neutropeniaNEX = number of excitationsNIH = National Institute of HealthOS = overall survival
52 GLOSSARY pB = peripheral blood PI = pulsatility index PSV = peak systolic VelocityRA =refractory anemiaRAEB = refractory anemia with excess blastsRAEB -T = refractory anemia with excess blasts in transformationRARS = refractory anemia with ringed sideroblastsRBC = red blood cellsRF = radio-frequencyRCMD = refractory cytopenia with multilineage dysplasiaRCMD-RS = refractory cytopenia with multilineage dysplasia with ringed sideroblastsRCUD = refractory cytopenia with unilineage dysplasia
53 GLOSSARY RN = refractory neutropenia ROI = region of interest RT = refractory thrombocytopeniaSCD = sickle cell diseaseSD = standard deviationSI = signal intensitySIR = signal intensity ratioSF = serum ferritinSNP-a = single-nucleotide polymorphismSQUID = superconducting quantum interface device.STOP = = Stroke Prevention Trial in Sickle Cell AnemiaSTOP II = Optimizing Primary Stroke Prevention in Sickle Cell Anemia
54 GLOSSARY T = thrombocytopenia TAMMV = time-averaged mean of the maximum velocity.TCCS = transcranial colour-coded sonographyTCD = transcranial doppler ultrasonographyTCDI = duplex (imaging TCD)TE = echo timeTR = repetition timeWHO = World Health OrganizationWPSS = WHO classification-based Prognostic Scoring System