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JEANIE CHEONG NEONATOLOGIST ROYAL WOMEN’S HOSPITAL, MELBOURNE, AUSTRALIA Neonatal mortality and...

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JEANIE CHEONG NEONATOLOGIST ROYAL WOMEN’S HOSPITAL, MELBOURNE, AUSTRALIA Neonatal mortality and encephalopathy
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JEANIE CHEONG

NEONATOLOGISTROYAL WOMEN’S HOSPITAL,

MELBOURNE, AUSTRALIA

Neonatal mortality and encephalopathy

Perinatal mortality related to HIE

Worldwide (Lawn 2010) 5th most common cause of death in children under 5

years 23% per annum since 2000 (≈814,000 deaths in 2008)

New Zealand 2007-2010 14.8% of neonatal deaths attributed to HIE

Neonatal encephalopathy (NE)

Neonatal neurological syndrome Depressed conscious level Abnormal tone and power Feeding difficulties Seizures

Incidence: 1-6 per 1000 live births

Aetiology: Hypoxia-ischaemia (HIE) in 30-50%

Outcome: Death (15%) Severe neurological deficit (25%)

(Badawi 98, Cowan 03, Ferriero 04, Volpe 08)

Clinical evaluation

Biochemistry

Electrophysiology

Neuroimaging

Diagnostic & Prognostic tools in HIE

Clinical evaluation

Evidence of fetal distress Cord or early neonatal acidaemia Deterioration of fetal heart rate pattern

Sentinel intrapartum event E.g. Uterine rupture, cord prolapse, placental abruption

Depression at birth

Overt early neonatal neurological syndrome Depressed conscious level Abnormal tone and power Feeding difficulties Seizures

Diagnosis: History suggestive of intrapartum insult

(MacLennan 99, Volpe 08)

Duration of fetal acidaemia >1 hour

Major resuscitation 6.4 fold in abnormal neurological outcome Positive pressure ventilation, intubation and CPR in

infants with severe fetal acidaemia

Delayed onset breathing

Prognosis: Resuscitation

(Low 84, Ambalavanan 06, Salhab 04)

Time to onset of breathing

Death or severe neurological deficit

9 minutes 42%

20 minutes 88%

Severity of acute encephalopathy syndrome Sensitive for mild or severe encephalopathy Not so for moderate encephalopathy

Seizures 40 fold in adverse sequelae Prognosis worse if early onset and difficult to control ? Greater injury to the brain

seizure burden associated with Lac/Cho & NAA/Cho independent of structural changes on MRI

Duration of neurological abnormalities Low risk if normalisation by 1-2 weeks

Prognosis: Neurologic evaluation

(Finer 83, Levene 86, Robertson 93, Dubowitz 98, Miller 02 & 04, Caravale 03)

“Traditional signs of recovery” Apgar scores

Signs of recovery e.g.Early establishment of suck feedsVisual responsivenessHead growth

have low sensitivity/specificity for predicting neurodisability

Prognosis: Other clinical aspects

(Nelson 81, Mercuri 97, 99 & 00, Stark 06)

Biochemistry

Most biochemical markers have low sensitivity & specificity for diagnosis of HIE

Reflect severity of neurological syndrome

E.g. Glucose, serum lactate, calcium, sodium, pH

Excitatory amino acids & creatine kinase-BB in CSF, inflammatory markers, brain specific proteins (research only)

Diagnosis

(de Praeter 91, Volpe 08)

Increased risk of death or severe disability Hypoglycaemia

If glucose <2.2mmol/L in the first 30 minutes

OR ↑ by 18-fold for death or disability peripheral neutrophil counts in first 96

hrs High % nucleated RBC/WBC High lactate in cord blood

Prognosis

(Salhab 04, Morkos 07, Haiju 08)

Electrophysiology

Patterns reflect pathological varieties of HIE Diffuse cortical & thalamic necrosis

discontinuity, burst suppression, voltage suppression, isoelectric EEG

Periventricular leukomalaciaexcessive sharp waves positive vertex or rolandic

Prognosis Severity & duration of abnormalities Normalisation within 1 week associated with

favourable outcome

Conventional EEG

(Wertheim 94, Biagioni 01, Okumura 02, Caravale 03, Murray 06)

aEEG background pattern: Reflect severity of HI insult Prognostic in the first 6 hours Normalisation within 24 hours in 10-50% of

abnormal aEEG Rapid recovery - good outcome PPV if combined with clinical evaluation or MRI Quantitative aEEG-based index (Cerebral health

index/b)Research tool

Amplitude integrated EEG (aEEG)

(Eken 95, Hellstrom-Westas 95, Toet 99, van Rooij 05, de Vries 05, Shalak 03, Leijser 07, Hathi 09)

aEEG in severe HIE

Seizures Burst suppression

Visual evoked potentials (VEP) & somatosensory evoked potentials (SSEP) Predictive if done within 6 hours

Near infrared spectroscopy (NIRS) Direct measure of cerebral blood flow Predictive if done in the first few days Research tool only

Evoked potentials & NIRS

(de Vries 91, Taylor 92, Eken 95, Meek 99)

Neuroimaging

Abnormalities in HIE Normal (in 50%) Non-specific cerebral oedema “Slit-like” ventricles not prognostic (60% controls) Acute cortical lesions poorly demonstrated

Basal ganglia & thalamic echogenicity

Haemorrhagic necrosis High PPV of poor outcome if persistent

Cranial ultrasound

(Babcock 83, Siegel 84, Eken 94, Rutherford 94)

Pourcelot resistive index (RI) Anterior cerebral artery RI<0.55

Reflects high cerebral blood flow velocityIndicative of severityAssociated with poor outcome

Predictive within 24-48 hours

Cranial ultrasound: Doppler

(Levene 89, Ilves 04)

Doppler: Low RI

Systolic

Diastolic

Patterns of injury in HIE Diffuse cortical neuronal injury: “reversal

sign” Basal ganglia & thalamic injury: ↓

attenuation Not sensitive in mild/moderate HI injury

Computed tomography (CT)

“Reversal” sign “Isoattenuation” of deep nuclear grey matter

Most accurate diagnostic imaging modality

Timing of injury “peripartum” 245 infants with acute NE & intrapartum

HI MRI findings:

80% acute HI lesions4% antenatal lesions4% another disorder16% normal

MR imaging and spectroscopy

(Rutherford 04, Cowan 03)

MRI pattern of injury

Nature of insult Estimated incidence

Outcome

Basal ganglia & thalamus

Severe “prolonged” insult

40-80% Severe cognitive and motor deficits

Watershed white matter & cortex

Prolonged “partial” asphyxia

40-60% Cognitive deficits > motor

Basal ganglia, thalamus, brainstem

Severe abrupt “total” asphyxia

10-20% Mortality 35%Long term feeding problems

Cerebral white matter

Hypoglycaemia, chronic haemodynamic instability

15% Mild cognitive deficits

MRI patterns, nature of insult & outcome

(Rutherford 98, Barkovich 98, Cowan 00, Barnett 02, Martinez-Biarge 11, Volpe 12)

MRI: Severe HIE pattern of injury

Day 4 T2-weighted MRI

MRI: Watershed white matter injury

Day 3 Diffusion weighted MRI (DW-MRI)

Direct measure of brain metabolitesMetabolite profiles not specific to HIEReflect severity of insultPredictive of poor outcome

Lac/Cr, Lac/NAA, Lac/Cho NAA/Cr myo-inositol/Cr

Proton MRS

(Hanrahan 99, Cheong 06, Maneru 01, Miller 02, Robertson 01, Soul 01, Zarifi 02, Barkovich 06)

Conventional T1-W/T2-W imaging Normal on Day 1, abnormal by 3-4 days

Diffusion imaging Abnormalities apparent early “Pseudo-normalise”

Proton MRS Abnormalities appear early lactate (tissue necrosis & cell death) NAA (neuronal & oligodendroglial

injury)

Importance of TIMING in interpretation

32 studies (n=860) Sensitivity (95% CI)

Specificity (95% CI)

Conventional MRI(Day 1-30)

0.91 (0.87-0.94) 0.51 (0.45-0.58)

1H MRS in deep nuclear grey matter (Day 1-30) Lac/NAA **

0.82 (0.74-0.89) 0.95 (0.88-0.99)

Prognostic value of MR biomarkers in HIE

(Thayyil 10)

Late MRI (days 8-30) high sensitivity, low specificity compared with early MRI (days 1-7)

Posterior limb of the internal capsule (PLIC) sign & brain water ADC poor discriminatory powers

Study Day of MRIMedian (IQR)

MRI differences in hypothermia group

Prognostic utility

Rutherford 10(TOBY)

64 cooled67 normothermia

8 (5-11) • basal ganglia, thalamus, white matter, PLIC abnormalities

Predictive accuracy 0.84 (cooled) vs 0.81 (normothermia)

Cheong in press(ICE)

66 cooled61 normothermia

6 (3-7) • white matter & cortical gray matter abnormalities on T1/T2

• No difference in DWI

PPV 88% for T1/T2 & DWI

No effect on prognostic utility with hypothermia

Hypothermia & MRI

MRI/DWI/MRS in HIE

Severe HIE

Moderate HIE

Neonatal encephalopathy (esp HIE) is an important cause of perinatal mortality

Many modalities available in diagnosis & prognosis of HIE

MRI & MRS have greatly improved & refined our ability to prognosticate

However....

Conclusion

“No neurodiagnostic technique is capable of diminishing the

importance of the clinical evaluation of the infant in assessment of

outcome in HIE.

Clinical and specialised diagnostic approaches are of value only when

used in concert”(Volpe 08)


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