Plasmodium Sequelae: Sickle Cell Disease and Stroke

1
Plasmodium SequelaeSickle Cell Disease and
Stroke

• Joshua Field MD
• March 4, 2005

2
Case

• Chief complaint pain
• 41 year-old African-American female with SS
  disease presented to ER with left arm pain.
• In ER, had two witnessed tonic-clonic seizures.
  Each lasted 30 seconds and the episodes followed
  by post-ictal confusion.
• Treated with ativan and loaded with dilantin.
• Head CT was negative.

3
Case

• Transferred to the NeuroICU
• PMH
• 1. SS disease no history of CVA, acute chest
  syndrome. Frequent admissions. Monthly
  transfusions.
• Pulmonary hypertension
• Chronic renal insufficiency-baseline creatinine
  2.0
• 2. HTN
• Medications hydrea, folate, oxycontin, norvasc

4
Case

• FH SS trait
• SH single, lives with 3 teenage sons. No
  alcohol, tobacco, drugs.
• Exam Lethargic, but arousable.
• VS 36.8 92 16 158/98
• Neuro EOMI, PERRL, normal facial strength,
  strength 4/5 in upper and lower extremities,
  symmetric, 3 reflexes throughout, toes
  downgoing, no papilledema.

5
Case

• Labs
• CBC wbc19.5, hemoglobin12, platelets357
• Reticulocyte count 2.7
• Serum creatinine2.0
• Electrolytes normal
• Urine drug screen positive opiates
• Radiology
• Head CT negative

6
Case

• CSF
• Clear
• 2 nucleated cells/microliter
• 1 PMNs
• 87 Lymphocytes
• 12 Monocytes
• Protein 41
• Glucose 70

7
Case

• Hospital course
• Transferred to 3200 hematology 24 hours following
  admission.
• Neurology questioned pseudoseizures.

8
NEJM 330(23) 1994

• Data from the Cooperative Study of Sickle Cell
  Disease around 4000 patients, birth to 66 years
  of age.
• Study to determine life expectancy, circumstances
  of death, and risk factors.
• SS Males, 42 Females, 48.
• 85 of children and adults live to 20.

9
NEJM 330(23) 1994
60 autopsies
10
NEJM 330(23) 1994
11
NEJM 330(23) 1994

• Risk factors for early death
• Fetal hemoglobin percentage
• Acute chest syndrome
• Renal failure
• Seizures
• White-cell count

12
Blood 91(1) 1998

• Data from Cooperative Study of Sickle Cell
  Disease.
• Study investigated rates and risk factors for
  stroke.
• At entry 153 strokes in 4,082 patients.
• Prevalence 3.75
• SS 4.01

13
Blood 91(1) 1998

• During study 87 of 3,647 patients had a stroke.
• Incidence 0.46 events per 100 patient years.
• SS 0.61 events per 100 patient years.
• SS recurrence 14, following initial CVA.
• lt20 6.4 events per 100 patient years.
• gt20 1.6 events per 100 patient years.

14
Blood 91(1) 1998
15
Blood 91(1) 1998

• SS risk factors
• Infarctive stroke
• Prior TIA RR56
• Anemia RR1.85/1g/dL decrease
• Acute chest syndrome within 2 weeks RR7
• Acute chest syndrome RR2.39 per event/year
• SBP RR 1.31/10mmHg increase
• Hemorrhagic stroke
• Anemia RR1.6/1g/dL decrease
• WBC RR1.94/5X109 increase

16
NEJM 326(9) 1992

• Primary prevention who is at risk?
• Transcranial Doppler ultrasonography to predict
  stroke risk.
• 190 patients with SS disease ages 3 to 18.
• Flow velocity greater than 170 cm/second through
  the middle cerebral artery deemed abnormal.

17
NEJM 326(9) 1992

• 23 of 190 patients had abnormal ultrasound.
• Followed for 29 months.
• 7 patients had strokes.
• 6/7 had abnormal ultrasounds (Plt.00001).

18
STOP NEJM 339(1) 1998

• Blood transfusions prevent recurrent strokes.
• Prophylactically transfuse patients with abnormal
  transcranial doppler ultrasounds (gt200 cm per
  second).
• 130 children
• 67 standard
• 63 transfusion (hemoglobin S)

19
STOP NEJM 339(1) 1998

• Results (Plt.001)
• 12 strokes
• 11 in standard cohort
• 1 in transfusion cohort
• Risk of stroke was 92 lower in the transfusion
  group.

20
Blood 81(5) 1993

• Treatment of an acute event
• Simple transfusion

21
Blood 81(5) 1993

• Exchange transfusion
• Acute or impending cerebrovascular episodes,
  whether caused by infarction, hemorrhage,
  hypoxemia, or transient ischemia, are absolute
  indications for exchange transfusion.

22
Journal of Pediatrics 88(382) 1976

• Post stroke therapy
• Transfusion therapy
• 3 children were transfused following a stroke.
• Baseline angiogram demonstrate disease.
• At one year, repeated angiogram and noted almost
  complete resolution artery narrowing.

23
Pediatrics 96(2) 1980

• When to discontinue transfusions?
• 12 children with history of stroke
• Chronically transfused to maintain hemoglobin S lt
  20
• 10 patients stopped transfusions at 1-2 years.

24
Pediatrics 96(2) 1980

• 7 of 10 patients developed recurrent strokes when
  transfusions were stopped.
• Average time to recurrent stroke 3 months.

25
Journal of Pediatrics 118(3) 1991

• When to discontinue transfusions?
• 10 patients with sickle cell disease and history
  of stroke.
• Transfused for an average of 9.5 years (5-12
  years), then stopped.
• Within 12 months of stopping therapy, 5/10
  patients had a recurrent ischemic event.

26
Journal of Pediatrics 131 1997

• When to stop transfusions?
• 9 patients with sickle cell disease and stroke.
• Transfusions were discontinued after an average
  of 6.3 years (1.5-16.5 years).
• No recurrent events.
• Average duration of follow-up was 9 years.

27
Blood 79(7) 1992

• Could we lighten up on the lt30 requirement?
• 15 patients with sickle cell disease and a
  history of stroke, ages 10-21.
• Following at least 4 years of chronic
  transfusions to maintain hemoglobin S lt 30, were
  changed to a threshold of lt50.

28
Blood 79(7) 1992

• Average follow-up was 84 months.
• No recurrent strokes.
• Transfusions were decreased by an average of 67.

29
Blood 94(9) 1999

• Is hydroxyurea effective in preventing stroke
  recurrence?
• 16 pediatric patients with sickle cell disease
  and history of stroke and a contraindication to
  transfusions.
• Initiated on hydroxyurea 15 mg/kg/day and dose
  escalated to 30 mg/kg/day.

30
Blood 94(9) 1999

• 3 patients had recurrent strokes, occuring 3-4
  months following discontinuation of transfusions.
• Maximal benefit of hydroxyurea?

31
Journal of Pediatrics 145 2004

• Is hydroxyurea effective in preventing stroke
  recurrence?
• 35 children with SS disease and CVA
• 15 abrupt discontinuation of transfusions, two
  weeks later initiated on hydroxyurea.
• 20 overlapped transfusions and hydroxyurea for an
  average of 6 months.

32
Journal of Pediatrics 145 2004

• 5/15 children stopped abruptly had recurrent
  events.
• 2/20 overlapped had recurrent events.
• Noted that all seven strokes demonstrated
  decreased hydroxyurea efficacy fetal hemoglobin,
  poor compliance, inadequate duration of therapy.
• Best to overlap and follow electropheresis.

33
Bone Marrow Transplantation

• NEJM 335(6) 1996
• 22 children, matched sib allogeneic transplants.
• 12/22 indication was stroke.
• 15 engrafted with full donor chimerism, 1 mixed.
• 2 deaths.

34
Bone Marrow Transplantation

• Blood 90 1997
• 9 patients, matched sib allogeneic transplants.
  Stroke indication in 1 patient.
• 1 death.
• Bone Marrow Transplant 19(112) 1997
• 26 patients, matched sib allogeneic transplants.
  Stroke indication 10 patients.
• 2 deaths.

35
Bone Marrow Transplantation

• Bone Marrow Transplantation 22 1998
• 50 patients, matched sib allogeneic transplants.
  Stroke indication in 6 patients.
• 2 deaths.

36
Pediatrics 84(6) 1989

• What about a different endpoint?
• 21 children with sickle cell disease and no
  history of stroke and 21 comparison siblings.
  Ages 7-16.
• Subjected to
• Wechsler Intelligence Scale for Children
• Beery Developmental Test of Visual Motor Skills
• Detroit Test of Learning Aptitude
• Social Competence Scale
• Woodcock-Johnson Psychoeducational Battery

37
Pediatrics 84(6) 1989

• Children with sickle cell disease scored about 1
  standard deviation below their siblings in all
  cognitive testing.
• IQ
• SS 77.7
• SA/AA 94.3

38
Questions

• Should we transfuse all children with sickle cell
  disease to prevent cognitive impairment?
• Hydroxyurea prophylaxis?
• Hydroxyurea post-CVA in place of transfusion?
• Is the data applicable to adults (especially BMT
  data)?

39
Case

• Hospital course continued
• Day following transfer to hematology service,
  patient was found on bathroom floor confused.
• Placed in bed and subsequently had a 30 second
  tonic-clonic seizure.
• Treated with ativan, re-loaded with dilantin.
• Intubated for airway protection and transferred
  to 89ICU.

40
Case

• Head CT new left parietal, occipital and right
  occipital infarcts.
• Emergent RBC exchange.
• Extubated 2 days later.
• Residual deficit diplopia.
• Follow-up for chronic transfusion therapy.
• What to do????