Neonatal stroke

Last updated December 09, 2023

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.^[1] This description includes both ischemic events, which results from a blockage of vessels, and hypoxic events, which results from a lack of oxygen to the brain tissue, as well as some combination of the two.^[2]^[3] One treatment with some proven benefits is hypothermia, but may be most beneficial in conjunction with pharmacological agents.^[4] Well-designed clinical trials for stroke treatment in neonates are lacking, but some current studies involve the transplantation of neural stem cells and umbilical cord stem cells; it is not yet known if this therapy is likely to be successful.^[4]

Presentation

A neonatal 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).^[2] 80% of neonatal strokes are ischemic, and their presentation is varied, making diagnosis very difficult.^[2] The most common manifestation of neonatal strokes are seizures, but other manifestations include lethargy, hypotonia, apnoea, and hemiparesis.^[2] Seizures can be focal or generalized in nature.^[6] Stroke accounts for about 10% of seizures in term neonates.^[2]

Disorders that Increase Risk of Neonatal Stroke
Type of Disorder	Disorder
Maternal:	Autoimmune disorders Coagulation disorders Prenatal cocaine exposure Congenital heart disease Diabetes Trauma
Placental:	Placental thrombosis Placental abruption Placental infection Chorioamnionitis
Blood, Homocysteine, and Lipid:	Polycythemia Disseminated intravascular coagulopathy Prothrombin mutation Lipoprotein (a) deficiency Factor VIII deficiency Factor V Leiden mutation
Other Infectious:	Central nervous system (CNS) infection Systemic infection

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,^[2] diabetes, and trauma.^[6] Placental disorders that increase the risk of stroke include placental thrombosis, placental abruption, placental infection, and chorioamnionitis.^[2] 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.^[2] Infectious disorders such as central nervous system (CNS) infection or systemic infection may also contribute.^[2]

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.^[7]

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.^[5] The pathophysiology of neonatal stroke may include thrombosis and thrombolysis, and vascular reactivity.^[7] Apoptosis mechanisms may have a more prominent role in developing an ischemic brain injury in neonatal humans than in adult brain ischemia,^[5] as a majority of cells die in the environment where edema developed after a neonatal stroke.^[8] There is an increased inflammatory response after hypoxia-ischemia, which corresponds to extensive neuronal apoptosis.^[9] Apoptosis involves the mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF), which activate caspase-dependent and -independent execution pathways, respectively.^[5] Injury may also occur due to O₂ accumulation via the production of O₂ by microglia, a type of glial cell that are responsible for immune response in the CNS, but their role in injury after neonatal stroke is still relatively unknown.^[9] 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 neuronal viability and the potential for a prolonged therapeutic window for alleviating the progression of cell death.^[8]

Diagnosis

Neonatal strokes occur in approximately 1 in 4000 births, but this number is likely much higher due to lack of noticeable symptoms at time of birth.^[1] They generally present with seizures,^[6] but only half to three quarters of cases have identifiable causes.^[1] 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.^[10] Neonatal strokes can be confirmed with neuroimaging or neuropathalogical 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.^[2]

Prevention

Some evidence suggests that magnesium sulfate administered to mothers prior to early preterm birth reduces the risk of cerebral palsy in surviving neonates.^[11] 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.^[4] This approach might be more acceptable if the pharmacologic agents were endogenously occurring substances (those that occur naturally in an organism), such as creatine or melatonin, with no adverse side-effects.^[4] Because of the period of high neuronal plasticity 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.^[4] This may be done by enhancing the growth of axons and dendrites, synaptogenesis and myelination of axons with systemic injections of neurotrophins or growth factors which can cross the blood–brain barrier.^[4]

Treatment

Treatment remains controversial with regards to the risk/benefit ratio, which differs significantly from treatment of stroke in adults.^[2] Presence or possibility of organ or limb impairment^[2] and bleeding risks^[12] are possible with treatments using antithrombotic agents.

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.^[4] This treatment does not completely protect the injured brain and may not improve the risk of death in the most severely hypoxic-ischemic neonates and has also not been proven beneficial in preterm infants.^[4] 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.^[4]

Other treatments

A successful use of urokinase in a newborn with an aortic clot has been reported, but the bleeding risks associated with thrombolytic agents are still unclear.^[2]

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.^[2] In the case of extremely high intracranial pressure, surgical removal of hematoma may be beneficial.^[13]

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.^[5] Cerebral palsy is the most common physical disability in childhood, and it is characterized by a lack of control of movement.^[14] Other neurological defects that can occur after a neonatal stroke include hemiparesis and hemi-sensory impairments ^[15] Some studies suggest that when tested as toddlers and preschoolers, children who previously had neonatal strokes fall within normal ranges of cognitive development.^[15] Less is known about longer-term cognitive outcome, but there has been evidence that cognitive deficits may emerge later in childhood when more complex cognitive processes are expected to develop.^[15]

Research direction

Well-designed clinical trials for stroke treatment in neonates are lacking.^[4] Recent clinical trials show that therapeutic intervention by brain cooling beginning up to six hours after perinatal asphyxia reduces cerebral injury and may improve outcome in term infants, indicating cell death is both delayed and preventable ^[5]

Pancaspase inhibition and Casp3-selective inhibition have been found to be neuroprotective in neonatal rodents with models of neonatal brain injury, which may lead to pharmacological intervention ^[5] In a study done by Chauvier, et al., it is suggested that a Caspase inhibitor, TRP601, is a candidate for neuroprotective strategy in prenatal brain injury conditions.^[5] They found a lack of detectable side effects in newborn rodents and dogs.^[5] This may be a useful treatment in combination with hypothermia.^[5]

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.^[4] In order to model human fetal or neonatal brain injury, one needs a species in which a similar proportion of brain development occurs in utero, the volume of white to grey matter is similar to the human brain, an insult can be delivered at an equivalent stage of development, the physiological outcome of the insult can be monitored, and neurobehavioral parameters can be tested.^[4] Some animals that meet these criteria are sheep, non-human primates, rabbits, spiny mice, and guinea pigs.^[4]

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.^[4]

Related Research Articles

Porencephaly is an extremely rare cephalic disorder involving encephalomalacia. It is a neurological disorder of the central nervous system characterized by cysts or cavities within the cerebral hemisphere. Porencephaly was termed by Heschl in 1859 to describe a cavity in the human brain. Derived from Greek roots, the word porencephaly means 'holes in the brain'. The cysts and cavities are more likely to be the result of destructive (encephaloclastic) cause, but can also be from abnormal development (malformative), direct damage, inflammation, or hemorrhage. The cysts and cavities cause a wide range of physiological, physical, and neurological symptoms. Depending on the patient, this disorder may cause only minor neurological problems, without any disruption of intelligence, while others may be severely disabled or die before the second decade of their lives. However, this disorder is far more common within infants, and porencephaly can occur both before or after birth.

Cerebrovascular disease includes a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often damaged or deformed in these disorders. The most common presentation of cerebrovascular disease is an ischemic stroke or mini-stroke and sometimes a hemorrhagic stroke. Hypertension is the most important contributing risk factor for stroke and cerebrovascular diseases as it can change the structure of blood vessels and result in atherosclerosis. Atherosclerosis narrows blood vessels in the brain, resulting in decreased cerebral perfusion. Other risk factors that contribute to stroke include smoking and diabetes. Narrowed cerebral arteries can lead to ischemic stroke, but continually elevated blood pressure can also cause tearing of vessels, leading to a hemorrhagic stroke.

<span class="mw-page-title-main">Cerebral edema</span> Excess accumulation of fluid (edema) in the intracellular or extracellular spaces of the brain

Cerebral edema is excess accumulation of fluid (edema) in the intracellular or extracellular spaces of the brain. This typically causes impaired nerve function, increased pressure within the skull, and can eventually lead to direct compression of brain tissue and blood vessels. Symptoms vary based on the location and extent of edema and generally include headaches, nausea, vomiting, seizures, drowsiness, visual disturbances, dizziness, and in severe cases, death.

Stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functioning properly.

Perinatal asphyxia is the medical condition resulting from deprivation of oxygen to a newborn infant that lasts long enough during the birth process to cause physical harm, usually to the brain. It remains a serious condition which causes significant mortality and morbidity. It is also the inability to establish and sustain adequate or spontaneous respiration upon delivery of the newborn, an emergency condition that requires adequate and quick resuscitation measures. Perinatal asphyxia is also an oxygen deficit from the 28th week of gestation to the first seven days following delivery. It is also an insult to the fetus or newborn due to lack of oxygen or lack of perfusion to various organs and may be associated with a lack of ventilation. In accordance with WHO, perinatal asphyxia is characterised by: profound metabolic acidosis, with a pH less than 7.20 on umbilical cord arterial blood sample, persistence of an Apgar score of 3 at the 5th minute, clinical neurologic sequelae in the immediate neonatal period, or evidence of multiorgan system dysfunction in the immediate neonatal period. Hypoxic damage can occur to most of the infant's organs, but brain damage is of most concern and perhaps the least likely to quickly or completely heal. In more pronounced cases, an infant will survive, but with damage to the brain manifested as either mental, such as developmental delay or intellectual disability, or physical, such as spasticity.

Cerebral hypoxia is a form of hypoxia, specifically involving the brain; when the brain is completely deprived of oxygen, it is called cerebral anoxia. There are four categories of cerebral hypoxia; they are, in order of increasing severity: diffuse cerebral hypoxia (DCH), focal cerebral ischemia, cerebral infarction, and global cerebral ischemia. Prolonged hypoxia induces neuronal cell death via apoptosis, resulting in a hypoxic brain injury.

Intracerebral hemorrhage (ICH), also known as hemorrhagic stroke, is a sudden bleeding into the tissues of the brain, into its ventricles, or into both. An ICH is a type of bleeding within the skull and one kind of stroke. Symptoms can vary dramatically depending on the severity, acuity, and location (anatomically) but can include headache, one-sided weakness, numbness, tingling, or paralysis, speech problems, vision or hearing problems, memory loss, attention problems, coordination problems, balance problems, dizziness or lightheadedness or vertigo, nausea/vomiting, seizures, decreased level of consciousness or total loss of consciousness, neck stiffness, and fever.

<span class="mw-page-title-main">Cerebral infarction</span> Medical condition

Cerebral infarction is the pathologic process that results in an area of necrotic tissue in the brain. It is caused by disrupted blood supply (ischemia) and restricted oxygen supply (hypoxia), most commonly due to thromboembolism, and manifests clinically as ischemic stroke. In response to ischemia, the brain degenerates by the process of liquefactive necrosis.

<span class="mw-page-title-main">Periventricular leukomalacia</span> Degeneration of white matter near the lateral ventricles of the brain

Periventricular leukomalacia (PVL) is a form of white-matter brain injury, characterized by the necrosis of white matter near the lateral ventricles. It can affect newborns and fetuses; premature infants are at the greatest risk of neonatal encephalopathy which may lead to this condition. Affected individuals generally exhibit motor control problems or other developmental delays, and they often develop cerebral palsy or epilepsy later in life. The white matter in preterm born children is particularly vulnerable during the third trimester of pregnancy when white matter developing takes place and the myelination process starts around 30 weeks of gestational age.

Intrauterine hypoxia occurs when the fetus is deprived of an adequate supply of oxygen. It may be due to a variety of reasons such as prolapse or occlusion of the umbilical cord, placental infarction, maternal diabetes and maternal smoking. Intrauterine growth restriction may cause or be the result of hypoxia. Intrauterine hypoxia can cause cellular damage that occurs within the central nervous system. This results in an increased mortality rate, including an increased risk of sudden infant death syndrome (SIDS). Oxygen deprivation in the fetus and neonate have been implicated as either a primary or as a contributing risk factor in numerous neurological and neuropsychiatric disorders such as epilepsy, attention deficit hyperactivity disorder, eating disorders and cerebral palsy.

Targeted temperature management (TTM) previously known as therapeutic hypothermia or protective hypothermia is an active treatment that tries to achieve and maintain a specific body temperature in a person for a specific duration of time in an effort to improve health outcomes during recovery after a period of stopped blood flow to the brain. This is done in an attempt to reduce the risk of tissue injury following lack of blood flow. Periods of poor blood flow may be due to cardiac arrest or the blockage of an artery by a clot as in the case of a stroke.

Neonatal encephalopathy (NE), previously known as neonatal hypoxic-ischemic encephalopathy, is defined as a encephalopathy syndrome with signs and symptoms of abnormal neurological function, in the first few days of life in an infant born after 35 weeks of gestation. In this condition there is difficulty initiating and maintaining respirations, a subnormal level of consciousness, and associated depression of tone, reflexes, and possibly seizures. Encephalopathy is a nonspecific response of the brain to injury which may occur via multiple methods, but is commonly caused by birth asphyxia, leading to cerebral hypoxia.

Mild total body hypothermia, induced by cooling a baby to 33-34°C for three days after birth, is nowadays a standardized treatment after moderate to severe hypoxic ischemic encephalopathy in full-term and near to fullterm neonates. It has recently been proven to be the only medical intervention which reduces brain damage, and improves an infant's chance of survival and reduced disability.

A silent stroke is a stroke that does not have any outward symptoms associated with stroke, and the patient is typically unaware they have suffered a stroke. Despite not causing identifiable symptoms, a silent stroke still causes damage to the brain and places the patient at increased risk for both transient ischemic attack and major stroke in the future. In a broad study in 1998, more than 11 million people were estimated to have experienced a stroke in the United States. Approximately 770,000 of these strokes were symptomatic and 11 million were first-ever silent MRI infarcts or hemorrhages. Silent strokes typically cause lesions which are detected via the use of neuroimaging such as MRI. The risk of silent stroke increases with age but may also affect younger adults. Women appear to be at increased risk for silent stroke, with hypertension and current cigarette smoking being amongst the predisposing factors.

A hypothermia cap is a therapeutic device used to cool the human scalp. Its most prominent medical applications are in preventing or reducing alopecia in chemotherapy, and for preventing cerebral palsy in babies born with neonatal encephalopathy caused by hypoxic-ischemic encephalopathy (HIE). It can also be used to provide neuroprotection after cardiac arrest, to inhibit stroke paralysis, and as cryotherapy for migraine headaches.

Erythropoietin in neuroprotection is the use of the glycoprotein erythropoietin (Epo) for neuroprotection. Epo controls erythropoiesis, or red blood cell production.

Ulegyria is a diagnosis used to describe a specific type of cortical scarring in the deep regions of the sulcus that leads to distortion of the gyri. Ulegyria is identified by its characteristic "mushroom-shaped" gyri, in which scarring causes shrinkage and atrophy in the deep sulcal regions while the surface gyri are spared. This condition is most often caused by hypoxic-ischemic brain injury in the perinatal period. The effects of ulegyria can range in severity, although it is most commonly associated with cerebral palsy, mental retardation and epilepsy. N.C. Bresler was the first to view ulegyria in 1899 and described this abnormal morphology in the brain as “mushroom-gyri." Although ulegyria was first identified in 1899, there is still limited information known or reported about the condition.

A neonatal seizure is a seizure in a baby younger than age 4-weeks that is identifiable by an electrical recording of the brain. It is an occurrence of abnormal, paroxysmal, and persistent ictal rhythm with an amplitude of 2 microvolts in the electroencephalogram,. These may be manifested in form of stiffening or jerking of limbs or trunk. Sometimes random eye movements, cycling movements of legs, tonic eyeball movements, and lip-smacking movements may be observed. Alteration in heart rate, blood pressure, respiration, salivation, pupillary dilation, and other associated paroxysmal changes in the autonomic nervous system of infants may be caused due to these seizures. Often these changes are observed along with the observance of other clinical symptoms. A neonatal seizure may or may not be epileptic. Some of them may be provoked. Most neonatal seizures are due to secondary causes. With hypoxic ischemic encephalopathy being the most common cause in full term infants and intraventricular hemorrhage as the most common cause in preterm infants.

Cerebrolysin is a mixture of enzymatically treated peptides derived from pig brain whose constituents can include brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and ciliary neurotrophic factor (CNTF).

Perinatal stroke is a disease where an infant has a stroke between the 140th day of the gestation period and the 28th postpartum day, affecting up to 1 in 2300 live births. This disease is further divided into three subgroups, namely neonatal arterial ischemic stroke, neonatal cerebral sinovenous ischemic stroke, and presumed perinatal stroke. Several risk factors contribute to perinatal stroke including birth trauma, placental abruption, infections, and the mother's health.

References

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