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Stroke in the newborn: Classification, manifestations, and diagnosis

Stroke in the newborn: Classification, manifestations, and diagnosis
Literature review current through: Jan 2024.
This topic last updated: Oct 18, 2023.

INTRODUCTION — Perinatal stroke may be defined as an acute neurologic syndrome with chronic sequelae due to cerebral injury of vascular origin occurring between 20 weeks gestation and 28 days postnatal life. These disorders include focal cerebral injury due to arterial ischemic stroke, cerebral venous thrombosis, and primary intracerebral hemorrhage. Perinatal stroke is a common cause of acute neonatal encephalopathy, and may manifest as seizures, altered mental status, and sensorimotor deficits. It is an important cause of chronic neurologic disability.

The epidemiology, pathogenesis, clinical features, and diagnosis of perinatal stroke are reviewed here. Management and prognosis are reviewed elsewhere. (See "Stroke in the newborn: Management and prognosis".)

Neonatal encephalopathies that resemble perinatal stroke can be seen in association with periventricular and intraventricular hemorrhage, diffuse cerebral injury following global cerebral hypoxic-ischemic insults, and periventricular leukomalacia that typically occurs in preterm infants. These disorders are reviewed briefly here and discussed in more detail separately. (See "Etiology and pathogenesis of neonatal encephalopathy" and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis" and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome".)

CLASSIFICATION — Perinatal stroke encompasses cerebrovascular events that occur as early as 20 weeks of gestation up to 28 postnatal days [1]. Modern definitions of perinatal stroke incorporate the timing of the condition and major clinical-anatomic stroke subtypes.

Temporal classification is based on neuroimaging and clinical features, and distinguishes two groups [1]:

Acute perinatal stroke: events which can be verified by clinical and radiologic features as occurring from birth to 28 days of postnatal life; the clinical presentation is that of an acute encephalopathy in the neonatal period, typically involving seizures and altered mental status, and less often a focal neurologic deficit on examination.

Presumed perinatal stroke: events whose exact time of onset are inferred as perinatal (birth to 28 days of life) based upon clinical and imaging findings; the clinical presentation involves a chronic, static, focal neurologic deficit or seizures emerging during the first year of life in the absence of an acute neonatal encephalopathy, prompting imaging that reveals remote arterial territory infarction or periventricular venous infarction [2].

The major clinical-anatomic subtypes comprise the following [1]:

Arterial ischemic stroke, where the infarct conforms to vascular occlusion in an arterial territory

Hemorrhagic stroke, including intracerebral, subarachnoid, or intraventricular hemorrhage

Cerebral sinovenous thrombosis (CSVT), which may or may not cause infarction and hemorrhagic infarction

Periventricular venous infarction (PVI), involving a focal acute or chronic infarction in the periventricular white matter, not conforming to an arterial territory, often associated with evidence of germinal matrix hemorrhage

Cerebral ischemic infarction may be due to arterial occlusion, hypoperfusion in a watershed territory, or venous outflow obstruction. In the absence of imaging confirmation of a clot or vessel occlusion, the precise vascular mechanism may be difficult to define with certainty.

Arterial ischemia — The pathogenesis of perinatal arterial ischemic stroke is complex and multifactorial [3-5]. Thorough investigation of stroke risk factors in a consecutive cohort of perinatal arterial ischemic stroke may reveal one or more potential stroke risk factors in up to 75 percent of infants. However, true cause and effect for these factors in individual cases can rarely be proven unequivocally, and establishing a causal role for many risk factors awaits larger, more definitive, prospective or case-controlled studies. Advances in neuroimaging and progress in understanding fetal-maternal risk factors and placental disorders have led to a better understanding of the causes of perinatal stroke [5-9].

Causes of arterial ischemic stroke can be grouped into three types of pathophysiologic mechanisms (figure 1):

Emboli of cardiac, transcardiac, or aortic arch origin

Disorders of the cerebral arteries

Thrombosis due to disturbed hemostasis

These disorders may originate from maternal, placental, or fetal/neonatal conditions, or a combination. These mechanisms are not mutually exclusive, and multiple mechanisms may coexist and contribute to a stroke event in a given patient. In a single center cohort of 94 cases of perinatal arterial ischemic stroke, a systematic and hierarchical classification system based upon clinical and neuroanatomic features was applied to categorize patients into the following major etiologic groups [5,6]:

Embolism, 33 percent

Meningitis/sepsis, 9 percent

Trauma, 7 percent

Primary thrombosis (proven and prothrombotic conditions), 4 percent

Arteriopathy, 4 percent

Other causes (multifactorial including blood loss, hypoxic-ischemic events, extracorporeal membrane oxygenation), 17 percent

Unclassifiable, 26 percent

Most cases of perinatal arterial ischemic stroke result from arterial infarction in the distribution of the middle cerebral artery [4,5]. The main branch, a distal cortical branch, or smaller lenticulostriate branches can be involved [5,6,10-12]. In a consecutive cohort study of 94 infants with 166 perinatal arterial ischemic strokes confirmed by MRI, the proportion of infarcts in the distribution of the middle cerebral, anterior cerebral and posterior cerebral arteries was 51, 19, and 18 percent, respectively; cerebellar infarcts made up another 9 percent [5].

Although perinatal hypoxia-ischemia is sometimes implicated in the pathogenesis of arterial ischemic stroke, hypoxia and/or ischemia rarely are documented. Conversely, term newborns with well-defined neonatal encephalopathy can have arterial or venous ischemic stroke with or without diffuse watershed ischemic injury. As an example, a prospective cohort study of 124 term neonates with neonatal encephalopathy identified focal arterial or venous ischemic stroke in 5 percent of cases [13]. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)

Thromboembolism — Thromboembolism is considered a common cause of perinatal cerebral infarction. However, a clear embolic source is seldom identified. Newborns are thought to be at risk for emboli to cerebral vessels for several reasons [4,6,7,14-17]:

Thrombosis of placental vessels normally occurs as pregnancy ends, and emboli may be released into the fetal circulation as the placenta separates at birth. In addition, placental pathology may lead to direct embolization into the fetal circulation or cause an inflammatory and prothrombotic state that promotes thrombus formation in the placenta and fetus [7].

Venous clots can cross through the patent foramen ovale and be directed to cerebral arterial vessels.

Right-to-left shunts occur in congenital heart lesions, which permit emboli to enter the cerebral circulation.

Emboli may result from thrombi that develop along indwelling umbilical vessel catheters.

Border zone infarction — Watershed or border zone regions exist along the boundaries of major arterial territories in the parasagittal cortical regions of the term infant. These regions are prone to ischemia under conditions of global brain hypoperfusion or oxygen deprivation [18]. When cerebral oxygen delivery falls during perinatal hypoxic-ischemic events, a characteristic pattern of ischemic lesions develops in border zone regions. Such lesions may be asymmetric or focal despite the fact that the pathophysiology involves a systemic or global hypoperfusion. (See "Etiology and pathogenesis of neonatal encephalopathy".)

Risk factors — The role of maternal obstetric factors and intrapartum events is controversial and incompletely understood [4]. However, case series and case-control studies suggest that there are a number of maternal risk factors for neonatal arterial ischemic stroke, including the following:

Autoimmune and prothrombotic abnormalities such as antiphospholipid syndrome [19]

Preeclampsia [20]

Diabetes [21]

Placental thrombosis or abruption [22]

Prolonged rupture of membranes [20,23]

Twin-twin transfusion [24]

Chorioamnionitis [20]

Intrapartum maternal fever [23,25]

Smoking during pregnancy [26]

Cocaine abuse [27-29]

History of infertility [20]

In various case series and case-control studies, neonatal factors associated with arterial ischemic stroke have included the following:

Early sepsis or meningitis [21,25]

Hypoxia-ischemia [21,30]

Dehydration and/or hypernatremia [21]

Hypoglycemia [25]

Polycythemia [21]

Disseminated intravascular coagulation [21]

Certain inherited metabolic disorders [21]

Low five-minute Apgar score [25]

COL4A1 mutations [31,32]

Prothrombotic disorders — Prothrombotic disorders may contribute to perinatal stroke and influence outcome [6,33,34], but the evidence for an association is weak and inconsistent. Inherited prothrombotic disorders that are possible risk factors for perinatal arterial ischemic stroke include factor V Leiden; congenital deficiency of protein C, protein S, or antithrombin; increased lipoprotein(a); prothrombin gene mutation; and the methylenetetrahydrofolate reductase C677T homozygote (MTHFR TT) genotype. Antiphospholipid antibodies in the neonate may arise de novo in the infant or may sometimes result from placental transfer of maternal antibodies that are directed against anticoagulant proteins [35,36]. (See "Factor V Leiden and activated protein C resistance" and "Protein C deficiency" and "Protein S deficiency" and "Antithrombin deficiency" and "Antiphospholipid syndrome: Obstetric implications and management in pregnancy", section on 'Neonatal APS'.)

The following reports convey the range of findings:

A prospective, population-based case-control study compared 135 children who had a history of confirmed perinatal stroke classified by MRI, including neonatal arterial ischemic stroke (n = 46), arterial presumed perinatal stroke (n = 34), and fetal periventricular venous infarction (n = 55) [37]. Compared with 77 healthy control subjects, there was no difference between groups in 12 of 14 thrombophilia parameters measured at 12 months of age, including all common thrombophilias. In addition, the total number of possible abnormalities were similar between cases and controls. These results suggest only a minimal association between thrombophilia markers and perinatal stroke. However, they do not exclude a possible role of disordered coagulation at the time of perinatal stroke.

Evidence supporting an association of prothrombotic conditions with perinatal stroke comes from an earlier meta-analysis of 22 observational studies that included 1526 children and neonates with arterial ischemic stroke and 2700 control subjects [34]. Summary odds ratios (OR) for arterial ischemic stroke were as follows:

Two or more genetic thrombophilias, OR 18.8 (95% CI 6.5-54.1)

Protein C deficiency, OR 11.0 (95% CI 5.1-23.6)

Antiphospholipid antibodies/lupus anticoagulant, OR 7.0 (95% CI 3.7-13.1)

Elevated lipoprotein(a), OR 6.5 (95% CI 4.5-9.6)

Factor V Leiden mutation, OR 3.7 (95% CI 2.8-4.9)

Antithrombin III deficiency, OR 3.3 (95% CI 0.7-15.5)

Prothrombin gene mutation, OR 2.6 (95% CI 1.7-4.1)

MTHFR TT genotype, OR 1.6 (95% CI 1.2-2.1)

Protein S deficiency, OR 1.5 (95% CI 0.3-6.9)

Age group (perinatal/neonatal versus older children) did not significantly affect the reported odds ratios [34]. The strength of these findings is limited by the observational methodology of the included studies, the uncertain quality of the control subjects, and the potential for confounding from transient acquired abnormalities of some thrombophilic factors [34,38].

Cerebral sinovenous thrombosis — Cerebral sinovenous thrombosis (CSVT) can cause venous infarction, often associated with hemorrhage [14]. Seizures and altered consciousness are common manifestations of CSVT.

Physiologic factors may predispose to CSVT (figure 2). Placental lesions may lead to an inflammatory and prothrombotic state that promotes thrombus formation in the placenta and fetus [7]. Thrombosis may be precipitated by damage to the cerebral sinus structures immediately beneath the sagittal and lateral sinus caused by the cranial molding that accompanies the birth process [39,40]. After birth, changes in head position and external pressure can reduce blood flow in the jugular vein and superior sagittal sinus, potentiating thrombosis in susceptible individuals [41].

In the Canadian Pediatric Ischemic Stroke Registry, a majority of the 69 newborns with CSVT had risk factors for thrombosis [42]. The most common predisposing factors were perinatal complications (eg, hypoxia at birth, premature rupture of the membranes, maternal infection), which were found in 51 percent. Dehydration and head and neck disorders were present in 30 and 16 percent of cases, respectively. Among 49 newborns tested, prothrombotic disorders were identified in 20 percent.

In the series of 30 patients from San Francisco, all but one were born at or near term [43]. Similar to the Canadian registry, perinatal complications were frequent. Prothrombotic disorders were identified in four of seven patients tested. Seven infants presented either before or after surgery for congenital heart disease. Nine were treated with extracorporeal membrane oxygenation (ECMO) for persistent pulmonary hypertension of the newborn, representing 5 percent of patients treated with ECMO during that period. The mechanism may be retrograde thrombosis of the venous system following occlusion of the right internal jugular vein by the ECMO catheter.

Hemorrhagic stroke — Hemorrhagic stroke refers to acute neurologic syndromes resulting from intracranial hemorrhage of nontraumatic origin. It has two main forms:

Hemorrhagic conversion of ischemic infarction of arterial or venous origin

Primary intracerebral hemorrhage

Hemorrhagic conversion of ischemic infarction is a major cause of neonatal hemorrhagic stroke. Most cases of primary intracerebral hemorrhage are idiopathic, but some are attributed to bleeding diatheses (eg, thrombocytopenia, hemophilia, and other coagulopathies) or, rarely, to vascular anomalies (eg, cavernous malformations, arteriovenous malformations, and aneurysms). Pathogenic variants in COL4A1, COL4A2, COL5A1, and other genes may cause prenatal or postnatal hemorrhagic stroke [31,32,44-46].

Periventricular hemorrhagic infarction is particularly common in premature infants. (See 'Periventricular hemorrhagic infarction' below.)

There are limited data regarding hemorrhagic stroke in newborns [47-49]. In a cohort of over 323,000 live births in northern California from 1993 to 2003, a retrospective review identified 20 cases of perinatal hemorrhagic stroke, including 19 with intracerebral hemorrhage and one with subarachnoid hemorrhage [47]. The following observations were noted:

Etiologies included thrombocytopenia (20 percent) and cavernous malformation (5 percent), but most were idiopathic (75 percent).

Each of the 20 cases was randomly matched with three controls by age and birth facility. On univariate case-control analysis, the predictors of perinatal hemorrhage were fetal distress, emergency cesarean delivery, prematurity, and postmaturity but not birth weight. Maternal characteristics did not differ between cases and controls. On multivariate analysis, independent predictors of perinatal hemorrhage were fetal distress and postmaturity.

A subsequent population-based, case-control study from Alberta, Canada identified 86 cases of neonatal hemorrhagic stroke and matched them with control infants in a 4 to 1 ratio [48]. The following outcomes were reported:

Of the 86 cases, primary intracerebral hemorrhage accounted for 59 percent, hemorrhagic transformation for 35 percent, and presumed perinatal hemorrhagic stroke for 6 percent.

Among the 51 cases of primary intracerebral hemorrhage, most were idiopathic (67 percent).

As these findings illustrate, no definitive cause can be determined for many cases of primary intracerebral hemorrhage, and this problem may persist even after extensive evaluation. For example, the location or size of a hemorrhage may be suggestive of an arteriovascular malformation or aneurysm, but the anomaly may not be demonstrated by imaging, perhaps because it is obliterated as a result of the hemorrhage.

Additional risk factors for hemorrhagic stroke include extracorporeal membrane oxygenation (ECMO), coarctation of the aorta with or without hypertension, venous thrombosis, and vitamin K deficiency [14,50-52]. All babies should receive vitamin K supplementation at birth in order to prevent vitamin K deficient bleeding, as discussed separately. (See "Overview of vitamin K", section on 'Vitamin K-deficient bleeding in newborns and young infants'.)

Neonatal alloimmune thrombocytopenia (NAIT) is a rare disorder in which fetal platelets contain an antigen inherited from the father that the mother lacks. The mother may form antibodies against the foreign (paternal) antigen; these antibodies cross the placenta and bind to the fetal platelets. Clearance of the antibody-coated platelets results in fetal/neonatal thrombocytopenia. Intracranial hemorrhage, which may occur antenatally, is responsible for most of the morbidity and mortality of this condition. (See "Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy management", section on 'Clinical presentation'.)

Periventricular hemorrhagic infarction — Periventricular hemorrhagic infarction is part of the spectrum of germinal matrix and intraventricular hemorrhage [53]. It is most common in premature infants, but can also been seen in term and near-term infants. It occurs in approximately 15 to 20 percent of premature infants with intraventricular hemorrhage [54]. The mechanism is thought to be obstruction of the medullary and terminal veins by the associated intraventricular hemorrhage, resulting in periventricular venous congestion, ischemia, and venous hemorrhagic infarction [55]. The infarction is asymmetric, in contrast with the symmetric infarction that is typical of periventricular leukomalacia. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis".)

The incidence of periventricular hemorrhagic infarction increases with decreasing gestational age and weight. In one retrospective series of 5774 infants with birth weight ≤2500 g, the incidence of periventricular hemorrhagic infarction was 0.1, 2.2, and 10 percent for infants weighing 1500 to 2500 g, 750 to 1500 g, and <750 g, respectively [56]. The mortality rate of infants with periventricular hemorrhagic infarction is 30 to 60 percent [56-60].

Periventricular leukomalacia — Periventricular leukomalacia (PVL) refers to injury of cerebral white matter that occurs in a characteristic distribution and consists of periventricular focal necrosis, with subsequent cystic formation, and more diffuse cerebral white matter injury. PVL is the major form of brain white matter injury that affects premature infants.

In the preterm infant, the periventricular white matter is vulnerable to ischemic insult [61]. However, PVL also may result from injury due to other causes, such as infection or cytokine exposure. The diagnosis of PVL is typically made by routine screening ultrasound examination, while MRI provides greater sensitivity and anatomical characterization [62,63].

PVL often has no overt clinical signs in affected infants, although some have weakness that is more prominent in the lower than upper extremities. This typically evolves to spastic diplegia later in infancy. Hemorrhagic PVL, unlike middle cerebral artery territory lesions, frequently involves the legs more than the arms and face, except in very extensive lesions. Hemorrhagic PVL is usually on the left side, or is worse on the left than the right side.

EPIDEMIOLOGY — Perinatal stroke is not rare; the estimated incidence of ischemic perinatal stroke ranks second only to the incidence of ischemic stroke in older adults, and exceeds the incidence in childhood by approximately 10-fold [3,5,47,64]. Arterial ischemic stroke, hemorrhagic stroke, and cerebral venous thrombosis account for 70, 20, and 10 percent of acute symptomatic perinatal stroke, respectively [5,47].

The incidence of perinatal stroke has been estimated from several reports that vary in definition, diagnosis, and ascertainment of cases. A population-based study from Switzerland with prospectively collected data found that the incidence of neonatal arterial ischemic stroke was 13 per 100,000 births, or 1 per 7700 [65]. However, there are few population-based prospective studies of the incidence of perinatal stroke in the MRI era, and estimates relying on diagnostic code searches of administrative databases grossly underestimate the incidence. More accurate estimates may be obtained from expanded and verifiable search strategies designed to capture both acutely symptomatic neonates and infants with presumed perinatal stroke. Studies employing such methods suggest that the combined incidence of perinatal arterial ischemic stroke and intracerebral hemorrhage in North America is approximately 45 per 100,000 live births annually, or 1 per 2200 [47,48,64]:

A retrospective population-based cohort study identified 60 children with perinatal arterial ischemic stroke born between 1997 and 2003 in Northern California [64]. This yielded an estimated annual incidence of 29 per 100,000 live births, or 1 per 3500, for ischemic stroke.

A subsequent population-based study from Alberta, Canada identified 86 cases of neonatal hemorrhagic stroke [48]. The overall incidence of neonatal hemorrhagic stroke was 1 in 6300 live births (16 per 100,000).

Although these results suggest that perinatal stroke occurs approximately once in 2200 births, this incidence is still likely to be an underestimate because it is based largely on retrospective cohort studies relying in part on administrative database search strategies, and does not include all cases of cerebral sinovenous thrombosis.

CLINICAL MANIFESTATIONS — Common clinical manifestations of perinatal stroke include encephalopathy, seizures, hypotonia, focal neurologic deficits, respiratory impairments, and feeding problems.

Clinical features of arterial ischemic stroke — Children in the presumed perinatal stroke group present during infancy with chronic focal neuromotor impairments due to perinatal vascular insults arising from either arterial or venous infarctions [2,66,67].

Among infants with acute perinatal arterial ischemic stroke, the most common presenting clinical signs are seizures, altered mental status, and abnormal tone [1,8]. Other signs may include hemiparesis and respiratory and feeding difficulties. Seizures are the presenting or predominant symptom in 48 to 88 percent [5,8,10,68,69]. Focal seizures are typically contralateral to the affected hemisphere in neonates with unilateral cerebral infarction [10]. Seizure onset typically occurs on the first day after birth. Among newborns with seizures, infarction is one of the most common causes along with neonatal encephalopathy, intracranial infections, and intracranial hemorrhage (table 1) (see "Etiology and prognosis of neonatal seizures").

In a retrospective study of newborns with seizures who were diagnosed with arterial ischemic stroke (n = 27) or hypoxic-ischemic encephalopathy (n = 35), the presence of delayed seizure onset (≥12 hours after birth) and focal motor seizures were independent predictors of stroke [70].

Because most strokes that are clinically apparent affect the middle cerebral artery, the arm and face are likely to be more affected than the leg. The left hemisphere is more commonly involved than the right in perinatal ischemic stroke [5,71]. Many infants with unilateral lesions have a hemiparesis, although this may be difficult to detect except by the most experienced clinician. The hemiparesis may appear as asymmetry of spontaneous movements. However, hemiparesis caused by perinatal stroke is first detected in infancy (median six months in one series) in some patients after a normal neonatal course [39,66,72]. Infants with bilateral lesions typically have a mild quadriparesis [10]. Primitive reflexes, such as Moro and tonic neck reflexes, may be exaggerated.

Sensory deficits may occur if the parietal and occipital lobes are affected. Ischemic stroke in the territory of the posterior cerebral artery frequently results in a visual field defect such as a homonymous hemianopia or quadrantanopia [68]. Diencephalic injury may result in disturbed temperature control and sleep-wake cycles.

Infants with parasagittal injury (see 'Border zone infarction' above) have neurologic signs consistent with the distribution of the lesion. Affected infants have hypotonia and weakness of the proximal extremities. Upper limbs, especially the shoulder girdle region, are affected more than lower. The diagnosis is confirmed by MRI ideally, or by ultrasonography or CT.

Clinical features of CSVT — Most newborns with CSVT have neurologic signs, particularly seizures and alterations in consciousness.

Among 69 newborns with CSVT in the Canadian registry, focal or generalized seizures occurred in 71 percent [42]. Diffuse neurologic signs, such as decreased level of consciousness and jitteriness, occurred in 58 percent of cases, and focal signs, including hemiparesis and cranial nerve palsies, were seen in 29 percent. Similar clinical presentations were reported among 84 prospectively enrolled neonates with isolated symptomatic CSVT in the International Pediatric Stroke Study (IPSS) [73].

In the Canadian Pediatric Ischemic Stroke Registry, venous thrombosis was more likely to occur in a superficial than deep location (80 versus 39 percent) [42]. The superior sagittal and lateral sinuses were affected most often (62 and 39 percent, respectively) [42].

Brain edema and areas of hemorrhagic infarction, especially involving periventricular white matter, frequently accompany CSVT [14]. Infarction or hemorrhage may be present as isolated lesions or may be combined. In the IPSS, 67 newborns with CSVT had complete data regarding parenchymal lesions, and neuroimaging findings included the following [73]:

Both ischemic infarction and hemorrhage in 39 percent

Hemorrhagic infarction or other hemorrhage in 19 percent

Isolated infarction in 7 percent

No hemorrhage or infarct in 34 percent

All hemorrhages in the IPSS were observed before initiation of antithrombotic treatment [73]. Other studies have also reported high rates of hemorrhagic infarction with perinatal CSVT:

In a report from the Canadian Registry, 29 of 69 newborns (42 percent) with CSVT had parenchymal infarcts [42]. Nearly all were hemorrhagic.

In a retrospective multicenter European study of 52 neonates with CSVT proven by MRI or magnetic resonance venography (MRV), the rate of parenchymal hemorrhagic infarction was 79 percent [74].

The spectrum of anatomic lesions associated with CSVT in term newborns includes periventricular white matter infarction and intraventricular hemorrhage, lesions previously associated with premature birth [75,76]. Although limited by small numbers, one study reported that most preterm infants with CSVT presented with injury involving the entire periventricular white matter (5 of 6 cases), while most term infants with CSVT presented with focal punctate white matter lesions associated with restricted diffusion (15 of 20) and thalamic hemorrhage (11 of 20) [77]. In both groups, intraventricular hemorrhage was common (4 of 6 preterm and 16 of 20 term cases).

Clinical features of hemorrhagic stroke — There are limited data regarding the clinical manifestations of hemorrhagic stroke in newborns, but most affected infants present in the first days of life with encephalopathy, seizures, hypotonia, focal weakness, apnea, or poor feeding [47,48,78].

Periventricular hemorrhagic infarction (part of the spectrum of germinal matrix and intraventricular hemorrhage) predominantly affects preterm infants. The presentation can be clinically silent, stuttering, or catastrophic. The stuttering course evolves over hours to several days. It is characterized by nonspecific findings including an altered level of consciousness, hypotonia, decreased spontaneous and elicited movements, and subtle changes in eye position and movements. A clinically silent syndrome occurs in 25 to 50 percent of cases, but can be detected by routine ultrasonographic screening. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis", section on 'Clinical features'.)

Vascular anomalies such as cavernous hemangiomas, arteriovenous malformations (AVMs), and aneurysms are rare causes of neonatal hemorrhagic stroke (see 'Hemorrhagic stroke' above). Locations of AVMs include the vein of Galen (the most common), cerebral hemispheres, thalamus and third ventricle, and choroid plexus. Most infants with vein of Galen malformations present with heart failure [79]. The outcome of AVM-related bleeding depends upon the location and extent of the hemorrhage and the amount of secondary injury caused by mass effect and hydrocephalus. The arterial embolization procedure used to eliminate flow through an AVM may be complicated by bleeding.

When aneurysmal rupture occurs, the intracerebral hematoma is usually large, and associated with subarachnoid, and often intraventricular, hemorrhage [51,80,81]. Rupture of an aneurysm causes an acute increase in intracranial pressure and severe neurologic deterioration. Seizures occur commonly and typically are focal.

WHEN TO SUSPECT PERINATAL STROKE — The diagnosis of perinatal stroke should be suspected in any newborn with signs or symptoms of encephalopathy, seizures, lethargy, hypotonia, feeding difficulties, apnea, or focal neurologic deficits.

EVALUATION AND DIAGNOSIS — Once a newborn is suspected to have perinatal stroke, initial evaluation includes brain imaging to define the lesion as well as neurovascular imaging and laboratory studies to investigate potential underlying causes. Most infants who are acutely symptomatic with stroke present with seizures, warranting a complete evaluation to exclude other etiologies of seizures, including systemic infection.

The diagnosis of perinatal stroke is confirmed by the presence of one or more relevant ischemic or hemorrhagic brain lesions on neuroimaging that account for the clinical presentation.

Brain imaging — MRI is the preferred brain imaging modality and should be performed in all neonates with suspected perinatal stroke or seizures to evaluate for the presence of intracranial hemorrhage, ischemic stroke, brain malformations, and evidence of hypoxic-ischemic damage [1,82,83]. The diagnosis of ischemic and hemorrhagic stroke is confirmed by cranial MRI or CT (image 1). These studies define the extent and vascular territory of the infarct, the number of lesions, and the presence or absence of hemorrhage. MR or CT imaging also confirms the presence and location of CSVT and associated infarction and/or hemorrhage (image 2). MRI, especially when used with venography (MRV), has greater sensitivity and specificity to detect venous and sinus thrombosis than CT or Doppler ultrasonography [42].

MRI is superior to CT, as it lacks radiation exposure and may detect small or early infarcts that are not apparent on CT [3,82]. However, MRI sometimes cannot be obtained in the ill neonate because it requires more preparation and a longer scanning time than CT. Cranial ultrasonography, the primary imaging technique used to detect intraventricular hemorrhage and periventricular leukomalacia, is less useful for detecting ischemic stroke because of the peripheral location of most infarcts.

Early infarction can be visualized with MRI using diffusion-weighted imaging (DWI) before the lesion can be seen with conventional MRI or CT [84-86]. This technique is based upon the decrease in the rate of diffusion of water molecules that occurs within minutes after an ischemic insult. The decreased rate of diffusion is detected as a bright signal on DWI that is thought to reflect cytotoxic edema or necrosis.

The temporal evolution of diffusion abnormalities seen on MRI is distinct in neonates compared with older children and adults. Diffusion-weighted MRI sequences may underestimate the full extent of infarct during the first 24 hours and after day five. T2 and fluid-attenuated inversion recovery (FLAIR) MRI sequences are more reliable than diffusion at day seven and later in term newborns [87].

The site of the occluded vessel is inferred from the location and extent of the infarct in most cases [5,30,39].

Large wedge-shaped infarcts involving the cortex in characteristic distributions result from occlusion of major cerebral arteries, predominantly the middle cerebral artery, which can occur due to embolism originating from any of several points of origin – transcardiac from the fetal-placental circulation or neonatal venous circulation, intracardiac from the fetus or neonate, or artery-to-artery from the proximal cervicocephalic arteries. A large vessel occlusion can also occur from in-situ thrombosis involving an intrinsic arteriopathy or infectious arteritis. In many cases, the exact cause and site of origin of a presumed thrombotic or embolic occlusion cannot be determined with certainty. Findings on vascular imaging obtained acutely can be helpful in distinguishing between thromboembolic occlusion from an extracranial site and an intrinsic arteriopathy.

Small subcortical infarcts in the white matter, basal ganglia, thalamus, and brainstem, ranging in size from several millimeters to several centimeters in diameter, are caused by occlusion of small arteries arising from the stem of the major cerebral arteries, such as the lenticulostriate branches from the proximal middle cerebral artery supplying the caudate and putamen.

A single thrombosis in a large cerebral artery that subsequently embolizes can result in multiple infarcts within the same vascular territory, depending upon the distribution of emboli. By contrast, infarcts in multiple vascular distributions suggest multiple emboli originating from the fetal-placental circulation, the heart, or aorta.

Ultrasonography is an imaging technique that is commonly used for fetal and neonatal screening. Head ultrasound may be performed first for neonates with suspected stroke if MRI is not immediately available [82]. Head ultrasound is readily accessible, noninvasive, portable, fast, and does not involve ionizing radiation. However, the diagnostic effectiveness of ultrasonography is operator dependent, and ultrasound is less sensitive than MRI. One report found that head ultrasound in the first three days after birth detected only 68 percent of arterial ischemic infarcts evident on brain MRI; small cortical infarcts in the anterior and posterior circulation were often missed [88]. Head ultrasound can visualize thalamic and intraventricular hemorrhage associated with cerebral sinovenous thrombosis or periventricular hemorrhagic infarction, and may detect thrombosis of superficial venous sinuses or absence of a vessel, suggesting occlusion due to thrombosis [82]. However, it is insensitive for detecting parietal hemorrhage and for visualizing the deep cortical veins [89]. In a retrospective registry of 52 neonates with cerebral sinovenous thrombosis, head ultrasound detected only 63 percent of cases compared with MRI [74].

Neurovascular imaging — Noninvasive neurovascular imaging, most often with magnetic resonance angiography (MRA) and magnetic resonance venography (MRV), can provide important information about stroke pathophysiology, as illustrated by the following points:

MRA can identify congenital vascular anomalies of the intracranial vessels that would predispose to the occurrence of a stroke during birth, such as PHACE, which refers to a neurocutaneous syndrome of posterior fossa brain malformations, hemangiomas, arterial anomalies, cardiac anomalies and coarctation of the aorta, and eye abnormalities [90,91]. (See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications", section on 'PHACE syndrome'.)

Similarly, MRA can identify carotid artery dissection and congenital anomalies of the aortic arch and cervical vessels that may cause perinatal stroke.

Detection of a vascular occlusion (or lack thereof) may be diagnostic in terms of the stroke mechanism (eg, cardioembolism versus large artery occlusive disease versus other causes).

MRA and MRV together may clarify the territory of the infarct when its radiologic appearance is ambiguous regarding arterial versus venous origin. As an example, bilateral deep gray and periventricular white matter infarcts are much more suggestive of venous than arterial infarction, but this is difficult to prove without appropriate vascular imaging.

Many experts believe that vascular trauma and congenital vascular anomalies causing perinatal stroke are probably underdiagnosed, and will be missed if the evaluation fails to include cervical and intracranial vascular imaging. In a multicenter cohort study of 248 infants with acute symptomatic perinatal ischemic stroke, vascular imaging using MRA was obtained in 49 percent, compared with CT angiography and catheter angiography in 4 percent and 3 percent, respectively [71]. Vascular abnormalities, including large vessel occlusions, dissection, and congenital vasculopathies, were seen in 22 percent of those imaged. In a systematic review that identified nine cases of perinatal ischemic stroke attributed to dissection, eight patients had experienced instrumental or traumatic delivery, or urgent Caesarean section; dissection was documented by neuroimaging in only six of the nine patients [92].

Note that thrombotic occlusions of large cerebral arteries can move rapidly to distal branches and thus may not always be apparent on imaging performed many hours or days after the occlusion occurs, as is usually the case with perinatal stroke. In addition, occlusion of small vessels may be below the limit of detection.

Cerebral artery flow velocity measured by transcranial Doppler sonography may be decreased in the involved vessel in newborns with cerebral infarction [93,94]. This technique is more useful in the evaluation of sinovenous thrombosis than ischemic stroke. (See 'Cerebral sinovenous thrombosis' above.)

Conventional catheter angiography is rarely used to evaluate newborns with ischemic stroke, particularly since it has been supplanted by noninvasive imaging methods such as MRA.

Evaluation for seizures — Most infants who are acutely symptomatic with stroke present with seizures. In these cases, a comprehensive, expedited evaluation should be performed to exclude other etiologies of seizures, including systemic infection. The diagnosis of neonatal seizures is based upon clinical observation combined with electroencephalography (EEG) monitoring. Studies should include a complete blood count with leukocyte differential, examination of the cerebrospinal fluid (CSF), and cultures of the blood and CSF. Serum concentrations of glucose, calcium, and electrolytes should be measured, and the urine should be screened for toxic substances. Studies to detect inborn errors of metabolism may be indicated in some circumstances (eg, persistent seizures). (See "Clinical features, evaluation, and diagnosis of neonatal seizures".)

The gold standard for neonatal seizure diagnosis is multi-channel video EEG monitoring. The EEG may demonstrate a specific seizure focus. Changes in background activity may suggest more generalized brain involvement, and may be an early indication that hemiparesis will develop [95]. Periodic lateralized epileptiform discharges (PLEDs) may be associated with structural cerebral lesions, including localized abnormalities such as cerebral infarction [96].

The clinical diagnosis and treatment of neonatal seizures is discussed in detail separately. (See "Clinical features, evaluation, and diagnosis of neonatal seizures" and "Treatment of neonatal seizures".)

Echocardiogram — Newborns with ischemic stroke or hemorrhagic transformation of ischemic stroke should have an echocardiogram to detect structural heart disease with right-to-left shunt as a potential underlying etiology. The yield of this study is low in the absence of a congenital anomaly. However, rare conditions that may lead to brain infarctions, such as atrial thrombosis, can be found [97].

Coagulation testing — As discussed earlier (see 'Prothrombotic disorders' above), the association between thrombophilia markers and arterial perinatal stroke is minimal. Therefore, it is likely that no added prognostic or treatment information will be gained from routinely performing comprehensive thrombophilia profiles in infants with either acute neonatal arterial ischemic stroke or presumed perinatal stroke. Coagulation testing should be obtained only in highly selected cases of neonatal arterial ischemic stroke, with emphasis on those children with either a strong family history of thrombotic disease or those with multiple sites or a large burden of thrombosis.

Coagulation testing is suggested for all neonates with CSVT, as abnormal findings may impact decisions about antithrombotic treatment and testing other family members for inherited thrombophilias. However, coagulation testing has limited clinical utility, in part because levels of protein C, protein S, antithrombin, and factor XI in neonates are approximately 30 percent of levels in adults [1,98].

In those selected cases deemed appropriate for evaluation, testing may be performed in the infant at the time of discharge or post-hospital follow-up examination because of the large volume of blood required to perform all studies. Testing may also include screening the parents before or after testing the child. For children elected to have thrombophilia testing, the following factor studies should be obtained at presentation:

Maternal blood should be tested for antinuclear antibodies, lupus anticoagulants, and anticardiolipin antibody. (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)

Both parents should be tested for deficiencies of protein S and protein C. A family history of thrombosis or consanguinity renders this diagnosis more likely. Alternatively, parental testing may be postponed and narrowed down after results of studies on the infant are available. (See "Protein C deficiency" and "Protein S deficiency".)

Protein S, protein C, and antithrombin concentrations should be measured in the newborn at the time of acute presentation if evidence of other clots is present. Because normal values of these proteins are low in newborns, interpretation requires knowledge of neonatal norms for these values. Infants with low levels should be retested at three to four months of age, and if levels are persistently abnormal, such infants may benefit from consultation with a pediatric thrombosis expert. (See "Protein C deficiency" and "Protein S deficiency" and "Antithrombin deficiency".)

Pathologic examination of the placenta should be performed to detect infarcts or clots.

Prothrombin time and activated partial thromboplastin time should be measured at the initial presentation, especially if there is bleeding associated with the stroke.

Homocysteine concentration can be measured in maternal serum (see "Inherited thrombophilias in pregnancy"). In the United States, newborn screening is available for homocystinuria in many states; this disorder is rare.

Additional studies should be obtained when the infant is approximately three months of age. The infant should be tested for the factor V Leiden and prothrombin G20210A mutations. (See "Factor V Leiden and activated protein C resistance" and "Prothrombin G20210A".)

MANAGEMENT AND PROGNOSIS — The management and prognosis of perinatal stroke is reviewed separately. (See "Stroke in the newborn: Management and prognosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in children".)

SUMMARY AND RECOMMENDATIONS

Perinatal stroke encompasses cerebrovascular events that occur as early as 20 weeks of gestation and up to 28 postnatal days. Temporal classification is based on neuroimaging and distinguishes two groups (see 'Classification' above):

Acute perinatal stroke, verified by clinical and radiologic features as occurring from birth to 28 days of postnatal life; the clinical presentation is mainly that of an acute encephalopathy in the neonatal period, sometimes accompanied by a focal neurologic deficit.

Presumed perinatal stroke, with the time of onset inferred as perinatal (birth to 28 days of life) based upon clinical and imaging findings; the clinical presentation involves a chronic, static, focal neurologic deficit or seizures emerging during the first year of life.

The major clinical-anatomic subtypes of perinatal stroke comprise the following (see 'Classification' above):

Arterial ischemic stroke, where the infarct conforms to occlusion of an arterial territory

Hemorrhagic stroke, including parenchymal, subarachnoid, or intraventricular hemorrhage

Cerebral sinovenous thrombosis, which may cause infarction and hemorrhagic infarction

Periventricular venous infarction

Perinatal stroke is not rare; the estimated incidence of ischemic perinatal stroke ranks second only to the incidence of ischemic stroke in the elderly, and exceeds the incidence in childhood by approximately 10-fold. (See 'Epidemiology' above.)

Common clinical manifestations of perinatal stroke include encephalopathy, seizures, hypotonia, focal neurologic deficits, respiratory impairments, and feeding problems. (See 'Clinical manifestations' above.)

The diagnosis of perinatal stroke should be suspected in any newborn with unexplained seizures, encephalopathy, lethargy, hypotonia, feeding difficulties, apnea, or focal neurologic deficits. Initial evaluation includes brain imaging to define the lesion as well as neurovascular imaging and laboratory studies to investigate potential underlying causes. Most infants who are acutely symptomatic with stroke present with seizures, warranting a complete evaluation to exclude other etiologies of seizures, including systemic infection. MRI is the preferred imaging modality and should be performed in all neonates with suspected perinatal stroke or seizures to evaluate for the presence of intracranial hemorrhage, ischemic stroke, brain malformations, and evidence of hypoxic-ischemic damage. (See 'Evaluation and diagnosis' above.)

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Topic 6157 Version 39.0

References

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