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G-EXJ-1030713 May 2012 TRANSCRANIAL DOPPLER ULTRASONOGRAPHY (TCD) FOR ASSESSMENT OF STROKE RISK IN SICKLE CELL DISEASE NOTE: These slides are for use in.

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Presentation on theme: "G-EXJ-1030713 May 2012 TRANSCRANIAL DOPPLER ULTRASONOGRAPHY (TCD) FOR ASSESSMENT OF STROKE RISK IN SICKLE CELL DISEASE NOTE: These slides are for use in."— Presentation transcript:

1 G-EXJ-1030713 May 2012 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 are to 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 2 G-EXJ-1030713 May 2012 Outline ● Sickle cell disease (SCD) ● Transcranial Doppler (TCD) –TCD in SCD –TCD Equipment –Guidelines for TCD in SCD ● Summary LIC = liver iron concentration; MRI = magnetic resonance imaging; SF = serum ferritin; SIR = signal intensity ratio; SQUID = superconducting quantum interface device.

3 G-EXJ-1030713 May 2012 Sickle Cell Disease (SCD)

4 4 G-EXJ-1030713 May 2012 What is SCD? ● An inherited disorder affecting haemoglobin (Hb) synthesis ● Sickle cell erythrocytes have a mutant form of Hb and HbS –resulting from Glu→Val mutation in 6th codon of β-globin chain ● HbS turns normally pliable erythrocytes into rigid, sickle-shaped cells ● The irregular erythrocyte morphology leads to –episodes of vascular occlusion and acute pain –progressive organ damage ● Children have increased risk of infection and stroke ● Life expectancy may be shortened HbS = sickle cell haemoglobin. Schnog JB, et al. Neth J Med. 2004;62:364-74. Image from www2.med.umich.edu/prmc/media/newsroom/downloadImages.cfm?ID=656.

5 5 G-EXJ-1030713 May 2012 Clinical manifestations of SCD AnaemiaRed cell survival ~ 17 days (120 days in healthy people) 1 PainAcute and chronic 1 Central nervous systemOvert stroke, silent stroke, and neurocognitive impairment 1–3 Pulmonary Recurrent acute chest syndrome, pulmonary hypertension, and chronic sickle lung disease 1,2 SkinChronic ulcers, typically around the ankles 1 Joints Osteonecrosis (avascular necrosis) of femoral and humeral heads 1,2 EyesRetinal ischaemia, detachments – “sickle retinopathy” 1,2 Kidneys Inability to concentrate urine; proteinuria progressing to nephrotic syndrome; end-stage renal failure 4 CardiovascularCardiac decompensation and cardiomyopathy 1 1 Schnog JB, et al. Neth J Med. 2004;62:364-74. 2 Claster S, Vichinsky EP. Br Med J. 2003;327:1151-5. 3 Prengler M, et al. Ann Neurol. 2002;51:543-52. 4 Ataga KI, Orringer EP. Am J Hematol. 2000;63:205- 11.

6 6 G-EXJ-1030713 May 2012 Prevalence of SCD ● The frequency of the HbS gene is highest in populations in which malaria is (or was) endemic 1,2 ● Approximately 200,000 new cases of SCD occur in Africa every year 1 ● Recent population migrations have led to an increase in disease frequency in other areas 1 Weatherall DJ, Clegg JB. Bull World Health Organ. 2001;79:704-12. 2 Modell B, Darlison M. Bull World Health Organ. 2008;86:480-7. 3 Sickle cell disease: screening, diagnosis, management, and counseling in newborns and infants – clinical practice guideline number 6 AHCPR 1993;Publication 93-0562. 4 Sickle Cell Society. Sickle Cell Society Publication SC4 2005: www.sicklecellsociety.org/pdf/SC4.pdf. Image from Christianson A, et al. March of Dimes Global Report on Birth Defects: the hidden toll of dying and disabled children. 2006 (www.marchofdimes.com/MOD-Report- PF.pdf). <0.1 0.1-0.19 0.2-0.99 1-4.9 5-9.9 1—18.9 ≥19 –in the USA, SCD affects over 50,000 African-American individuals and occurs in 1 out of 375 newborns 3 –annually, more than 6,000 conceptions in the Caribbean and Central and South America are affected by SCD 2 –> 1 out of 2,400 live births (all ethnic groups) are affected in England, where 12,500 individuals live with the disease 4 Births with a pathological Hb disorder per 1,000 live births <0.1 0.1-0.19 0.2-0.99 1-4.9 5-9.9 1—18.9 ≥19 Global distribution of pathological Hb disorders, 1996 (WHO)

7 7 G-EXJ-1030713 May 2012 Management and treatment of SCD ● BMT is the only curative treatment for SCD that is currently available 1,2 –introduces stem cells that express normal Hb –availability of suitable matched donors is a major limitation ● Other current treatments aim at preventing and managing SCD complications ● HU promotes the production of HbF-expressing RBCs –HU treatment reduces the occurrence of painful crises and hospital admissions, 3 and may reduce the risk of stroke 4,5 ● Transfusion therapy to increase Hb and decrease sickle cell proportions in the blood is a major therapeutic approach –transfusion can reduce the risk of stroke and other SCD complications 6,7 BMT = bone marrow transplantation; HbF = fetal haemoglobin; HU = hydroxyurea. 1 Hoppe CC, Walters MC. Curr Opin Oncol. 2001;13:85-90. 2 Walters MC, et al. Blood. 2000;95:1918-24. 3 Charache S, et al. N Engl J Med. 1995;332:1317-22. 4 Ware RE, et al. J Pediatr. 2004;145:346-52. 5 Zimmerman SA, et al. Blood. 2007;110:1043-7. 6 Styles LA, Vichinsky E. J Pediatr. 1994;125:909-11. 7 Adams RJ, et al. N Engl J Med. 1998;339:5-11.

8 G-EXJ-1030713 May 2012 Transcranial Doppler (TCD)

9 9 G-EXJ-1030713 May 2012 TCD – a non-invasive diagnostic tool ● TCD – a safe, non-invasive diagnostic tool 1,2 –allows indirect real-time evaluation of intracranial cerebral circulation via ultrasonography 1,2 ● Ultrasonic beam bounces off erythrocytes within an artery 2 —reflected signal is processed to obtain a waveform that allows –accurate determination of blood flow velocities 1,2 –accurate determination of flow direction 2 –addition of calculated parameters (e.g. PI) 2 ● Blood flow velocities are used to predict stroke risk 3 1 Aaslid R, et al. J Neurosurg. 1982;57:769-74. 2 Kassab MY, et al. J Am Board Fam Med. 2007;20:65-71. 3 Adams RJ, et al. N Engl J Med. 1992;326:605-10. 4 McCarville MB, et al. Am J Roentgenol. 2004;183:1117-22. Typical TCD sonographic recording from MCA (velocity scale on left) 4 cm/ s 220 200 180 160 140 120 100 80 60 40 20 0 –20 –40 –60 –80 –100 –120 48 DEPTH 118 MEAN 0.72 PI 163 SYS 6 SAMPLE 40 POWER MCA = middle cerebral artery; PI = pulsatility index.

10 10 G-EXJ-1030713 May 2012 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 life ● Peak velocities approaching 100 cm/s are observed between the age of 4 and 6 years, after which blood flow velocity declines steadily throughout life MV = mean velocity. Adams RJ, et al. Normal values and physiological variables. In: Newell D, Aaslid R, editors. Transcranial Doppler. New York: Raven Press; 1992. 41-48. 120 100 80 60 40 20 0 010203040506070 Age (years) MCA MV (cm/s)

11 11 G-EXJ-1030713 May 2012 Accepted guidelines for normal TCD study: blood flow velocities in an adult ArteryWindowDepth (mm) Direction in relation to probe Mean ± SD flow velocity (cm/s) Middle cerebralTemporal30–60Toward55 ± 12 Anterior cerebralTemporal60–85Away50 ± 11 Posterior cerebralTemporal60–70Bidirectional40 ± 10 Terminal internal carotidTemporal55–65Toward39 ± 09 Internal carotid (siphon)Orbital60–80Bidirectional45 ± 15 OphthalmicOrbital40–60Toward20 ± 10 VertebralOccipital60–80Away38 ± 10 BasilarOccipital80–110Away41 ± 10 Kassab MY, et al. J Am Board Fam Med. 2007;20:65-71. Ringelstein EB, et al. Ultrasound Med Biol. 1990;16:745-61.

12 12 G-EXJ-1030713 May 2012 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 thin A.Transtemporal window insonates MCA anterior cerebral artery posterior cerebral artery terminal portion of ICA before its bifurcation B.Transorbital window insonates ophthalmic artery ICA at siphon level C.Transforaminal (occipital) window insonates distal vertebral arteries basilar artery D.Submandibular window insonates more distal portions of the extracranial ICA ICA = internal carotid artery. Kassab MY, et al. J Am Board Fam Med. 2007;20:65-71. Image from www.gehealthcare.com/usen/ultrasound/ products/cmetcd.html. Accessed Nov 2010. B A C D

13 G-EXJ-1030713 May 2012 TCD In SCD

14 14 G-EXJ-1030713 May 2012 Rationale for TCD in SCD ● Approximately 11% of patients with SCD have a stroke by 20 years of age, with a peak incidence in the first decade of life 1 ● Stroke accounts for ~ 10% of all mortality in SCD (Figure) 2 ● Silent infarct identified by MRI is a significant predictor of overt stroke in children 3 33–48% 9.8% 7.0% 6.6% Patients (%) 0 10 20 30 40 50 60 InfectionStrokeTherapy complications Splenic sequestration Causes of death in SCD 2 MRI = magnetic resonance imaging. 1 Ohene-Frempong K, et al. Blood. 1998;91:288-94. 2 Manci EA, et al. Br J Haematol. 2003;123:359-65. 3 Miller ST, et al. J Pediatr. 2001;139:385-90.

15 15 G-EXJ-1030713 May 2012 Flow velocity as predictor of stroke in SCD ● SCD – associated with progressive occlusion of large intracranial arteries 1 ● Arteries most frequently affected 1 –MCA –intracranial ICA ● Abnormal TAMMV (≥ 200 cm/s) in MCA or ICA is –strongly associated with increased stroke risk in children 2 –indication for blood transfusion 3 TAMMV = time-averaged mean of the maximum velocity. 1 Kassab MY, et al. J Am Board Fam Med. 2007;20:65-71. 2 Adams RJ, et al. Ann Neurol. 1997;42:699-704. 3 Adams RJ, et al. N Engl J Med. 1998;339:5-11. 4 Abboud MR, et al. Blood. 2004;103:2822-6. Correlation between blood flow velocity and category used to predict stroke risk 2,4 TAMMV, cm/s Predictive category ≤ 170Normal 171–199Borderline ≥ 200Abnormal

16 16 G-EXJ-1030713 May 2012 Correlation between abnormal TCD velocities and stenoses on MRA in children with SCD ● Study rationale –MRA is frequently used to study blood flow in the brains of children with SCD –do 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 stroke ● TCD can identify flow abnormalities indicative of stroke risk before MRA lesions become evident Abboud MR, et al. Blood. 2004;103:2822-6. Overall, 100 patients with TCD velocities in the abnormal category underwent MRA examination Patients with abnormal MRA had significantly higher TCD velocities (p < 0.001) Overall, 4/13 patients with abnormal MRA had strokes compared with 5/40 patients with normal MRA (p < 0.03)

17 17 G-EXJ-1030713 May 2012 Correlation between TAMMV on TCD and stenoses on MRA in SCD ● Study rationale –relationship between neuroimaging abnormalities and TCD is unclear in adult patients with SCD –imaging abnormalities reported in up to 44% of children with SCD; prevalence in adults unknown ● Differences: adults vs children –frequency of imaging abnormalities in adults—higher than in children –TCD velocities in adults with intracranial stenoses—lower than in children Silva GS, et al. Stroke. 2009;40:2408-12. Overall, 50 adults (> 16 years) with SCD were examined with MRI, MRA, and TCD Patients with intracranial stenoses on MRA had significantly higher TAMMV than those without (p = 0.01) TAMMV 123.5 cm/s allowed diagnosis of MCA or ICA intracranial stenoses with 100% sensitivity and 73% specificity

18 18 G-EXJ-1030713 May 2012 Consistency of TCD velocities in SCD patients with different ethnic backgrounds ● TCD and TCCS performed in –12 African children with SCD (Group A) –12 age-matched healthy Africans (Group B) –12 age-matched healthy Caucasians (Group C) ● Results –PI and depth values in MCA and BA were similar with TCD and TCCS in all 3 groups –TAMMV, PSV, and EDV in MCA and BA were higher in Group A with both TCD and TCCS evaluation –similar lower values in African and Caucasian healthy controls ● Conclusions –ethnic background does not seem to influence TCD velocity –internationally accepted reference values for blood velocities can be used BA = 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. Mean of PSV ( ● ), TAMMV ( ■ ), and EDV ( ▲ ) on TCD (open) and TCCS (solid) in the 3 groups of patients Middle cerebral artery A BC 40 60 80 100 120 140 160 180 Mean velocity (cm/s) Patient group

19 19 G-EXJ-1030713 May 2012 TCD, neurological exam, and MRI—association with overall morbidity and mortality in SCD Increasing morbidity/ mortality Increasing neuropsychological deficits TCD normal; exam normal; MRI normal TCD normal; exam normal; silent infarct TCD high; exam normal; silent infarct TCD high; exam normal; MRI normal Stroke Haemorrhage Neuro exam: normalabnormal Platt OS. Hematology Am Soc Hematol Educ Program. 2006:54-7.

20 20 G-EXJ-1030713 May 2012 TCD testing and transfusion therapy—STOP Overall, 1,934 children aged 2–16 years with SCD screened 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 stroke Ongoing transfusions to reduce HbS concentration to < 30% total Hb (n = 63) Standard care (n = 67) RANDOMIZED STOP = Stroke Prevention Trial in Sickle Cell Anemia. Adams RJ, et al. N Engl J Med. 1998;339:5-11.

21 21 G-EXJ-1030713 May 2012 Adams RJ, et al. N Engl J Med. 1998;339:5-11. 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 risk ● After 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) 0 5 10 15 20 25 30 35 40 Transfusion (n = 63) Standard care (n = 67) Percentage 92% difference (p < 0.001) 1/63 (1.6%) 11/67 (16.42%) Children with stroke

22 22 G-EXJ-1030713 May 2012 Adams RJ, et al. N Engl J Med. 1998;339:5-11. TCD findings as stroke predictors in SCD— STOP findings ● TCD findings as predictors of stroke –baseline results of TCD studies abnormal on the side on which stroke occurred: all cases abnormal on the opposite side: 6 patients –TCD and MRI findings were significant predictors of stroke when considered separately (p = 0.010 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)

23 23 G-EXJ-1030713 May 2012 STOP II = Optimizing Primary Stroke Prevention in Sickle Cell Anemia. 1 Adams RJ, et al. N Engl J Med. 1998;339:5-11. 2 Adams RJ, et al. N Engl J Med. 2005;353:2769-78. TCD testing and transfusion therapy in SCD— consequences of STOP findings ● STOP trial outcome led to –early termination of the study 1 –widespread implementation of TCD screening and transfusion therapy as the standard of care in paediatric patients at high risk of stroke –initiation of the STOP II trial to determine when transfusion can be safely terminated 2

24 24 G-EXJ-1030713 May 2012 TCD testing and transfusion therapy in SCD—STOP II Prospective, randomized, controlled, multicentre treatment trial Adams RJ, et al. N Engl J Med. 2005;353:2769-78. Overall, 79 children with SCD aged 2–16 years –were at high risk of stroke based on TCD findings and had received transfusions for ≥ 30 months –TCD had normalized, and patients had no severe MRA lesions at the start of STOP II Overall, 38 continued chronic transfusion therapy Overall, 41 discontinued chronic transfusion therapy No neurological event Overall, 14 (34%) reverted to high-risk TCD; 2 developed stroke 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 findings

25 25 G-EXJ-1030713 May 2012 TCD screening in SCD—impact on annualized stroke rate ● Retrospective cohort of all children with SCD within a large managed-care plan ● Stroke incidence rates were estimated before (pre-TCD) and after (post-TCD) first TCD screening ● Since STOP, TCD use increased 6-fold ● Annualized stroke rate decreased from 0.44 to 0.19 per 100 person-years from pre- to post-TCD Armstrong-Wells J, et al. Neurology. 2009;72:1316-21. Pre-TCDPost-TCD Annualized stroke rate 0.44 0.19 0 0.1 0.2 0.3 0.4 0.5 Annualized stroke rate per 100 patient-years

26 26 G-EXJ-1030713 May 2012 High conversion rate from ‘‘borderline’’ to ‘‘abnormal’’ TCD findings if untreated Review of TCD examinations in 274 untreated children with SCD (HbSS and HbSβ 0 -thalassaemia; excluding those receiving HU or transfusions) HbSS = sickle cell anaemia. 1 Hankins JS, et al. Br J Haematol. 2008;142:94-9. 2 Adams RJ, et al. Blood. 2004;103:3689- 94. 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% Conclusion—therapy should be considered for the prevention of conversion to abnormal TCD velocities 1 ● During the STOP trial, such conversion to abnormal velocities most likely occurred in younger patients and in those with higher initial flow velocities 2

27 27 G-EXJ-1030713 May 2012 TCD and stroke risk in children with HbSC disease—study rationale ● Rationale for study –most studies of TCD and stroke risk are centred on patients with HbSS –HbSC disease—caused by co-inheritance of HbS and HbC –clinical features of HbSC and HbSS overlap, but with HbSC cerebrovascular disease and stroke are less common –lifetime risk of stroke is 2–3% »50–100 times greater risk than that of general paediatric population –value of TCD for stroke prevention in HbSC is unknown HbC = haemoglobin C; HbS = haemoglobin S; HbSC = haemoglobin SC. Deane CR, et al. Arch Dis Child. 2008;93:138-41.

28 28 G-EXJ-1030713 May 2012 TCD and stroke risk in children with HbSC disease—design and results Mean TAMMV = 94 cm/s (98th centile of 128 cm/s) Retrospective audit of routine TCD scans and clinical data from 46 children (mean age 8.1 years) with HbSC disease Significantly less than published ranges for HbSS 1 child had stroke at age 5 years, when TAMMV = 146 cm/s Deane RC, et al. Arch Dis Child. 2008;93:138-41. Conclusions TAMMV > 128 cm/s could indicate the possibility of significant cerebrovascular disease in HbSC No evidence on which to base a programme of primary stroke prevention in HbSC TCD measurement is likely to function as a screen for those requiring further investigation

29 G-EXJ-1030713 May 2012 TCD Equipment

30 30 G-EXJ-1030713 May 2012 TCD equipment ● Wide range of TCD equipment is available –from small and portable to large and stationary machines ● Portable machines can be used at bedside for reliable evaluation of cerebral vasculature Image from www.viasyshealthcare.com/prod_serv/prodDetail.aspx?config=ps_prodDtl&prodID=158. Accessed Nov 2010.

31 31 G-EXJ-1030713 May 2012 Transcranial Doppler devices TCD = non-duplex (non-imaging TCD)TCDI = duplex (imaging TCD) Higher cost 1 –Buying a dedicated TCD doppler is expensive: app 30.000-45.000 Euro Many hospitals have sonography equipment 1 –Buying separate imaging transducer for already existing doppler machine costs app. 5.000-8.000 Euro Used Stroke Prevention Trial in Sickle Cell Anemia Study (STOP) trial 1 Effectively identifies major intracranial arteries 2 Risk of inaccurate velocity is lower than with TCD 2 May reveal unexpected vascular findings (e.g. aneurysm, vascular malformation) 1 Important: measurements obtained with TCDI are significantly lower than those obtained with TCD sonography 1–4 –should be considered when predicting the risk of stroke in children with SCD 1 McCarville MB, et al. AJR Am J Roentgenol. 2004;183:1117-22. 2 Krejza J, et al. Am J Neuroradiol. 2007;28:1613-8. 3 Jones AM, et al. Pediatr Radiol. 2001;31:461-9. 4 Jones A, et al. Pediatr Radiol. 2005;35:66- 72.

32 32 G-EXJ-1030713 May 2012 Transcranial Doppler devices (cont.) TCD = non-duplex (non-imaging TCD)TCDI = duplex (imaging TCD) McCarville MB, et al. AJR Am J Roentgenol. 2004;183:1117-22.

33 33 G-EXJ-1030713 May 2012 TCD machines and manufacturers ● Nicolet Biomedical –SONARA, SONARA/tek 1 ● Compumedics Germany GmbH 2 –analog: Smart-/EZ-Dop ®, Multi-Dop ® Pro –digital: Doppler-Box™, Multi-Dop ® T digital, Multi-Dop ® X digital 1 http://www.akumed.no/1862/158_SONARA_Family_Brochure.pdf. Accessed Nov 2010. 2 Image from www.dwl.de/script/show.php?page=0038&lang=&start=. Accessed Nov 2010. Multi-Dop ® T digital Doppler-Box™

34 34 G-EXJ-1030713 May 2012 TCD machines (non-duplex) ● Rimed Ltd. 1 –Digi-Lite™ ● Spencer Technologies 2 –ST 3 DIGITAL 1 Image from http://rimed.com/site/down/RIMED005Catalogue%20v8%20by%20pages%20high%20resoultion.pdf. Accessed Nov 2010. 2 Image from www.spencertechnologies.com/pdf/ST3_Spec_Sheet.pdf. Accessed Nov 2010. Rimed’s probe holder Digi-Lite TM ST 3 DIGITAL

35 35 G-EXJ-1030713 May 2012 TCDI allows artery visualization ● Advances in TCD result in the imaging of intracranial arteries ● Conventional colour orientation for TCDI examinations TCDI = imaging TCD. Image from www.gehealthcare.com/usen/ultrasound/ products/cmetcd.html. Accessed Nov 2010. Blood flow towards the transducer Blood flow away from the transducer

36 36 G-EXJ-1030713 May 2012 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 studied 1 ● TCDI identified the major intracranial arteries more effectively than did TCD 1 ● Difference between TCDI and TCD velocities similar to that found in previous studies 2 and should be considered when used for stroke risk prediction 3 ● Risk of inaccurate velocity sampling is lower with TCDI than with TCD 1 MRA = magnetic resonance angiography 1 Krejza J, et al. Am J Neuroradiol. 2007;28:1613-8. 2 Jones AM, et al. Pediatr Radiol. 2001;31:461-9. 3 Jones A, et al. Pediatr Radiol. 2005;35:66-72. TCDTCDI Found arteries (%)94.9%99.3% Mean depth of insonation (all arteries)No significant difference Velocities (right and left sides) Significantly lower (~ 20%) with TCDI vs TCD Similar 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.

37 37 G-EXJ-1030713 May 2012 TCDI machines and manufacturers ● Siemens medical 1 –e.g. Acuson Sequoia 512 2 ● GE Healthcare 3 –e.g. LOGIQ line –e.g. Vivid line ● Philips Healthcare 4 –e.g. HD line Vivid E9 1 www.medical.siemens.com/webapp/wcs/stores/servlet/StoreCatalogDisplay~q_catalogId~e_-1~a_langId~e_- 1~a_storeId~e_10001.htm. Accessed Nov 2010. 2 www.sequoiaultrasound.com/pdf/sequoiaultrasound.com/Sequoia_512_Brochure.pdf. Accessed Nov 2010. 3 www2.gehealthcare.com/portal/site/usen/gehchome. Accessed Nov 2010. 4 www.healthcare.philips.com/main/products/ultrasound/index.wpd. Accessed Nov 2010. Acuson Sequoia 512 LOGIQ 9 HD15

38 G-EXJ-1030713 May 2012 Guidelines for TCD in SCD

39 39 G-EXJ-1030713 May 2012 STOP strategy for primary stroke prevention: opinions of leading neurologists ● Adoption of the STOP trial primary prevention strategy could lead to –prevention of 100–200 strokes/year –more children reaching adulthood with normal arterial vessels –reduced prevalence of severe arterial disease and moyamoya syndrome ● Transfusion in the short term is manageable with a number of beneficial effects beyond stroke prevention ● Requiring 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 lost Adams RJ, et al. Ann Neurol. 2003;54:559-63.

40 40 G-EXJ-1030713 May 2012 US and UK guidance for TCD screening in SCD— based on STOP findings ● 1998 – National Heart, Lung, and Blood Institute clinical alert 1 ● 2004 – Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology—TCD assessment 2 ● 2009 – National Health Service Antenatal and Newborn Screening Programmes 3 1 NIH. Clinical alert from the NHLBI. 1997 Sept 18. www.nhlbi.nih.gov/new/press/nhlb-18a.htm. 2 Sloan MA, et al. Neurology. 2004;62:1468-81. 3 NHS. Transcranial Doppler scanning for children with sickle cell disease. 2009 Mar. www.library.nhs.uk/GUIDELINES FINDER/ViewResource.aspx?resID=315317. “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])” “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”

41 41 G-EXJ-1030713 May 2012 Identification and management of stroke risk in children with SCD—NIH guidelines www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf. Accessed Nov 2010. Child with HbSS, aged > 2 years, with no symptoms Neuropsychologic al testing TCD unavailable TCD Abnormal (  200 cm/s) Confirm abnormal MRI/MRA Chronic transfusion Normal (< 200 cm/s) Repeat TCD every 3–12 months* Abnormal exam Low risk Observation High risk based on other information † Protocol treatment or clinical trial Or treatment options –observation for progression –HU –transfusion –other (e.g. antiplatelet agents) Evaluate educational needs based on results *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 pressure

42 42 G-EXJ-1030713 May 2012 TCD scanning decision tree: NHS guidelines www.library.nhs.uk/GUIDELINESFINDER/ViewResource.aspx?resID=315317. Accessed Nov 2010. 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. Inadequate scan/ low velocities Normal < 170 cm/s Borderline 170–199 cm/s Abnormal  200 cm/s Children aged 2–16 Initial TCD scan If child is uncooperative, consider rescanning when appropriate. If due to a poor scanning window, consider an alternative technique Repeat TCD scan in 1 year. In older children who have already had several normal scans, the time interval might be extended to 2 years Re-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 earlier Discuss stroke risk and consider chronic transfusion. A re-scan might be considered appropriate depending on the blood velocity and individual clinical circumstances

43 G-EXJ-1030713 May 2012 Summary

44 44 G-EXJ-1030713 May 2012 Summary—SCD ● SCD is an inherited Hb disorder. Symptoms include episodes of acute pain and ischaemic stroke due to vascular occlusion by sickle-shaped erythrocytes ● BMT is the only curative therapy 1,2 ● Current therapies are aimed at the prevention and treatment of complications –treatment with HU has been shown to reduce the occurrence of painful crises 3 and to lower TCD velocities in patients with SCD 4 ● Intermittent or chronic transfusion therapy is a major therapeutic approach that is becoming increasingly utilized to reduce the risk of stroke and other SCD clinical manifestations 5,6 1 Hoppe CC, Walters MC. Curr Opin Oncol. 2001;13:85-90. 2 Walters MC, et al. Blood. 2000;95:1918-24. 3 Carache S, et al. N Engl J Med. 1995;332:1317-22. 4 Zimmerman SA, et al. Blood. 2007;110:1043-7. 5 Styles LA, Vichinsky E. J Pediatr. 1994;125:909-11. 6 Adams RJ, et al. N Engl J Med. 1998;339:5-11.

45 45 G-EXJ-1030713 May 2012 Summary—TCD ● TCD is a safe, inexpensive, and non-invasive diagnostic tool 1 –intracranial arterial blood flow velocities are presented as wave-form recording –blood flow velocities predict stroke risk ● Intracranial arteries are examined (insonated) via 4 acoustic windows in the skull 1 ● Imaging TCD adds further information 2 –visualization of arteries –enables angle-corrected blood velocity measurement 1 Kassab MY, et al. J Am Board Fam Med. 2007;20:65-71. 2 Krejza J, et al. AJR Am J Roentgenol. 2000;174:1297-303.

46 46 G-EXJ-1030713 May 2012 Summary—TCD in SCD ● Children and teenagers with SCD: very high risk of stroke and stroke-related morbidity and mortality 1–3 ● TAMMV ≥ 200 cm/s in MCA or intracranial ICA indicates high stroke risk in children 4 ● Landmark STOP trial: TCD screening can identify patients with high-risk SCD 5 ● TCD screening, accompanied by transfusion therapy in high-risk patients, has reduced the annualized stroke rate in SCD 6 ● High proportion of untreated children with SCD and ‘‘borderline’’ TCD velocities converts to high risk over time 7 ● US and UK guidelines recommend TCD screening for children with SCD aged 2–16 years 8,9 1 Ohene-Frempong K, et al. Blood. 1998;91:288-94. 2 Manci EA, et al. Br J Haematol. 2003;123:359-65. 3 Miller ST, et al. J Pediatr. 2001;139:385-90. 4 Adams RJ, et al. Ann Neurol. 1997;42:699-704. 5 Adams RJ, et al. N Engl J Med. 1998;339:5-11. 6 Armstrong-Wells J, et al. Neurology. 2009;72:1316-21. 7 Hankins JS, et al. Br J Haematol. 2008;142:94-9. 8 NIH. Clinical alerts from the NHLBI. 1997 Sept 18. 9 www.library.nhs.uk/GUIDELINESFINDER/ViewResource.aspx?resID=315317. Accessed Nov 2010.

47 G-EXJ-1030713 May 2012 GLOSSARY OF TERMS

48 48 G-EXJ-1030713 May 2012 GLOSSARY ● AML = acute myeloid leukemia ● APFR = Atrialp peak filling rate ● BA = basilar artery ● ß-TM = Beta Thalassemia Major ● ß-TI = Beta Thalassemia Intermedia ● BM = bone marrow ● BTM = bone marrow transplantation ● BW = bandwidth ● CFU = colony-forming unit ● CMML = chronic myelomonocytic leukemia ● CT2 = cardiac T2*. ● DAPI = 4',6-diamidino-2-phenylindole

49 49 G-EXJ-1030713 May 2012 GLOSSARY ● DFS = = disease-free survival. ● DysE = dyserythropoiesis ● ECG = electrocardiography ● EDV = end-diastolic velocity ● EF = ejection fraction ● EPFR = early peak filling rate ● FatSat = fat saturation ● FAQ = frequently asked questions ● FDA = Food and Drug Administration ● FISH = fluorescence in situ hybridization. ● FOV = field of view ● GBP = Currency, pound sterling (£)

50 50 G-EXJ-1030713 May 2012 GLOSSARY ● Hb = hemoglobin ● HbE = hemoglobin E ● HbF = fetal hemoglobin ● HbS = sickle cell hemoglobin. ● HbSS = sickle cell anemia. ● HIC = hepatic iron concentration ● HU = hydroxyurea ● ICA = internal carotid artery. ● ICT = iron chelation therapy ● IDL = interface description language ● IPSS = International Prognostic Scoring System ● iso = isochromosome

51 51 G-EXJ-1030713 May 2012 GLOSSARY ● LIC = liver iron concentration ● LVEF = left-ventricular ejection fraction ● MCA = middle cerebral artery ● MDS = Myelodysplastic syndromes ● MDS-U = myelodysplastic syndrome, unclassified ● MRA = magnetic resonance angiography ● MRI = magnetic resonance imaging ● MV = mean velocity. ● N = neutropenia ● NEX = number of excitations ● NIH = National Institute of Health ● OS = overall survival

52 52 G-EXJ-1030713 May 2012 GLOSSARY ● pB = peripheral blood ● PI = pulsatility index ● PSV = peak systolic Velocity ● RA =refractory anemia ● RAEB = refractory anemia with excess blasts ● RAEB -T = refractory anemia with excess blasts in transformation ● RARS = refractory anemia with ringed sideroblasts ● RBC = red blood cells ● RF = radio-frequency ● RCMD = refractory cytopenia with multilineage dysplasia ● RCMD-RS = refractory cytopenia with multilineage dysplasia with ringed sideroblasts ● RCUD = refractory cytopenia with unilineage dysplasia

53 53 G-EXJ-1030713 May 2012 GLOSSARY ● RN = refractory neutropenia ● ROI = region of interest ● RT = refractory thrombocytopenia ● SCD = sickle cell disease ● SD = standard deviation ● SI = signal intensity ● SIR = signal intensity ratio ● SF = serum ferritin ● SNP-a = single-nucleotide polymorphism ● SQUID = superconducting quantum interface device. ● STOP = = Stroke Prevention Trial in Sickle Cell Anemia ● STOP II = Optimizing Primary Stroke Prevention in Sickle Cell Anemia

54 54 G-EXJ-1030713 May 2012 GLOSSARY ● T = thrombocytopenia ● TAMMV = time-averaged mean of the maximum velocity. ● TCCS = transcranial colour-coded sonography ● TCD = transcranial doppler ultrasonography ● TCDI = duplex (imaging TCD) ● TE = echo time ● TR = repetition time ● WHO = World Health Organization ● WPSS = WHO classification-based Prognostic Scoring System


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