Neonatal encephalopathy

Dr . Hesham Ahmed Shapan

MBBS
DCH
MRCPCH
definitions
Anoxia: complete lack of oxygen.
Hypoxia: decreased oxygenation of cells and organs.
Hypoxemia: decreased arterial oxygen saturation.
Ischemia: insufficient blood flow to maintain normal
function of organs.
Asphyxia: impaired blood gas exchange leading to
hypoxemia.
HIE/NE : it is a clinical neurological syndrome associated
with asphyxia which is a combination of hypoxia and

:specific neurologic syndrome in newborn ,

from low oxygen and blood flow to brain due to perinatal
leading to brain injury.

:intrauterine distress with depression at birth

manifested neurological signs at immediate postnatal period.

:clinical syndrome ccc by subnormal level of

consciousness or seizures and often accompanied by difficulty
with initiating and maintaining respiration and depression of
tone and reflexes in the early life of term newborn.
 Neonatal encephalopathy
a disturbance in neurologic function demonstrated by
1.difficulty in maintaining respirations,
2.Hypotonia
3.altered level of consciousness
4.depressed or absent primitive reflexes
5.Seizures
6.Poor feeding
7.Apnea
8.Abnormal hearing screen
(NE does not imply HIE. NE may represent a metabolic disorder,
infection,
drug exposure, or neonatal stroke, but it is the preferred terminology to
describe a
incidence
25 per 1000 term live births

73 per 1000 preterm live births

15 and50% moderate to severe cases, respectively.

perinatal asphyxia was ~1.6 per 10,000 live births.

Risk Factors for HIE
Preconception
Fertility medications
IDDM
Thyroid disease
Advanced maternal age
Nulliparous
Antepartum
Multiple gestation
Placental abruption
IUGR
Severe PET
APH
Post term
Intrapartum
Induction of labor
Maternal fever
Emergency CS
Instrumented delivery
Cord prolapse
Mal presentation
Lack of trained personnel
etiologies:

1)antenatal 69%
2)Intra natal 5%
3)Both 20 %
4) Post natal 6%
Etiologies:
1. Maternal factors: hypertension, hypotension, infection,
hypoxia, diabetes, maternal vascular disease, and in
utero exposure to toxins
2. Placental factors :abruption, infarction, fibrosis
3. Uterine rupture
4. Umbilical cord: prolapse, true knot, compression.
5. Fetal factors: anemia (hemorrhage), infection,
hydrops.
6. Neonatal factors: CCHD, PPHN, cardiomyopathy,
shock, respiratory failure.
●Maternal:
impaired oxygenation (asthma, pulmonary embolism, pneumonia)
inadequate perfusion of maternal placenta (cardiorespiratory arrest,
maternal hypotension, preeclampsia, chronic vascular disease)

●Placental:
placental abruption , cord prolapse, true knot, or uterine rupture

●Fetal:
impaired fetal oxygenation/perfusion (asphyxia , feto-maternal
hemorrhage)
 Direct
fetal hypoxia decreased injury/lesions
cerebral flow
a)maternal a)CCHD a) trauma
hypoventilation
b) hypotension due b) Stroke and hemorrhage
b)Respiratory failure to blood loss or c) CNS infections
c) premature separation spinal anesthesia
of placenta d) syndromes& genetic
c) severe anemia disorders
d) cord compression or d) Shock
knotting/prolapse e)IEM

e) Placental f)Cerebral malformations

insufficiency
pathophysiology
Molecular mechanisms
1)Decreased cerebral blood flow and energy failure

2)Reperfusion injury(diving reflex and blood diversion)

3)Neuronal excitotoxicity

4)Oxidative stress (free radicals)

5)Inflammatory process

6)cell death

7)Repair and neuroplasticity

brief asphyxia prolonged

severe but brief asphyxia makes

diversion of blood flow to vital loss of pressure auto-
deep nuclear structures of the regulation and
brain does not occur. disturbances in cerebral
perfusion
decrease in cerebral blood
hence results in the typical pattern flow
of injury to the subcortical and anaerobic metabolism
brainstem nuclei.
cellular energy failure
diffuse injury to both cortical
and subcortical structures
Detailed molecular events
1)Decreased cerebral blood flow and energy failure:
Increased NO synthase (decreased ability to auto-regulate blood flow)
BP fluctuation in recovery
Decreased glucose supply& neuronal death
Increased mitochondrial toxins
Increased lactate accumulation
2)excito-toxicity:
Increased glutamate which stimulates(NMDA/AMPA)receptors leading to neuro-degeneration
Glutamate can be seen in CSF
This mechanism can be seen in cases of energy depletion (HIE /hypoglycemia/seizures)
NMDA/AMPA receptor blockers offered marked neuro-protection
Magnesium-sulphate is a receptor blocker and has prevented white matter degeneration in sheep ( also
recently used in PT human babies and shown decreased incidence of CP.
3)Oxidative stress
increased free radicals and accumulation of superoxide
due to lack of oxygen
the most promising antioxidant is melatonin as it can interfer with all cascade
and melatonin trials shown improvement of outcome

4)inflammatory
injury stimulates immune system and increase cytokines and chemokines
aggravation of excitotoxic cascade
involved cytokines are IL6/ TNF-a/ IL1b/ (seen in CSF)
anti inflammatory agents used for neuroprotection are all promising
(steroids /erythropoietin/etanercept/melatonin)

5)cell death
apoptotic(delayed) cell death
necrotic(immediate) cell death is a main cause of severity and major disability
Treatment according to these mechanisms:
1) Cooling
2) Antioxidant and anti-inflammatories
3) NMDA modulator(N methyl D aspartate)
4) Growth factors
5) Stem cells
Diagnostic approach
Markers of acute hypoxia-ischemia
1) Apgar score of <5 at 5 minutes and 10 minutes
2) Umbilical artery pH <7.0,or BE ≥12 or both
3) Consistent acute brain injury on brain MRI or MRS
4) Presence of MOF

Additional factors

1) A sentinel event occurring during labor as ruptured uterus or placental abruption.

2) FHR abnormalities
3) Neuroimaging with pattern of brain injury that is typical of HIE including deep
nuclear gray matter or watershed injury
4) No evidence of other factors contributing to encephalopathy
 highly suspected HIE

1. Prolonged (>1 hour) antenatal acidosis

2. Fetal HR <60 beats per minute
3. Apgar score ≤3 at ≥10 minutes
4. Need for positive pressure ventilation for >1 minute or first
cry delayed >5 minutes
5. Seizures within 12 to 24 hours of birth
6. Burst suppression or suppressed background pattern on
EEG or aEEG
NEUROLOGIC
SIGNS
A.Encephalopathy
Mild encephalopathy : hyper alert or jittery and not responding to stimuli.
Moderate and severe encephalopathy : impaired responses to stimuli such as light,
touch, or even noxious stimuli. Wide range of DCL
The background pattern by EEG or aEEG is useful to determinethe severity.
B. Brainstem and cranial nerves
abnormal or absent brainstem reflexes, including pupillary, corneal, and gag reflexes.
abnormal eye movements ,gaze and ocular bobbing.
facial weakness and weak or absent suck and swallow with poor feeding.
apnea or abnormal respiratory patterns.
C. Motor abnormalities:
Hypotonia.weakness and abnormal posture
primitive reflexes may be diminished In severe HIE,.
hypotonia may evolve later into spasticity
hypertonia within the first days means that insult may have occurred in the
antepartum period.
D. Seizures up to 50% and usually start within 24 hours .
Seizures indicate that the encephalopathy is not mild.
1. Seizures may be subtle, tonic, or clonic (may seem like jittering or
clonus)
2. EEG is the gold standard for diagnosing neonatal seizures( as often
subclinical )
3. Seizures may compromise respiration so adequate support needed to
avoid additional hypoxic injury.
E.Increased ICP and cerebral oedema
Staging the severity
Encephalopathy scoring

This score should be recorded

daily for the first four days after
birth for all affected babies.
Other organs
kidney
ATN/ oliguria/ rise in serum creatinine.
Cardiac
Myocardial ischemia and hypotension
ECG: may show ST depression and T-wave inversion.
Echo: decreased LV contractility /elevated VED pressure/pulmonary hypertension.
fixed HR may indicate severe brainstem injury.
Pulmonary PPHN, hemorrhage , edema and meconium aspiration.
Hematologic
thrombocytopenia
DIC ( poor production of clotting factors by liver and poor production of platelets
by the BM)
Hepatic injury may be manifested by elevation of enzymes.
extensive damage leading to DIC, hypoglycemia, slowed metabolism of
medications.
GIT : NEC
% of organs affected

0 (22%)
CNS only (16%)
CNS +1or more of organs (46%)
MO affected without CNS (16%)
 evaluation
1. Prenatal history complications of pregnancy with risk factors associated
with neonatal depression and any pertinent family history
2. Perinatal history concerns of labor and delivery including fetal heart rate
(FHR) tracing, biophysical profile , sepsis risk factors, cord pH
3.perinatal events such as placental abruption, Apgar scores, resuscitation,
and immediate postnatal blood gases
4. Postnatal data
a. Admission physical exam esp. neurologic exam
b. Clinical course including presence of seizures , oliguria,
cardiorespiratory dysfunction, and treatment given
c. Laboratory testing, including blood gases, electrolytes,
evidence of injury to end organs other than the brain

d. Imaging studies (cranial US /MRI/MRS)

e. EEG and aEEG

f. Placental pathology
 Management
1) Evaluation and staging
2) Investigations
3) Treatment
4) Discharge / palliative care
5) Follow up
6) Outcome prediction
Investigations
1.Cord blood: for umbilical artery pH and base deficit
2.CBC and differential to evaluate for possible infection,
hemorrhage, thrombocytopenia.
3.ABG, glucose, and electrolytes.
4.LFTand RFT are measured to identify injury to other end organs.
5.PT,PTT and D-dimer should be performed if there is bleeding to rule
out DIC
6.testing for IEM including ammonia, lactate and pyruvate, serum amino acids, and
urine organic acids.
7.cultures if sepsis suspected.
8. LP if suspected CNS infection (fever, elevated WBCs, positive blood CS).
9.CK MB for suspected myocardial ischemia
9.EEG to determine seizures and to evaluate the background
electrical activity
EEG is usually obtained on the first day and EEG monitoring is
continued for at least 24 or longer if electrographic seizures are
present.
Normal EEG during first 3 days has good prognosis
10.The amplitude integrated EEG is helpful tool for seizure activity
and provide assessment of cerebral function.
CFM
Normal trace upper margin >10 microvolts and lower margin >5
microvolts
Moderately abnormal trace upper margin >10 microvolts and lower
margin<5 microvolts
Severely abnormal upper margin below 10 microvolts and lower
margin below 5 microvolts
 IMAGING
1.MRI at 4 to 7 days of age. Specific findings on brain MRI can be useful for
determining the pathogenesis and prognosis
Areas of altered signal in thalamus, BG and PLIC indicate poor prognosis
2.Cranial US is not as sensitive as MRI unless suspecting ICH
a)initial increase in echogenicity, indistinct sulci and narrow ventricles
b)After age 2–3 days, increased echogenicity of thalami and parenchymal
echodensity
c)After 1 week, parenchymal cysts, ventriculomegaly and cortical atrophy
may develop
3.CT has poor sensitivity for injury detection PLUS radiation exposure
 Advanced neuroimaging
1.D W I
can show abnormalities within hours of an HI insult that may be useful in
the diagnosis of HIE .
DWI depending on the timing of the study.
a.Early DWI scans will usually show restricted diffusion in brain regions affected by
hypoxia-ischemia.
b.At 7 to 10 days of age:there is pseudo-normalization of diffusion, so DWI can appear
normal despite the presence of HI injury.
c.After 7 to10 days, diffusion is usually increased in regions of injury.
d. Hypothermia appears to delay the time to pseudo-normalization of diffusion. Thus,
DWI data need to be interpreted carefully within the context of the historyand clinical
course of the newborn with HIE.
2. Proton magnetic resonance spectroscopy (MRS)
measures the relative concentrations of various metabolites .
Elevated lactate, decreased N-acetylaspartate (NAA)
and alterations of the ratios of these two metabolites in relation to choline or creatine can indicate HIE
and helpwith determining neurologic prognosis.

3. Susceptibility-weighted imaging may be useful for the detection of hemorrhage, including

hemorrhagewithin areas of ischemic injury.

4. Magnetic resonance (MR) angiography or venography may occasionally be useful if there is

suspicion ofvascular anomalies, thromboembolic disease, or sinus venous thrombosis, which can
occasionally be found inassociation with HIE.
Patterns of injury
1)Acute profound injury : BG thalamus
2)Partial asphyxia: white matter (watershed injury from white to
grey matter)
3)Complete: BG white matter and worst neuro outcome than
any other areas
4)Focal and multifocal injury:assoc with strokes
5)23%of HIE have white matter immaturity
6) Dec GA inc incidence of white matter injury
7)Wallerian degeneration(corticospinal tct)follow MCA stroke
treatment
A)supportive management
Maintenance of adequate ventilation and oxygenation
Maintenance of sufficient perfusion (avoidance of hypotension or hypertension)
Maintenance of normal metabolic status (glucose, nutrition, pH)
Control of seizures
Control of brain edema
(avoid fluid overload) due to ATN and SIADH
(decreasing ICP has no effect)
Isotonic glucose-containing IV fluids at 40 mL/kg/day

B)Therapeutic hypothermia is the treatment of choice for neonates meeting

criteria for presumed HIE
Therapeutic hypothermia — Therapeutic hypothermia, maintained for 72 hours at 33 to 35°C (91.4
to 95.0°F) and started within the first 6 hours after delivery, is the only proven neuroprotective
therapy for treatment of HIE.
 WHEN TO CONSIDER TREATMENT
WITH TOTAL BODY COOLING
Treatment criteria
Babies meeting criteria A and B for treatment with cooling
Criterion A ≥1 of:
1.Apgar score ≤5 at 10 min after birth
2.Continued need for resuscitation, including ETT or mask ventilation at 10 min after birth
3.Acidosis within 60 min of birth (defined as umbilical cord, arterial or capillary pH <7.0)
4.Base deficit ≥16 mmol/L in umbilical cord or any blood sample within 60 min of birth
Criterion B
Seizures OR moderate-to-severe encephalopathy, consisting of:
1.altered state of consciousness (reduced or absent response to stimulation) and
2.abnormal tone (focal or general hypotonia, or flaccid) and
3.abnormal primitive reflexes (weak or absent suck or Moro response)
 Maintaining cooling
Cooling should be maintained using appropriate selective head cooling or whole body cooling equipment.

The target rectal temperature when using selective head cooling is 34.5 °C, maintained for 72 hours,
followed by slow rewarming (over 12 hours) to 37.2 °C .
During whole body cooling the target rectal temperature is 33-34° C, for 72 hours, followed by slow
rewarming (over 12 hours) to 37.2 °C (normothermia).
The investigations and monitoring listed in the TOBY Register data form should be carried out on each
infant treated with cooling. It is essential that continuous rectal temperature monitoring should be
performed, with hourly recordings documented.
 Rewarming procedures
Cooling is concluded after 72 hours (The rectal temperature should be allowed to rise by no more than
0.2-0.3°C per hour, to 37+/- 0.2°C).

Re-warming can be carried out by adjusting the thermostat set point of the cooling equipment or the
incubator in increments of 0.2-0.3°C hourly.

The infant’s temperature must be carefully monitored for 24 hours after normothermia has been achieved
to prevent rebound hyperthermia.
 Adverse effects

Therapeutic hypothermia is generally well-tolerated, but short-term

adverse effects in the randomized trials included:
1.sinus bradycardia
2.thrombocytopenia
3.Subcutaneous fat necrosis
4.hypercalcemia.
 DISCHARGE AND FOLLOW-UP
1.Arrange clinic follow-up in 4–6 weeks for babies discharged

2.Repeat cranial ultrasound scan before discharge

3.Arrange hearing screen

4.For babies with moderate and severe encephalopathy and in those with
seizures due to encephalopathy, arrange MRI scan as an outpatient (if not
already performed as an inpatient), preferably7–14 days of life
outcome
ACOG&AAP criteria to develop CP
a) essential
1) metabolic acidosis (PH less than 7)
2) early onset signs in infant 34 week or more
3) quadriplegic or dyskinetic type
4) exclusion of other causes like trauma or infection

b) pointers only
1)hypoxic event
2)fetal BC
3)APGAR 0-3 at 5 min
4)MOF at 72 hours
5)acute non focal abnormalities on neuroimaging
Progress of injury
a)motor : commonest is qplegic CP then dyskinetic and others are unlikely
:occur in more than 1/3 of survivors and increase with severity
: more than 1/3 of moderate HIE and1/4 of mild HIE will have minor motor
deficit not defined as CP

b)visual & hearing: 1/4 of cases will have visual impairment up to blindness after mod or
severe NE and risk increase with associated hypoglycemia
: it occurs due to injury to visual cortex leading to cortical blindness
: also due to BG or thalamus injury in form of decreased visual
acuity or visual field defects
:SNHL 2ry to BS injury
: more with severe cases and ~ 18 % of moderate cases
c) Cognitive : 30 to 50 % of moderate to severe NE are affected
:not linked to CP
:deficit can occur with N IQ
:more common with watershed injury
:behavioral and emotional problems also seen
schhol age children may have reading spelling arithmetic
problems
:lange difficulties
:ASD should be considered in follow up

d)epilepsy : ½ of survivors of moderate /severe HIE will have epilepsy

:more common if child have CP
Outcome prediction
1)VEP
2)SSEP(somatosensory evoked pot)
Absence of cortical response is associated with inc adverse effects
3)EEG
4)Amplitude integrated EEG

5)MRI according ( pattern of injury)

(BG and PLIC and watershed linked to severe motor and cognitive deficit)
N imaging don’t exclude future ND delay
 OUTCOME
SEVERITY DEATH NEURO SEQUELAE NORMAL

MILD 0 0 100 %

MOD 5% 25% 70%

SEVERE 80% 20% 0%

ALL CASES 13% 14% 73%

Differences between FT PT
AREA PRETERM FULLTERM

CORTEX _ +

CB _ +

THALAMUS + +

DEEP NUCLEI + +

BS + +

HIPPOCAMPUS + +
Outcome variability after intro of cooling
Outcome in order of severity Without cooling Standard cooling

1)death 30 % 29 %

2)Major disability 60 % 41 %

3)CP 36% 21%

4) Decreased GMFCS (2 to 5) 41% 22%

5)Visual deficit 1% 1%

6) SNHL 10% 4%

7)epilepsy 16% 10%

8) Survival with no disability 28% 45%