Neonatal stroke, similar to a
stroke which occurs in adults, is defined as a disturbance to the blood supply of the developing brain in the first 28 days of life.
[Aden, U. (2009). Neonatal Stroke Is Not a Harmless Condition. Stroke, 40, 1948-1949. .] This description includes both
Ischemia events, which results from a blockage of
blood vessel, and hypoxic events, which results from a lack of oxygen to the brain tissue, as well as some combination of the two.
[Sehgal, A. (2011). Perinatal Stroke: a case-based review. European Journal of Pediatrics. .][Derugin, N., Donna Ferriero, Vexler, Z. S. (1998) Neonatal reversible focal cerebral ischemia: a new model. Neuroscience Research 32, 349-353.] One treatment with some proven benefits is hypothermia, but may be most beneficial in conjunction with pharmacological agents.
[Rees, S., Harding, R., Walker, D. (2011). The biological basis of injury and neuroprotection in the fetal and neonatal brain. International Journal of Developmental Neuroscience, 29, 551-563.] Well-designed
for stroke treatment in
infant are lacking, but some current studies involve the transplantation of neural stem cells and umbilical cord
; it is not yet known if this therapy is likely to be successful.
Neonatal strokes may lead to cerebral palsy, learning difficulties, or other disabilities.[Chauvier, D., Renolleau, S., Holifanjaniaina, S., Ankri, S., Bezault, M., Schwendimann, L., et al. (2011). Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor. Cell Death & Disease, 2, 203. .] A neonatal stroke occurs in approximately 1 in 4000 births, but is likely much higher due to the lack of noticeable .
Presentation
A
infant stroke is one that occurs in the first 28 days of life, though a late presentation is not uncommon (as contrasted with
perinatal stroke, which occurs from 28 weeks
gestation through the first 7 days of life).
80% of neonatal strokes are ischemic, and their presentation is varied, making diagnosis very difficult.
The most common manifestation of neonatal strokes are
, but other manifestations include lethargy,
hypotonia,
apnoea, and
hemiparesis.
Seizures can be focal or generalized in nature.
[Chabrier, S., Buchmüller, A. (2003). Editorial Comment−Specificities of the Neonatal Stroke. Stroke, 34, 2892-2893. .] Stroke accounts for about 10% of seizures in term
infant.
| + Disorders that Increase Risk of Neonatal Stroke |
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| Maternal: |
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Autoimmune disorders
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Coagulation disorders
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Prenatal cocaine exposure
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Congenital heart disease
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Diabetes
-
Trauma
|
| : | |
| Blood, Homocysteine, and Lipid: |
-
Polycythemia
-
Disseminated intravascular coagulopathy
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Prothrombin mutation
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Lipoprotein (a) deficiency
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Factor VIII deficiency
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Factor V Leiden mutation
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| Other Infectious: | |
Risk factors
Many different risk factors play a role in causing a neonatal stroke. Some maternal disorders that may contribute to neonatal strokes include: autoimmune disorders,
coagulation disorders, prenatal cocaine exposure,
infection, congenital heart disease,
, and trauma.
disorders that increase the risk of stroke include placental
thrombosis, placental abruption, placental infection, and
chorioamnionitis.
Other disorders that may increase the risk of a neonatal stroke are blood,
homocysteine and
lipid disorders, such as
polycythemia, disseminated intravascular coagulopathy, prothrombin mutation, lipoprotein (a) deficiency,
factor VIII deficiency (hemophilia A), and factor V Leiden mutation.
Infectious disorders such as central nervous system (CNS) infection or
systemic disease may also contribute.
Many infants who have a neonatal stroke also follow an uncomplicated pregnancy and delivery without identifiable risk factors, which exemplifies the necessity for further research on this subject.[Miller, S.P., Wu, Y.W., Lee, J., Lammer, E. J., Iovannisci, D. M., Glidden, D. V., et al.(2006). Candidate Gene Polymorphisms Do Not Differ Between Newborns With Stroke and Normal Controls. Stroke, 37, 2678-2683. .]
Mechanism
A neonatal stroke in the developing brain involves
excitotoxicity,
oxidative stress, and
inflammation, which accelerate cell death through
necrosis or
apoptosis, depending on the region of the brain and severity of stroke.
The
pathophysiology of neonatal stroke may include
thrombosis and
thrombolysis, and vascular reactivity.
Apoptosis mechanisms may have a more prominent role in developing an ischemic brain injury in neonatal humans than in adult brain ischemia,
as a majority of cells die in the environment where edema developed after a neonatal stroke.
[Alberi, L., Chi, Z., Kadam, S. D, Mulholland, J. D., Dawson, V. L., Gaiano, N., et al. (2010). Neonatal Stroke in Mice Causes Long-Term Changes in Neuronal Notch-2 Expression That May Contribute to Prolonged Injury. Stroke, 41, 564-571. .] There is an increased inflammatory response after hypoxia-ischemia, which corresponds to extensive neuronal apoptosis.
[Faustino, J. V., Wang, X., Johnson, C. E., Klibanov, A., Derugin, N., Wendland, M. F., Vexler, Z. S. (2011) Microglial cells contribute to endogenous brain defenses after acute neonatal focal stroke. The Journal of Neuroscience, 31(36), 12992-13001] Apoptosis involves the
mitochondrion release of
cytochrome c and apoptosis-inducing factor (AIF), which activate caspase-dependent and -independent execution pathways, respectively.
Injury may also occur due to O
2 accumulation via the production of O
2 by
microglia, a type of
Neuroglia that are responsible for immune response in the CNS, but their role in injury after neonatal stroke is still relatively unknown.
As observed by Alberi,
et al., progressive
atrophy in the ipsilateral hemisphere over three weeks after the stroke occurred, suggesting that a neonatal stroke has long-lasting effects on
viability and the potential for a prolonged therapeutic window for alleviating the progression of cell death.
Diagnosis
Neonatal strokes occur in approximately 1 in 4000 births, but this number is likely much higher due to lack of noticeable
at time of birth.
They generally present with seizures,
but only half to three quarters of cases have identifiable causes.
Diagnosis often occurs around 36 hours after onset of neonatal stroke due to the interval between stroke and clinical presentation, if any occurs at all.
[ Govaert, P., Smith, L., Dudink, J. (2009) Diagnostic management of neonatal stroke. Seminars in Fetal and Neonatal Medicine, 14(5), 323-328] Neonatal strokes can be confirmed with
neuroimaging or
neuropathology studies, and other various imaging techniques can be used to diagnose neonatal strokes, such as
ultrasound, Doppler sonography, computerized tomography (CT) scan, CT angiography, and multimodal MR.
Prevention
Some evidence suggests that magnesium sulfate administered to mothers prior to early
preterm birth reduces the risk of
cerebral palsy in surviving neonates.
[Reeves, S., A., Gibbs, R., S., Clark, S., L. (2011). Magnesium for fetal neuroprotection. American Journal of Obstetrics and gynecology, 204, (3), 202.e1-202.e4] Due to the risk of adverse effects treatments may have, it is unlikely that treatments to prevent neonatal strokes or other hypoxic events would be given routinely to pregnant women without evidence that their
fetus was at extreme risk or has already sustained an injury or stroke.
This approach might be more acceptable if the pharmacologic agents were
endogeny occurring substances (those that occur naturally in an organism), such as
creatine or
melatonin, with no adverse
side effect.
Because of the period of high
neuroplasticity in the months after birth, it may be possible to improve the neuronal environment immediately after birth in neonates considered to be at risk of neonatal stroke.
This may be done by enhancing the growth of
and
,
synaptogenesis and
of axons with systemic injections of
or
which can cross the blood–brain barrier.
Treatment
Treatment remains controversial with regards to the risk/benefit ratio, which differs significantly from treatment of stroke in adults.
Presence or possibility of organ or limb impairment
and bleeding risks
[Zeevi, B., Berant, M. (1999) Spontaneous aortic arch thrombosis in a neonate. Heart, 81, 560] are possible with treatments using
antithrombotic.
Therapeutic hypothermia
Hypothermia treatment induced by head cooling or systemic cooling administered within six hours of birth for 72 hours has proven beneficial in reducing death and neurological impairments at 18 months of age.
This treatment does not completely protect the injured brain and may not improve the risk of death in the most severely
cerebral hypoxia-
ischemia neonates and has also not been proven beneficial in preterm infants.
Combined therapies of hypothermia and pharmacological agents or growth factors to improve neurological outcomes are most likely the next direction for damaged neonatal brains, such as after a stroke.
[
]
Other treatments
A successful use of urokinase in a newborn with an aorta clot has been reported, but the bleeding risks associated with thrombolytic agents are still unclear.
Heparin, an anticoagulant, treatments have been used in cases of cerebro-venous sinus thrombosis (CVST) in order to stop thrombosis extension and recurrence, to induce thrombosis resolution, and to prevent further brain damage.[Sandberg, D. I., Lamberti-Pasculli, M., Drake, J.M., Humphreys, R. P., Rutka, J. T. (2001) Spontaneous intraparenchymal haemorrhage in full-term neonates. Neurosurgery, 48, 1042–1049.]
Prognosis
Of the infants that survive, there may be as many as 1 million a year that develop cerebral palsy, learning difficulties or other disabilities.[Himmelmann, K., Ahlin, K., Jocobsson, B., Cans, C., Thorsen, P. (2011) Risk factors for cerebral palsy in children born at term. Acta Obstetrics et Gynecologica Scandinavica,90, 1070-1081.] Other neurological defects that can occur after a neonatal stroke include hemiparesis and hemi-sensory impairments [Westmacott, R., MacGregor, D., Askalan, R., and deVeber, G. (2009). Late Emergence of Cognitive Deficits After Unilateral Neonatal Stroke. Stroke, 40, 2012-2019. .] Some studies suggest that when tested as toddlers and preschoolers, children who previously had neonatal strokes fall within normal ranges of cognitive development.
Research direction
Well-designed for stroke treatment in neonates are lacking.
Pancaspase inhibition and Casp3-selective inhibition have been found to be Neuroprotection in neonatal rodents with models of neonatal brain injury, which may lead to pharmacological intervention
MRI has proven valuable for defining brain injury in the neonate, but animal models are still needed to identify causative mechanisms and to develop neuroprotective therapies.
Transplantation of neural stem cells and umbilical cord stem cells is currently being trialed in neonatal brain injury, but it is not yet known if this therapy is likely to be successful.
Further reading
