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
05
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Female Male
05
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Grade 3 Grade 4
01
02
03
0
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.