Stroke and Sickle Cell Disease

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Stroke and Sickle Cell Disease

• Allison King, MD, MPH
• September 17, 2009

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Case Study

• 5 year old boy with Hgb SS
• Cant move his right arm
• Crying
• What are the mothers or health care providers
  concerns?
• What are the possible causes?

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Objectives

• Describe the epidemiology of strokes in sickle
  cell disease (SCD)
• Describe the two major types of strokes
• Describe the risk factors associated with strokes
• Describe the outcomes of children with strokes
  and SCD
• Describe the treatment of strokes in children
  with SCD

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Objectives

• Describe the epidemiology of strokes in sickle
  cell disease (SCD)
• Describe the two major types of strokes
• Describe the risk factors associated with strokes
• Describe the outcomes of strokes in children with
  SCD
• Describe the treatment of strokes in children
  with SCD

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Stroke and SCD in the US

• Over 70,000 Americans have SCD
• 1000 children are born per year with SCA
• Approximately 18,000 children are at risk each
  year for stroke
• Children can suffer a stroke as young as 18 months

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Epidemiology

• 11 of children with Hgb SS will have a stroke by
  18 years of age
• Peak ages 2-12 years of age
• Frequency
• 0.5-1 per year
• 20 of children with Hgb SS will have a silent
  infarct by 14 years of age
• More common in younger children

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Complications of SCD CSSCD
All rates expressed per 100 patient-years.
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Objectives

• Describe the epidemiology of strokes in sickle
  cell disease (SCD)
• Describe the two major types of strokes
• Describe the risk factors associated with strokes
• Describe the outcomes of strokes in children with
  SCD
• Describe the treatment of strokes in children
  with SCD

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A stroke occurs when

• The brain needs more oxygen and energy than the
  body can provide
• A blood vessel in the brain is blocked so that
  blood flow to a portion of the brain occurs
• A patient bleeds into their head

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infarction
hemorrhage
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Overt Stroke

• Obvious neurological change
• Hemiparesis
• Weakness
• Seizures
• Aphasia
• Large vessels are usually involved
• Internal carotid, MCA, ACA

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Histological Findings

• Intimal thickening
• Fibroblast proliferation
• Smooth muscle cell proliferation
• Fragmentation/splitting of the internal elastic
  membrane
• Superimposed thrombus

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Hypotheses for Etiology

• Intimal hyperplasia
• Clumping and congestion of sickled cells
• Recurrent endothelial injury from sickled cells
• Is thrombosis a secondary process or incremental
  in vessel narrowing?
• Other hypercoagulable states
• Rarely associated with sinus thrombosis

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Associated stenotic lesions in the dICA and
proximal MCA are shown
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Silent Stroke (Infarct)

• Often are detected because a parent or teacher
  remarks on behavior changes
• Decline in school performance

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Silent Stroke (Infarct)

• Normal neurological exam
• Abnormal MRI
• Tends to happen in smaller vessel distribution
• Lesions are typically smaller than overt strokes
• Frontal and parietal lobes most common

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Stroke and SCD

• Combining overt and silent strokes
• 30 of children with SCD will have a stroke
  before age 18
• Significant public health problem

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Objectives

• Describe the epidemiology of strokes in sickle
  cell disease (SCD)
• Describe the two major types of strokes
• Describe the risk factors associated with strokes
• Describe the outcomes of strokes in children with
  SCD
• Describe the treatment of strokes in children
  with SCD

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Predictors from the CSSCD
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Overt Stroke Risk and Prediction

• Transcranial Doppler (TCD) flow velocity
• Silent cerebral infarction
• Genetic factors
• Nocturnal hypoxemia
• Parvovirus infection

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Stroke TCD Flow Velocity

• Basics of TCD
• Pioneered by Robert Adams and colleagues
• Non-invasive and painless procedure
• Measurement of flow velocities in large
  intracranial arteries around the circle of Willis
• Permits detection of stenosis
• Distal internal carotid artery
• Proximal middle cerebral artery
• Antecedents of overt stroke

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Bernoulli Principle
a constriction increases velocity and decreases
pressure
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Adams et al. NEJM 19983395-11.
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Stroke TCD Flow Velocity

• Limitations and unanswered questions
• Morbidity of chronic transfusions
• Inconvenience
• Iron overload and chelation
• Alloimmunization and infection
• Number needed to treat
• Approximately 10 children will have to be
  chronically transfused to prevent one stroke in
  one child each year
• Optimal duration of transfusions not yet known
• Role of hydroxyurea

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Stroke Silent Infarction

• Silent cerebral infarction
• CSSCD (Miller et al. J Ped 2001139385.)
• On average, identified at 6 years of age
• 14-fold increased incidence of new overt stroke
• 1.45 vs. 0.11 per 100 patient-years
• Mean follow-up of 5.2 years

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Stroke Genetic Factors

• Familial risk of stroke Driscoll et al. Blood
  20031012401
• Number of families in which 2 children with SCD
  who had strokes was larger than expected by
  chance (P0.0012)
• HLA alleles associated with stroke
• Increased or decreased risk
• Oakland (Styles et al. Blood 2000953562)
• CSSCD (Hoppe et al. Blood 20031012865)
• Adhesion molecules and stroke risk Taylor et al.
  Blood 20021004303-9.
• VCAM1 G1238C protected against stroke
• OR 0.35 (0.15-0.83, P0.04)

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Stroke Genetic Factors

• Gene interactions and risk of stroke
• CSSCD (Hoppe et al. Blood 20041032391-6.)
• 104 polymorphisms of 65 genes
• Large vessel stroke IL4R, TNF, ADRB2
• Small vessel stroke VCAM1, LDLR
• TNF (-308GG) homozygosity and TNF (-308GG)
  carrier status strongly increased the risk of
  stroke (OR 5.5 2.3-13.1)

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Stroke Nocturnal Hypoxemia

• Hypoxemia is common among patients with Hgb SS
• Nocturnal hypoxemia Kirkham et al. Lancet
  20013571656.
• Associated with CNS events (stroke, TIA,
  seizures)
• Predictor mean overnight oxygen saturation
• Hazard ratio of 0.82 for every 1 increase in
  saturation (P0.003)
• Causal association not established
• Screening for and appropriate management of
  nocturnal hypoxemia might be useful to predict
  and prevent stroke

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Stroke Parvovirus Infection

• Parvovirus B19
• Cause of transient aplastic crisis
• CNS events after crisis Wierenga et al. J Pediatr
  2001139438.
• 58-fold increased crude risk in the 5-week
  interval after infection
• Most strokes coincident with acutely severe
  anemia
• Several had seizures and one had transient
  cortical blindness 2 - 5 weeks after infection
• Increased awareness of the potential neurologic
  complications of parvovirus is needed

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Objectives

• Describe the epidemiology of strokes in sickle
  cell disease (SCD)
• Describe the two major types of strokes
• Describe the risk factors associated with strokes
• Describe the outcomes of strokes in children with
  SCD
• Describe the treatment of strokes in children
  with SCD

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Overt Stroke

• Aphasia
• Hemiparesis
• Usually diagnosed because of weakness on one side
  of the body

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Clinical Features of Overt Strokes and Silent
Cerebral Infarcts
Mutually Exclusive
Armstrong FD, Thompson RJ Jr, Wang W, et al.
Cognitive functioning and brain magnetic
resonance imaging in children with sickle cell
disease. Neuropsychology Committee of the
Cooperative Study of Sickle Cell Disease.
Pediatrics 199697864-870. Moser FG, Miller ST,
Bello JA. The spectrum of brain MR abnormalities
in sickle cell disease. AJNR 199617965-972.
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How are children affected?

• Study of children with silent stroke
• 14/19 (74) were retained a grade or required
  special academic services
• 7/19 (37) had poor academic achievement on
  either Reading or Math measures (gt 1.5 SD below
  mean)

Schatz J, Brown RT, Pascual JM, Hsu L, DeBaun MR.
Poor school and cognitive functioning with silent
cerebral infarcts and sickle cell disease.
Neurology 2001561109-1111.
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Neurocognitive Evaluation of 19 Children with
Silent Cerebral Infarcts
Schatz J, Brown RT, Pascual JM, Hsu L, DeBaun MR.
Neurology 2001561109-1111
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Common DeficitsBoth overt and silent strokes

• Frontal lobe lesions
• Attention deficits (directing and maintaining)
• Memory deficits
• Diffuse lesions both frontal and parietal lobes
• Visual-spatial deficits
• Attention deficits
• Memory deficits
• Decreased memory (and attention) skills are
  associated with poor performance in reading,
  writing, and arithmetic

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Educational Outcomes

• Students with SCD and infarcts (N 23)
• 20 graduated from high school in four years
• Average FS IQ
• 75 (past failure) vs. 93 (no failure), p .002

King, et al. J of School Health, 2006
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Objectives

• Describe the epidemiology of strokes in sickle
  cell disease (SCD)
• Describe the two major types of strokes
• Describe the risk factors associated with strokes
• Describe the outcomes of strokes in children with
  SCD
• Describe the treatment of strokes in children
  with SCD

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Overt Stroke - Treatment

• Blood transfusion therapy
• Goal is to decrease Hgb S from baseline (90) to
  lt 30
• Requires transfusing the patient every 3-4 weeks
• 85 relative reduction in frequency of repeat
  stroke

Anterior and middle cerebral artery Distal middle
cerebral artery
Pegelow CH. Adams RJ, McKie V, et al. Risk of
recurrent stroke in patients with sickle cell
disease treated with erythrocyte transfusions.
Journal of Pediatrics 1995126896-899.
Moran CJ, Siegel MJ, DeBaun MR. Sickle Cell
Disease Imaging of Cerebrovascular
Complications. Radiology 1998 206311-321.
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Silent Strokes Is there a treatment?
Pegelow CH, Wang W, Granger S, et al. Silent
Infarcts in Children with Sickle Cell Anemia and
Abnormal Cerebral Artery Velocity. Arch of Neur
2001582017-2021.

• No therapy has been established
• Keeping Hgb S lt 30 may be a reasonable strategy
  
• Unknown risks and benefits of transfusion therapy
  in this population
• Phase II Trial at SLCH
• Ongoing randomized clinical Phase III trial to
  test hypothesis that this therapy will result in
  a reduction of new or progressive silent infarcts

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Therapy Bone Marrow Transplant

• 22 children (lt 16 years of age) transplanted with
  matched sibling donors
• 20/22 survived
• 2 died from stroke and GVHD
• 16/22 engrafted
• Reason for transplant
• Stroke (12)
• Recurrent ACS (5)
• Recurrent pain crises (5)

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Therapy Bone Marrow Transplant
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Future Directions in BMT and SCD
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Other Interventions

• Rehabilitation for children with strokes
• Feasibility trial
• Cognitive intervention
• Working memory
• Executive function

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Hypotheses

• Targeted memory strategy rehabilitation will
  have a greater improvement in
• memory skills and
• academic achievement
• of children with SCD, cerebral infarcts, and
  memory deficits than in the same group of
  children who receive general tutoring

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Demographics

• 5 male, 6 female
• Mean age 11.6 yrs (range 8 16)
• Mean FSIQ 90 (range 57 116)
• 7 overt, 4 silent

Two year feasibility program with goal of 10
students
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Treatment Other Considerations

• Decrease adhesion
• Poloxamer 188 (used in trial for pain)
• Anti-platelet or anticoagulant drugs
• Aspirin used in non SCD-stroke
• No data to support ASA use in SCD
• Statins
• Not currently used

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Conclusions

• Stroke is a devastating complication of SCD
• Need partnership for progress
• Basic science
• Translational research
• Clinical research