Stroke in the newborn: Management and prognosis

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 management and prognosis of perinatal stroke are reviewed here. Other clinical aspects are discussed separately. (See "Stroke in the newborn: Classification, manifestations, and diagnosis".)

Germinal matrix hemorrhage and intraventricular hemorrhage, which predominantly affect preterm infants, are reviewed elsewhere. (See "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".)

MANAGEMENT

General measures — Management of perinatal stroke is supportive. It should be directed at treatment of underlying conditions and prevention of further injury. Thus, it is important to ensure adequate oxygenation and ventilation; control seizures; correct dehydration and anemia; and monitor and correct metabolic disturbances, including acidosis, hypoglycemia, hypocalcemia, and electrolyte disorders [1]. If infection is suspected, antibiotic treatment should be started until culture results are available.

Seizures — Seizures should be treated with antiseizure medications [2]. Because clinical identification of seizures is unreliable in neonates, prolonged video-electroencephalogram monitoring may be necessary to accurately characterize the extent, nature, and localization of clinical versus electrographic seizures. (See "Clinical features, evaluation, and diagnosis of neonatal seizures".)

Management of arterial ischemic stroke — Treatment of perinatal ischemic stroke with antiplatelet agents or anticoagulants is rarely indicated [1,2]. Except for the supportive care and treatment of seizures noted above, management in most cases consists of observation and monitoring. Because most thromboembolic strokes in infants do not recur or progress, this approach avoids the complications associated with antithrombotic therapy.

However, selected infants may benefit from treatment with aspirin, unfractionated heparin, or low molecular weight heparin (LMWH). In accord with national guidelines and available data, we suggest treatment with antithrombotic therapy using either aspirin, unfractionated heparin, or LMWH for neonates who have or may be at risk for recurrent arterial ischemic stroke due to documented systemic or cardiac risk factors (eg, thrombophilia, complex congenital heart disease not including patent foramen ovale, or a documented cardioembolic source) [1,3,4]. (See "Neonatal thrombosis: Management and outcome".)

In contrast to older children or adults, hyperacute reperfusion therapy such as thrombolysis or mechanical thrombectomy is rarely if ever used to treat stroke in newborns since it is seldom possible to ascertain the exact time of stroke onset in the perinatal period. Additionally, mechanical thrombectomy is technically rarely feasible because the endovascular devices are not compatible with the small vessel caliber of the newborn [1].

Growth factors and cell-based therapies during the acute phase have attracted much interest in perinatal brain injury research. A feasibility and safety study of intranasal administration of mesenchymal stromal cell (MSC) exosomes given to 10 term newborns with MRI-confirmed arterial ischemic stroke by day-of-life 7 supported the feasibility of this strategy and showed reassuring safety signals at four months [5]. A phase II clinical trial of darbepoetin, a derivative of erythropoietin, for acute neonatal arterial ischemic stroke is underway [6], based on favorable results from a phase I study [7]. Much research is needed to further define dosing, timing, long-term safety, and efficacy of these treatments.

Management of CSVT — Given the available data, we suggest initial anticoagulation with unfractionated heparin or LMWH for neonates with acute perinatal cerebral sinovenous thrombosis (CSVT) with or without associated intracranial hemorrhagic infarction or parenchymal hemorrhage [2]. Anticoagulation should be continued after the acute period for at least six weeks using LMWH. Repeat imaging with MRI and MRV at the targeted endpoint of therapy (six weeks) may be useful in guiding duration of therapy. For neonates who have not achieved clinically significant recanalization, we suggest extending the duration of anticoagulation therapy for up to six months with the aim of attaining partial or full recanalization of thrombosed sinuses.

Nevertheless, the role of systemic anticoagulation for the treatment of acute perinatal CSVT remains controversial. This issue is reflected by inconsistency in the use of anticoagulation for this disorder [1]. As an example, in the International Pediatric Stroke Study, approximately one-half of neonates with CSVT were treated with anticoagulation using heparin or LMWH [8]. Nevertheless, accumulating observational evidence supports the safety of anticoagulation for perinatal CSVT:

●A single-center prospective observational study found that clot propagation, often with new or progressive infarction, occurred in newborns with CSVT significantly more often in those who did not receive anticoagulation compared with those who did (10 of 35 [28 percent] versus 1 of 22 [5 percent]) [9]. Moreover, the use of anticoagulation was not associated with life-threatening hemorrhage.

●In a single-center cohort study in the Netherlands, 7 of 10 infants with thalamic hemorrhage due to CSVT received anticoagulation, and none had new hemorrhage referable to this therapy [10].

●A 2018 systematic review and meta-analysis identified no randomized trials, but data from mainly retrospective studies supported the safety and potential benefit of treating neonates with anticoagulation, including those with hemorrhage [11].

A 2019 scientific statement from the American Heart Association/American Stroke Association states that anticoagulation with LMWH or unfractionated heparin may be considered for neonates with CSVT, particularly those with clinical deterioration or radiologic evidence of propagating thrombus; for neonates who are not initially treated with anticoagulation, serial imaging at five to seven days from onset should be considered to exclude thrombus propagation [1].

For neonates with CSVT without significant intracerebral hemorrhage, the 2012 American College of Chest Physicians (ACCP) guidelines suggest initial anticoagulation with unfractionated heparin or LMWH and subsequent anticoagulation with LMWH for a minimum of six weeks but no longer than three months [3]. One approach discussed by the ACCP is to assess for recanalization at six weeks and to stop anticoagulants if recanalization is complete or, if incomplete, to continue anticoagulation for an additional six weeks (total three months) and then stop. For neonates with CSVT who have significant hemorrhage, the ACCP suggests either anticoagulation or supportive care with radiologic monitoring of the thrombosis at five to seven days and anticoagulation if thrombus propagation is noted at that time.

Management of intracerebral hemorrhage — We recommend the following measures for neonates with intracerebral hemorrhage [1]:

●Correction of markedly low platelet counts

●Replacement of deficient coagulation factors for neonates who have coagulation factor deficiency

●Ventricular drainage for those who develop hydrocephalus, followed by shunting if hydrocephalus persists

Note that all neonates should receive prophylactic administration of vitamin K1 (0.5 to 1 mg by intramuscular injection) as part of routine management to prevent vitamin K deficient bleeding (see "Overview of the routine management of the healthy newborn infant", section on 'Vitamin K'). A presumptive diagnosis of vitamin K deficient bleeding can be made in an infant presenting with bleeding or neurologic symptoms and either a prolonged prothrombin time (PT) or international normalized ratio (INR), or a history of not receiving vitamin K prophylaxis at birth. Such infants should be treated immediately with parenteral vitamin K, 1 to 2 mg intravenously or subcutaneously. For severe bleeding episodes, fresh frozen plasma or prothrombin complex concentration may be administered in addition to vitamin K. (See "Overview of vitamin K", section on 'Vitamin K-deficient bleeding in newborns and young infants'.)

Surgical evacuation of intracerebral brain hemorrhage can reduce elevated intracranial pressure, but it is not clear whether this intervention improves outcome [1].

Germinal matrix hemorrhage and intraventricular hemorrhage occur most often in preterm infants. Treatment is supportive and directed towards preservation of cerebral perfusion, minimization of any further brain injury, and early detection of complications. Ongoing surveillance includes serial head ultrasound examinations for the early detection of posthemorrhagic ventricular dilation. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome".)

Vascular imaging may be helpful to exclude structural vascular lesions as the source of intracerebral hemorrhage, such as brain arteriovenous malformation (AVM), arteriovenous fistula (AVF), or cavernous malformation, but the precise role and timing of imaging is unclear [1]. Brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) will identify large complex AVMs, AVFs, and vein of Galen malformations, but small AVMs or aneurysms may be missed by MR-based imaging. While conventional angiography is considered the gold standard for diagnosing cerebral AVM, this procedure is technically more challenging and higher-risk in newborns than in older children, and is used primarily to guide surgical intervention for lesions such as AVM or aneurysms. However, recurrence of neonatal hemorrhagic stroke (of any cause) is rare, and AVMs and aneurysms are uncommon causes in this age group [12]. Considering that the risk of angiography is relatively high, and the probability of diagnosing an actionable lesion not seen on magnetic resonance is practically nil, conventional angiography for diagnostic purposes during the neonatal period is almost never indicated. If noninvasive imaging suggests an AVM or aneurysm, then conventional angiography may be useful to optimize safety and timing of treatment, based upon consultation with surgeons and interventional radiologists.

Rehabilitation — Programs incorporating physical, occupational, and speech therapy may help to improve functional outcomes for children with perinatal stroke [13]. Innovative rehabilitative interventions combining different modalities have emerged; these include intensive unilateral or bimanual therapies, with or without constraint, sometimes combined with noninvasive cortical stimulation technologies [14,15]. Multidisciplinary long-term clinical care models offer families, caregivers, and children added benefit [16,17].

We suggest comprehensive long-term monitoring of neurodevelopmental status and family well-being, and institution of individually tailored interventions targeting the full spectrum of disabilities over the entire age continuum. These interventions should include attention to the behavioral health of the child, the health and well-being of the family and caregivers, and the optimal integration of the child into home and school environments.

PROGNOSIS — Perinatal stroke may cause long-term impairments in sensory and motor function (including cerebral palsy), cognition, language, behavior, mood, and vision, as well as epilepsy. However, there is a wide variation in morbidity and mortality that depends in part upon the location and extent of brain injury, and the presence of comorbid medical problems. The evidence for prognosis of specific subtypes of perinatal stroke is reviewed in the sections that follow. The bulk of the data pertain to arterial ischemic stroke, which is the most common subtype of perinatal stroke. Motor impairments can be predicted with reasonable confidence from a combination of factors that include the combined findings of damage to the corticospinal tracts on early MRI and clinical examination indicators of early motor impairment during infancy [18]. Prediction of language and cognitive impairments and epilepsy from data available during the neonatal period is less well defined.

Prognosis of arterial ischemic stroke — Long-term development is normal in approximately 19 to 41 percent of infants with perinatal ischemic infarction [19-23]. As an example, a study involving 46 children with perinatal cerebral infarction who were followed for 18 to 164 months (mean 42 months) found that neurodevelopmental outcome was normal in 33 percent and abnormal in 67 percent [20]. Among the 31 children with abnormal neurodevelopmental outcome, multiple disabilities were present in nearly 75 percent; cerebral palsy and cognitive impairment occurred in 71 and 61 percent, respectively.

Another study of 102 patients with perinatal arterial ischemic stroke performed serial head circumference measurement over a median of 3.2 years; head circumference growth declined and remained below normal trajectories, and smaller head circumference was associated with poor outcome on the Pediatric Stroke Outcome Measures (PSOM), which assesses language, cognition, behavior, and sensorimotor function [24].

A mechanism for recovery in some cases may be growth of undamaged brain at the margins of the infarction [25].

Motor disability and cerebral palsy — Motor disability is common after perinatal ischemic stroke, with frank hemiparesis in approximately 25 to 30 percent and milder neuromotor dysfunction in another 30 percent of infants with unilateral infarction [26,27]. It develops in nearly all cases in which infarction involves the entire vascular territory of the middle cerebral artery. It is less likely to occur (<10 percent) if a cortical branch or only the lenticulostriate vessels are affected.

Perinatal arterial infarction is the major known cause for cerebral palsy [28], accounting for approximately 30 percent of hemiplegic cerebral palsy cases among children born at term [29,30]. The development of cerebral palsy after perinatal stroke appears to be associated with infarct size, infarct location, and a delayed clinical presentation [18,31]. (See "Cerebral palsy: Epidemiology, etiology, and prevention".)

These observations are supported by a retrospective population-based study that identified 36 infants with perinatal stroke who were observed for at least 12 months [22]. Abnormal outcomes occurred in 29 patients (81 percent), and included cerebral palsy in 21 (58 percent), epilepsy in 14 (39 percent), language delay in 9 (25 percent), and behavioral abnormalities in 8 (22 percent). Cerebral palsy was associated with a delayed presentation (ie, the infant was considered neurologically normal before one month of age, but was later diagnosed with an old arterial stroke). In addition, the risk for cerebral palsy was associated with large infarct size and neuroimaging localization to Broca's area, Wernicke's area, internal capsule, or basal ganglia. (See "Cerebral palsy: Classification and clinical features".)

Diffusion-weighted magnetic resonance imaging (MRI) obtained between 3 and 10 days of age, and diffusion tensor imaging tractography at three months of age, can identify signal abnormalities representing probable Wallerian degeneration in the descending motor pathways (eg, corticospinal tract) projecting from the primary infarct (image 1) [32-34]. When present, involvement of the corticospinal tract is predictive of later occurrence of motor impairment. Additional signs of connectivity-driven acute imaging abnormalities may be seen in thalamocortical and transcortical systems, and they carry an increased risk of long-term impairment [15].

Cognitive impairment — In earlier studies, cognitive impairment occurred in approximately 20 to 25 percent of infants with unilateral infarction [26]. Bilateral involvement or a large lesion increased the risk of poor outcome. A later study found that school-aged survivors of perinatal arterial ischemic stroke had below-average full-scale intelligence quotient (IQ) scores (mean 87, 95% CI 80-94) compared with the normative sample (mean 100) [35]. Lower cognitive performance was associated with basal ganglia and thalamic involvement and the development of postnatal epilepsy.

Cognitive deficits may emerge with time, as suggested by findings from a longitudinal study of 26 children who presented with neonatal seizures and were diagnosed with unilateral perinatal infarction [36]. The children showed no differences from published norms on measures of intellectual ability when tested as preschoolers (mean age 4.8 years). However, mild but statistically significant declines in full scale IQ scores were present when they were retested at school age (mean age 8.9 years). The declines reflected impairment in nonverbal reasoning, working memory, and processing speed. In another report of 40 children with perinatal arterial ischemic stroke who were assessed at age 3 to 16 years, factors associated with poor performance on attention and executive functioning measures were larger infarct volume, comorbid epilepsy, and presumed perinatal arterial ischemic stroke [37].

Mounting evidence suggests that children with a history of perinatal stroke have an increased risk over the general population for the development of a wide range of cognitive, language, and neurobehavioral impairments during childhood, including autism [38-41]. These observations support the importance of establishing long-term care systems and involvement of appropriately qualified professionals who address language, learning, and neurobehavioral assessment and treatment throughout childhood.

Epilepsy — Epilepsy is a common consequence of perinatal stroke, with an estimated prevalence of 10 to 40 percent among children presenting with acute perinatal stroke and 19 to 67 percent among children presenting in delayed fashion with infantile hemiplegia [22,42-45]. A more extensive acute infarct as measured on MRI is associated with a higher risk of epilepsy, while the occurrence of seizures during the neonatal period is not a reliable predictor of later epilepsy [31,43].

Stroke recurrence — The recurrence risk for cerebral or systemic thromboembolic events after perinatal arterial ischemic stroke appears to be low, with the possible exception of children with congenital heart disease. In a prospective case-controlled study that included 215 infants followed a median of 3.5 years, recurrent thromboembolism occurred in 3 percent [46]. Similarly, a population-based study from California that identified 84 cases of perinatal arterial ischemic stroke reported that the five-year cumulative recurrence rate for any stroke was 1 percent [47]. By contrast, among 135 children with congenital heart disease and acute arterial ischemic stroke in a Canadian registry, the risk of stroke recurrence 10 years after a sentinel stroke was 27 percent [48].

Prognosis of CSVT — Most newborns (93 to 97 percent) with cerebral sinovenous thrombosis (CSVT) survive the acute period [8,49]. However, a retrospective study from the Netherlands of 52 neonates with CSVT who had follow-up at a median age of 19 months reported a mortality rate 19 percent [50], while another retrospective study from Texas of 67 neonates with CSVT and a median follow-up of six years reported a mortality of 27 percent [51].

The neurologic outcome in survivors of CSVT is variable.

●In the Canadian registry, neurologic deficit and seizures occurred in 61 and 20 percent, respectively [49,52]. Most neurologic deficits consisted of motor impairment.

●In an observational study from a tertiary center in Indianapolis, outcome data were available for 29 of 41 survivors [53]. Of these, only six (21 percent) had normal development. The remaining 23 (79 percent) had long-term impairments, including cognitive impairment in 16 patients, motor impairment (cerebral palsy) in 18, and epilepsy in 11.

●In the study from the Netherlands, there were 42 survivors at follow-up (median age 19 months), and normal development was noted in 45 percent, while moderate to severe neurologic impairments were present in 48 percent [50]. The Texas study, with 49 survivors at follow-up, reported a favorable neurologic outcome in 53 percent, defined by a Pediatric Stroke Outcome Measure (PSOM) score of 0 (normal) to 0.5 (mild deficit, normal function); an unfavorable outcome was observed in 47 percent, defined by higher PSOM scores [51].

Prognosis of hemorrhagic stroke — Outcomes from neonatal hemorrhagic stroke vary widely, though data are limited. Mortality in different studies ranges from 4 to 25 percent [12,54-57]. Adverse outcomes among survivors are estimated to affect 30 to 77 percent and may include cerebral palsy, cognitive impairment, and epilepsy [54,56-59].

As examples, in a population-based registry study of 86 infants with neonatal hemorrhagic stroke, there were three deaths (4 percent), which all occurred beyond the neonatal period [12]. With follow-up available for 50 cases at a median of 37 months, poor neurologic outcome was observed in 42 percent [12]. Impairments included sensorimotor deficits, language and epilepsy. There were no recurrence of hemorrhagic stroke. Interventions beyond the neonatal period included ventriculoperitoneal shunt placement, epilepsy surgery, and arteriovenous malformation embolization. More favorable outcomes were reported in a prospective cohort study of 26 neonates with spontaneous hemorrhagic stroke (parenchymal and intraventricular) [57]. With follow-up available at two years for 20 children, full recovery occurred in 45 percent, mild deficits in 30 percent, moderate deficits in 5 percent, and death in 20 percent.

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

●Management of perinatal stroke is mainly supportive. Adequate oxygenation and ventilation should be ensured. Dehydration and anemia should be treated. Metabolic disturbances, such as acidosis, hypoglycemia, hypocalcemia, or electrolyte disorders, should be monitored and corrected. Antibiotic treatment is started until culture results are available if infection is suspected. Seizures should be treated with anticonvulsant medications. (See 'Management' above.)

●Most thromboembolic strokes in infants do not recur or progress. However, for neonates who have or may be at risk for recurrent arterial ischemic stroke due to documented systemic or cardiac risk factors for thromboembolic events, we suggest treatment with antithrombotic therapy using aspirin, unfractionated heparin, or low molecular weight heparin (Grade 2C). (See 'Management of arterial ischemic stroke' above.)

●For neonates with acute cerebral sinovenous thrombosis (CSVT), with or without significant secondary hemorrhage, we suggest anticoagulation therapy with unfractionated heparin or low molecular weight heparin (Grade 2C). (See 'Management of CSVT' above.)

●For neonates with intracerebral hemorrhage, reasonable interventions include the correction of severe thrombocytopenia, replacement of deficient coagulation factors, vitamin K administration for all, and ventricular drainage for those who develop hydrocephalus, followed by shunting if hydrocephalus persists. (See 'Management of intracerebral hemorrhage' above.)

●Perinatal stroke may cause long-term impairments in motor function (including cerebral palsy), cognition, language, behavior, mood, and vision, as well as epilepsy. However, there is a wide variation in morbidity and mortality that depends in part upon the location and extent of brain injury. (See 'Prognosis' above.)