Keywords neonatal intracranial hemorrhage - neonatal cerebral thrombosis - anticoagulant therapy
- cerebral sinus venous thrombosis - treatment timing
Introduction
Cerebral sinus venous thrombosis (CSVT) is a focal or diffuse interruption of cerebral
blood flow, resulting from occlusion of venous sinuses or cerebral veins, with or
without intraparenchymal hemorrhage. Despite being a rare event in the neonatal period,
with an estimated annual incidence of around seven cases per 1 million neonates,[1 ] CSVT represents a pathological condition of increasing interest in the neonatal
field.[2 ] The wide spectrum of onset clinical manifestations makes it difficult to obtain
an early diagnosis. Moreover, this condition is complicated by high morbidity and
mortality in the neonatal period and there is still an open debate regarding the management
of anticoagulant therapy and its timing.[3 ]
[4 ] Low molecular weight heparin in patients with CSVT may cause an intraparenchymal
hemorrhage or may worsen it when already present at diagnosis, while a watchful wait
with a supportive treatment may result in thrombus propagation and consequently additional
brain damage.[4 ]
[5 ]
We present a neonate with CSVT who has been successfully treated with heparin at an
early time, despite the presence at diagnosis of a cerebellar hemorrhage. Parental
informed consent was taken to publish the case.
Case Report
A 391/7 weeks of gestation male neonate weighting 3,200 g, was admitted to our neonatal intensive
care unit (NICU) at 13 hours of life because of neurological symptoms such as difficulty
in sucking, hypotonia, hyperflexion of the upper limbs and extension of the lower
limbs, associated with mild respiratory distress and hyperglycemia.
He was born from a pregnancy obtained by homologous intracytoplasmic sperm injection
(ICSI). The maternal TORCH complex serologies, the vaginal and straight swabs were
negative and no signs of chorioamnionitis were reported. Fetal ultrasound scans (US)
performed during pregnancy were reported as normal. Maternal coagulation screenings
were negative. The mother had received therapy with acetylsalicylic acid during pregnancy
and levothyroxine as a therapy for gestational hypothyroidism.
The baby was born from an urgent cesarean section performed because of a pathologic
cardiotocographic pattern (type II) and a meconium-stained liquor. The newborn did
not require any respiratory assistance at birth and the APGAR score was 9 both at
1 and 5 minutes. The arterial cord gas analysis showed a mild metabolic acidosis (pH:
7.08; BE: −11.2), the modified Sarnat score was normal, and then no indications to
proceed to hypothermic treatment were identified. The newborn was admitted to the
nursery for cardiorespiratory and glycemic monitoring and subsequently to the rooming-in
ward after a clinical re-evaluation resulted as normal. At 13 hours of life, neurological
symptoms such as difficulty in sucking, hypotonia, hyperflexion of the upper limbs,
and extension of the lower limbs, associated with mild respiratory distress and hyperglycemia
were observed.
The brain US performed at the admission to the NICU, showed a hyperechoic lesion in
the posterior cranial fossa, extending in the median area above the cerebellum. This
finding was consistent with cerebellar hemorrhage. Due to the term gestational age
and the clinical history, a diagnosis of CSVT was hypothesized and an emergency cerebral
computed tomography angiography was performed at 20 hours of life. The exam confirmed
the presence of an intraparenchymal acute hemorrhage located in the left cerebellar
hemisphere, with upward transtentorial herniation and compression on the brainstem
and fourth ventricle. The lesion was associated with thrombosis of the Erofilo's Torcularis
and the posterior part of the superior sagittal sinus and incomplete thrombosis of
the left transverse sinus and straight sinus ([Fig. 1 ]). The newborn started anti-convulsant therapy with barbiturates after onset of apneic
crisis requiring noninvasive respiratory assistance. The electroencephalogram showed
a symmetrical low-voltage electrical activity with sporadic anomalies on the posterior
regions, especially on the left side.
Fig. 1 (A, B ) Noncontrast enhanced CT scan. (C, D ) CT angiography scan. CT scan showed acute hemorrhage located in the left cerebellar
hemisphere (asterisk in A), exerting mass effect (IV ventricle compression, upward
transtentorial herniation, and crowding of foramen magnum were noted). A high density
of posterior superior sagittal sinus was noted (arrows in B). CTA showed multiple
filling defects, representing thrombosis, in the posterior superior sagittal sinus
(“empty delta” sign, arrow in C) and Erofilo's torcularis region (arrow in D).
Early treatment with low molecular weight heparin at a prophylaxis dosage (75 IU/kg
every 12 hours) was started at 48 hours of life to prevent the propagation of thrombosis.
The cerebral US performed before starting the treatment had already documented the
stability of the hemorrhage. Due to the consistent risk of hemorrhage expansion at
this early stage, brain US monitoring was planned every 8 hours to check the evolution
of the hemorrhage. The serial brain US showed a stable hemorrhage and mild ventricular
dilation (lateral and third ventricles). The anticoagulant therapy was progressively
increased in relation to the anti-Xa factor monitoring, up to a therapeutic dose of
155 IU/kg every 12 hours. Cerebral magnetic resonance imaging (MRI) performed on the
seventh day of life confirmed the size stability of the cerebellar hemorrhage and
showed partial recanalization of the Erofilo's torcularis, with the persistence of
small filling defect in the transverse sinus ([Fig. 2 ]). According to neurological stability and absence of apneic crisis, respiratory
assistance was discontinued on the 14th day of life. Predischarge cerebral US showed
a cavitated lesion in the site of the cerebellar hemorrhage and a stable mild ventriculomegaly.
The newborn was discharged on the 23rd day of life in good general health on heparin
therapy and barbiturates. A scheduled follow-up clinic was planned including brain
US, neurosurgical and neurological evaluation, and blood tests. At 45 days of life,
the follow-up brain US showed an almost complete regression of the bleeding. The brain
MRI performed at this stage documented the expected regression of the hemorrhagic
lesion in the posterior cranial fossa, the decompression of the brainstem, the resolution
of the herniation, and the reduction of the supratentorial ventricular dilation. Brain
MRI also showed a residual focal thinning of the Silvio aqueduct and an irregular
appearance of the posterior portion of the superior sagittal sinus and of the mesial
portion of the left transverse sinus. The remaining dural venous sinuses and internal
cerebral veins were patent ([Fig. 3 ]).
Fig. 2 (A ) Spin echo (SE) T1 weighted sequence, axial plane. (B ) Turbo SE (TSE) T2 weighted sequence, coronal plane. (C ) Magnetic resonance venography (MRV), axial plane (D ) MRV, and MIP reconstruction. MR showed left cerebellar hemorrhage compressing the
IV ventricle (arrow in A) and causing ventricular dilatation (B). MRV showed a filling
defect in the left transverse sinus (arrow in C) and reduced lumen of the posterior
sagittal sinus (arrow in D) and of the rectus sinus (asterisk in d), as for partial
recanalization.
Fig. 3 (A ) TSE T2 weighted sequence, axial plane. (B ) MRV, MIP reconstruction. MR showed the chronic phase of the hemorrhage. A hemosiderin-lined
cavity was detected in the left cerebellar (asterisk in A). Reduced expansion of the
left posterior cranial fossa was noted. No signs of vascular malformation were detected.
MRV showed focal reduction of the lumen of the posterior sagittal sinus.
The brain MRI performed at age 7 months documented a complete recanalization of Erofilo's
torcularis and transverse sinus ([Fig. 4 ]). As a consequence, the anticoagulant therapy was discontinued. At the 10-month
follow-up control, the child was found in good general health and showed normal weight,
length, and head circumference. The neurologic assessment performed at the same age
showed mild axial hypotonia and convergent strabismus related to a cortical visual
impairment.
Fig. 4 First row shows the computed tomography angiography at diagnosis: the green arrow
indicates patent right transverse sinus and the red arrow indicates nonopacified proximal
left transverse sinus. The second row shows the contrast-enhanced magnetic resonance
angiography at follow-up: the green arrow shows the right patent transverse sinus
and the red arrow shows the left patent transverse sinus.
Discussion
The clinical history of the reported case was suggestive of CSVT, thus allowing a
prompt neuro-radiological diagnosis. In fact, the intraparenchymal hemorrhage, the
symptoms observed, and the clinical features identified, such as medically assisted
pregnancy, gestational age at term, urgent cesarean section, and mild fetal distress,
were coherent with the hypothesis of CSVT. Once the CSVT diagnosis was confirmed,
the therapeutic management was not univocal. The currently available literature regarding
neonates with CSVT does not include RCTs and it is not conclusive about therapeutic
management. In the case of intraparenchymal hemorrhage associated with CSVT, current
guidelines, and protocols suggest watchful waiting and supportive therapy with re-evaluation
of MRI at 5 to 7 days.[6 ]
[7 ]
[8 ]
[9 ] However, the currently available data show more favorable outcome rates (39–50%)[10 ] and lower thrombus propagation frequencies (3%)[11 ] in infants undergoing early anticoagulation therapy (within 72 hours of diagnosis)
compared with untreated infants (20% favorable outcome and 25% thrombus propagation,
respectively[12 ]). Intraparenchymal hemorrhages already present at the time of CSVT diagnosis have
been reported in 30 to 80% of cases.[13 ] Noteworthy, bleedings related to anticoagulant therapy have been reported in only
8% of treated cases while thrombus propagation has been associated with a high risk
of new venous infarction (40%).[13 ]
The duration of anticoagulant therapy is also controversial. The British Committee
for Standards in Haematology stated that children with CSVT and no intraparenchymal
hemorrhage should receive anticoagulant therapy with heparin, continued for a minimum
of 3 months in cases of reversible provoking illness, and for 6 months in the absence
of provoking illness, and for longer periods of time in patients with a long-lasting
or genetic risk factor or with persistent symptomatic venous outflow obstruction.
Moreover, it is recommended that repeated imaging should be considered prior to stopping
anticoagulant therapy.[8 ] The European Pediatric Neurology Society guidelines on the anticoagulant treatment
of CSVT in children and neonates stated that half of the recurrences of thrombosis
occur within 3 months, and two-thirds within 6 months, after the initial accident.
For this reason, a 3 to 6-month period has been proposed as the standard duration
of anticoagulation in most studies, although the duration of treatment should be adapted
to each situation.[14 ] On the other hand, the American College of Chest Physicians stated that for neonates
with CSVT without significant intraparenchymal hemorrhage, anticoagulation is suggested
for a total duration between 6 weeks and 3 months.[7 ] Faced with this controversy over the duration of treatment, we chose to be cautious
with our patient and to extend the anticoagulant therapy until we had documented the
complete recanalization of the venous sinuses by neuroimaging.
Multicenter RCT studies are needed to decide the optimal management of this condition.
In the meanwhile, the discussion of this clinical case is an occasion to re-open a
debate regarding the efficacy, safety, and duration of enoxaparin early administration
in neonates with CSVT and active hemorrhage on the basis of the recent encouraging
results reported in the literature.
