Changing Pattern of Brain Injury in the Term Infant Jeffrey M Perlman MB Ch B Professor of Pediatrics Weill Cornell Medical College NYPH Komansky Center for Child Health New York, NY
I have no Financial Disclosures or Conflicts of Interest Relevant to this Presentation
Background • Perinatal brain injury in term infants remains a significant clinical problem and an important cause of perinatal mortality and morbidity. • The most common identified problem has been hypoxic-ischemic encephalopathy • Other causes include symptomatic intracranial hemorrhage and focal cerebral infarction. • Recently we have perceived a change in the pattern of perinatal brain injury.
Is this Perceived Observation Important ? • Prevention • Treatment
Methods
We undertook a retrospective chart review in order to characterize the incidence, etiology, clinical manifestations and outcome of term infants who are admitted to intensive care with symptomatic perinatal brain injury
Methods (cont) • Perinatal characteristics - including FTHR tracings, clinical symptoms, neuroimaging, EEG, and placental pathology. • Perinatal depression was defined as need for face mask ventilation ± intubation and/or hypotonia. • HIE was defined as low Apgar Score at 10 minutes ± fetal acidemia, need for CPR and subsequent encephalopathy.
Results • Jan 2004 - Dec 2009 there were 29,597 term deliveries • 33/29597 (1.1/1000) presented with symptoms potentially attributed underlying brain injury • Incidence of symptomatic perinatal brain injury - HIE 0.27/1000 - IVH/IPH 0.17/1000 - Subdural Hemorrhage 0.34/1000 - Focal Cerebral Infarction 0.14/1000
Specific Intracranial Lesions Identified
Hypoxic-Ischemic Changes
Intraventricular Hemorrhage
Focal Cerebral Infarction
Intraparenchymal Hemorrhage
Subdural Hemorrhage
Clinical and Pathological Characteristic of the Intracranial Lesions HIE (n=8)
Stroke (n=4)
3198 ± 430
3561 ± 248
38 ± 1.2
40 ± 1.0
39 ±1.1
Nulliparous
7/8 (88%)
2/4 (50%)
3/5(60%)
In vitro fertilization
3/8 (38%)
Sex (male)
3/8 (38%)
2/4 (50%)
2/5 (40%)
8/10 (80%)
Maternal Fever
4/8 (50%)
2/4(40%)
3/5 (60%)
6/10 (60%)
Meconium-stained AF
6/8 (75%)
1/4 (25%)
1/5 (20%)
1/10 (10%)
FTHR abnormality
4/8 (50%)
2/4(40%)
1/5 (20%)
4/10 (40%)
Cesarean section Delivery
4/8 (50%)
3/4 (75%)
2/5 (40%)
2/10 (20%)
Vacuum Extraction
2/8 (25%)
Intubation in DR
4/8 (50%)
CPR in DR Cord arterial pH
Birth Weight [g] Gestational Age [wks]
0
IPH/IVH (n=5)
3257 ± 287
0
SDH (n=10) 3401 ± 527 40 ± 0.7 6/10(60%) 0
0
2/10 (20%)
1/ 4(25%)
0
3/10 (30%)
3/8 (38%)
1/4 (25%)
0
7.06±0.18
7.16±0.09
10 Min Apgar Score ≤ 5
2/8(25%)
1/4 (25%)
Apnea
2/8(25%)
0
Clinical Seizures
6/8 (67%)
EEG Seizures Histologic Chorioamnionitis Fetal Vasculopathy Abnormal Outcome/ Died
0
7.06± 0.08 0
0 7.20±0.11 1/10(10%)
4/5 (80%)
1/10(10%)
3/ 4(75%)
1/5 (20%)
1/10(10%)
3/6 (50%)
3/3 (100%)
2/5 (66%)
0/5
2/5 (40%)
0/4
1/3(33%)
4/5(80%)
0/5
3/4 (75%)
1/3 (33%)
0/5
6/8(66%)
1/4 (25%)
0/4
Bold = Statistically significant P 7.00 No DR resuscitation Normal Apgar scores HIE Renal dysfunction Neuro-imaging changes (consistent with HIE)
50%
50%
Subacute Brain Injury • Postulate that the onset is close to the onset of labor • Auto resuscitation • Labor then maybe uncomplicated or there maybe FHRT abnormalities (usually not regarded as significant
Intracerebral/Intraventricular Hemorrhage • Intracranial Hemorrhage is uncommon. • Maybe found within the GM, ventricles or parenchyma. • Thalamus - a common site of bleeding and frequently includes IVH as well. • Predisposing factors include prior - Hypoxia-ischemia - Sepsis, and coagulopathy • Primary IVH is rare in the term infant • Arises from residual germinal matrix, choroid plexus and thalamus. • Predisposing factors include - Prior hypoxia-ischemia, coagulopathies and AVM.
Clinical Presentation • Sudden onset of marked neurologic abnormalities - seizures, evidence of ↑ ICP, bulging fontanel or blood in CSF • Presentation maybe more subtle with apnea, hypotonia and/or subtle seizures • Neuroimaging i.e. cranial ultrasound, CT or MRI readily establishes the diagnosis. • The prognosis is often good.
Subdural Hemorrhage • • • •
SDH was the most common lesion identified (0.34/1000) Presentation is often a depressed and hypotonic infant Clinical seizures are rare Outcome is good
Chamnanvanaki et al Pediatric Neurol 2002;301-304
Focal Cerebral Infarction
Focal Cerebral Infarction in Term Infants (1 in 2300 - 4000) Acute Neonatal Stroke Maternal Factors Pre-eclampsia Thrombophilia
Intrapartum Factors Chorioamnionitis
Apgar score unremarkable Cord pH unremarkable Triaged to NBN
Thrombus Emboli
Vascular insufficiency
Clinical Signs Seizures (80%) Hypotonia Encephalopathy Irritability
Cerebral Ischemia
Reperfusion
Infection and/or the fetal inflammatory response as a potential contributing factor to brain injury during hypoxia-ischemia
Foundation Fact
There is a paucity of data with regard to chorioamnionitis, inflammatory mediator release and neonatal neurologic findings in term infants.
Inflammation and Brain Injury Clinical Observations • Chorioamnionitis and/or cord blood inflammatory cytokines i.e. IL-6, IL-1 and TNF- concentrations have been associated with white matter injury (WMI) and/or cerebral palsy. Specifically umbilical cord IL-6 concentration was associated with a six-fold in WMI. • The fetal inflammatory response (funisitis) is associated with the highest cytokine levels; this response may be biologically more important than the maternal effects.
Yanowitz Pediatr Res 2002;51:310, Leviton Pediatr Res.1999;46:566 Yoon, Am J Obstet & Gynecol 96, 97
Objectives •
Determine which inflammatory cytokines are elevated in symptomatic term newborns exposed to mothers with chorioamnionitis when compared to healthy controls
•
Determine the postnatal changes in cytokine concentrations at 3 time intervals from birth to 36 hours
•
Determine if any of the cytokines studied are correlated with short term neonatal neurological outcomes
Study Design Study Period (7/99 to 1/01) Term Newborns exposed to Clinical Chorioamnionitis n=1660
95% Asymptomatic Triaged to NBN n=1571
5% Symptomatic Triaged to NICU n=89 n=18 back to NBN
n=10 No consent
n=61 Enrolled
Short Term Neurologic Outcomes Depression at Birth: BMV > 2 min or intubation in delivery room, or Apgar < 6 at 5 min
Abnormal Neurological Examination: Modified Dubowitz Score, normal score:15 2 (mean ± SD) Posture - Arm traction - Arm recoil - Leg recoil Popliteal angle - Head lag - Abnormal movement
HIE and/or Seizures: HIE defined as Apgar Score < 3 at 5 min + Cord pH < 7.00 + Encephalopathy (Sarnat 2-3) + Non CNS dysfunction following a sentinel event.
CHARACTERISTICS OF CHORIO INFANTS (n = 61) Gestational age (weeks) Birth Weight (grams) TemperatureC (at 30 min) Apgar at 5 min Median(25%,75%) Cord pH Abnormal WBC at birth Multiple Abnormal WBC Positive blood cultures Days in Hospital
40 0.2 3496 88 37.5 0.1 8 ( 6, 9 ) 7.15 0.4 n=40 (66%) n=28 (47%) None 7 1 days
IL-6, IL-8, RANTES IN CORD BLOOD: CONTROL VS CHORIO
Rantes
IL‐8
IL‐6
Control
*p
