Neonatal Stroke

1
Neonatal Stroke

• September 24, 2004
• Jennifer Dean, MD

2
Case Presentation

• CD is a 1 day old male infant
• Born at term to a 29 yo G2P0 now 1 mother with
  negative serologies
• Via C-section for failure to progress
• Apgars 8 and 9 and admitted to regular nursery

3
Case Presentation

• Noted to have twitching movements of extremities
  on DOL 1
• CBC, Blood Cx, and Glucose were sent
• Head CT revealed left parietal infarct with
  overlying abnormal cortex
• Had another seizure episode and was loaded with
  Phenobarbital and transferred to SLCH NICU.

4
MRI Results

• Left middle cerebral artery territory (posterior
  division) acute cerebral infarction that
  demonstrates elevated T2 signal compatible with
  edema, diffusion restriction and vascular
  engorgement. This likely represents an infarct of
  less than three days duration. No hemorrhage
  associated with the infarction is seen.
• Small left globus pallidus hemorrhage

5
Further Workup

• LP
• TC 8899 Nuc 62. Protein 101, Glucose 61, Culture
  and HSV PCR negative
• Cardiac Echo small patent PFO with left to
  right shunt

6
More results

• Moms Protein S low
• Coagulation studies on CD revealed
• PT 14.3 PTT 31.6
• Newborn Screen nml
• Serum Phosphatidylserine ab - negative
• Protein S, free 53
• Protein C 38
• Antithrombin III 83
• Prothrombin G 20210 gene mutation detected
  heterozygosity for a point mutation

7
Definition

• Cerebrovascular event around the time of birth
• With pathological or radiological evidence of
  focal arterial infarction
• Hemorrhagic lesions, generalized ischemic lesions
• Perinatal (from 28 weeks into pregnancy to 7 days
  old)
• Neonatal (under 28 days old)

8
Incidence

• Symptomatic perinatal stroke occurs in 1 in 4000
  term infants
• Difficult to determine
• Ultrasonography not a sensitive indicator of
  perinatal stroke
• Early discharge and often asymptomatic patients
• Ischemic stroke after the first month of life
  occurs in 1 in 30,000

9
Clinical Presentation

• Seizures most common
• Hypotonia, lethargy, and apnea
• Can be diagnosed retrospectively in patients who
  are failing to reach milestones or have
  hemiparesis

10
Pathophysiology

• Features of perinatal period that influence
  coagulation state
• Presence of fetal hemoglobins
• Fetal proteins
• High hematocrit and blood viscosity
• Concentrations of procoagulant and anticoagulant
  proteins change with gestational and postnatal age

11
Risk factors for stroke

• Cardiac disorders
• Congenital heart disease
• Patent ductus arteriosus
• Pulmonary valve atresia
• Blood, homocysteine, and lipid disorders
• Polycythemia
• Disseminated intravascular coagulopathy
• Factor-V Leiden mutation
• Protein-S deficiency
• Protein-C deficiency
• Prothrombin mutation
• Homocysteine
• Lipoprotein (a)
• Factor VIII
• Infectious disorders
• CNS infection
• Systemic infection

• Maternal disorders
• Autoimmune disorders
• Coagulation disorders
• Anticardiolipin antibodies
• Twin to twin transfusion syndrome
• In utero cocaine exposure
• Infection
• Placental disorders
• Placental thrombosis
• Placental abruption
• Placental infection
• Fetomaternal hemorrhage
• Vasculopathy
• Vascular maldevelopment
• Trauma and catheterization
• Birth asphyxia
• Dehydration
• Extracorporeal membrane oxygenation

Nelson KB - Stroke in newborn infants. Lancet
Neurol - 01-MAR-2004 3(3) 150-8
12
Factor V Leiden mutation

• Found to be the most common defect associated
  with hereditary venous thrombosis in adults
• Mutation at the cleavage site for APC u
  inactivation of clotting factor V at a reduced
  rate u effects the protein C/protein S natural
  inhibitor system u increased tendency for
  thrombosis

13
Prothrombin G 20210 mutation

• Genetic polymorphism in the 3 untranslated
  region of prothrombin gene
• G to A transition at nucleotide 20210
• Associated with elevated levels of prothrombin
  and a threefold increased risk of venous
  thromboembolism in adults

14
FVLM and Prothrombin 20210in neonates

• A study of 33 children with acute ischemic stroke
• 11 had neonatal stroke 22 had stroke after
  neonatal period
• Needed documentation of acute stroke by CT or MRI
• All patients tested for APC-resistance, Factor V
  Leiden mutation, and Prothrombin G 20210 mutation

15
Results

• None of the 11 patients with neonatal stroke had
  F-V-LM or Prothrombin 20210 mutation
• 6 of the 22 patients with childhood stroke had
  F-V-LM (18 of stroke population)
• Differs from other studies where prevalence was
  higher (36)
• 1 of 22 patients had prothrombin G 20210

16

• Multicenter case-control study
• 91 stroke patients and 182 control subjects
• Age was birth to 28 days
• Tested for F-V-LM, Prothrombin 20210 mutation,
  MTHFR C667T, APC, antithrombin activities, free
  protein S, total protein S, and protein C

17
Results

• 62 of 91 stroke pts (68.1) had at least 1
  prothrombotic risk factor
• Compared to 44 of 182 controls (24.2)

18
Results

• Antithrombin deficiency, protein S deficiency, or
  ACA IgG were not found to be risk factors

19
Therapy

• Supportive Therapy
• Anticonvulsants, maintenance of adequate
  perfusion, hydration and use of
  antibiotics/antivirals
• Polycythemia corrected by pheresis or hydration
• Using thrombolytic, heparin, or LMWH have not
  been well studied

20
Outcome

• Varies widely among studies
• Normal outcome in survivors of 33
• Visual impairment
• Not easily predicted by infarct location
• Language
• Prosodoic deficits with unilateral brain damage
• Hemiplegia
• Abnormal EEG in first week after stroke
• Infarction involving the internal capsule

21

• Study of 24 infants with neonatal stroke
• 23/24 pts presented with seizures on DOL 1
• Tested for Factor VIIIc, protein C, protein S,
  antithrombin III, F-V-LM, prothrombin G 20210
• Follow-up at 6, 12, 18, and 24 months and then
  yearly

22
Outcome

• Prevalence of F-V-LM 24
• Those pts with F-V-LM showed additional
  hemorrhages and were associated with a high risk
  of poor neurologic outcome
• Significant with P .003

23
Recurrence risk

• From Canadian Pediatric Ischemic Stroke Registry
• Neonatal stroke 3 to 5

24
Conclusions

• Neonatal stroke is multifactorial
• Screening for prothrombotic disorders can be
  helpful for anticipatory guidance for families
• More studies evaluating therapy are needed