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Journal of Neonatal-Perinatal Medicine xx (20xx) x–xx
DOI:10.3233/NPM-1816
IOS Press

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Perinatal carotid artery ischemic stroke:
Report of two cases

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a Department of Medical Sciences, Pediatric Section, University of Ferrara, Italy

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b Child Neurology and Clinical Neurophysiology, Pediatric University Hospital, Padua, Italy

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c Department of Neurosciences, Neuroradiology Unit, University of Salerno, Salerno, Italy

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d Neonatal Intensive Care Unit, Pediatric University Hospital, Padua, Italy

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Received 26 February 2018

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Revised 04 October 2018

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Accepted 08 March 2019

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Abstract. The mechanisms of perinatal stroke are poorly understood but preclinical studies point to the crucial role of
perinatal inflammation. Carotid artery occlusion represents a very rare and severe cause of perinatal stroke. We describe two
cases diagnosed with extensive ischemic stroke due to carotid artery occlusion. In both cases, we demonstrated placental
vasculopathy. High levels of C-reactive protein in mother and/or neonates suggested inflammatory mechanism as a potential
trigger. Both cases underwent hypothermic treatment without complications because of initial diagnosis of perinatal asphyxia.
The prognosis at the time of the last follow up was severe including cerebral palsy, epilepsy and cognitive impairment. Our
cases contribute to the actual debate on pathogenic mechanisms and treatment options for this rare condition.

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A. Suppieja,b,∗ , E. Toffolib , I. Festab , C. Cervesib , A. Cappellarib , R. Manarac ,
M. Magarottod and E. Cainellib

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Keywords: Neonate, inflammation, hypothermia, thrombophilia, seizures, outcome

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Perinatal arterial ischemic stroke includes a variety of conditions in which blood flow disruption in a
cerebral artery, occurring between 20 weeks of fetal
life and 28 days of postnatal life, damages a focal
area of cerebral tissue [1]. Clinical signs occurring
in the neonatal period with MRI evidence of acute
stroke [2, 3] define neonatal arterial ischemic stroke
(NAIS). NAIS must be distinguished from presumed
perinatal arterial ischemic stroke in which clinical manifestations present after the neonatal period

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1. Introduction

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∗ Address for correspondence: Agnese Suppiej, M.D., Depart-

ment of Medical Sciences, Pediatric Section, University of
Ferrara, Via Aldo Moro, 8, 44124 Ferrara, Italy. Tel.: +39
0039 3473677013; Fax: +39 0532 23 78 48; E-mail: agnese.
suppiej@unife.it.

(usually motor asymmetry after few months of life)
and which is associated to brain imaging evidence of
remote infarction, which could have occurred in the
perinatal period [4].
Carotid artery occlusion is a very rare and severe
cause of NAIS, less than 20 cases have been reported
so far, representing 0.5% of all documented causes
[5–16]. The clinical presentation can be nonspecific
with early seizures within a general clinical picture of
encephalopathy [17]. Thus, encephalopathy resulting
from large vessel occlusion and massive hemispheric
ischemia can be misdiagnosed as hypoxic ischemic
encephalopathy [18]. Moreover, birth asphyxia is a
risk factor for perinatal stroke and the two conditions
may coexist. Nowadays neonates fulfilling criteria
of post asphyxia encephalopathy undergo hypothermic treatment, but hypothermia is not at present

1934-5798/19/$35.00 © 2019 – IOS Press and the authors. All rights reserved

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2. Methods
Out of a population of 104 neonates enrolled in the
neonatal intensive care unit of the University Hospital
of Padua for hypothermic treatment between February 2009 and December 2016, two suffered from
carotid artery occlusion and stroke. Maternal and
neonatal data, placental histology and brain and arterial MRI data were collected. Our institutional criteria
of enrollment for hypothermia have been previously
described. The follow-up program for neonates managed with hypothermia at our Institution includes
neurological examination at 1, 3, 6, 9, 12, 18, 24, 36
months, and at 4 and 5 years of age and also standardized assessment of development with the Griffiths
Mental Development Scales.
The coagulation panel adopted at our institution
includes: prothrombin time, partial thromboplastin
time, protein S activity and antigen, protein C activity and antigen, APC sensitivity ratio, Leiden factor
V◦ mutation, prothrombin gene mutation G20210A,
coagulation factors II-VIII-IX-XI, fibrinogen, plasminogen activator, plasminogen activator inhibitor,
anti-cardiolipin antibodies (IgG and IgM), anti beta2
glycoprotein 1 antibodies (IgG and IgM).
The hospital ethical committee approved the retrospective review of the clinical records, imaging and
cognitive data for this study.

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3.1. Case 1

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A female infant was born at 40+4 weeks in a
first level hospital, following an uneventful pregnancy. She underwent emergency cesarian section
due to dynamic dystocia and a pathological cardiotocographic tracing. Birthweight was 2900 g (10th
centile), length 52 cm (50th centile) and head circumference 35 cm (50th centile). Apgar scores were 6-7-7
(1’–5’–10’). She needed positive pressure ventilation with laryngeal mask for respiratory depression at
birth. Funicular pH was 7.01 and BE -16.2. Troponin
level was 0,29 ug/l (normal values 0–0,045). She
developed moderate encephalopathy (Sarnat score 2).
At three hours of life, she developed focal seizures.
Phenobarbital was started with good seizure control. She also had a high temperature (CT 38.2◦ C)
from the first day of life and persistently elevated
level of C-reactive protein (14,2 mg/dl at birth and
21,2 mg/dl at 24 hours). Her platelet count was
100.000 m3 ; she was treated with antibiotics. Hemoculture was negative. She was promptly transferred to
a central hospital where therapeutic hypothermia was
started at 5:30 hours of life. Cranial ultrasounds on
the first day of life showed diffuse hyperechogenicity on the right hemisphere and median line shift
to the left. Brain CT scan revealed an extensive
ischemic area in the right hemisphere, involving
anterior and middle cerebral artery territories, and
showed a marked cerebral regions shift to the left; a
thrombus in the right carotid artery was also identified. Magnetic resonance imaging (MRI) performed
on the same day confirmed the extensive stroke
involving the right hemisphere, sparing the occipital areas and showed brain swelling resulting in
an 8 mm shift to the left of the median cerebral
regions. The intracranial tract of the right internal
carotid artery was poorly visualized on magnetic
resonance angiography. Diffusion-weighted imaging
revealed Wallerian degeneration of the corticospinal
tract along the brainstem, suggesting prenatal vascular insult (Fig. 1). Supra-aortic vessels echo Doppler,
performed on day 2, revealed internal right carotid
artery occlusion just after its origin, with preservation of the right subclavian and anonymous artery.
Supra-aortic vessels echo doppler and T1W fatsat sequence on day 6 MRI showed an unchanged
thrombosis of the right internal carotid with no
evidence of carotid wall dissection. Coagulation
studies showed reduced levels of protein C and

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3. Case summary

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recommended for perinatal stroke. In the literature,
there is no clear consensus on the best treatment for
NAIS; possible options such as antithrombotic therapy and therapeutic hypothermia are at present not
included in the International Guidelines [19]. However, the adult literature discusses on their use in
severe cases such as large and/or multiple embolic
strokes in the setting of extra cerebral large vessels
thrombosis [20].
The mechanisms of NAIS have been considered multifactorial but recently research pointed
to systemic and local inflammation as fundamental independent risk factors [21–23]. These results
have important implications for the management of
patients, since infection and inflammation could be
the target of neuroprotective treatments.
The aim of the present study was to contribute to
the to the actual debate on pathogenesis and treatment options for NAIS by reporting on maternal
and perinatal risk factors and long-term outcome of
two neonates with carotid artery occlusion who were
treated with hypothermia.

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protein S, subsequently normalized at the age of
10 months.
The histological examination of the placenta
showed a thrombotic process of the fetal vessels.
Laboratory tests performed on maternal blood were
unremarkable except for an elevated level of Creactive protein (78.99 mg/L) and a high level of
anti-cardiolipin antibodies (IgG 22.44 GPL, normal
values <15.00).
MRI follow-up at 2 and 15 months of age showed
the expected evolution of the hemispheric ischemic
area with no recanalization of the right internal
carotid artery (Fig. 1).
At 15 months, there was an additional evolution of
the ischemic lesion involving the right hemisphere,
sparing the thalamus and part of the occipital and
temporal lobes. The right internal carotid artery as
well as the anterior and middle right cerebral arteries
had not re-canalized (images not shown).
At one year, the developmental assessment with
the Griffiths Mental Development Scales indicated
impairment (<3◦ percentile) in all subscales (locomo-

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Fig. 1. Hemispheric ischemic area with no recanalization of right internal carotid artery. Legend: A) Diffusion weighted images one day after
birth showing hyperintensity of the right hemisphere consistent with ischemia. The right thalamus (black arrowheads) and the right cerebral
peduncle (not shown) are also hyperintense suggesting that the stroke was recent but not hyperacute (prenatal stroke?). B) Axial T2-weighted
images at the age of 2 months showing the evolution of the ischemic regions of the right hemisphere into diffuse encephalomalacia and atrophic
right thalamus. C) MR angiography at the age of 2 months showing the persisting absence of the right internal carotid artery (short arrows)
and the narrowing of the right posterior cerebral artery (arrowhead) due to decreased metabolism (the same artery was pseudo-hypertrophic
during the acute phase because of compensatory activation, not shown).

tors, personal-social, hearing and language, eye-hand
co-ordination and performance). Motor functions
were the most impaired, with impact on the maturation of all other functions. Language repertoire
was poor, the visual contact was rare and interaction
abilities were impaired. The child developed focal
epilepsy at the age of 3 years, well controlled by
carbamazepine.
At 4 years, the neurological examination revealed
bilateral spastic cerebral palsy with a more severe
impairment of the left side, cognitive deficit, strabismus and low vision.
3.2. Case 2
A female infant born at 38+4 weeks by Cesarean
section due to pathological cardio-tocographic tracing. Pregnancy elapsed with intrauterine growth
restriction from 34th week gestation. Birth weight
was 2730 gr (10th centile), length was 47 cm (10th
centile) and head circumference was 33.5 (10–25th
centile). Apgar scores were 5–8–8 (1’–5’–10’).

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middle and anterior cerebral territories and other
ischemic lesions in the territories of right middle
cerebral artery. Willis circle study showed extra and
intra-cranial occlusion of the left internal carotid,
stenosis of the right posterior cerebral artery and, to
a lesser extent, of the right sylvian branches (Fig. 2).
The coagulation panel was normal for gestational
age. The placenta was small and showed various
wide, white areas, suggesting ischemic origin. Coagulation studies performed on maternal blood showed
increased levels of IX factor, XI activity, fibrinogen
and plasminogen activity, while lupus anticoagulant,
antinuclear and anti-phospholipid antibodies were
negative.
The MRI follow-up at 22 days of life showed
regular evolution of the ischemic areas. Magnetic resonance angiography revealed initial re-canalization
of intracranial left internal carotid. Clinical follow up
at one year of age using the developmental assessment
with Griffiths Mental Development Scales showed
impairments (<3◦ percentile) in 4/5 subscales (locomotors, personal-social, eye-hand co-ordination and

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Funicular pH was 6.94, EB -19.6 mmol/L. At
birth, she presented hypotonia, apnea and cyanotics,
and required resuscitation with endotracheal suction of stained amniotic fluid. She had moderate
grade encephalopathy (Sarnat score 2). Therapeutic
hypothermia begun at 4:30 hours of life. The troponin
level on day 1 was high (0.451 ug/L), but returned
to normal range on day 3. The electrocardiogram
showed signs of transient myocardial ischemia. There
was an increased level of C-reactive protein (19 mg/L
at birth, increased at 40 mg/L at 24 hours of life) for
which she received antibiotic therapy. Hemoculture
was negative. During the first day of life the electroencephalographic monitoring showed electrical seizure
patterns both in left temporal regions and, independently, in right occipital regions, with absent or subtle
clinical correlate. She received phenobarbital treatment and seizures ceased. Transcranial ultrasounds
performed on day 1 showed periventricular hyperechogenicity, particularly in the parietal region. The
MRI performed on day 2 showed multiple strokes:
a large left hemisphere ischemia involving both the

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Fig. 2. Extra and intra-cranial occlusion of the left internal carotid, stenosis of right posterior cerebral artery and, in lesser extent, of the
right sylvian branches. Legend: A) Axial diffusion weighted images at the age of 2 days showing acute ischemia in the left hemisphere
(temporal-mesial and basal occipital lobes were partially spared, not shown); note the concomitant ischemia in the contralateral occipital lobe;
a further small acute ischemia was observed in the right inferior parietal lobule in the supply territory of the middle cerebral artery, not shown,
suggesting a multi embolic pathogenesis. B) Axial T2-weighted images at the age of 12 days showing the evolution into encephalomalacia
of the ischemic regions. C) MR angiography at the age of 2 days showing the occlusion of the left internal carotid artery; note the pseudohypertrophy of the left intracranial arteries, more evident at the level of the middle cerebral artery branches (∗ ). Note also the distal occlusion
of the right posterior cerebral artery (arrowhead), consistent with a multi embolic pathogenesis.

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4. Discussion
The two cases of neonatal arterial ischemic stroke
reported in the present study occurred because
of fetal-placental thromboembolic events associated
with carotid artery occlusion, a rare but severe cause
of neonatal arterial ischemic stroke. Perinatal inflammation, probably induced by infection was a common
mechanism in both cases. Indeed, they had persistently an elevated level of c-reactive protein and
underwent antibiotic treatment; case 1 had also fever
and her mother had elevated level of C-reactive
protein.
Both cases had evidence of maternal hypercoagulable status. The mother of case 1 had high levels
of anti-cardiolipin antibodies. The mother of case
2 had increased levels of IX factor, XI activity,
and fibrinogen and plasminogen activity. Follow-up
studies were not performed precluding the possibility of confirming a permanent thrombophilia status.
Moreover, in both cases histological examination of
the placenta showed thrombotic/ischemic changes
suggesting placental vasculopathy. MRI evidence
of Wallerian degeneration of the corticospinal tract
along the brainstem suggested a prenatal vascular insult in case 1 while pregnancy elapsed with
intrauterine growth restriction from 34th week in
case 2.
Other etiologies specifically implicated in the
occlusion of large extracranial vessels such as the
internal carotid artery, were ruled out in our patients.
Traumatic dissection of the internal carotid artery,
can occur secondary to traumatic events during delivery, particularly in the case of fetal macrosomia and
shoulder dystocia [5, 9]. In rare cases, spontaneous
carotid artery dissection may be an intrinsic fetal

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and placental vascular disease. Both our cases underwent cesarean section. In the case with emergency
cesarean section and dynamic dystocia, brain MRI
and magnetic resonance angiography investigations
did not detect signs of traumatic injury to the carotid
artery wall. They did not have fetal subarachnoid and
intraventricular hemorrhage therefore other causes of
carotid artery occlusion such as vascular spasms were
unlikely [11].
In view of new treatment strategies, it is important
to understand causative events underlying perinatal stroke. The hypothesis of a multifactorial
etiology involving maternal, placental, fetal and
neonatal risk factors is at present a major focus
of research [5]. The most recent evidence, however, points to maternal-fetal inflammation as the
single most important independent mechanism of
NAIS [20]. Infection/inflammation can explain the
co-occurrence of other important risk factors for
stroke. Indeed, birth asphyxia, is also a powerful
inducer of sterile inflammation and inflammation has
a pro-coagulant effect. Our two cases of perinatal
arterial ischemic stroke from carotid occlusion confirm the role of pre/perinatal inflammation, within a
multifactorial etiology. We searched and found signs
of inflammation even in the case with absent fever as
well as additional risk factors such as maternal thrombophilia, placental vascular pathology and hypoxic
ischemic encephalopathy.
One other interesting feature of the present study
is that we recruited our two cases from a prospective single center cohort of patients, fulfilling criteria
for therapeutic hypothermia; they constituted about
2 % of the total population of patients recruited.
Both of them had a combination of carotid artery
stroke, depression at birth with metabolic acidosis and encephalopathy. In the first hours of life,
the diagnosis of hypoxic ischemic encephalopathy was hypothesized, making them eligible for
hypothermic treatment. This treatment is not at
present recommended for perinatal stroke; however, the clinician’s decision after the diagnosis of
stroke was to continue the treatment, monitoring
closely all possible side effects. We could not prove
possible benefits; however, therapy was without
complications.
Perinatal stroke in the context of carotid artery
occlusion represents the most severe type of arterial ischemic stroke occurring in the perinatal period.
Prognosis is worse than other types of NAIS [5].
Accordingly, both our cases developed cerebral palsy.
Moreover, in both cases re-canalization of affected

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performance), while linguistic abilities were adequate. Motor was the most affected function; all
non-motor functions where motor disabilities could
have an interference on the tests were also slightly
involved but, with good interaction abilities. At 2
years of age, Griffiths Mental Development Scales
showed an adequate development of linguistic and
personal/social abilities. Motor functions persisted in
being severely impaired (<3◦ percentile) due to right
hemiparesis.
At 4 years, clinical examination revealed unilateral
spastic cerebral palsy (right hemiplegia), cognitive
impairment and difficulties in modulation of emotional states.

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5. Conclusions

Our study points to the importance of searching for
carotid artery thrombosis in the work up of perinatal
stroke, particularly when atypical presentation and/or
multiple vascular territories are involved. Information on placental pathology as well as on maternal
thrombophilia must be part of the routine workup.
Perinatal inflammation must also be appreciated both
in mothers before birth and in neonates, because
of its importance in pathogenesis and of its implications for prevention and management. The poor
long-term prognosis in perinatal stroke due to carotid
artery occlusion prompts further research efforts, to
evaluate treatment strategies that could improve the
outcome.

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Financial disclosure statement: no authors
declared potential or actual interests are disclosed.
Statements of human rights: For this type of study,
formal consent is not required.

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arteries did not occur. Treatment of perinatal stroke
is a challenge for clinicians. The main issue in stroke
management is to preserve brain tissue by restoring cerebral blood flow; the treatment of choice in
adults is systemic thrombolysis with tissue plasminogen activator, in a 3- to 4.5-hour time window. In
children and even more in neonates, there is no
consensus on both intravenous thrombolysis as well
as endovascular therapy of arterial stroke, because
of the substantial lack of data on efficacy and
safety [25].
Furthermore, in neonates, timing is a crucial issue
considering that stroke often occurs before birth,
as in our cases, hindering any acute strategy. In
addition, International Guidelines for treatment of
perinatal arterial ischemic stroke do not recommend anticoagulation in arterial stroke [26]. Even if
stroke recurrence is negligible in NAIS, neonates may
undergo thrombus propagation particularly when
spontaneous recanalization does not occur in the first
week of life. Anticoagulation therapy was recently
introduced in neonatal cerebral sinovenous thrombosis [26], to prevent thrombus propagation, but not
in arterial ischemic stroke. Considering the outcome
severity and the lack of recanalization of occluded
vessels in our patients, we question if antithrombotic therapy could have been of benefit. Indeed,
our cases confirm that NAIS subtypes have different
prognosis. Stroke subtype should guide a decisionmaking tailored to the patient. In conditions with
the worst prognosis, such as carotid artery occlusion,
particularly when recanalization does not occur, or
thrombosis progresses, anticoagulation could be an
option.

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