Cerebral infarcts in patients with sickle cell disease
Download
1 / 29

Cerebral Infarcts in Patients with Sickle Cell Disease - PowerPoint PPT Presentation


  • 96 Views
  • Uploaded on

Cerebral Infarcts in Patients with Sickle Cell Disease. Miguel R. Abboud , MD Professor of Pediatrics Hematology -Oncology Chairman, Department of Pediatrics and Adolescent Medicine American University of Beirut Medical Center Beirut , Lebanon. Definitions.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Cerebral Infarcts in Patients with Sickle Cell Disease' - sorley


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
Cerebral infarcts in patients with sickle cell disease
Cerebral Infarcts in Patients with Sickle Cell Disease

Miguel R. Abboud, MD

Professor of PediatricsHematology-OncologyChairman, Department of Pediatrics and Adolescent MedicineAmerican University of Beirut Medical Center Beirut, Lebanon


Definitions
Definitions

Adams RJ, et al. Hematology Am Soc HematolEduc Program. 2001:31-46.


Stroke subtype by age

Ischaemic stroke1

54% of cerebrovascular accidents

Highest in 1st decade and after 30 years

Peak incidence at 2–5 years

Haemorrhagic stroke1

Highest in 2nd decade

Silent stroke/infarct

Radiologic findings consistent with white matter disease1

10%–30% of patients with sickle cell disease (SCD)1

Associated with cognitive deficiencies1 and higher stroke risk2

Stroke Subtype by Age

1. Verduzco LA, et al. Blood. 2009;114:5117-5125. 2. Miller ST, et al. J Pediatr. 2001;139:385-390.


Risk factors for infarctive stroke
Risk Factors for Infarctive Stroke

  • Multivariate predictors (P <.05 for each)1

    • Prior transient ischaemic attack (TIA): Relative risk (RR) = 56

    • Anaemia: RR = 1.85 per 1 g/dLHb decrease

    • Recent acute chest syndrome: RR = 7

    • Acute chest syndrome rate: RR = 2.39 per event/year

    • Hypertension: RR = 1.31 per 10 mmHg increase

  • Additional predictors

    • Silent infarcts: RR = 142

    • Nocturnal hypoxia: Hazard ratio (HR) = 0.85 per 1% increase in O2saturation3

1. Ohene-Frempong K, et al. Blood. 1998;91:288-294. 2. Miller ST, et al. J Pediatr. 2001;139:385-390.

3. Kirkham FJ, et al. Lancet. 2001;357:1656-1659.


Cerebral infarcts in patients with sickle cell disease

Stroke Recurrence Risk After Initial Simple vs Exchange Transfusion

All children received scheduled chronic blood transfusion therapy for at least 5 years after the first stroke and initial therapy

RR = 5.0 (1.3–18.6; P= .02)

8/14

8/38

Transfusion Type

Hulbert ML, et al. J Pediatr. 2006;149:710-712.


Management of stroke and prevention of recurrence
Management of Stroke and Prevention of Recurrence

Study population with transfusion vs

historical control subjects without transfusion2

  • Ischaemic stroke is treated with emergent simple or exchange blood transfusion1

  • Without transfusion, 70% will recur within 2–3 years1

  • With chronic transfusion, risk of recurrence is reduced by 90%1

Cumulative observation time = 191.7 patient-years

8/60

10/15

1. Josephson CD, et al. Transfus Med Rev. 2007;21:118-133. 2. Pegelow CH, et al. J Pediatr. 1995;126:896-899. 3. Powars D, et al. Am J Med. 1978;65:461-471.

Transfusion2

NoTransfusion3


Hydroxyurea for secondary stroke prevention switch
Hydroxyurea for Secondary Stroke Prevention—SWiTCH

Aim of study: [hydroxyurea + phlebotomy = alternative arm] vs [transfusions + deferasirox = standard arm] for 30 months to prevent secondary stroke and reduce transfusional iron overload

Alternative armHydroxyurea + phlebotomy

n = 67

161 paediatric patients with SCD and documented stroke and iron overload enrolled in SWiTCH

133 patients randomized 1:1

Standard armTransfusions + deferasirox

n = 66

Prediction: increased recurrence of stroke events in alternative arm but counterbalanced by better management of iron overload with phlebotomy

Ware RE, et al. Blood. 2010;116:Abstract 844.


Cerebral infarcts in patients with sickle cell disease

SWiTCH—Stroke Recurrence Higher with Hydroxyurea than with Transfusions1

Study was terminated early2 due to the marked increase in secondary stroke risk with hydroxyurea compared with transfusion therapy and no benefit of phlebotomy over chelation in reducing iron overload

7/67

0/66

Hydroxyurea + Phlebotomy

Transfusion + Deferasirox

1. Ware RE, et al. Blood. 2010;116:Abstract 844. 2. NIH. Press release. June 4, 2010. Accessed 11/21/11 at: http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=2709.


Importance of transcranial doppler screening in scd annual stroke risk
Importance of Transcranial Doppler Screening in SCDAnnual Stroke Risk

  • Baseline risk from Cooperative Study of Sickle Cell Disease (CSSCD) is approximately 0.5%–1%1

    • −If prior stroke, annual stroke risk is approximately 30%2

    • Increased risk of infarctive stroke with TIA, lower baseline Hb, prior and recent acute chest syndrome (CSSCD study, no prior stroke), but yearly risk not quantitated1

    • If abnormal transcranial Doppler (TCD), annual risk is 10%–13% per year3

    • If MRI “silent lesions,” annual risk is approximately 2%–3%4

    • Severe arterial lesions on angiography?

      • −Assumed to be bad,5 but yearly risk has not been quantitated

1. Ohene-Frempong K, et al. Blood. 1998;91:288-294. 2. Powars D, et al. Am J Med. 1978;65:461-471. 3. Adams RJ. Arch Neurol. 2007;64:1567-1574. 4. Miller ST, et al. J Pediatr. 2001;139:385-390. 5. Abboud MR, et al. Blood. 2011;118:894-898.


Stroke free probability is increased with long term transfusions in children with scd
Stroke-Free Probability Is Increased with Long-Term Transfusions in Children with SCD

Paediatric patients with SCD and abnormal TCD velocity were randomized to transfusion or standard care to prevent first stroke

Median follow-up = 21.1 months

P <.001

11/67

12/130

1/63

*Includes 1 patient with intracerebral haematoma.

Adams RJ, et al. N Engl J Med. 1998;339:5-11.


Early tcd screening and intervention
Early TCD Screening and Intervention

  • Predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort (n = 217, SS/Sβ0)

  • Screenedwith TCD early and yearly since 1992

  • MRI/MRA every 2 years after age 5 years(or earlier in case of abnormal TCD)

  • Transfusions for abnormal TCD and/or stenoses

  • Hydroxyurea to symptomatic patients with no macrovasculopathy

  • Stem cell transplantation for those with HLA genoidentical donor

  • Mean follow-up 7.7 years (1609 patient-years)

Bernaudin F, et al. Blood. 2011;117:1130-1140.


Cumulative risks in scd cohort with tcd screening
Cumulative Risks in SCD Cohort with TCD Screening

  • Cumulative risks by 18 years of age

    • Stroke: 1.9% (95% CI 0.6%–5.9%) compared with 11%

    • Abnormal: TCD 29.6% (95% CI 22.8%–38%) plateau at age 9 years

    • Stenosis: 22.6% (95% CI 15.0%–33.2%)

    • SI: 37.1% (95% CI 26.3%–50.7%) age 14 years

  • All cerebral event risk by 14 years 49.9% (95% CI 40.5%–59.3%)

  • Independent predictive factors for cerebral risk

    • Baseline reticulocytescount: HR 1.003 per 1 x 109/L increase

    • Lactate dehydrogenase: HR 2.78 per 1 IU/mL increase

  • Conclusion: Early TCD screening and intensification therapy reduced risk of stroke by age 18 years from 11% to 1.9%

    • 50% cumulative cerebral risk suggests more preventive intervention is needed

Bernaudin F, et al. Blood. 2011;117:1130-1140.


Tcd and transfusions in patients with silent infarcts conclusions
TCD and Transfusions in Patients with Silent Infarcts—Conclusions

  • Early TCD and transfusions effective in preventing strokes

  • TCD does not screen for risk of silent infarcts

  • Most patients who develop silent infarcts have normal TCD

  • Different strategies needed

BernaudinF, et al. Blood. 2011;117:1130-1140.


Stop ii trial transfusion and stroke prevention
STOP II Trial—Transfusion and Infarcts—Conclusions Stroke Prevention

  • 79 subjectshavingnormalized TCD under transfusion wererandomized1

    • 38 to continuecRCTtherapy

    • 41 to discontinuecRCTtherapy

  • No neurologic events in the cRCTgroup1

4.9%

Patients with Neurologic Events (%)

34.1%

STOP II trial terminated after 2 years and concluded that it is unsafe to stop blood transfusions in patients who are at high risk of stroke2

Abbreviations: cRCT, chronic red cell transfusion; TCD, transcranial Doppler.1. Adams RJ, et al. N Engl J Med. 2005;353:2769-2778. 2. NIH. Press release. December 5, 2004. Accessed 11/21/11 at: http://www.nhlbi.nih.gov/new/press/04-12-05.htm.

Graphic courtesy of Dr. Miguel R. Abboud.


Stop trial transfusion therapy vs standard care for prevention of secondary silent brain infarcts
STOP Trial—Transfusion Infarcts—Conclusions Therapy vsStandard Care for Prevention ofSecondary Silent Brain Infarcts

Outcome after observation for 36 months in patients who had silent infarcts at baseline and who were randomized to transfusion or standard care

*Includes 1 patient with new or worse lesion prior to stroke.

Pegelow CH, et al. Arch Neurol. 2001;58:2017-2021.


Stop ii trial effect of discontinuing transfusion on silent brain infarcts on mri
STOP II Trial—Effect of Discontinuing Transfusion on Silent Brain Infarcts on MRI

*1 patient had no follow-up MRI.

†3 patients had lesion number decrease; 1 reverting to normal scan.

Abboud MR, et al. Blood. 2011;118:894-898.


Stop ii trial effect of discontinuing transfusion on silent brain infarcts on mri1
STOP II Trial—Effect of Discontinuing Transfusion on Silent Brain Infarcts on MRI

At study end, 3/37 (8.1%) patients in the continued-transfusion group developed new brain MRI lesions compared with 11/40 (27.5%) in the transfusion-halted group (P = .03)

*1 patient had no follow-up MRI.

†3 patients had lesion number decrease; 1 reverting to normal scan.

Abboud MR, et al. Blood. 2011;118:894-898.


Consequence of stroke prevention with blood transfusions
Consequence of Stroke Prevention with Blood Transfusions Silent Brain Infarcts on MRI

Paediatric patients with SCD and abnormal TCD velocity were randomized to transfusion or standard care to prevent first stroke.

IRON OVERLOAD is an inevitable consequence of chronic transfusions in patients with SCD

Median follow-up = 21.1 months

Initial serumferritin

164 ± 155ng/L

P <.001

1-year serumferritin

1804 ± 773ng/L

2-year serumferritin

2509 ± 974ng/L

11/67

12/130

1/63

*Includes 1 patient with intracerebralhaematoma.

Adams RJ, et al. N Engl J Med. 1998;339:5-11.


Cerebral infarcts in patients with sickle cell disease

Organ Dysfunction in Silent Brain Infarcts on MRISickle Cell Disease and β-Thalassaemia

SCD n = 43

β-Thal n = 30

*P-value = not significant; P-value significant for all other comparisons.Vichinsky E, et al. Am J Hematol. 2005;80:70-74.


Cerebral infarcts in patients with sickle cell disease

  • Organ injury may require a critical iron level with prolonged exposure

  • SCD biology and its secondary inflammatory state may be protective factors

  • Inflammation may decreaseorgan injury by restricting iron to shielded sites within the reticuloendothelial system (RES) and delaying the release of iron from the RES system

  • The 2 diseases may have different transport and storage proteins

Vichinsky E, et al. Am J Hematol. 2005;80:70-74.


Cerebral infarcts in patients with sickle cell disease

Possible Explanations for Absence of Cardiac Iron Overload in SCD

  • Nontransferrin-bound iron higher in thalassaemia major than SCD

  • Other factors

    • Splenic tissue

    • Ineffective erythropoiesis

    • Gastrointestinal iron metabolism

    • Urinary iron loss

Vichinsky E, et al. Am J Hematol. 2005;80:70-74.


Cerebral infarcts in patients with sickle cell disease

Kupffer in SCDCellSiderosis

HepatocyteSiderosis

With permission from Pierre Brissot, MD.


Cerebral infarcts in patients with sickle cell disease

How to Monitor Iron Status in SCD

  • Serum ferritin

    • Noninvasive, available, inexpensive

    • Confounded by several parameters

    • Use long-term trends and avoid using acute-phase values

  • Liver biopsy

    • Gold standard

    • Reveals pathology

    • Invasive

    • Sampling error

  • Magnetic resonance

    • Accurate

    • Expensive


Cerebral infarcts in patients with sickle cell disease

How to Manage Iron Overload in SCD

  • Chelating agents

    • Desferrioxamine

    • Deferasirox

    • Deferiprone

      • Licensed for thalassaemia major only1

  • Nonpharmacologic techniques

    • Erythrocytapheresis

    • Phlebotomy

1. Ferriprox (deferiprone). Summary of product characteristics. Leiden, Netherlands: Apotex; 1999.


Cerebral infarcts in patients with sickle cell disease

Chronic Transfusion Methods in SCD

1. Sickle Cell Society. Standards for the clinical care of adults with sickle cell disease in the UK. 2008.Accessed 11/29/11 at: http://www.sicklecellsociety.org/app/webroot/files/files/CareBook.pdf. 2. Kim HC, et al. Blood. 1994;83:1136-1142.


Iron chelation therapy is needed to treat iron overload
Iron in SCDChelation Therapy is Needed to Treat Iron Overload

1. Desferal (desferrioxamine). Summary of product characteristics. Camberly, UK: Novartis; 2010. 2. Exjade (deferasirox). Summary of product characteristics. Nuremberg, Germany: Novartis; 2006. 3. Ferriprox (deferiprone). Summary of product characteristics. Leiden, Netherlands: Apotex; 1999. Graphic courtesy of Dr. Miguel R. Abboud.


Cerebral infarcts in patients with sickle cell disease

Deferasirox vs Desferrioxamine—Measures of Iron Overload in SCD

LIC Reduction (SQUID)

Serum Ferritin Reduction

Deferasirox(n = 117)

Desferrioxamine(n = 56)

Deferasirox(n = 83)

Desferrioxamine(n = 33)

P = NS

P = NS

Data from Cochrane review of randomized-controlled trials that compared deferasirox with desferrioxamine. Abbreviations: LIC, liver iron concentration; SQUID, superconduction quantum interference device. Meerpohl JJ, et al. Cochrane Database Syst Rev. 2010;8:CD007477.


Cerebral infarcts in patients with sickle cell disease

Deferasirox vs Desferrioxamine—Measures of Satisfaction in SCD and Adherence

Data from Cochrane review of randomized-controlled trials that compared deferasirox with desferrioxamine. Meerpohl JJ, et al. Cochrane Database Syst Rev. 2010;8:CD007477.


Conclusions
Conclusions in SCD

  • Infarctive strokes are a devastating complication of SCD

  • Chronic transfusion regimens are very effective in preventing stroke recurrence as well as new strokes in patients with abnormal transcranial Doppler

  • Early transfusions seem effective in preventing development and progression of silent infarcts

  • Iron accumulation in sickle cell disease is different compared with thalassaemia

  • Iron chelators are effective in preventing iron overload in these patients