Brain Injury in Pre-Term Infants

Roy Maynard, M.D.

March 24, 2011

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Objectives for Brain Injury in Pre-Term Infants

• Identify types of brain injury in pre-term infants.

• Appreciate the incidence of Grade 1-IV intraventricular hemorrhages in very low birth weight infants.

• Understand the neurodevelopmental implications of Periventricular Leukomalacia in very low birth weight infants.

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Types of Brain Injury

• Periventricular Leukomalacia (PVL)

• Severe Intraventricular/Periventricular Hemorrhage (IVH/PVH)

• Posthemorrhagic Hydrocephalus

• Other patterns of neuronal injury

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IVH/PVH of the Pre-Term Infant

• Epidemiology

• Pathogenesis

– germinal matrix anatomy

– factors: • intravascular • vascular • extravascular

– spread of IVH

• Diagnosis and Management

• Neurodevelopmental Outcomes

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What is the magnitude of brain injury in pre-term infants?

Pre-Term Infants (BW<1500g)

No. born in U.S. ………………………..55,000/yr.

Survival…………………………………..90%

Incidence of:

IVH (Grade 3&4) ………………………3-21%

PVL ……………………………………. 2-5%

Morbidity in survivors:

Spastic/motor deficits…………………10%

Cognitive/behavioral…………………..25-50%

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21

16

11

9

6

43 3

9 8

0

5

10

15

20

25

501-750 751-1000 1001-1250 1251-1500 501-1500

Incidence: Grade 3 & 4 IVH

Children’s Minneapolis

% O

ccu

rre

nce

Vermont Oxford Network

Birth Weight (501-1500 grams)

No. Patients

1994-2002

38,576 46,183 50,253 59,403 194,415 465 483 516 617 2,081

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Incidence: PVL %

Occu

rre

nce

Birth Weight (501-1500 grams)

5

3

5

1

33

2 2

4

2

0

1

2

3

4

5

6

7

8

9

10

501-750 751-1000 1001-1250 1251-1500 501-1500

1994-2002

Vermont Oxford Network Children’s Minneapolis

No. Patients 38,576 465 46,183 483 50,253 516 59,403 617 194,415 2,081

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IVH/PVH of the Pre-Term Infant

• Epidemiology

• Pathogenesis

– germinal matrix anatomy

– factors: • intravascular • vascular • extravascular

– spread of IVH

• Diagnosis and Management

• Neurodevelopmental Outcomes

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Germinal Matrix (Primary site of IVH/PVH)

GM

3rd

4th

Monro

Magendie

CP

Luschka

Arachnoid Villi

Occipital

Horn

Germinal Matrix

Choroid Plexus

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Germinal Matrix

• Primitive cellular region ventrolateral to LV

– prominent: 26-32 weeks

– involuted: term

• Contains pluripotential migrating cells – neurons, astrocytes, oligodendroglia

• Contains immature blood vessels: – thin walls (lack muscularis layer)

– immature cell junctions & basal laminae

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IVH/PVH of the Pre-Term Infant

• Epidemiology

• Pathogenesis – germinal matrix anatomy

– factors: • intravascular • vascular • extravascular

– spread of IVH

• Diagnosis and Management

• Neurodevelopmental Outcomes

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Pathogenesis of IVH/PVH

Factors

• Intravascular

– regulation of CBF, BP, Blood volume

– platelet-capillary function

– blood-clotting function

• Vascular

• Extravascular

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Intravascular Factors

• Pressure-passive cerebral circulation factors: ↑ blood pressure will increase cerebral blood flow

• Increase in central venous pressure will increase cerebral venous pressure

• Increase pressure within the brain’s blood vessels may lead to rupture of fragile blood vessel(s) and bleeding

– Tracheal suctioning

– Pneumothorax

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Vascular Factors

Intrinsic properties of GM vessels

• Immature vascular structures – Larger and lack muscle/collagen

– Incomplete basal laminae

– More susceptible to rupture

• More susceptible to hypoxic/ischemic insult – Vascular border zone in GM

– Endothelium contain ↑ mitochondria

– ↑ need for oxidative metabolism

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Spread of IVH/PVH

• 40% stays in GM (Grade 1 IVH)

• 60% enters ventricles (Grade 2 & 3 IVH)

– Large IVH → obstructs CSF flow • Aqueduct of Sylvius, Luschka, Magendie

• Rapidly progressive hydrocephalus

– Small IVH → retards CSF absorption • Obliterative arachnoiditis of basilar cisterns

• Slow evolving hydrocephalus

• PV Hemorrhagic Infarction (Grade 4 IVH)

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IVH/PVH of the Pre-Term Infant

• Epidemiology

• Pathogenesis

– germinal matrix anatomy

– factors: • intravascular • vascular • extravascular

– spread of IVH

• Diagnosis and Management

• Neurodevelopmental Outcomes

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Diagnosis and Management

Grading IVH/PVH (Papile)

• Grade 1: GM hemorrhage only

• Grade 2: GM hemorrhage extending into LV without ventriculomegaly

• Grade 3: IVH with ventriculomegaly

• Grade 4: Intraparenchymal hemorrhage vs. Periventricular hemorrhagic infarction

J Pediatr 1978; 92: 529-34

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GM

Occipital

Horn Monro

Magendie

CP

Luschka

Arachnoid Villi

Normal Anatomy

3rd

4th

Germinal Matrix

Choroid Plexus

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GM Occipital

Horn Monro

Magendie

CP

Luschka

Arachnoid Villi

Grade 1 IVH (Blood in GM only)

3rd

4th Germinal Matrix

Choroid

Plexus

Blood

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GM

Monro

Magendie

CP

Luschka

Arachnoid Villi

Grade 2 IVH (Blood in LV without ventriculomegaly)

Occipital

Horn

3rd

4th Germinal Matrix

Choroid

Plexus

Blood

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Magendie

Lateral Ventricle

CP

Luschka

OBLITERATIVE

ARACHNOIDITIS

Slowly

Evolving

Hydrocephalus

Occipital

Horn

GM

Monro

Ventriculomegaly

Blood on

Arachnoid

Villi

3rd

4th

Grade 3 IVH (Blood in LV with ventriculomegaly)

Germinal Matrix

Choroid

Plexus

Blood

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Magendie

Lateral Ventricle

CP

Luschka

Occipital

Horn

GM

Monro Obstruction

at Foramen

of Monro

Arachnoid Villi Ventriculomegaly

3rd

4th

Grade 3 IVH (Blood in LV with ventriculomegaly)

Germinal Matrix

Choroid

Plexus

Blood

Rapidly

Progressive

Hydrocephalus

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GM Occipital

Horn Monro

Magendie

CP

Luschka

Arachnoid Villi

v

PVHI

3rd

4th

Grade 4 IVH (Periventricular Hemorrhagic Infarction)

Germinal Matrix

Choroid

Plexus

Blood

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PV Hemorrhagic Infarction

Pathogenesis

Germinal Matrix/IVH ↓

PV Venous Congestion ↓

PV Ischemia ↓

PV Hemorrhagic Infarction

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Begins as Grade 1-2 IVH

IVH

in right

lateral

ventricle

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Coronal Section

May Evolve to Grade 3 IVH

Massive IVH on right

• obstruction at

foramen of Monro

• unilateral

ventricular

dilatation

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IVH IVH

Periventricular Hemorrhagic Infarction

Early

Evolving

PVHI

Coronal Section

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Diagnosis and Management

Timing of IVH/PVH

• 90% occur within first 72H

– 50%: <24H

– 25%: >24H & <48H

– 15%: >48H & <72H

• 20-40% progress further

– Maximal extension occurs 3-5 days after

initial insult

Volpe: Neurology of the Newborn: 1995 Saunders

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Conclusions

• Most intracranial pathology in sick pre-term infants is clinically silent.

• Severe lesions most often occur in tiniest of pre-term neonates.

• Shift toward a delayed presentation of the clinically significant lesions.

Arch Pediatr Adolesc Med 2000; 154: 822-826

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Cranial Imaging of IVH/PVH

Ultrasonography

• Preferred diagnostic technique

equivalent resolution

portable, practical

CT Scan

MRI Scan

PET Scan

• Subdural hemorrhage

• Posterior fossa lesions

• Complicated cerebral lesions

Diagnosis and Management

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Coronal View

Normal Cranial Ultrasound

Lateral

Ventricle 3rd

Ventricle

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Coronal View

Lateral

Ventricle

Coronal View

Normal Cranial Ultrasound

3rd

Ventricle

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Coronal View

Normal Cranial Ultrasound

Choroid

Plexus

Lateral

Ventricle

3rd

Ventricle

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GM

Monro

Magendie

CP

Luschka

Arachnoid Villi

Grade 1 Intraventricular Hemorrhage

(Blood in GM only)

3rd

4th

Occipital

Horn

Germinal Matrix

Choroid

Plexus

Blood

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parasagittal view

Grade 1 IVH

SEH

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SEH

Acute Subependymal Hemorrhage

Bilateral Grade 1 IVH

Coronal View

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Acute Subependymal Hemorrhage

Left Parasagittal View

SEH CP

Grade 1 IVH

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GM

Monro

Magendie

CP

Luschka

Arachnoid Villi

Grade 2 IVH (Blood in LV without ventriculomegaly)

Occipital

Horn

3rd

4th Germinal Matrix

Choroid

Plexus

Blood

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Grade 2 IVH

Parasagittal View

Echogenic

blood fills

< 50% of

ventricle

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Grade 2 IVH

Posterior Coronal View

Clot in posterior

right horn

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Grade II IVH

parasagittalparasagittal view view

Clot in

Posterior

Horn on R

SEHSEH

Parasagittal View

Grade 2 IVH

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Magendie

Lateral Ventricle

CP

Luschka

Occipital

Horn

GM

Monro Obstruction

at Foramen

of Monro

Arachnoid Villi Ventriculomegaly

3rd

4th

Grade 3 IVH (Blood in LV with ventriculomegaly)

Germinal Matrix

Choroid

Plexus

Blood

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Grade 3 IVH

Large blood clot filling

and distending LV

Parasagittal View

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Magendie

Lateral Ventricle

CP

Luschka

OBLITERATIVE

ARACHNOIDITIS

Slowly

Evolving

Hydrocephalus

Occipital

Horn

GM

Monro

Ventriculomegaly

Blood on

Arachnoid

Villi

3rd

4th

Grade 3 IVH (Blood in LV with ventriculomegaly)

Germinal Matrix

Choroid

Plexus

Blood

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Posthemorrhagic Hydrocephalus

LV LV

Coronal View

Extraventricular Obstruction of CSF

From Obliterative Arachnoiditis

LV LV

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Grade III IVH

Coronal viewCoronal view

Dilated,Dilated,

blood-filledblood-filled

frontal hornsfrontal horns

Grade 3 IVH

Coronal View

Dilated,

blood-filled

frontal horn

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Grade 3 IVH

Hemorrhage in

Lateral Ventricle

Dilated lateral ventricle

Parasagittal View

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body

occipital

temporal

Hemorrhage

filling lateral

ventricle

Evolution of Grade 3 IVH

Parasagittal View

Initial scan

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Evolution of Grade 3 IVH

Retraction

of IVH clot

Ventricular

Dilatation

coronal view

F/U scan weeks later

Coronal View

F/U scan weeks later

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Evolution of Grade 3 IVH

F/U scan weeks later

Coronal View

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GM Occipital

Horn Monro

Magendie

CP

Luschka

Arachnoid Villi

v

PVHI

3rd

4th

Grade 4 IVH (Periventricular Hemorrhagic Infarction)

Germinal Matrix

Choroid

Plexus

Blood

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Bulging

SEH

Evolution of Periventricular

Hemorrhagic Infarction

coronal viewcoronal view

Day 7 (scan #1)Day 7 (scan #1)

Coronal View

Day 7 (scan #1)

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Increasing size

of crescentic

PVED PVHI

BulgingBulging

SEHSEH

Evolution of Periventricular

Hemorrhagic Infarction

coronal viewcoronal view

Day 7 (scan #2)Day 7 (scan #2)

Coronal View

Day 7 (scan #2)

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coronal viewcoronal view

Increasing size

of crescentic

PVED PVHI

Day 7 (scan #3)Day 7 (scan #3)

Evolution of Periventricular

Hemorrhagic Infarction

Coronal View

Day 7 (scan #3)

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Evolution of Periventricular

Hemorrhagic Infarction

coronal viewcoronal view

Large

Porencephalic

Cyst

2 months later2 months later

Coronal View

2 Months Later

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Periventricular Hemorrhagic Infarction

Parasagittal View

(9 days)

IVH

PED

Ventricular

dilatation

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Periventricular Hemorrhagic Infarction

Parasagittal View

(3 weeks of age) Cyst Formation

• tissue necrosis

• clot retraction

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Periventricular Hemorrhagic Infarction

Parasagittal View

(2 months of age)

Porencephalic

cyst

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Periventricular Leukomalacia

Periventricular Leukomalacia (PVL)

PVL has emerged as the prinicipal form of brain injury in the

premature infant

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1. Death of white matter (WM) in the

brain’s Periventricular (PV) region

2. Caused by decrease in O2 or blood

flow to PV WM area of brain

Periventricular white matter contains nerve fibers that carry messages from the brain to the body’s muscles

What is PVL?

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3. Most common Ischemic injury in

pre-term infants

4. Occurs in Border Vascular Zone

• end of arterial distributions

5. Diagnostic hallmarks include:

• Initial: PV echodensities

• Later: PV cystic changes

What is PVL?

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Surviving pre-term infants with PVL are at risk for the following:

• Cerebral Palsy (CP),

• intellectual impairment

• visual/hearing disturbances

Importance of Diagnosis?

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1. Periventricular vascular anatomic physiologic factors

2. Cerebral Ischemia and pressure-passive cerebral circulation

3. Maturation-dependent vulnerability of cerebral white matter Oligodendroglial precursors

Periventricular Leukomalacia

Pathogenesis (3 interacting factors)

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•

Basal Penetrator Vessels

Periventricular Vascular Anatomic Physiologic Factors

Short Penetrator Vessels

Periventricular Leukomalacia

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Clinical Correlates of PVL

Spastic

diplegia

Cognitive/Behavioral

Deficits

Cranial

Ultrasound

• Focal

Necrosis

• Diffuse

Pre-Oligo Injury

Clinical Correlates Diagnostic Methods

MRI/DWI

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1. Periventricular vascular anatomic physiologic factors

2. Cerebral Ischemia and pressure-passive cerebral circulation

3. Maturation-dependent vulnerability of cerebral white matter Oligodendroglial precursors

Periventricular Leukomalacia

Pathogenesis (3 interacting factors)

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CBF Autoregulation with Maturation 180 160 140 120 100 80 60 40 20 0

0 10 20 30 40 50 60 70 80

Premature

Newborn

Child

MABP (mmHg)

CB

F (

% o

f n

orm

al)

Normal Regulatory

Control Window

Narrow Regulatory

Control Window

Periventricular Leukomalacia

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1-week-old pre-term infant without

PVL. The periventricular echo-

texture is normal.

1-week-old pre-term infant. Peri-

ventricular echotexture is increased,

consistent with early changes of PVL.

PVL: Diagnosis & Management

Coronal View Coronal View

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PVL: Diagnosis & Management

Coronal View Parasagittal View

3-week-old pre-term infant. Multiple periventricular cysts

typical of established periventricular leukomalacia.

PVL Cysts

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Postnatal Treatment

Diagnosis and Management

• Postnatal resuscitation (NICU)

• Maximize risk for fluctuation CBF & BP – avoid unnecessary BP, suctioning, rapid

infusions, pneumothorax

– avoid ventilator asynchrony

• Correct coagulation disturbances

• Indomethacin

• Antioxidants (SOD)

• Management of post-hemorrhagic hydrocephalus

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IVH/PVH of the Pre-Term Infant

• Epidemiology

• Pathogenesis

– germinal matrix anatomy

– factors: • intravascular

• vascular

• extravascular

– spread of IVH

• Diagnosis and Management

• Neurodevelopmental Outcomes

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Neurodevelopmental Outcome

Classification

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70

17

12

64

18 18

39

31 31

21

13

66

11 11

79

0

10

20

30

40

50

60

70

80

Normal U/S Grade 1&2 IVH Grade 3 IVH Grade 4 IVH PVL

Neurodevelopmental Outcome 23-26 weeks GA (552 infants: 1986-1998) -- Mean Age: 48.6 months

% O

ccurr

ence

Normal Mild-Mod. Impaired Severely Impaired

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Q&A

Thank you for attending!