Michael R. DeBaun MD, MPH Director of Vanderbilt, Meharry Center of Excellence for Sickle Disease Professor of Pediatrics and Medicine Vanderbilt University School of Medicine Questions • What is the impact of primary stroke prevention in children with SCD? • What is the impact of blood transfusion therapy on secondary stroke prevention? – Should we increase the threshold from 30% to 50% • Should we perform exchange transfusion therapy at initial presentation for focal neurological examination? • How common is silent stroke and how should we transfuse for silent strokes?

Changing Epidemiology of Overt Strokes prior to 1998

Changing Epidemiology of Overt Strokes After 1998

Estimated Hazard Function based on recent literature and after routine use of TCD ; J Pediatr. 2010 Apr 29. 18 year old with hemoglobin SS is seen in the ED for an acute neurological deficit. What should be the initial management?

A. Simple transfusion only B. Exchange transfusion only with the goal to decrease hemoglobin S level less than 30% C. Simple transfusion and exchange transfusion with a goal to decrease hemoglobin S levels to less than 30%

Treatment of Acute Stroke

• Goals of treatment of acute stroke – Restore cerebral blood flow – Maximize tissue oxygen delivery – Reverse neurological injury – Prevent further neurological injury • Methods of treatment – Simple blood transfusion – Exchange blood transfusion (manual exchange vs. erythrocytapheresis) Consequence of Stroke in SCD

• High Recurrence Rate (Progressive) • Motor, Speech, Sensory Impairment • Cognitive Impairment • Excessive Iron Stores secondary to transfusions – Burden of Chelation Due to Transfusion Therapy • Death

Secondary Prevention of Overt Strokes

• Therapies for prevention of second strokes: –Chronic blood transfusion therapy – Allogeneic stem cell transplant – Hydroxyurea – Revascularization

Clinical History of Overt Strokes with

• 137 patients from 14 medical centers • Mean age at first stroke 6.3 years (range 1.4-14 years) • First strokes occurred between 1972 and 1995 • Mean follow-up 10.1 years (range 5-24 years) • 4 patients stopped transfusion therapy – 1 bone marrow transplant – 3 voluntarily discontinued therapy • 7 deaths Results • 23% of patients had recurrent stroke while receiving chronic blood transfusion therapy • Event rate 2.2 events/100 patient years – 1390 patient years of follow-up • Second strokes occurred with hemoglobin S levels of 1%, 9%, 22%, 25%, 26%, and 55% • Third strokes occurred with hemoglobin S levels of 8% and 30%

Strokes in Adults in SCA

Cause of death Age at first stroke Age at time of Yr receiving chronic (n = 7) (y) death (y) blood transfusion therapy

Cerebral 9.7 26.9 17.1 hemorrhage Cerebral 13.7 30.6 16.9 hemorrhage Infection – septic 4.8 24.6 16.3 pneumonia Multisystem organ 3.6 16.1 12.5 failure Other – acute chest 4.1 25.4 21.3 syndrome Other – 6.8 30.7 23.9 complications of SCD Other – 8.4 18.5 10.1 J Pediatr. 2002 Mar;140(3):348-54 Sickle Cell Disease Complications and Evidence-Based Recommendations for Acute Stroke JAMA. 2014;312(10):1033-1048

Transfusion Strength of Quality of Method Recommendation Evidence Consult an expert Exchange Consensus Panel Expertise and confirm with MRI Risk of recurrent stroke among patients without medical event presenting within 24 hours J Pediatr. 2006 Nov;149(5):710-2

1.0

.8

Type of Transfusion .6

exchange transfusion

Free Interval Free - .4 exchange transfusion -censored

simple transfusion .2

simple transfusion

0.0 -censored Cumulative Stroke Cumulative 0 5 10 15 20 25

Time from first stroke to second stroke (years after stroke) Use of exchange transfusion of primary therapy J Pediatr. 2006 Nov;149(5):710-2 Why is exchange transfusion better?

• Increases hemoglobin A without increasing viscosity • May improve tissue oxygen delivery • May limit volume of ischemic tissue Blood Transfusion and Viscosity

50 7 45 6

40

5

35

(mmHg)

4 2

30 pO Transfusion Transfusion 3 Pre – BLOOD VISCOSITY (cP) VISCOSITY BLOOD 25 Pre – Post – Post – 2 10 20 30 40 50 20 10 20 30 40 50 HEMATOCRIT (%) HEMATOCRIT (%)

Jan et al, Transfusion,1982, 22(1):19 Effect of total Hb and Hb S on regional CBF measured by Xe inhalation

150

150

140 140

130 130

120 120

110 110

100 100 CBF [mL/100g/min] CBF

CBF [mL/100g/min] CBF 90 90 80 8 8.5 9 9.5 10 10.5 11 11.5 80 5 10 15 20 25 30 35 40 45 50 55 Hb [g/dL] HbS [%]

r = -0. 68- p=.006 r = 0.8, p=.0003 (univariate) (univariate) Multivariate equation, only HbS was associated with CBF, r =0.7 Hurlet-Jensen et al, Stroke, 1994. Optimal post-stroke transfusion

• Hemoglobin approximately 10 to 12 g/dl to maximize oxygen delivery • Hemoglobin S less than 30%, to minimize viscosity

Opinion

• Transfusion with a goal of getting the hemoglobin S level to approximately 15% Time to Presentation for focal neurological deficits in children with SCD J Pediatr. 2006 Nov;149(5):710-2 • Time from symptom onset to medical presentation (n=124) – 81 (65%) presented within 24 hours – 25 (20%) presented within 1-3 days – 18 (15%) presented 3 or more days after onset (range 4 days-3 months) Time is brain

• Opinion supported by neurology literature – Every hour that a patient delays in blood transfusion therapy is an

Hypothesis

Despite transfusion, recurrent infarcts are common in children receiving regular blood transfusion for secondary stroke prevention Prospective single arm trial

• 7 centers, 40 children with strokes • Mean pre-transfusion Hb S concentration < 30% • Progressive cerebral infarcts occurred – 45% (18 of 40 children) • 7 had second overt strokes with S levels of – Hb S 10%, 17%, 21%, 28%, 38% and 48%. • 11 had new silent cerebral infarcts.

Incidence rates of recurrent strokes based on blood therapy, hydroxyurea therapy or no therapy were found to be 1.9 (95% CI 0.1.0, 2.9), 3.8 (95% CI 1.9 to 5.7), and 29.1 (95% CI 19.2 , 38.9) events per 100 patient years. Summary of Treatment of Stroke

• Recurrence Rate – 67 % without treatment (Am J Med. 1978;65(3):461-71) – 50% with cessation of transfusions (J Pediatr 1991; 118(3):377-82.) – 22% (2.2 per 100 pt yrs) with transfusion (J Pediatr. 2002;140(3):348-54 – *Risk higher in first 2 yrs after initial stroke • Initial treatment should include exchange transfusion (J Pediatr. 2006,149(5):710-2) • Approximately 45% of the patients that are rigorously transfused will have progressive disease (overt or silent strokes) – Progressive CNS lesions based on progressive vascolopathy Definition of Silent Cerebral Infarcts

• Cooperative Study for Sickle Cell Disease (AJNR Am J Neuroradiol.1996;17:965-972) – Increased signal on T2 weighted image on MRI with no history of a focal neurologic deficits • SLCH Sickle Cell Disease Stroke Group (J Child Neurol 1995; 10:88-92 ) – Increased signal on T2 weighted image on MRI • no history of a focal neurologic deficit • a normal neurological examination by a pediatric neurologist Epidemiology of Silent Cerebral Infarcts

Mean Age and SCI Prevalence (w/95% Interval) in hemoglobin SS

60

50

40

37.4 30 27.7 28.2

Prevalence Prevalence (%) 20

11.86 10

0 0 2 4 6 8 10 12 14 16 Mean Age in Years

REFERENCES: Br J Haematol. 2009;146(3):300-305.; Pediatr Blood Cancer. 2008;51(5):643-646. J Pediatr. 1998;132(6):994- 998. Blood 2011 Jan 27;117(4):1130-40

Why do silent cerebral infarcts occur? Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, gender and relative high systolic blood pressure Blood. 2012 Apr 19;119(16):3684-90

Opinion: low hemoglobin levels (< 9.0 g/dl), post transfusions are not optimal in primary in secondary stroke prevention • Acute anemic events are associated with overt strokes and silent ischemic events • Low baseline hemoglobin levels are associated with increase odds of overt strokes • Low baseline hemoglobin levels are associated silent cerebral infarcts in – Hemoglobin SS – Thalassemia intermedia – End stage renal disease

Meta-Analysis of Impact of Silent Cerebral Infarcts in SCD

Am J Hematol. 2014 Feb;89(2):162-7 Overt Stroke vs. Silent Cerebral Infarct

Silent Cerebral Overt Strokes Infarcts Frequency prior to 6th birthday 2-5% 35%

Global IQ 71 93

Primary prevention Transcranial doppler R34

Secondary prevention Blood transfusion Blood transfusion HLA matched sibling ? Evidence To Support the Clinical Significance of Silent Cerebral Infarcts

• Prevalent ~35% of SCA population • Gradient in global IQ (overt strokes, silent strokes, no lesions) • Associated with poor school performance • Progressive nature of silent strokes

Silent Cerebral Infarct Transfusion Trial: Multi-Center Clinical Trial Funded by NINDS 2003- 2013

• Primary Hypothesis: Prophylactic blood transfusion therapy in children with silent cerebral infarcts will result in at least 86% reduction in the proportion of patients with clinically evident strokes or new or progressive silent cerebral infarcts • 29 clinical sites (Canada, UK and France) • Statistical and Imaging Core Center • 10 year study Snapshot about the Participants (yearly income per capita in $8,500)

• 86 % (169 of 196) patients completed all exit data required • Monthly transfusions for 3 years (90 participants)

• 3-MRIs of the head

• 4-Neurology evaluations • 3-Cognitive Test Evaluations-WASI, BRIEF • 2-Quality of life assessments • 9% (18 of 196) patients completed partial exit data requirements • 5 % (9 of 196) patients did not complete any exit data

The Bottom Line • Risk of infarct recurrence and TIA for untreated silent cerebral infarct – 5.6 events per 100 patient years • Risk of infarct recurrence when treated with regular blood transfusion therapy for silent cerebral infarct – 2 events per 100 patient years • Risk of stroke with atrial fibrillation without warfarin treatment

– 4.4 events per 100 patient years (JAMA. 2001;285(22):2864-2870)

What do we tell families with overt strokes? • If a child has an overt stroke, after 5 years of regular transfusion – 45% will have new or progressive cerebral infarcts

What do we tell families about silent cerebral infarcts? • Regardless of treatment – Annual MRI – Annual academic and behavior inventory – At least one cognitive assessment • With no transfusion therapy, over a course of five years, 22% will have infarct recurrence (based on 5 events per 100 pt years) • With transfusion therapy~10% will have an infarct recurrence in five years (based on 2 events per 100 patient year) Summary of Treatment of Stroke

• Recurrence Rate – 67 % without treatment (Am J Med. 1978;65(3):461-71) – 50% with cessation of transfusions (J Pediatr 1991; 118(3):377-82.) – 22% (2.2 per 100 pt yrs) with transfusion (J Pediatr. 2002;140(3):348-54) – *Risk higher in first 2 yrs after initial stroke • Initial treatment should include exchange transfusion (J Pediatr. 2006,149(5):710-2) • Approximately 45% of the patients that are rigorously transfused will have progressive disease (overt or silent strokes) – Progressive CNS lesions based on progressive vascolopathy (Blood. 2011 Jan 20;117(3):772-9) Best evidence for regular blood transfusion therapy is standard care for • Overt strokes • Silent strokes • Preferred method, (~3000 transfusions, SIT Trial) – 1. apheresis ~ 10% – 2. exchange ~ 50% – 3. simple transfusion ~40%