e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 2 ( 2 0 1 8 ) 6 9 0 e7 1 7

Official Journal of the European Paediatric Neurology Society

Review article

Intracranial hemorrhage in neonates: A review of

etiologies, patterns and predicted clinical outcomes

Ai Peng Tan a, Patricia Svrckova b, Frances Cowan c, Wui Khean Chong b,

Kshitij Mankad b,*
a
Department of Diagnostic Imaging, National University Health System, 1E Kent Ridge Rd 119228, Singapore
b
Department of Radiology, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond St, London WC1N
3JH, UK
c
Dept. of Neonatology, Chelsea and Westminster Hospital NHS Foundation Trust, Imperial College, London, SW10
9NH, UK

article info abstract

Article history: Intracranial hemorrhage (ICH) in neonates often results in devastating neuro-
Received 13 August 2017 developmental outcomes as the neonatal period is a critical window for brain develop-
Received in revised form ment. The neurodevelopmental outcomes in neonates with ICH are determined by the
31 March 2018 maturity of the brain, the location and extent of the hemorrhage, the specific underlying
Accepted 18 April 2018 etiology and the presence of other concomitant disorders. Neonatal ICH may result from
various inherited and acquired disorders. We classify the etiologies of neonatal ICH into
Keywords: eight main categories: (1) Hemorrhagic stroke including large focal hematoma, (2)
Neonatal intracranial hemorrhage Prematurity-related hemorrhage, (3) Bleeding diathesis, (4) Genetic causes, (5) Infection, (6)
Type IV collagen genes Trauma-related hemorrhage, (7) Tumor-related hemorrhage and (8) Vascular malforma-
Cerebral venous sinus thrombosis tions. Illustrative cases showing various imaging patterns that can be helpful to predict
(CVST) clinical outcomes will be highlighted. Potential mimics of ICH in the neonatal period are
Intraventricular hemorrhage (IVH) also reviewed.
Germinal matrix hemorrhage (GMH) © 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights
Congenital brain tumors (CBTs) reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
2. Imaging of neonatal intracranial hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
3. Neonatal hemorrhagic stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
3.1. Idiopathic intraparenchymal hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
3.2. Hemorrhagic transformation of an existing arterial infarct . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693
3.3. Cerebral venous sinus thrombosis (CVST) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693

* Corresponding author. Great Ormond Street Hospital NHS Foundation Trust, London WC1N 3JH, United Kingdom.
E-mail addresses: ai_peng_tan@nuhs.edu.sg (A.P. Tan), psvrckova@nhs.net (P. Svrckova), f.cowan@imperial.ac.uk (F. Cowan), Kling.
Chong@gosh.nhs.uk (W.K. Chong), Kshitij.Mankad@gosh.nhs.uk (K. Mankad).
https://doi.org/10.1016/j.ejpn.2018.04.008
1090-3798/© 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 2 ( 2 0 1 8 ) 6 9 0 e7 1 7 691

3.4. Hypoxic-ischemic encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693

4. Prematurity-related ICH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
4.1. Germinal matrix hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
4.2. Cerebellar hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
4.3. Punctate white matter lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
5. Bleeding diathesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
5.1. Vitamin K deficiency associated bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
5.2. Fetal and neonatal alloimmune thrombocytopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697
5.3. Iatrogenic coagulopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
6. Genetic causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
6.1. COL4A1 and COL4A2 mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
6.2. Congenital thrombophilias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
7. Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
8. Traumatic intracranial hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
8.1. Birth-related trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
8.2. Non-accidental injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
9. Hemorrhage related to congenital brain tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
10. Vascular malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
10.1. Pial arteriovenous fistula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
10.2. Dural arteriovenous fistula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706
10.3. Intracranial aneurysm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706
11. Mimics of neonatal ICH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708
11.1. Dural sinus malformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708
11.2. Intracranial hemangioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708
11.3. Vein of Galen malformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 709
12. Clinical outcome in relation to neonatal ICH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 709
12.1. Subdural and subarachnoid hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711
12.2. Intraventricular hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711
12.3. Intraparenchymal hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711
13. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712
Funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712
Financial disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712

Abbreviations Hypoxic-ischemic encephalopathy HIE

Intracranial hemorrhage ICH
Apparent diffusion coefficient ADC
Intraventricular hemorrhage IVH
Arteriovenous fistula AVF
Magnetic resonance imaging MRI
Basal ganglia-thalamic BGT
Non-accidental injury NAI
Central nervous system CNS
Periventricular leukomalacia PVL
Cerebellar hemorrhage CH
Posterior fossa hemorrhage PFH
Cerebral venous sinus thrombosis CVST
Posterior limb of the internal capsule PLIC
Computed tomography CT
Primitive neuroectodermal tumour PNET
Congenital brain tumors CBTs
Punctate white matter lesions PWMLs
Cranial ultrasound cUS
Subarachnoid hemorrhage SAH
Diffusion-weighted imaging DWI
Subdural hemorrhage SDH
Dural sinus malformation DSM
Susceptibility-weighted imaging SWI
Extracorporeal membrane oxygenation ECMO
Type IV collagen a1 COL4A1
Fetal and neonatal alloimmune thrombocytopenia FNAIT
Type IV collagen a2 COL4A2
Germinal matrix hemorrhage GMH
Vein of Galen aneurysmal malformation VGAM
Glioblastoma multiforme GBM
Vitamin K deficiency associated bleeding VKDB
Herpes simplex virus HSV
Human parechoviruses HPeVs
692 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 2 ( 2 0 1 8 ) 6 9 0 e7 1 7
1. Introduction
Intracranial hemorrhage (ICH) is an important cause of
neonatal morbidity and mortality. Many inherited and ac-
quired disorders may cause neonatal ICH, although in a large
proportion of cases no etiology can be identified.1 An insult to
the brain during the neonatal period often results in signifi-
cant adverse neurodevelopmental outcomes as it is a critical
window for brain development.2 The neurodevelopmental
outcomes in neonates with ICH are determined by the matu-
rity of the brain, the location and extent of the lesion(s) as well
as the underlying etiology and the presence of other concur-
rent disorders. We classify the etiologies of neonatal ICH into
eight main categories (Fig. 1): (1) Neonatal hemorrhagic stroke,
(2) Prematurity-related hemorrhage, (3) Bleeding diathesis, (4)
Genetic causes, (5) Infection, (6) Trauma-related hemorrhage,
(7) Tumor-related hemorrhage and (8) Vascular malforma-
tions. The aim of this paper is to provide a comprehensive
review of these various underlying etiologies and confounders
by presenting illustrative cases, focusing on imaging patterns,
important differentiating features, and predictors of clinical
outcomes.
2. Imaging of neonatal intracranial
hemorrhage
Cranial ultrasound (cUS) is a readily available, portable and by
far the most common first line technique of intracranial im-
aging in neonates with suspected intracranial hemorrhage
(ICH). It utilizes the fontanelles of neonates as a sonographic
window to obtain real-time, structural assessment of the
intracranial contents. cUS is particularly valuable for assess-
ing the ventricular system and periventricular white matter,
with excellent inter-observer agreement for germinal matrix
hemorrhage (GMH) or intraventricular hemorrhage (IVH) and
cystic periventricular leukomalacia (PVL).3 The lack of
requirement of ionizing radiation and/or sedation or transport
of the neonate to the scanner renders it ideal for the often
daily follow up of evolving pathology, and investigation of the
sick neonate too unstable to be imminently transferred to the
computed tomography (CT) or magnetic resonance imaging
(MRI) scanner.
cUS has several important limitations: its reliance on
acoustic windows means that hemorrhage in the regions of
the brain's convexity (such as subdural or subarachnoid
hemorrhage) may be missed. cUS also has low sensitivity for
detecting pathology in the posterior fossa, although usage of
supplemental acoustic windows such as the mastoid fonta-
nelle, is helpful.4
If further characterisation of lesions is required, or clinical
suspicion persists despite seemingly normal CrUS appear-
ances, MRI is the gold standard for further imaging.5 Not only
is it not limited by acoustic windows and allows visualization
of the whole brain; the utilization of haemorrhage sensitive
sequences such as gradient echo T2* and susceptibility-
weighted imaging (SWI) is unprecedented in its sensitivity,6,7
detecting microhemorrhage previously undetected on cUS or
CT, so much so that the clinical significance of incidentally
detected microhemorrhage is sometimes brought into ques-
tion (see section on Prematurity-related hemorrhage: cere-
bellar hemorrhage later). A further advantage of MRI is the
ability to distinguish hemorrhage of different ages, utilizing
the differing magnetic properties of aging blood products.8
The use of CT for neonatal imaging is discouraged in cen-
ters where MRI is available, due to its use of ionizing radiation.
It has an excellent sensitivity for acute hemorrhage,9 but is
inferior to MRI in detecting aging hemorrhage or micro-
hemorrhage. MRI is also superior to CT in soft tissue resolu-
tion, allowing for assessment of white matter and grey matter
lesions alike.9
3. Neonatal hemorrhagic stroke
Hemorrhagic stroke represents approximately half of all
childhood strokes,10,11 as opposed to only about 10e20% in
adults.12e14 The incidence in term neonates is as high as 1 in
6000 of all live births with the majority of cases presenting
within the first week after birth,15,16 although delayed pre-
sentation after 28 days of age with a presumed perinatal
stroke based on clinical history and imaging has also been
described.17,18 Risk factors for hemorrhagic stroke include
congenital heart disease, fetal distress, and hemostatic ab-
normalities.16 It is important to recognise that neonatal
hemorrhagic stroke is not a single entity. The commonest
etiologies of hemorrhagic stroke are idiopathic intra-
parenchymal hemorrhage, hemorrhagic transformation of an
existing arterial infarct, cerebral venous sinus thrombosis
(CVST), and hypoxic-ischemic encephalopathy (HIE).15 Extra-
axial ICH, such as subdural (SDH) and subarachnoid hemor-
rhage (SAH), is common, and whilst these may be large, they
are more frequently small, infratentorial, asymptomatic and
quickly resorbed. In this paper, we adopt the broadest defini-
tion of hemorrhagic stroke, and discuss each etiology sepa-
rately. Preterm ICH is discussed in a separate section.
3.1. Idiopathic intraparenchymal hemorrhage
Neonates with isolated intraparenchymal hemorrhage usu-
ally present with seizures, though they may be encephalo-
pathic with altered mental status and/or neurological
deficits.15 Most cases in term infants are idiopathic, and tend
to occur supratentorially in the frontal, parietal and temporal
lobes.15,19,20 Unlike hemorrhagic transformation of an existing
arterial infarct (discussed later), the location of an idiopathic
intraparenchymal hemorrhage does not conform entirely to
an arterial territory (Fig. 2). Concurrent IVH may occur but is
usually small and associated ventriculomegaly is rare.
Recurrent hemorrhage is also extremely rare.15 Idiopathic
intraparenchymal hemorrhage is immediately apparent on
cUS, unlike ischemic infarcts, which may take 2e3 days to be
detected or clearly delineated.21 Serial cUS scanning or pro-
ceeding to CT/MRI is therefore advisable if there is clinical
concern.
 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 2 ( 2 0 1 8 ) 6 9 0 e7 1 7
Fig. 1 e Etiology-based classification of neonatal ICH.
3.2. Hemorrhagic transformation of an existing arterial
infarct
In a term neonate, arterial infarction most commonly occurs
in the left middle cerebral artery territory.22,23 There is con-
flicting information about how prevalent hemorrhagic
transformation of an existing arterial infarct (Fig. 3) is in
neonates: some studies report this as the most frequent
cause, occurring in 53% of neonatal hemorrhagic stroke,16
while others report is as rare as 5%15 or unusual.15,23 We
suspect major hemorrhagic transformation of an isolated
existing arterial infarct is in fact rare, and the higher reported
rate in some studies may reflect a multifactorial etiology
with disruption of systemic haemodynamics or systemic
coagulopathic derangement.
3.3. Cerebral venous sinus thrombosis (CVST)
Neonates are more likely to develop CVST than any other
pediatric age group.24 The most common presenting symptom
are seizures; the major predisposing factors include menin-
gitis and dehydration.24,25 A unilateral thalamic hemorrhage
(Fig. 4) almost always occurs in the context of CVST.26 IVH can
occur, and CVST is the most frequently identified cause of
symptomatic IVH in a term neonate.27 Lobar hemorrhage
693
(Fig. 5) not conforming to an arterial vascular territory can also
occur, with temporal hematoma being associated with a
thrombosed vein of Labbe
.28 As with idiopathic intra-
parenchymal hemorrhagic lesions, there is seldom evidence
of underlying ischemia in CVST and the etiology is more likely
to be related to impaired venous drainage.26,29
3.4. Hypoxic-ischemic encephalopathy
HIE is an important cause of acquired neurological deficit in
childhood. Severe asphyxia leading to HIE is one of the risk
factors for neonatal ICH, as it is associated with impaired ce-
rebral autoregulation as well as derangement in the coagula-
tion pathway.30,31 Rates of reported ICH in term infants with
HIE range from 8% to 39%.32,33 The location of hemorrhage is
most commonly within the subdural compartment, and con-
current SDH and IVH associated with HIE suggest systemic
derangement in hemostasis as the underlying cause.32 Ther-
apeutic cooling initiated within the first 6 h of birth has been
established as an effective treatment for some infants with
moderate to severe HIE, improving survival and outcome.34
Although there have been a couple of case reports of hemor-
rhage associated with therapeutic hypothermia, there was no
increased risk in the subgroup analysis of imaging from the
TOBY trial.32
694 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 2 ( 2 0 1 8 ) 6 9 0 e7 1 7

Fig. 2 e Neonatal hemorrhagic stroke: Idiopathic intraparenchymal hemorrhage. Axial (a) and coronal (b) non-contrast
enhanced computed tomography (CT) images show hyperdense hematoma in the frontal lobe extending into the adjacent
subarachnoid and subdural spaces. Generalised edema with cerebral sulcal effacement is also observed on the left with
rightward midline shift. Note that it does not conform to a single vascular territory, spanning both anterior and middle
cerebral artery territories, distinguishing it from a hemorrhagic transformation of an existing arterial infarct.

Fig. 3 e Neonatal hemorrhagic stroke: Hemorrhagic transformation of an existing arterial infarct in the right middle cerebral
artery territory. Axial MRI T2 weighted (a), diffusion weighted imaging (DWI) (b), apparent diffusion coefficient (ADC) map (c),
T1 weighted (d) and SWI images of a neonate demonstrate a wedge shaped area of signal hyperintensity in the right
cerebral hemisphere extending to and including the cortex with a corresponding low signal on the ADC map, in keeping
with an acute right MCA territory infarct. The SWI images demonstrate a small amount of punctate susceptibility weighted
artefact in the subcortical region, in keeping with a small amount of hemorrhagic transformation.

capillaries in the subependymal germinal matrix, which are

4. Prematurity-related ICH rich in immature vessels and poorly supported by connective
tissue. The germinal matrix starts to involute at 20e26
4.1. Germinal matrix hemorrhage weeks37,38 and is generally absent at term age39 though rem-
nants may remain in the caudothalamic notch and just pos-
The major type of ICH observed in premature infants is IVH; the terior to the thalami. This is the most common site for
rate and severity is inversely proportional to gestational age prematurity-related IVH (Figs. 6 and 7). Fluctuations in
and birth weight.35,36 IVH in premature infants arises from
 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 2 ( 2 0 1 8 ) 6 9 0 e7 1 7 695

Fig. 4 e Neonatal hemorrhagic stroke: Cerebral venous sinus thrombosis causing thalamic hemorrhage. (a) Axial T2-
weighted and (b) coronal T1-weighted images show an early subacute hematoma within the left thalamus. The high T1
signal and low T2 signal denotes the presence of early subacute blood product (intracellular methaemoglobin). Thrombus is
seen in the left internal cerebral vein, as demonstrated by signal dropout and mild blooming artefact due to its
paramagnetic effect (black arrow in a). Mild ventriculomegaly is noted.

Fig. 5 e Neonatal hemorrhagic stroke: Cerebral venous sinus thrombosis. Axial non-contrast enhanced CT images show
hyperdense thrombi within the transverse sinuses (a), superior sagittal sinus (b) and right cortical vein (white arrows in c). A
hemorrhagic venous infarction is also seen in the right fronto-parietal lobes (*). Generalised cerebral edema is evident.

hemostasis and immature autoregulation coupled with varying
intrathoracic pressures due to respiratory distress syndrome
and ventilation occurring in very sick infants also contribute to
alteration of cerebral blood flow which can result in IVH.40,41
Considerable anatomical variance in the deep venous
system in preterm newborns compared to term newborns
may also play a role in the increased rate of IVH seen in this
group.42 In particular, narrower curvature of the terminal
portion of the thalamostriate vein is associated with higher
rates of GMH in preterm neonates, presumably due to resul-
tant flow alteration, impaired drainage and shear stress.43
Papile's grading of the severity of GMH is widely used:
Grade I is confined to the subependymal germinal matrix and
is classically seen in the caudothalamic groove, Grade II is
defined by the presence of blood within normal-sized ventri-
cles, Grade III consists of IVH filling more than 50% of the
ventricle with ventricular dilatation, and Grade IV is accom-
panied by parenchymal hemorrhagic infarction (Fig. 6).44
Another widely used IVH grading scale was defined by
Volpe: Grade I is GMH with no or minimal IVH, in Grade II
there is IVH involving 10e50% of area on parasagittal view,
and Grade III has more than 50% ventricular area involved.
Parenchymal hemorrhage is commented on separately.45
Increasing grades of hemorrhage are associated with
adverse neurodevelopmental outcomes.46 Isolated grade I and
II GMH are generally associated with good long-term neuro-
developmental outcome. Long-term disability is more
commonly seen in grade III hemorrhage when post-
hemorrhagic ventriculomegaly is not adequately managed
and grade IV IVH survivors mainly when the parenchymal
lesion affects the cortico-spinal tracts.46e48 Outcome metrics
not related to motor development such as visual, cognitive,
and behavioral problems, may occur in those with frontal and
temporal grade IV IVH.49
4.2. Cerebellar hemorrhage
Another major type of ICH seen more commonly in premature
neonates is cerebellar hemorrhage (CH). In a retrospective
study of 1120 premature infants by Zayek et al., CH was the
second most common morbidity, occurring in 13%, after grade
III to IV IVH (20%).50 CH frequently occurs concurrently with
696 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 2 ( 2 0 1 8 ) 6 9 0 e7 1 7

Fig. 6 e Prematurity-related ICH: Germinal matrix hemorrhage, Papille Grade IV. Axial T1-weighted (a), coronal T2-weighted
(b) and axial T2-weighted images show hemorrhage within the caudothalamic grooves (white arrows in a), blood layering
within the dilated lateral ventricles (* in a) and a small area of intraparenchymal hemorrhage (black arrows in b). Cranial
ultrasound images (d,e) demonstrate bilateral echogenic parenchymal flaring, echogenic IVH, and a small focal echogenic
intraparenchymal hemorrhage on the left.

GMH (Fig. 7). Standard cUS has a very low sensitivity for
detecting CH, although increasing awareness of CH and the
use of mastoid views help detection.51 With increasing use of
MRI, in particular SWI, the diagnosis of even very small CH,
often clinically silent, has been made possible. Unlike cUS-
detectable CH, CH detected only on MRI is not related to an
unfavourable short-term neurodevelopmental outcome.52
Although a 5-fold increase in neurological abnormalities at
3e6 years in preterms with solely MRI-detected CH compared
to controls was reported,53 these were not associated with
functional impairments of ambulation, cerebral palsy or
cognitive deficits.53 This knowledge is important from a
prognostic view and for parental counselling after incidental
detection of cerebellar microhemorrhage.
4.3. Punctate white matter lesions
Increasing use of MRI in preterm neonates, and inclusion of
diffusion-weighted imaging (DWI) and SWI, have brought to
attention the existence of punctate white matter lesions
(PWMLs). Kersbergen et al. described two distinct types of le-
sions: linear and cluster lesions.54 The linear lesions (Fig. 8) are
more likely to be hemorrhagic in aetiology (low signal in-
tensity on SWI, more evident on T2 than T1-weighted imag-
ing, association with IVH) than the cluster lesions (Fig. 9); the
signal characteristics of the latter (more evident on T1 than
T2-weighted imaging, no signal dropout on SWI, restriction on
DWI) render them more likely a marker of gliosis and by
extension PVL.54e57
5. Bleeding diathesis
Bleeding disorders such as Vitamin K deficiency, alloimmune
thrombocytopenia and iatrogenic coagulopathy (such as seen
in neonates on extracorporeal membrane oxygenation or
ECMO) may result in neonatal ICH.
5.1. Vitamin K deficiency associated bleeding
Vitamin K is essential in the appropriate functioning of the
coagulation pathway. Vitamin K deficiency is a recognized risk
factor for ICH at any age, but neonates are especially suscep-
tible as vitamin K does not readily cross the placenta.58
Therefore, it is standard practice in most countries to give
prophylactic IM vitamin K to all newborns as an effective way
of reducing vitamin K deficiency associated bleeding (VKDB).59
VKDB occurs in approximately 35 per 100,000 live births.59 It is
classified into three groups according to time of onset; early
(within the first 24hrs after birth), classical (postnatal day 2 to
day 7), and late (2e12 weeks after birth). ICH is predominantly
seen in late VKDB.60 Known risk factors for late VKDB include
lack of vitamin K prophylaxis and being exclusively
breastfed.60e62 Patients suffering from vitamin K-dependent
clotting factor deficiency type 2, an extremely rare autosomal
recessive bleeding disorder arising from point mutations in
the VKORC1 gene, typically present with severe perinatal
ICH.63,64 The most frequent location of VKDB is subdural (56%),
followed by intraparenchymal (31%) and multicompartmental
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Fig. 7 e Prematurity-related ICH: Germinal matrix hemorrhage and cerebellar hemorrhage. Susceptibility-weighted (a,b) and
T2-weighted (c,d) images show signal dropout and blooming artefact secondary to GMH within the left caudothalamic
groove (white arrow in a) and cerebellar hemispheres (open white arrow in b) in a severely premature neonate. Signal
dropout and blooming artefact secondary to bilateral medullary vein thrombosis is also noted (black arrows in a), likely
related to superimposed sepsis/infection.

hemorrhage (13%) (Figs. 10 and 11).60 Correction of the clotting
derangement via Vitamin K and fresh frozen plasma admin-
istration is the mainstay of treatment. An approximately 20%
mortality and 53% morbidity has been reported.60,62
5.2. Fetal and neonatal alloimmune thrombocytopenia
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is
relatively rare, occurring in approximately 1 in 1000 live
births, predominantly in Caucasian populations.65 FNAIT is
caused by incompatibility in human platelet antigens, leading
to the maternal alloantibodies attacking fetal platelets,
resulting in fetal thrombocytopenia. The most commonly
involved antigen is HPA-1a, which tends to be associated with
the more severe cases.66
ICH due to FNAIT is reported to occur in 1 in 10,000 live
births,65 and the majority of cases of ICH occur antenatally:
54% before the third trimester and 67% before 34 gestational
weeks.67 First-borns are affected more often, and the
recurrence rate of FNAIT in subsequent pregnancies may be
as high as 80%. A multicenter cohort study by Tiller et al. has
reported a 35% mortality within the first 4 days after birth,
and severe neurological sequelae in a further 53% of
children.67
The current gold standard treatment for FNAIT is admin-
istration of weekly IVIg to the mother starting from the 2nd
trimester,68 which has been found to dramatically reduce the
occurrence of ICH even in the presence of continued low
platelet counts.69 In a neonate with suspected FNAIT, man-
agement should not be delayed by waiting for a laboratory
diagnosis which is complex and requires and experienced
laboratory; rather, empirical treatment with platelet trans-
fusions and IVIg administration to the neonate is recom-
mended.66 Given the early occurrence of ICH in the antenatal
period, and the resultant poor prognosis, early diagnosis and
early intervention are necessary; non-invasive antenatal tests
have been developed, but are not yet validated for use in
clinical practice.69
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Fig. 8 e Prematurity-related ICH: Punctate white matter lesions, linear pattern. Axial T2 weighted (a, c) MRI images
demonstrate multiple low signal punctate lesions in the periventricular white matter (a) and corona radiata (c) in a linear
distribution. These are much less conspicuous on the corresponding T1-weighted images (b, d) and are likely to be
hemorrhagic in etiology.

5.3. Iatrogenic coagulopathy

Iatrogenic coagulopathy is also a cause of neonatal ICH. ECMO
is widely used in specialist centers for neonates with severe
cardiorespiratory failure. Anticoagulation is required to pre-
vent thrombus formation in the circuit, and more non-
survivors of ECMO treatment die from ICH (Fig. 12) rather
than their primary cardiorespiratory disease.70 The rate of ICH
in neonates on ECMO ranges from 8.2% to 23% among survi-
vors, and up to 52% in autopsies.71e73 ICH has been attributed
to disturbance of cerebral auto-regulation secondary to fluc-
tuations in systemic pressures.70 The loss of arterial pulsa-
tility resulting from carotid artery cannulation in ECMO has
been hypothesized as a possible explanation for the increased
rate of neurological injury in veno-arterial ECMO compared to
veno-venous ECMO.70,73,74
6. Genetic causes
Genetic factors have been increasingly recognized as causes of
neonatal ICH, and physicians should understand risk factors
and identify vulnerable newborns. Screening for mutations or
polymorphisms in thrombophilic and collagen genes should
be considered in newborn infants with an atypical presenta-
tion of periventricular hemorrhagic infarction.75
6.1. COL4A1 and COL4A2 mutations
Type IV collagen a1 (COL4A1) and type IV collagen a2 (COL4A2)
chains form the principal component of vasculature, renal
and ocular basement membranes.76,77 They ensure the
maintenance of vascular tone and endothelial integrity.
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Fig. 9 e Prematurity-related ICH: Punctate white matter lesions, cluster pattern. Axial (a, b) and sagittal (c, d) MRI images
demonstrate punctate white matter lesions in a clustered distribution, better appreciated on the T1 (hyperintense lesions; b,
c) than T2-weighted (hypointense lesions; a, c). These are more likely a marker of gliosis than haemorrhage, as opposed to
the linear pattern punctate white matter lesions above.

Fig. 10 e Bleeding diathesis: Vitamin K deficiency associated bleeding: intraparenchymal, subdural and subarachnoid
hemorrhage. Axial T2-weighted (a), axial T1-weighted (b), and coronal T2-weighted (c) images show an early subacute
parenchymal hematoma in the right frontal lobe. There is also early subacute subdural and subarachnoid hemorrhage
along the right frontal convexity (*). The high T1 signal and low T2 signal denotes the presence of early subacute blood
product (intracellular methaemoglobin).

Mutations in COL4A1 gene were first associated with ce-
rebral microangiopathy and familial porencephaly, later with
neonatal and adult ICH, aneurysms, ocular manifestations of
variable types, and nephropathy.78 Disease onset may be in
the fetal period,79 resulting in the development of hemorrhage
and porencephalic cysts (Fig. 13). The imaging characteristics
of COL4A1 disease include porencephaly, leukoencephalop-
athy and intracranial aneurysms.78,80 Mutations in COL4A2
gene have also been reported to result in both sporadic and
familial porencephaly.81
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Fig. 11 e Bleeding diathesis: Vitamin K deficiency associated bleeding: subdural and subarachnoid hemorrhage,
complicated by acute infarction in the right cerebral hemisphere. The axial CT image (a) shows hyperdense SDH along the
bilateral cerebral convexities and interhemispheric falx. A small amount of hyperdense right acute SAH is also observed,
along with subtle loss of grayewhite matter differentiation in the right cerebral hemisphere. The axial T2-weighted (b)
image shows high signal bilateral subdural hemorrhage and oedema of the right cerebral hemisphere. DWI (c) and its
corresponding ADC map (d) confirm the presence of acute infarction in the right cerebral hemisphere, with sparing of the
basal ganglia and internal capsule.

It has been suggested that delivery by caesarean section to
avoid birth trauma may prevent occurrence of perinatal
parenchymal hemorrhage in humans with COL4A1 muta-
tion.76 This is, however, of questionable benefit given that in
most cases the ICH has taken place antenatally and the por-
encephaly has already developed.
Due to the extremely variable clinical expression, muta-
tions of type IV collagen genes are often underdiagnosed.
Testing for COL4A1 and COL4A2 gene mutation should be
considered in all neonates with a porencephalic cyst and/or
hemiparesis at birth as well as in neonates with ICH of un-
known etiology.79 Recently, genetic testing was also recom-
mended in neonates with hemolytic disease of unknown
etiology, especially when other COL4A1-related manifesta-
tions are identified.82
6.2. Congenital thrombophilias
Congenital thrombophilias have been associated with
venous and arterial infarctions, both of which may result
in neonatal ICH. Perhaps the best known example of an
inherited thrombophilia is the Factor V Leiden mutation.
Although multiple studies have supported the association
between thrombophilia and perinatal stroke, none has
confirmed a positive association that is both strong
and consistent.83e85 The role of genetic polymorphisms
involved in the coagulation pathway in the development
of IVH is probably a consequence of an increased risk
of thrombosis in the fine blood vessels within the
germinal matrix.85
7. Infections
Neonates are at high risk for acquiring infections due to their
specific central nervous system (CNS) structure as well as
functionally immature immune system. Premature neonates
with CNS infection also have a higher mortality rate compared
to their term counterpart.86,87 Intracranial infections are
known to be associated with ICH in the general population,
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Fig. 12 e Bleeding diathesis: iatrogenic coagulopathy: bilateral watershed infarctions with hemorrhagic transformation in a
neonate with low cardiac output state requiring veno-arterial ECMO. Axial non-contrast CT image (a) shows wedge-shaped
areas of hypoattenuation at the cortical border zones, in keeping with watershed infarctions. A small focus of hyperdense
hemorrhage is seen within the left parietal lobe (white arrow), along with minimal hyperdense subdural blood along the
interhemispheric falx (black arrow). Axial non-contrast CT image (b) acquired 5 days later showed marked progression of
the hemorrhagic conversion within the areas of infarction.

Fig. 13 e Genetic causes: COL4A1 mutation: porencephalic cavities. Two patients with COL4A1 mutation. Patient 1. T2*-
weighted gradient echo (a), T2-weighted (b) and T1-weighted (c) images demonstrate bilateral but asymmetrical
hemosiderin-lined (blooming artefact on T2*, low signal on T2, high signal on T1-weighted imaging) porencephalic cavities
within the basal ganglia and thalami. Similar changes are also seen within the right occipital lobe (black arrow in a). Patient
2. Axial CT image (d), T2*-weighted gradient echo (e) and coronal T2-weighted (f) images show bilateral large parasagittal
porencephalic cysts, lined by calcifications (characteristic high density comparable to bone on CT, blooming artefact on T2*).

although the pathophysiologic linkage between the two is damage and viral-induced thrombocytopenia are all sug-
often speculative in nature.88 In neonates, coagulopathy as a gested causes of ICH. In addition to ICH, CNS involvement in
result of disseminated intravascular coagulation in the meningoencephalitis can be complicated by empyemas and
context of systemic sepsis (Figs. 14 and 15), hepatocellular infarctions (Fig. 16).
702 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 2 ( 2 0 1 8 ) 6 9 0 e7 1 7
ICH is a known complication of herpes simplex virus (HSV)
encephalitis.89 HSV infection in neonates can be caused by
either HSV-1 or HSV-2, transmitted either through vertical
transmission before or during labor, or due to direct contact
with infected secretions in the neonatal period.90 Poor
neurological outcome is observed in survivors of severe HSV
infections.90 Bleeding diathesis, liver failure and septic shock
resulting in disseminated intravascular coagulation often ac-
companies severe HSV infection, predisposing patients to
ICH.91
The reported cases of ICH associated with human par-
echoviruses (HPeVs) usually occur within the first week from
disease onset, and it had been postulated that coagulopathy
may be the underlying mechanism.92 HPeVs are picornavi-
ruses associated with severe CNS infections, especially in
neonates and preterm infants.93 HPeV infection occurs soon
after birth, with antibody-positive sera in the first few months
of life.94 HPeVs are commonly transmitted via fecal-oral or
respiratory routes. Verboon et al. reported the presence of
diffuse signal abnormalities within the white matter with
punctate hemorrhages in HPeV encephalitis, typically
involving the corpus callosum, optic radiation, internal
capsule and cerebral peduncle.95 Similar findings may be seen
in rotavirus and enterovirus encephalitis.96 Listeria mono-
cytogenes, parvovirus B19 and cytomegalovirus infections are
also known to be causes of neonatal ICH.
8. Traumatic intracranial hemorrhage
Accidental head injuries in children younger than 2 years of
age are rarely associated with ICH. As a general rule, falls from
a height of less than 3 feet rarely result in significant head
injuries. Hence, a high index of suspicion for non-accidental
injury (NAI) should be maintained when ICH is seen in neo-
nates, especially in cases where there is an unclear history of
trauma.
8.1. Birth-related trauma
In the neonatal period, posterior fossa hemorrhage (PFH) is
not unusual and may be related to prolonged, difficult or
Fig. 14 e Infections: group B streptococcal septicemia with medullary vein thrombosis and porencephalic cyst. Axial T2-
weighted (a) and SWI (b,c) images in a 2 week old neonate show a hemosiderin-lined (low signal on T2 with blooming on
SWI*) porencephalic cyst in the right fronto-parietal lobes, along with bilateral medullary vein thrombosis (susceptibility
weighted low signal blooming artefact on SWI*).
traumatic instrumental deliveries (Fig. 17).97 Prolonged and
difficult delivery results in excessive cranial moulding and
stretching of the dura. When this occurs, venous structures
that traverse the subdural space may be disrupted, giving rise
to SDH (Fig. 18). The pterion is a large, relatively unprotected
sutural confluence, which makes this site vulnerable for
injury.98 PFH is usually seen within the subdural compartment
although CH may also be seen secondary to cerebellar lacer-
ation (associated with occipital osteodiastasis).99 Asymptom-
atic neonatal SDHs (Fig. 19), not apparently related to the
mode of delivery, have also been reported in up to 26% of
asymptomatic newborns.100 These are often seen within the
posterior fossa and posterior aspect of the cerebral hemi-
spheres, similar to those associated with a prolonged, difficult
delivery and NAI. Unlike NAI or traumatic delivery-related
hemorrhage, however, asymptomatic SDH typically does not
progress to chronic SDH and usually resolves completely by 4
weeks.101 In an imaging study of 97 consecutive neonates,
none of the incidental asymptomatic SDHs were interhemi-
spheric or of different ages, both features otherwise con-
cerning for NAI.100
It is important to note that even though in most cases,
birth-related ICH resolves spontaneously and has a favorable
outcome, there are instances of traumatic deliveries and large,
progressive hemorrhages with poor prognosis and high
morbidity. It is important to note that the poor outcome is
likely multifactorial, possibly due to coexistent HIE, prema-
turity, or hemodynamic instability as a result of perinatal fetal
compromise for which an expedited delivery needed to be
performed in the first place.
8.2. Non-accidental injury
NAI is the leading cause of severe head injuries in children,
especially those less than 2 years of age.102 Whilst uncommon
in the neonatal period, NAI should be suspected in neonates
that have been discharged and readmitted, as well as in long-
stay neonates with new or unexplained symptoms. Increased
irritability, vomiting, seizures and recurrent encephalopathy
are among the few common clinical presentations. Due to the
variable and often misleading clinical presentation, NAI is often
misdiagnosed as seizure disorder, sepsis or accidental injury.103
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Fig. 15 e Infections: sepsis with intraparenchymal hemorrhage, basal ganglia hemorrhage, and bilateral medullary vein
thrombosis. Axial T2-weighted (a,b) and T2*-weighted gradient echo (c) images in a 3-day-old, term-born neonate show
high signal intraparenchymal hemorrhage in the left fronto-parietal region (black arrow in a) and left basal ganglia (black
arrow in b). There is also extensive bilateral medullary vein thrombosis and periventricular hemorrhage, both low signal
with blooming artefact on T2*- weighted imaging.

Fig. 16 e Infections: extensive meningoencephalitis complicated by bilateral subdural empyemas, subdural hemorrhage
and multifocal acute infarctions. Axial and coronal CT images (a,b), coronal T2-weighted image (c), diffusion-weighted
image (d), ADC map (e) and axial post-contrast T1-weighted image (f) n a 10 day old neonate demonstrate thin slivers of
subdural hemorrhage along the interhemispheric falx and right tentorial leaflets (hyperdense on CT; black arrows in a and
b). Bilateral small subdural empyemas are also seen (* in a and f), along with generalised cerebral edema (c) and multifocal
acute infarctions (d, e) involving the supratentorial and infratentorial brain. Diffuse leptomeningeal enhancement is noted
(f).

SDH is the most common type of ICH in NAI (Figs. 20

and 21). An isolated intracranial finding of interhemispheric
SDH has a very high specificity for NAI, especially if it is
posteriorly located and associated with retinal hemor-
rhages.104e106 Parenchymal hemorrhages, most often due to
shearing injuries, are commonly situated at the grayewhite
matter junction or within major white matter tracts such as
the corpus callosum. Apart from ICH, NAI may manifest as
cerebral edema (Fig. 21), infarcts (Fig. 20) or HIE.
9. Hemorrhage related to congenital brain
tumors
Congenital brain tumors (CBTs; defined as brain tumors pre-
senting within 60 days from birth107) are rare, representing only
approximately 0.5e1.9% of all pediatric brain tumors.108 Pa-
tients often present with macrocephaly (due to the freely
expanding calvarial vault in the neonatal period108,109), and less
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Fig. 17 e Traumatic intracranial hemorrhage: birth-related trauma: intraparenchymal hemorrhage. Axial T2-weighted (a),
coronal T2-weighted (b) and susceptibility-weighted (c) MR images show marked posterior scalp swelling/hematoma (white
arrows in a and b) and low signal intraparenchymal hematoma in the left cerebellar hemisphere with surrounding edema.

Fig. 18 e Traumatic intracranial hemorrhage: birth-related trauma: subdural and subarachnoid hemorrhage. History of
difficult delivery. Axial CT images show a posterior scalp hematoma (* in a) and moulding of the occipital cranial vault
(white arrows in b). Small amount of acute hyperdense SDH is seen along the interhemispheric falx (black arrows in c and
d). Bilateral hyperdense scattered SAH is also observed (d).

frequently with signs of raised intracranial pressure. Up to
14e18% of CBTs show spontaneous hemorrhage and this has
been attributed to the high growth potential of these tumors.
The prognosis depends on the histopathological subtype as
well as the tumor location and general condition of the patient,
although CBTs generally have an unfavourable prognosis with
an overall survival rate of 28% for fetuses and neonates.110
CBTs are seen as a distinct entity from brain tumors in
older children. They are supratentorial in location in most
cases, while brain tumours in older children are frequently
seen in the infratentorial compartment. The majority of brain
tumors in older children comprise glial tumors (Fig. 22), while
teratoma (Fig. 23), a type of germ cell tumour, is the most
common tumor presenting neonatally, accounting for up to
 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 2 ( 2 0 1 8 ) 6 9 0 e7 1 7 705

Fig. 19 e Traumatic intracranial hemorrhage: birth-related: asymptomatic subdural hemorrhage. Asymptomatic incidental
subdural hemorrhage not related to a traumatic or prolonged labour and delivery in a 2-day old neonate; the scan was
performed for suspicion of ventriculomegaly on the antenatal ultrasound. Axial T1-weighted (a) and T2*-weighted gradient
echo (b) images show a thin sliver of subdural hematoma within the right posterior fossa, a classical location for an
idiopathic subdural hemorrhage post delivery. These typically do not progress to chronic SDH and resolve completely by 4
weeks.

30% of CBTs.109,111 Studies have shown that CBTs seen prior to
22 weeks gestation are often teratomas or hamartomas. After
32 weeks gestation, gliomas such as astrocytoma and glio-
blastoma multiforme (GBM) are more common.112,113
Furthermore, in congenital GBM, the clinical and molecular
characteristics are different from their adult counter-
parts.114,115 Germ cell tumors frequently occur prior to 32
weeks gestation and are probably derived from aberrant cells
during embryonic development. Other less common CBTs
include astrocytoma, medulloblastomas, other non-
medulloblastoma embryonic tumors (including supra-
tentorial primitive neuroectodermal tumour (PNET)), choroid
plexus papilloma, lipomas, hamartomas and craniophar-
yngiomas. The recently published 2016 World Health Organi-
zation (WHO) classification of tumors of the CNS involves a
major restructuring of the classification of non-
medulloblastoma embryonal tumors. The previously used
term, supratentorial PNET, had been removed from the diag-
nostic lexicon. Atypical teratoid/rhabdoid tumor (Fig. 24) is
now characterized by alterations in SMARCB1 (INI1) or rarely
SMARCA4 (BRG). CNS embryonal tumors with histological
features of AT/RT but do not exhibit the characteristic genetic
alteration is now classified under CNS embryonal tumor with
rhabdoid features.116 Detailed discussion of this new classifi-
cation is beyond the scope of this review article.
cUS and MRI are the main imaging modalities for tumour
evaluation. CBTs may appear echogenic on cUS, simulating a
focal hematoma. In recent years, fetal MRI has emerged as a
valuable imaging modality which has the potential of
providing useful information on CBTs. Clump-like tumoral
calcifications are often seen in teratoma. Two other CBTs
which may demonstrate tumoral calcifications are PNETs and
choroid plexus papilloma. In PNET, the calcifications are often
curvilinear and sparse as these are dystrophic calcifications
while those seen in teratomas are calcified matrix produced
by the tumour.108
10. Vascular malformations
In the neonatal period, Vein of Galen aneurysmal malfor-
mation (VGAM), dural sinus malformation (DSM) and pial
arteriovenous fistula (AVF) are the predominant vascular
malformations. These lesions however rarely present
with neonatal ICH. VGAM and DSM may mimic ICH, spe-
cifically SDH, and will be discussed in greater details in the
section of “Mimics of neonatal ICH”. Other vascular mal-
formations such as cavernoma, dural AVF and arterial an-
eurysms, although rare, have been observed in the
neonatal period.
10.1. Pial arteriovenous fistula
ICH as the initial presentation of pial AVF is uncommon in
children and was not reported till 2013.117 There have been
suggested associations between pial AVF and hereditary dis-
eases such as hemorrhagic hereditary telangiectasia
(HHT)118,119 and Klippel-Trenaunay-Weber syndrome.120
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Fig. 20 e Traumatic intracranial hemorrhage: Non-accidental injury: subdural and intraventricular hemorrhage,
parenchymal contusions and generalized cerebral atrophy. Axial T2-weighted (a), T2*-weighted gradient echo (b), sagittal
T1-weighted (c) and diffusion-weighted (d) images as well as corresponding ADC map (e) demonstrate bilateral large SDH (*),
small amount of IVH (white arrows in b) and bilateral frontal lobe injuries with cortical laminar necrosis (black arrows in a).
A focal area of restricted diffusion is seen in the right frontal lobe (black arrow in d), in keeping with recent ischemia/
contusion.

Fig. 21 e Traumatic intracranial hemorrhage: Non-accidental injury: subdural hemorrhage and cerebral oedema. Axial T2-
weighted (a), axial T1-weighted (b) and coronal T2-weighted (c) MR images show a right cerebral convexity SDH and
generalised cerebral edema, with loss of the normal grayewhite matter differentiation and generalised cerebral sulcal
effacement. Right uncal herniation is noted (black arrow in c), resulting in brainstem compression. Transfalcine herniation
is also present.

10.2. Dural arteriovenous fistula
Dural AVF accounts for approximately 10% of all intracranial
arteriovenous shunts in children, lower compared to the
10e20% estimated in the adult population.121 They are also
more commonly multifocal and run a more aggressive course
compared to those in adults.122 The sigmoid-transverse,
cavernous and superior sagittal sinuses are the most com-
mon locations. Dural AVFs in neonates, in whom direct arte-
riovenous shunting is severe at birth, tend to present with
congestive cardiac failure due to volume overload. Venous
ischemia/infarction and hemorrhage due to cerebral venous
hypertension are more common in older children.
10.3. Intracranial aneurysm
Intracranial aneurysms are extremely rare within the pedi-
atric population, ranging from 0.5 to 4.6%.123,124 To the best of
our knowledge, only 27 cases of neonatal intracranial aneu-
rysms have been reported till date. The development of
intracranial aneurysms in the neonatal period had been
associated with genetic disorders (neurofibromatosis Type 1,
 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 2 ( 2 0 1 8 ) 6 9 0 e7 1 7 707

Fig. 22 e Hemorrhage related to congenital brain tumors: Glioblastoma multiforme in a 5-day old neonate. Axial T2-
weighted (a), T2*-weighted gradient echo (b), axial T1-weighted (c) and axial T1-weighted post contrast MR images show a
large, mixed solid-cystic mass centred in the left frontal lobe. Surrounding parenchymal edema is present, with marked
rightward midline shift. Blood products of varying ages are seen within the mass, with small amount of blood layering
within its cystic component (black arrow in a). There is also small amount of IVH (*) and SDH (black arrow in b). Obstructive
hydrocephalus is noted.

Fig. 23 e Hemorrhage related to congenital brain tumors: Immature teratoma. Axial non-contrast CT image (a), axial T1-
weighted (b) and axial T2-weighted MR images show a large midline heterogeneous tumor with intratumoral hemorrhage.
Blood fluid layering is seen within one of its cystic component (black arrow in c). Blood layering is also present within the
posterior horns of the lateral ventricles (white arrows). Severe hydrocephalus and generalised cerebral sulcal effacement are
seen.
708 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 2 ( 2 0 1 8 ) 6 9 0 e7 1 7

Fig. 24 e Hemorrhage related to congenital brain tumors: Posterior fossa ATRT with high Ki67 proliferative index (WHO
grade IV). Non-contrast axial CT image (a), axial T2-weighted (b), axial T1-weighted (c), and axial T1-weighted post contrast
(d) MR images show a mixed solid-cystic mass within the posterior fossa with upstream ventricular dilatation and
transependymal CSF migration (white arrows in a). The mass is hyperdense on the non-contrast CT scan due to the
presence of tumoral hemorrhage. These hyperdense areas show corresponding T1 shortening, in keeping with subacute
blood products.

Ehlers-Danlos syndrome type IV, familial immune deficiency
syndrome), connective tissue disease and congenital heart
disease.
11. Mimics of neonatal ICH
Several potential mimics of ICH in the neonatal period include
DSM, intracranial hemangioma and VGAM.
11.1. Dural sinus malformation
DSM is seen on imaging as a blood-filled cavity within the
leaves of the dural sinus, and may potentially cause mass
effect upon adjacent cerebral parenchyma, cardiac insuffi-
ciency and consumptive coagulopathy. Thrombus formation
within the ectatic dural venous sinus is typically followed by
spontaneous regression (Fig. 25). On cUS, this condition may
mimic SDH in the region of the venous confluence (Fig. 26),
intraparenchymal hematoma or other intracranial vascular
anomalies such as VGAM.125,126 MRI allows better anatomical
localisation of the ectatic dural venous sinus between the
leaves of the dura and communication with the superior
sagittal sinus, compared to cUS. Patients with large DSM often
present at birth with signs of raised intracranial pressure and
some degree of cardiac failure. When associated with
thrombus formation, there is a high risk of venous ischemia
and hemorrhage.127,128 DSM with or without identifiable
thrombus can regress spontaneously. Good neurological
outcome can be expected in up to 70% of cases.129
11.2. Intracranial hemangioma
Intracranial hemangiomas are another potential mimic of
neonatal ICH. On MR imaging, they are seen as extra-axial
lesion with high signal intensities on T1-weighted and
 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 2 ( 2 0 1 8 ) 6 9 0 e7 1 7 709

T2-weighted images, simulating a late subacute extra-axial
hematoma (Fig. 27). The presence of intralesional calcifica-
tions and intense contrast enhancement are useful diagnostic
clues.130,131 Similar to DSM, neonates with large intracranial
hemangioma commonly present with macrocephaly and/or
signs of raised intracranial pressure.130,131 There is also often
presence of concurrent cutaneous lesions. Intracranial hem-
angiomas have the potential to grow and regress spontane-
ously over time.132 Hence, surgical excision is reserved for
large lesions or when signs of raised intracranial pressure are
seen.130 Small intracranial hemangiomas on the other hand,
could be followed for regression, especially if there is associ-
ated cutaneous disease,133 since it has been reported that
intracranial hemangiomas may regress in a manner parallel
to concurrent cutaneous disease.134
11.3. Vein of Galen malformation
VGAM, another potential mimic of neonatal ICH, is rare, with
an incidence of approximately 1 in 25,000 births. It occurs due
to a congenital connection between intracranial arteries and
persistent embryonic prosencephalic vein of Markowski, an
embryonic precursor of the vein of Galen, resulting in a high-
flow arteriovenous fistula.135 The median prosencephalic vein
of Markowski usually regresses during the 11th week of
gestation, and by 3 months of gestation the posterior part of it
joins the internal cerebral veins and basal veins to form the
vein of Galen. Failure of the normal degeneration of the me-
dian prosencephalic vein and persistence of its primitive
arteriovenous fistulous connections are postulated to be the
underlying cause of VGAM. High output cardiac failure is the
most common presentation in the neonatal period. Infants on
the other hand commonly present with increasing head
circumference and hydrocephalus. The Lasjaunias classifica-
tion divides VGAM into the choroidal type (Fig. 28; multiple
direct, high-flow shunts converge on a fistula site at the
anterior aspect of the median prosencephalic vein) and mural
type (single or multiple fistulae within the inferolateral wall of
the median prosencephalic vein). The choroidal type is the
more common and more complex subtype, causing high-
output cardiac failure in neonates.136 The mural type is
often associated with absence/stenosis of dural sinuses and
contains fewer fistulas with slower flow.137 Due to the pres-
ence of venous outflow restriction and hence reduced cardiac
return, they often do not develop severe cardiac failure in the
neonatal period and tend to present later in infancy with hy-
drocephalus, developmental delay or seizures.138 Until the
advent of endovascular treatment, VGAMs in the neonatal
period with severe congestive heart failure were almost uni-
versally fatal.
12. Clinical outcome in relation to neonatal
ICH
Clinical outcomes in neonates with ICH vary with the maturity
of the brain, the underlying etiology, location and extent of the
lesion as well as the presence of other concurrent disorders.

Fig. 25 e Mimics of neonatal ICH: Dural sinus malformation. Axial T2-weighted image (a), sagittal T1-weighted image (b)
and time-of-flight MR venogram acquired at 4 days of age show a partially thrombosed DSM, mimicking a SDH. There is also
marked ventriculomegaly and absence of the septum pellucidum. Axial T2-weighted (d) and sagittal T1-weighted post
contrast MR images obtained 3 months later demonstrate spontaneous regression of the DSM. There is however interval
progression of supratentorial hydrocephalus, presumably due to disturbances in venous outflow.
710 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 2 ( 2 0 1 8 ) 6 9 0 e7 1 7

Fig. 26 e Mimics of neonatal ICH: Dural sinus malformation. Fetal MRI (a) shows a low signal structure at the venous
confluence (*) on a T2-weighted image, mimicking SDH. Axial non-contrast CT (b), axial T2-weighted (c) and sagittal T1-
weighted (d) MR images acquired on day 1 after birth confirmed the presence of a DSM with partially calcified thrombi (white
arrows in b) between the leaves of the dura and in continuity with the superior sagittal sinus (white arrows in d). No
evidence of hydrocephalus.

Fig. 27 e Mimics of neonatal ICH: Intracranial hemangioma. Axial non-contrast CT images (a,b) and the axial T1-weighted
post contrast MR image show a large, well circumscribed extra-axial mass in the left middle cranial fossa. This mass is
hyperdense on non-contrast CT and mimics an intracranial hematoma. Erosion of the inner table of the left temporal cranial
vault (white arrows in b) is noted. After contrast administration, thick dural enhancement is seen adjacent to the mass,
along the left temporal convexity.
 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 2 ( 2 0 1 8 ) 6 9 0 e7 1 7 711

12.1. Subdural and subarachnoid hemorrhage 12.3. Intraparenchymal hemorrhage

SDH is the commonest type of ICH in neonates, most of which
are small, asymptomatic and resolve without significant
consequence on neurodevelopment.139 The neuro-
developmental outcome of neonates with SAH is also generally
thought to be good, although the location and extent as well as
presence of complications from the SAH may play a role.
12.2. Intraventricular hemorrhage
The clinical outcome of neonates with IVH depends largely on
the severity of bleed, presence of concurrent white matter
injury and other complications such as post-hemorrhagic
ventricular dilatation and parenchymal infarctions. O'Shea
et al. reported that infants with IVH not accompanied by white
matter injury have only a slightly increased risk of major
developmental impairments. On the other hand, when IVH
was associated with concurrent white matter injury, there
was a strong association with CP, impaired mental and motor
development as well as visual dysfunction.47 Brouwer et al.
reported that most preterm infants with IVH with evolving
ventriculomegaly do not develop cognitive impairment, CP or
epilepsy providing the neurosurgical intervention is early,
thus avoiding prolonged periods of raised intracranial pres-
sure, periventricular edema and distortion of the developing
axonal pathways.140 This emphasized the importance of early
surgical intervention in preterm infants with progressive
post-hemorrhagic ventricular dilatation.
For intraparenchymal hemorrhage, outcomes depend on the
site of the lesion, particularly whether it affect the cortico-
spinal tracts, the central gray matter, or the cerebellum.
Outcome is almost always better if lesions are isolated and
unilateral compared to multiple or bilateral. It is also impor-
tant to note whether lesions occur on the background of other
abnormalities such as CSVT, infection or HIE. Any underlying
genetic disorders such as COL4A1 mutation may indepen-
dently influence outcome. Bilateral CP can be predicted if
there is bilateral basal ganglia-thalamic (BGT) injury and
particularly so if the normal signal from the posterior limb of
the internal capsule (PLIC) is not seen. This has been best
investigated in large cohorts of infants with HIE where over
90% of infants with severe bilateral BGT injury will develop
severe CP. Hence, preservation of normal signal in the BGT
and within the PLIC were the best predictor of good motor
outcome.141 Functional feeding and communication impair-
ments were strongly related to the severity of motor impair-
ment, especially in children with BGT and brainstem injuries.
However, this pattern of bilateral BGT injury is not common
with hemorrhage alone. Unilateral injury such as may occur
with neonatal ischemic arterial stroke or grade IV hemor-
rhagic parenchymal infarction affecting the corticospinal
tracts (leading either directly or indirectly to Wallerian
degeneration in the cerebral peduncles and brainstem) will
lead to contralateral unilateral CP or a hemiplegia, but other
outcomes may be good. Unilateral thalamic hemorrhage, even

Fig. 28 e Mimics of neonatal ICH: Vein of Galen aneurysmal malformation (choroidal type). Fetal MRI images in the sagittal
(a) and axial (b) planes, acquired at 28 weeks of gestation, demonstrate dilatation of the median prosencephalic vein of
Markowski (*), which usually regresses during the 11th week of gestation. There is also persistence of the falcine sinus
(white arrow in a). Axial non-contrast CT image (c) shows a mildly hyperdense midline structure, corresponding to the
dilated median prosencephalic vein (may mimic a subdural hematoma). Cerebral angiography (d) revealed a choroidal type
VGAM, with arterial supply from distal pericallosal and posterior cerebral artery branches. High flow shunts are seen
converging onto the anterior aspect of the median prosencephalic vein. The pericallosal and left posterior choroidal supplies
were embolized. Axial T2-weighted MR image (e) acquired post embolization showed partial thrombosis of the dilated
median prosencephalic vein.
712 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 2 ( 2 0 1 8 ) 6 9 0 e7 1 7
though it is extremely near the PLIC, often does not lead to a
hemiplegia and anterior thalamic involvement may be asso-
ciated with a favorable clinical outcome. However, extensive,
predominantly posterior thalamic involvement is associated
with increased risk of subsequent epilepsy and electrical
status epilepticus in slow wave sleep (ESES), becoming
apparent between 2 and 4 years of age. This is frequently
associated with a decline in cognitive function. Such thalamic
lesions, as well as lesions involving the optic radiation and
any lesion directly in the primary visual region are highly
likely to lead to visual deficits.142,143 Salamon et al. reviewed
outcomes for hemorrhagic parenchymal lesions in preterms
that involve frontal and temporal lobes. They found that there
were no motor deficits but a considerable burden of cognitive,
behavioral and visual problems.49 Widespread PWMLs may
cluster in the centrum semiovale, in the line of the cortico-
spinal tract and lead to a mild CP.
In infants without major cerebral injury, poor cognitive,
language and behavioural outcomes may be attributed to
delayed cerebral atrophy secondary to cerebellar injury.144 Allin
et al. found that a reduction in cerebellar hemispheres' volume
was associated with a decline in mental but not motor func-
tion.145 Although larger cerebellar injuries have been associated
with autism spectrum behaviors, smaller hemorrhages, espe-
cially those only detectable on MRI are not at 2 years and at
early school-age associated with severe outcomes.52
13. Conclusions
ICH is the leading cause of neonatal morbidity and mortality.
The underlying etiology may be either inherited or acquired
and can be classified into 8 main categories, as illustrated in
our review article. Clinical outcomes in neonates with ICH
varies with the maturity of the brain, underlying etiology,
location and extent of the lesion as well as the presence of
other concurrent disorders.
Funding source
No funding was secured for this study.
Financial disclosure
The authors have no financial relationships relevant to this
article to disclose.
Conflict of interest
None.
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