Aims

• Pathophysiology of post haemorrhagic

ventricular dilatation

• Diagnosis

• Prognosis following PHVD

• Treatment. New evidence 2017

Gene polymorphisms associated with IVH

Coagulation: Methyltetrahydrofolate reductase MTHFR

Factor V Leiden (hypercoaguable)

Prothrombin F2

Inflammation: Il-1beta

IL-6

TNF

Vascular integrity: Collagen 4A1

Endothelial NO synthase

Superoxide dismutase

Ment L. Pediatric Research 2014

Archives of Disease in Childhood, 1981, 56, 416-24

Cerebral structure and intraventricular haemorrhage in the neonate: a real-time ultrasound study MALCOLM I LEVENE, JONATHAN WIGGLESWORTH, VICTOR DUBOWITZ Department of Paediatrics and Neonatal Medicine, Institute of Child Health, Hammersmith Hospital, London

43% of infants with birthweight <1500g

had IVH.

Measurements to diagnose PHVD •AHW, anterior horn width

•FHR, frontal horn ratio

•p97, 97th percentile according to Levene

•OD, thalamo-occipital distance

•VI, ventricular index.

Brouwer AJ, et al. European perspective on the diagnosis and treatment of PHVD.

Arch Dis Child Fetal Neonatal Ed. 2012;97:F50-5.

Ventricular width used in diagnosis of PHVD Criterion for intervention in posthaemorrhagic ventricular dilatation

Davies et al. Arch Dis Child 2000

AHW 97% 3 mm

3rd ventricle 97% 3 mm

Thal–occ 97% 24 mm

Horsch S Ultrasound in Med Biol 2008

Frontal horn

short x long axis

v MRI vent volume

r = 0.97

Olischar M, Acta Paed 2009

Worsening of aEEG with worsening PHVD

Nishimaki S,J Ultrasound Med 2004

Doppler Resistance Index > 0.85.

Ventriculomegaly trial ADC 1994

PHVD

48% <70 on Griffiths

90% neuromotor impairment

76% marked disability

56% multiple impairments

9% visual impairment

6% hearing impairment

IVH3 IVH3+shunt IVH4 IVH 4+shunt

MDI median

73 61 72 50

PDI median

82 51 75 49

Cerebral palsy

23% 57% 37% 85%

Visual Impaired

17% 24% 21% 33%

Prognosis of severe IVH + /- shunt

Bayley scales at 18-22 m in extremely low birth wt

infants

Adams-Chapman et al Pediatrics 2008

PHVD at 2 years

Jary S, et al. Impaired brain growth and neurodevelopment in preterm infants

with PHVD. Acta Paediatr. 2012;101:743-8

Parenchymal hemorrhagic infarction <3 days

Global cerebral injury over many weeks

from : Pressure

Distortion

Inflammation

Free radical injury

. Intracranial pressure 15 mm Hg

Loss of diastolic velocities

Anterior cerebral artery

Raised intracranial pressure in PHVD

Kaiser & Whitelaw Archives Dis Ch 1985

Inflammation * Inflammatory cytokines in CSF

Savman K. Acta Paediatrica 2002

Free radical damage * Free iron in CSF of PHVD

Savman K. Pediatr Research 2001

Repair tissue wrapped around

The brain stem

Laminin stained in PHVD

Repair gone wrong.

Transforming Growth Factor beta

upregulates extra cellular matrix proteins

and is stored in Platelets.

Whitelaw A et al. Pediatric Research 1999 46: 576-80.

Cherian S, Whitelaw A,

Thoresen M et al

Brain Pathology 2004;14:

305-11.

7 day old rat

Intraventricular injection

of blood is followed by

Ventricular dilatation

2 weeks later in 77%

Posthaemorrhagic hydrocephalus rat model

Immunostaining for TGF beta 1 (brown)

Control no blood IVH + dilatation

Cherian S. Brain Pathology 2004;14: 305-11.

Repeated early lumbar punctures/ventricular taps

Diuretic drugs to reduce CSF production

Intraventricular fibrinolytic therapy

External ventricular drain

Ventricular reservoir and repeated taps

Third ventriculostomy

Choroid plexus coagulation

Ventriculoperitoneal shunt after CSF clears and protein <1.5g/l

NONE ARE EFFECTIVE AND SAFE

Daily head circumference Twice weekly (minimum) cranial ultrasound Tap CSF by LP if head growth is excessive (2

mm/day)or if suspected pressure. Insert reservoir if repeat LPs needed or

impossible. Repeat taps to control excess head growth and

pressure. When 2500g reached and CSF protein <1.5g/L

stop tapping and observe head growth If ventricular/head expansion continues,

shunt.

The object is to remove cytokines, free iron and the blood which is the source of the cytokine reaction.

Early reduction in pressure and ventricular

distention

•Intraventricular catheters

•Intraventricular tPA 0.5 mg/kg

• Wait 8 hours then Irrigation with artificial CSF

•Drainage adjusted to keep ICP < 7 mm hg

•Irrigation until fluid clears (72 hrs)

•Remove catheters.

DRIFT

Scott ventricular catheter FG8 (Codman)

PHVD before DRIFT

Extensive intraventricular blood and debris

and hemispheric oedema on the

damaged side

Post DRIFT

Debris cleared and

Less oedema

Before DRIFT After 48 hours DRIFT

DRIFT decompresses the ventricles early

Inclusion Criteria: IVH and age <29 days

1. Both ventricular widths 4 mm > 97th centile.

OR

2. Frontal diagonal > 1mm over 97th %

Third ventricular width > 1 mm over 97th %

Thalamo-occipital dimension > 1 mm over 97th %.

OR

3. One ventricle 4 mm > 97th % with obvious midline shift.

DRIFT Randomised trial

Aim to reduce in the short term death or shunt surgery

and in the long term death or severe disability

Daily head circumference Twice weekly (minimum) cranial ultrasound Tap CSF by LP if head growth is excessive (2

mm/day)or if suspected pressure. Insert reservoir if repeat LPs needed or

impossible. Repeat taps to control excess head growth and

pressure. When 2500g reached and CSF protein <1.5g/L

stop tapping and observe head growth If ventricular/head expansion continues,

shunt.

RESULTS at 2 years post term

Treatment DRIFT Standard Odds Ratio

N 39 38

Dead 3 5

Severely disabled 18 22

Dead /disabled 21 (54%) 27 (71%) 0.48 (0.19, 1.22)

Adjusted 0.25 (0.08, 0.82)

Severe cognitive disability in survivors

MDI <55 11/36 (31%) 19/33 (58%) 0.32 (0.12, 0.87)

Adjusted 0.16 (0.04, 0.54)

Median MDI 68 <50

PDI<55 14 (40%) 18 (55%) 0.54 (0.20, 1.45)

Adjusted 0.19 (0.05, 0.81)

DRIFT 10 82% follow-up at 10 years

Cognitive assessment

Motor assessment

Visual assessment

Behavioural assessment.

Use of special education

Karen Luyt

Sally Jary

Helen Miller

Cathy Williams

DRIFT at 10 years

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Female Male

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Grade 3 Grade 4

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02

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Standard DRIFT

Blind or perceives light only Useful but not fully correctable

Normal with corrections No concerns

DRIFT Standard

Good /correctable vision 85% 71%

Cerebral palsy 61% 58%

Alive without cog impairment 72% 44%

Special school 29% 44%

Speech Therapy 35% 61%

A randomised controlled

trial was performed to

study whether very early

intervention (ventricular

index (VI) >p97) reduces

the need for ventriculo-

peritoneal (VP) shunt

placement, compared

with later intervention

(VI > p97+4mm).

ISRCTN43171322

Early (62) Later (64) P-value

day of randomization (median, range) -day of 1st intervention after randomization (median, range)

9 (2-22)

1 (1-11)

9 (3-21)

6 (2-19)

ns

<0.001

LPs 62 (97%) 36 (58%) <0.001

Reservoirs 40 (62%) 27 (43%) <0.05

Day of reservoir after randomization VP shunt

6 (2-15)

12(19%)

10 (5-28)

14(23%)

<0.001

Dead or shunt 19 (31%) 23 (36%) 0.53

Model: P4 rats injected intraventricularly with 100 microlitres blood L & R

Randomised P6 to: Intraventricular injection of:

105 Human umbilical cord blood Mesenchymal Stem cells

OR 105 fibroblasts intraventricularly

OR No intraventricular treatment

H UCB MScells prevented Post-Haemorrhagic Hydrocephalus

reduced TUNEL +ve cells (Apoptosis)

reduced neuromotor abnormality

reduced inflammatory cytokines and TGF beta in

CSF

Improved Corpus Callosum thickness

Myelin Basic protein

IV almost equally effective if dose bigger.

So Yoon Ahn , PAS, San Francisco, May 8th 2017.

9 preterm infants with grade 3 IVH

Injected intraventricularly <7 days after diagnosis

5 x 106 Umbilical derived ”induced” mesenchymal stem

cells in 1 ml

OR 1 x 107 cells in 2 ml.

Phase 2a randomized trial started 2017.