Transcript TCD for assessment of stroke risk in SCD

TRANSCRANIAL DOPPLER
ULTRASONOGRAPHY (TCD)
FOR ASSESSMENT OF
STROKE RISK
IN SICKLE CELL DISEASE
G-EXJ-1030713
May 2012
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Outline
● Sickle cell disease (SCD)
● Transcranial Doppler (TCD)
– TCD in SCD
– TCD Equipment
– Guidelines for TCD in SCD
● Summary
2
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LIC = liver iron concentration; MRI = magnetic resonance imaging;
SF = serum ferritin; SIR = signal intensity ratio;
SQUID = superconducting quantum interface device.
Sickle Cell
Disease (SCD)
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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.
4
G-EXJ-1030713 Schnog JB, et al. Neth J Med. 2004;62:364-74.
Image from www2.med.umich.edu/prmc/media/newsroom/downloadImages.cfm?ID=656.
May 2012
Clinical manifestations of SCD
Anaemia
Red cell survival ~ 17 days (120 days in healthy people)1
Pain
Acute and chronic1
Central nervous system
Overt stroke, silent stroke, and neurocognitive impairment1–3
Pulmonary
Recurrent acute chest syndrome, pulmonary hypertension, and
chronic sickle lung disease1,2
Skin
Chronic ulcers, typically around the ankles1
Joints
Osteonecrosis (avascular necrosis) of femoral and
humeral heads1,2
Eyes
Retinal ischaemia, detachments – “sickle retinopathy”1,2
Kidneys
Inability to concentrate urine; proteinuria progressing to nephrotic
syndrome; end-stage renal failure4
Cardiovascular
Cardiac decompensation and cardiomyopathy1
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1Schnog
JB, et al. Neth J Med. 2004;62:364-74. 2Claster S, Vichinsky EP. Br Med J. 2003;327:1151-5.
M, et al. Ann Neurol. 2002;51:543-52. 4Ataga KI, Orringer EP. Am J Hematol. 2000;63:205-
3Prengler
11.
Prevalence of SCD
● The frequency of the HbS gene is highest in populations in which
malaria is (or was) endemic1,2
● Approximately 200,000 new cases of SCD occur in Africa every year1
● Recent population migrations have led to an increase in disease
frequency in other areas
– in the USA, SCD affects over 50,000
African-American individuals and occurs in
1 out of 375 newborns3
<0.1
0.1-0.19
– annually, more than 6,000 conceptions in
the Caribbean and Central and South
America are affected by SCD2
0.2-0.99
1-4.9
5-9.9
1—18.9
≥19
– > 1 out of 2,400 live births (all ethnic
groups) are affected in England, where
12,500 individuals live with the disease4
Births with a pathological Hb disorder per 1,000 live births
Global distribution of pathological Hb disorders, 1996 (WHO)
1Weatherall DJ, Clegg JB. Bull World Health Organ. 2001;79:704-12. 2Modell B, Darlison M. Bull World Health Organ.
2008;86:480-7. 3Sickle cell disease: screening, diagnosis, management, and counseling in newborns and infants –
clinical practice guideline number 6 AHCPR 1993;Publication 93-0562. 4Sickle Cell Society. Sickle Cell Society
6
Publication SC4 2005: www.sicklecellsociety.org/pdf/SC4.pdf. Image from Christianson A, et al. March of Dimes Global
G-EXJ-1030713 Report on Birth Defects: the hidden toll of dying and disabled children. 2006 (www.marchofdimes.com/MOD-ReportMay 2012
PF.pdf).
Management and treatment of SCD
● BMT is the only curative treatment for SCD that is currently available1,2
– 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 stroke4,5
● 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 complications6,7
BMT = bone marrow transplantation;
HbF = fetal haemoglobin;
HU = hydroxyurea.
7
1
2001;13:85-90. 2Walters MC, et al. Blood. 2000;95:1918-24. 3Charache S, et
G-EXJ-1030713 Hoppe CC, Walters MC. Curr Opin Oncol.
al. N Engl J Med. 1995;332:1317-22. 4Ware RE, et al. J Pediatr. 2004;145:346-52. 5Zimmerman SA, et al. Blood.
May 2012
6
7
2007;110:1043-7. Styles LA, Vichinsky E. J Pediatr. 1994;125:909-11. Adams RJ, et al. N Engl J Med. 1998;339:5-11.
Transcranial
Doppler (TCD)
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TCD – a non-invasive diagnostic tool
● TCD – a safe, non-invasive diagnostic tool1,2
– allows indirect real-time evaluation of
intracranial cerebral circulation via
ultrasonography1,2
Typical TCD sonographic
recording from MCA
● Ultrasonic beam bounces off erythrocytes
within an artery2—reflected signal is
processed to obtain a waveform that allows
– accurate determination of blood
flow velocities1,2
– accurate determination of flow direction2
– addition of calculated parameters (e.g.
PI)2
cm/
s
220
200
180
160
140
120
100
80
60
40
20
0
–20
–40
–60
–80
–100
–120
(velocity scale on left)4
● Blood flow velocities are used to predict
stroke risk3
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MCA = middle cerebral artery; PI = pulsatility index.
1Aaslid
R, et al. J Neurosurg. 1982;57:769-74. 2Kassab MY, et al. J Am Board Fam Med. 2007;20:65-71.
RJ, et al. N Engl J Med. 1992;326:605-10. 4McCarville MB, et al. Am J Roentgenol. 2004;183:1117-22.
3Adams
48
DEPTH
118
MEAN
0.72
PI
163
SYS
6
SAMPLE
40
POWER
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
120
MCA MV (cm/s)
100
80
60
40
20
0
0
10
20
30
40
50
60
Age (years)
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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.
70
Accepted guidelines for normal TCD study:
blood flow velocities in an adult
Artery
Window
Depth (mm)
Direction in
relation to probe
Mean ± SD flow
velocity (cm/s)
Middle cerebral
Temporal
30–60
Toward
55 ± 12
Anterior cerebral
Temporal
60–85
Away
50 ± 11
Posterior cerebral
Temporal
60–70
Bidirectional
40 ± 10
Terminal internal carotid
Temporal
55–65
Toward
39 ± 09
Internal carotid (siphon)
Orbital
60–80
Bidirectional
45 ± 15
Ophthalmic
Orbital
40–60
Toward
20 ± 10
Vertebral
Occipital
60–80
Away
38 ± 10
Basilar
Occipital
80–110
Away
41 ± 10
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Kassab MY, et al. J Am Board Fam Med. 2007;20:65-71.
Ringelstein EB, et al. Ultrasound Med Biol. 1990;16:745-61.
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
B. Transorbital window insonates
•
ophthalmic artery
•
ICA at siphon level
C. Transforaminal (occipital) window insonates
•
distal vertebral arteries
•
basilar artery
A
D
D. Submandibular window insonates
•
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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.
C
TCD In SCD
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Rationale for TCD in SCD
60
33–48%
50
Patients (%)
● Approximately 11% of patients
with SCD have a stroke by 20
years of age, with a peak
incidence in the first decade of
life1
40
30
20
9.8%
● Stroke accounts for ~ 10% of all
mortality in SCD (Figure)2
● Silent infarct identified by MRI
is a significant predictor of overt
stroke in children3
10
7.0%
6.6%
0
Infection
Stroke
Therapy
Splenic
complications sequestration
Causes of death in SCD2
MRI = magnetic resonance imaging.
14
G-EXJ-1030713 1Ohene-Frempong K, et al. Blood. 1998;91:288-94. 2Manci EA, et al. Br J Haematol. 2003;123:359-65. 3Miller ST, et al.
J Pediatr. 2001;139:385-90.
May 2012
Flow velocity as predictor of stroke in SCD
● SCD – associated with progressive occlusion of large
intracranial arteries1
● Arteries most frequently affected1
– MCA
– intracranial ICA
● Abnormal TAMMV (≥ 200 cm/s) in MCA
or ICA is
TAMMV, cm/s
Predictive
category
≤ 170
Normal
171–199
Borderline
≥ 200
Abnormal
Correlation between blood flow velocity and
category used to predict stroke risk2,4
– strongly associated with increased
stroke risk in children2
– indication for blood transfusion3
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TAMMV = time-averaged mean of the maximum velocity.
1Kassab
3Adams
MY, et al. J Am Board Fam Med. 2007;20:65-71. 2Adams RJ, et al. Ann Neurol. 1997;42:699-704.
RJ, et al. N Engl J Med. 1998;339:5-11. 4Abboud MR, et al. Blood. 2004;103:2822-6.
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?
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)
●
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
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Abboud MR, et al. Blood. 2004;103:2822-6.
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
Patients 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 TCD
●
TAMMV 123.5 cm/s allowed diagnosis of
MCA or ICA intracranial stenoses with
100% sensitivity and 73% specificity
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
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Silva GS, et al. Stroke. 2009;40:2408-12.
Consistency of TCD velocities in SCD patients
with different ethnic backgrounds
●
–
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
–
●
Middle cerebral artery
TCD and TCCS performed in
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
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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.
180
160
Mean velocity (cm/s)
●
140
120
100
80
60
40
A
B
Patient group
C
Mean of PSV (●), TAMMV (■), and EDV (▲) on TCD
(open) and TCCS (solid) in the
3 groups of patients
TCD, neurological exam, and MRI—association
with overall morbidity and mortality in SCD
Haemorrhage
Stroke
TCD high; exam normal;
MRI normal
Increasing
morbidity/
mortality
TCD high; exam normal; silent infarct
TCD normal; exam normal; MRI normal
TCD normal; exam normal; silent infarct
Increasing neuropsychological deficits
Neuro exam: normal abnormal
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Platt OS. Hematology Am Soc Hematol Educ Program. 2006:54-7.
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
RANDOMIZED
Ongoing transfusions to reduce HbS
concentration to < 30% total Hb
(n = 63)
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STOP = Stroke Prevention Trial in Sickle Cell Anemia.
Adams RJ, et al. N Engl J Med. 1998;339:5-11.
Standard care
(n = 67)
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
40
Children with stroke
35
● 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)
Percentage
30
25
92% difference
(p < 0.001)
20
11/67 (16.42%)
15
10
5
1/63 (1.6%)
0
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Adams RJ, et al. N Engl J Med. 1998;339:5-11.
Transfusion
Standard care
(n = 63)
(n = 67)
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)
22
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Adams RJ, et al. N Engl J Med. 1998;339:5-11.
TCD testing and transfusion therapy in SCD—
consequences of STOP findings
● STOP trial outcome led to
– early termination of the study1
– 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 terminated2
23
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STOP II = Optimizing Primary Stroke Prevention in Sickle Cell Anemia.
1Adams
RJ, et al. N Engl J Med. 1998;339:5-11. 2Adams RJ, et al. N Engl J Med. 2005;353:2769-78.
TCD testing and transfusion therapy in
SCD—STOP II
Prospective, randomized, controlled, multicentre treatment trial
Overall, 79 children with SCD aged
Overall, 38 continued
chronic transfusion
therapy
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
No neurological event
Overall, 41 discontinued
chronic transfusion
therapy
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
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Adams RJ, et al. N Engl J Med. 2005;353:2769-78.
TCD screening in SCD—impact on annualized
stroke rate
Annualized stroke rate
0.5
● Retrospective cohort of all children
with SCD within a large managed-care plan
0.44
● 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
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Armstrong-Wells J, et al. Neurology. 2009;72:1316-21.
Annualized stroke rate
per 100 patient-years
0.4
0.3
0.19
0.2
0.1
0
Pre-TCD
Post-TCD
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%
Conclusion—therapy should be considered for the prevention
of conversion to abnormal TCD velocities1
●
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During the STOP trial, such conversion to abnormal velocities
most likely occurred in younger patients and in those with
higher initial flow velocities2
HbSS = sickle cell anaemia.
1Hankins
94.
JS, et al. Br J Haematol. 2008;142:94-9. 2Adams RJ, et al. Blood. 2004;103:3689-
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
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HbC = haemoglobin C;
HbS = haemoglobin S;
HbSC = haemoglobin SC.
Deane CR, et al. Arch Dis Child. 2008;93:138-41.
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 disease
Mean TAMMV = 94 cm/s
Significantly less than published
ranges for HbSS
(98th centile of 128 cm/s)
1 child had stroke at age 5 years,
when TAMMV = 146 cm/s
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
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Deane RC, et al. Arch Dis Child. 2008;93:138-41.
TCD Equipment
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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
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Image from www.viasyshealthcare.com/prod_serv/prodDetail.aspx?config=ps_prodDtl&prodID=158. Accessed Nov
2010.
Transcranial Doppler devices
TCD = non-duplex (non-imaging TCD)
TCDI = duplex (imaging TCD)
• Higher cost1
– Buying a dedicated TCD doppler is
expensive: app 30.000-45.000 Euro
• Many hospitals have sonography equipment1
– 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) trial1
• Effectively identifies major intracranial arteries2
• Risk of inaccurate velocity is lower than with
TCD2
• May reveal unexpected vascular findings (e.g.
aneurysm, vascular malformation) 1
• Important: measurements obtained with TCDI
are significantly lower than those obtained with
TCD sonography1–4
– should be considered when predicting the
risk of stroke in children with SCD
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1McCarville
MB, et al. AJR Am J Roentgenol. 2004;183:1117-22. 2Krejza J, et al. Am J Neuroradiol.
2007;28:1613-8. 3Jones AM, et al. Pediatr Radiol. 2001;31:461-9. 4Jones A, et al. Pediatr Radiol. 2005;35:6672.
Transcranial Doppler devices (cont.)
TCD = non-duplex (non-imaging TCD)
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TCDI = duplex (imaging TCD)
McCarville MB, et al. AJR Am J Roentgenol. 2004;183:1117-22.
TCD machines and manufacturers
● Nicolet Biomedical
– SONARA, SONARA/tek1
● Compumedics Germany GmbH2
– analog: Smart-/EZ-Dop®,
Multi-Dop® Pro
– digital: Doppler-Box™,
Multi-Dop® Tdigital, Multi-Dop® Xdigital
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Doppler-Box™
http://www.akumed.no/1862/158_SONARA_Family_Brochure.pdf. Accessed Nov 2010. 2Image
from www.dwl.de/script/show.php?page=0038&lang=&start=. Accessed Nov 2010.
1
Multi-Dop®Tdigital
TCD machines (non-duplex)
● Rimed Ltd.1
– Digi-Lite™
Rimed’s probe holder
Digi-LiteTM
● Spencer Technologies2
– ST3 DIGITAL
ST3 DIGITAL
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1Image
from http://rimed.com/site/down/RIMED005Catalogue%20v8%20by%20pages%20high%20resoultion.pdf.
Accessed Nov 2010. 2Image from www.spencertechnologies.com/pdf/ST3_Spec_Sheet.pdf. Accessed Nov 2010.
TCDI allows artery visualization
● Advances in TCD result in the imaging
of intracranial arteries
● Conventional colour orientation for
TCDI examinations
Blood flow
towards the
transducer
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Blood flow
away from the
transducer
TCDI = imaging TCD.
Image from www.gehealthcare.com/usen/ultrasound/ products/cmetcd.html. Accessed Nov 2010.
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
studied1
Found arteries (%)
Mean depth of insonation (all arteries)
Velocities (right and left sides)
TCD
TCDI
94.9%
99.3%
No significant difference
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.
●
TCDI identified the major intracranial arteries more effectively than did TCD1
●
Difference between TCDI and TCD velocities similar to that found in previous studies 2
and should be considered when used for stroke risk prediction3
●
Risk of inaccurate velocity sampling is lower with TCDI than with TCD1
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MRA = magnetic resonance angiography
1Krejza J, et al. Am J Neuroradiol. 2007;28:1613-8. 2Jones AM, et al. Pediatr Radiol. 2001;31:461-9.
3Jones A, et al. Pediatr Radiol. 2005;35:66-72.
TCDI machines and manufacturers
● Siemens medical1
– e.g. Acuson Sequoia 5122
● GE Healthcare3
– e.g. LOGIQ line
Acuson Sequoia 512
Vivid E9
– e.g. Vivid line
● Philips Healthcare4
– e.g. HD line
LOGIQ 9
1www.medical.siemens.com/webapp/wcs/stores/servlet/StoreCatalogDisplay~q_catalogId~e_-1~a_langId~e_-
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1~a_storeId~e_10001.htm. Accessed Nov 2010.
2www.sequoiaultrasound.com/pdf/sequoiaultrasound.com/Sequoia_512_Brochure.pdf. Accessed Nov 2010.
3www2.gehealthcare.com/portal/site/usen/gehchome.
Accessed Nov 2010.
Accessed Nov 2010.
4www.healthcare.philips.com/main/products/ultrasound/index.wpd.
HD15
Guidelines for
TCD in SCD
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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
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Adams RJ, et al. Ann Neurol. 2003;54:559-63.
US and UK guidance for TCD screening in
SCD— based on STOP findings
●
1998 – National Heart, Lung, and Blood Institute clinical alert1
“Since the greatest risk of stroke occurs in early childhood, it is recommended that
children ages 2–16 receive TCD screening”
●
2004 – Therapeutics and Technology Assessment Subcommittee of the
American Academy of Neurology—TCD assessment2
“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])”
●
2009 – National Health Service Antenatal and Newborn Screening Programmes3
“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”
40
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1NIH.
Clinical alert from the NHLBI. 1997 Sept 18. www.nhlbi.nih.gov/new/press/nhlb-18a.htm.
MA, et al. Neurology. 2004;62:1468-81. 3NHS. Transcranial Doppler scanning for children with sickle cell disease.
2009 Mar. www.library.nhs.uk/GUIDELINES FINDER/ViewResource.aspx?resID=315317.
2Sloan
Identification and management of stroke risk in
children with SCD—NIH guidelines
Child with HbSS, aged > 2 years, with no symptoms
Evaluate
educational
needs based on
results
Neuropsychologic
al testing
TCD
unavailable
TCD
Abnormal
( 200 cm/s)
Normal (< 200 cm/s)
Confirm abnormal
Repeat TCD every
3–12 months*
High risk based on
other information†
Low risk
Protocol treatment
or clinical trial
Observation
MRI/MRA
Abnormal exam
Chronic transfusion
Or treatment options
– observation for
progression
– HU
– transfusion
*Optimal frequency of re-screening not established; younger children with velocity closer to
200 cm/s should be re-screened more frequently.
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†Prior
transient ischaemic attack, low steady-state Hb, rate and recency of acute chest
syndrome, elevated systolic blood pressure
www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf. Accessed Nov 2010.
– other (e.g.
antiplatelet
agents)
TCD scanning decision tree: NHS guidelines
Children aged 2–16
Initial TCD scan
Inadequate scan/
Normal
Borderline
Abnormal
low velocities
< 170 cm/s
170–199 cm/s
 200 cm/s
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
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.
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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.
www.library.nhs.uk/GUIDELINESFINDER/ViewResource.aspx?resID=315317. Accessed Nov 2010.
Summary
G-EXJ-1030713
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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 therapy1,2
● Current therapies are aimed at the prevention and treatment
of complications
– treatment with HU has been shown to reduce the occurrence of painful
crises3 and to lower TCD velocities in patients
with SCD4
● 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 manifestations5,6
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1Hoppe
CC, Walters MC. Curr Opin Oncol. 2001;13:85-90. 2Walters MC, et al. Blood. 2000;95:1918-24. 3Carache S, et
al. N Engl J Med. 1995;332:1317-22. 4Zimmerman SA, et al. Blood. 2007;110:1043-7. 5Styles LA, Vichinsky E.
J Pediatr. 1994;125:909-11. 6Adams RJ, et al. N Engl J Med. 1998;339:5-11.
Summary—TCD
● TCD is a safe, inexpensive, and non-invasive diagnostic tool1
– 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 skull1
● Imaging TCD adds further information2
– visualization of arteries
– enables angle-corrected blood velocity measurement
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1Kassab
MY, et al. J Am Board Fam Med. 2007;20:65-71. 2Krejza J, et al. AJR Am J Roentgenol. 2000;174:1297-303.
Summary—TCD in SCD
● Children and teenagers with SCD: very high risk of stroke and stroke-related
morbidity and mortality1–3
● TAMMV ≥ 200 cm/s in MCA or intracranial ICA indicates high stroke risk in
children4
● Landmark STOP trial: TCD screening can identify patients with high-risk SCD5
● TCD screening, accompanied by transfusion therapy in high-risk patients, has
reduced the annualized stroke rate in SCD6
● High proportion of untreated children with SCD and ‘‘borderline’’ TCD velocities
converts to high risk over time7
● US and UK guidelines recommend TCD screening for children with SCD aged
2–16 years8,9
1Ohene-Frempong
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K, et al. Blood. 1998;91:288-94. 2Manci EA, et al. Br J Haematol. 2003;123:359-65. 3Miller ST, et
al. J Pediatr. 2001;139:385-90. 4Adams RJ, et al. Ann Neurol. 1997;42:699-704. 5Adams RJ, et al. N Engl J Med.
1998;339:5-11. 6Armstrong-Wells J, et al. Neurology. 2009;72:1316-21. 7Hankins JS, et al. Br J Haematol.
2008;142:94-9. 8NIH. Clinical alerts from the NHLBI. 1997 Sept 18.
9www.library.nhs.uk/GUIDELINESFINDER/ViewResource.aspx?resID=315317. Accessed Nov 2010.
GLOSSARY
OF TERMS
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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
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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 (£)
49
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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
50
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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
51
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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
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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
53
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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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