Outcomes After Perinatal Arterial Ischemic Stroke

We describe a neonate born at term with arterial ischemic stroke (AIS) who has been followed in our pediatric stroke follow-up clinic for the past 2 years.The male patient was born at 39- and 5/7-weeks’ gestation to a 35-year-old gravida 2, para 1 woman. The pregnancy was uncomplicated. However, a nonreassuring fetal heart tracing during spontaneous labor prompted delivery via cesarean section, and there was concern for chorioamnionitis at the time of delivery owing to maternal fever to 103 °F (39.4 °C). The patient had Apgar scores of 8 and 9 at 1 and 5 minutes after birth, respectively. His birth parameters were notable for a length of 52 cm (77th percentile), head circumference of 34 cm (18th percentile), and weight of 3.08 kg (21st percentile).At age 24 hours, the patient was noted to have spontaneous apneic events. His physical examination at that time was notable for mild encephalopathy and decreased movements of the right-sided upper and lower extremities compared with the left. An electroencephalogram (EEG) was obtained to evaluate the apneic events, and this showed that they were associated with focal seizure activity arising from the left central and parietal regions. The seizures were also accompanied by subtle eye fluttering. The infant ultimately required intubation because of the frequency of the apneic events associated with the seizures. The initial workup included head ultrasonography that did not show any evidence of acute intracranial pathology, followed by brain magnetic resonance imaging (MRI) scan, which showed a large region of acute ischemia involving the left cerebral hemisphere in the left middle cerebral artery (MCA) territory (Figure 1A–C). Magnetic resonance angiography was then obtained and revealed occlusion at the level of the proximal segment (M1) of the left MCA (Figure 1D). Additional workup included a laboratory evaluation for thrombophilia, a lumbar puncture for cerebrospinal fluid (CSF) analysis, an echocardiogram, and venous Doppler ultrasonography of the extremities. The thrombophilia evaluation was positive for a heterozygous factor V Leiden gene variant, and CSF analysis was without evidence of infection. The echocardiogram showed a patent foramen ovale with left-to-right shunting but no intracardiac thrombus, and venous Doppler ultrasonography of the extremities were negative for thrombosis. Placental pathology was not obtained. The patient’s family history was negative for a clotting disorder. Maternal blood work was remarkable for positive antiphospholipid antibodies.Over the course of his admission, the patient’s mental status improved, and his motor examination appeared more symmetric. His seizures responded well to treatment with lorazepam and phenobarbital followed by a phenobarbital maintenance dose of 8 mg/kg/day, and he was able to successfully wean off phenobarbital before discharge. Our Neurology team monitored the infant and informed the family about the diagnosis of stroke and risk for motor, cognitive, and language developmental delays as well as epilepsy. The family was particularly worried about the developmental implications of the patient’s stroke. He was discharged home after 35 days with a plan to follow-up with Neurology and Hematology. A referral was placed for developmental follow-up with Early Childhood Intervention, a statewide program for patients with developmental delays or medical diagnoses that may impact development.Our patient is now 2 years old and has been closely followed in our Pediatric Stroke Program every 3–6 months. He has not experienced any symptoms concerning for stroke recurrence. Initially following his birth hospitalization, his parents reported decreased spontaneous and purposeful movements of his right upper extremity when compared with the left. His lower extremities appeared symmetric. Over time, he was noted to develop increased spastic tone in his right upper extremity, which was more pronounced distally (fingers, hand, and wrist) than proximally (elbow, arm, and shoulder). His parents noted that he kept his right hand in a fisted position and close to his body, strongly preferring to use his left upper extremity to reach for and grab objects. As he continued to gain motor skills, an asymmetry in the strength and tone of his lower extremities became more evident, especially when he began walking at age 13 months. His ability to continue to make motor gains and participate in therapy appeared to be affected by his increased tone. He was referred to physical medicine and rehabilitation for tone management, and it was recommended that he undergo bracing and chemodenervation therapy, both of which were thought to be helpful. He now meets the criteria for right spastic hemiparetic cerebral palsy (CP), Gross Motor Function Classification System level II. He participates in physical and occupational therapy weekly. Currently, his language appears unaffected. He started to communicate using single words and later 2-word phrases at appropriate ages. He was evaluated by speech and language pathology, and there were no delays observed. He has not had any further events concerning for seizure. He has had 2 routine EEGs, both of which were notable for epileptiform discharges and focal slowing localized to the left centroparietal region. Left hemispheric dysfunction (slowing and poorly formed sleep architecture) when compared with the right was also evident on the EEGs. He remains off antiseizure medications (ASMs).We describe a term neonate who was found to have frequent electroclinical focal motor seizures arising from the left hemisphere secondary to neonatal AIS (NAIS) involving the left MCA territory. Stroke workup did not reveal any major risk factors for stroke. Maternal blood work was notable for positive antiphospholipid antibodies.Perinatal stroke affects 1 of 1100 births1 and carries with it the potential for long-term impacts on motor, cognitive, and behavioral functioning as well as a risk of epilepsy. Perinatal stroke is defined as a stroke occurring between the 20th week of gestation and 28 days after birth2 and can be arterial ischemic, hemorrhagic, or venous in origin. A stroke diagnosed in the neonatal period is classified as NAIS, neonatal hemorrhagic stroke (NHS), or neonatal cerebral sinus venous thrombosis (NCSVT), depending on etiology. Like our patient, neonates diagnosed with stroke often present with seizures, and most patients diagnosed with a perinatal stroke present in the neonatal period. When the stroke is diagnosed after the neonatal period, it is classified as an arterial presumed perinatal ischemic stroke (APPIS), presumed perinatal hemorrhagic stroke, or periventricular venous infarction. Patients diagnosed with these types of strokes typically present as infants or children with hemiparesis, often manifesting as early-handedness, and/or epilepsy.Given that our patient presented acutely, we will focus on the presentation, risk factors, diagnosis, management, and outcomes of AIS diagnosed in the neonatal period. NAIS is the most common perinatal stroke type, accounting for 40%-80% of perinatal stroke cases and 60% of those that present acutely.3,4Seizures are the most common presenting symptom of NAIS, seen in up to 80%-94% of affected neonates5–7 with a typical onset between 12 and 72 hours after delivery.8–10 Other reported presenting symptoms are nonspecific and include apnea, encephalopathy, hypotonia, irritability, and poor feeding. Many of these symptoms overlap with those seen in other types of perinatal stroke, including NHS and NCSVT, as well as in infants with hypoxic-ischemic encephalopathy (HIE) or sepsis.Like most neonates with AIS, our patient presented with focal motor seizures, and in this case, an onset approximately 24 hours after delivery, a typical time frame for seizure onset after NAIS. The initial clinical concern was for apneic events; in a neonate, apneic events may be a manifestation of seizure and warrant evaluation with an EEG if there is no other known cause. On his initial examination, he was also noted to have a mild encephalopathy, and this was consistent with his EEG background activity. Like apnea, this is a nonspecific symptom but also warrants further evaluation in the absence of a known cause. Finally, our patient had a motor asymmetry at the time of presentation. This is not always seen in the neonatal period immediately after AIS but suggests an asymmetric process and should raise concern for NAIS or NHS.In most patients with NAIS, a definitive etiology remains unidentified despite thorough diagnostic evaluation. Several risk factors for perinatal stroke have been identified, although most associations are weak and vary among studies.11,12 It is likely that NAIS occurs in utero or around the time of birth because of interactions among infant, maternal, and intrapartum/placental processes.13 A list of reported risk factors is shown in Table 1.Our patient had several risk factors for NAIS, including fetal heart rate abnormalities, maternal fever, maternal antiphospholipid antibodies (prothrombotic), a heterozygous factor V Leiden gene variant in the neonate, and male sex. Placental abnormalities could not be ruled out because of the absence of placental pathology.There is no strong evidence base or standard of care for the diagnosis and etiologic evaluation of perinatal stroke.15,16 Neuroimaging with MRI allows for the differentiation of the various subtypes of perinatal stroke. In acute NAIS, diffusion-weighted imaging demonstrates hyperintensity of the infarcted territory with corresponding hypointensity on the apparent diffusion coefficient map, as seen in our patient (Figure 1A and 1B). Delineating the infarcted territory can be particularly helpful in differentiating ischemic injury caused by NAIS from HIE or NCSVT, which may present similarly to NAIS. Concurrently obtained blood-sensitive sequences (ie, gradient recalled echo sequence or susceptibility-weighted imaging) allow for the identification and characterization of hemorrhage, which, like HIE and NCSVT, can present similarly to NAIS. Magnetic resonance angiography allows for the identification of any associated or causative cerebrovascular abnormalities or thromboses, the latter of which was seen in our patient (Figure 1D).In a neonate who is too unstable to travel to the MRI scanner, head ultrasonography or head computed tomography (CT) can be used. As seen in our case, head ultrasonography is less sensitive for the detection of NAIS than MRI, with a recent study demonstrating a sensitivity of 87% for an expert evaluator (neonatologist with expertise in cranial ultrasonography) and 72% for a nonexpert evaluator (clinicians caring for the patient at the time of the stroke).17 Head CT scans may show hypodensity in the area of infarction, although this may not manifest for up to 24 hours after stroke onset.14 Small infarcts can be particularly challenging to identify on head CT, and artifacts from adjacent bony structures can make posterior fossa strokes especially difficult to detect.14 Moreover, head CT scans require exposure to ionizing radiation, which is associated with an increased risk of cancer.18As for our patient, EEG may be the first clue to the presence of a stroke, especially if the EEG is obtained before definitive head imaging. EEG may show focal seizures and/or focal background abnormalities (eg, asymmetry, focal epileptiform discharges, and/or lateralized rhythmic or periodic patterns) that may be a clue to the presence of a stroke, rather than an alternative etiology in which more diffuse or multifocal abnormalities would be expected (eg, HIE or sepsis).In addition to brain imaging, neonates with AIS often undergo echocardiography to identify a potential cardiac contribution or source. As seen in our patient, a patent foramen ovale is an expected finding in a neonate; however, echocardiography may identify other types of structural heart disease that were not diagnosed in utero. More rarely, an intracardiac thrombus may be found. Investigations for prothrombotic disorders have not been found to be informative, and an extensive hematologic evaluation is not recommended in the absence of associated systemic thrombosis and/or a concerning family history.4,19 Of note, these recommendations have not been universally adopted, and our patient and his mother did undergo thrombophilia evaluation. This was notable for a heterozygous factor V Leiden variant in the neonate and antiphospholipid antibodies in the mother. It is difficult to know whether the heterozygous factor V Leiden variant contributed to increasing our patient’s stroke risk, but it is not considered to be an ongoing risk factor for recurrence. The maternal antiphospholipid antibodies may have contributed to an increased hypercoagulable state and risk of thrombosis around the time of delivery. Placental pathology may be informative in NAIS; in many patients, abnormalities such as chorioamnionitis or fetal vessel or umbilical cord thrombi are identified, and these may be causative or contributory to the stroke.20 Although the maternal fever in our case raised concern for chorioamnionitis, unfortunately, placental pathology was not obtained. Neonates may also undergo lumbar puncture to rule out meningitis. Lumbar puncture is not strictly necessary if a stroke is diagnosed before CSF sampling unless the neonate is demonstrating other signs of infection or the stroke occurs in a pattern typical of that seen in meningitis (ie, multifocal strokes of the arterial perforators that supply the deep gray matter).The acute management of NAIS focuses on neuroprotective measures to prevent secondary brain injury, including treating seizures. In neonates whose stroke is complicated by seizures, treatment with ASM is indicated. Trials in mixed cohorts of neonates suggest that phenobarbital is more effective than levetiracetam for neonatal seizures,21 and indeed, this was effective in treating our patient’s seizures. It is important to note that seizures may be electrographic only (eg, subclinical or nonconvulsive) and detectable only by EEG, suggesting that a full-montage EEG or, at minimum, cerebral function monitoring should be obtained. Seizures triggered by NAIS are considered acute symptomatic and typically resolve within a few days.22 A recent study suggests that it is safe to discontinue ASMs for neonates with acute symptomatic seizures before hospital discharge, as was done in our case; there was no difference in neurodevelopmental outcome or epilepsy at 24 months in a large, multicenter cohort of neonates with acute symptomatic seizures based on discontinuation as compared with maintenance of ASMs at hospital discharge.23 There is no indication for seizure prophylaxis in neonates with stroke without seizures. Other neuroprotective measures are extrapolated from studies in adults with stroke and children with other types of acute brain injury and include maintaining normothermia, normovolemia, and normoglycemia.There is no evidence to suggest that hyperacute interventions used in children and adults, such as thrombolysis or thrombectomy, are beneficial in neonates, and given the unclear timing of onset, neonates with AIS would not meet criteria for treatment with these therapies, which require identification of an infarct within a prespecified amount of time from when a patient was last known to be at their baseline. There is also no evidence to support the treatment of neonates with AIS with therapeutic hypothermia, although this is the standard of care for neonates with HIE. Antiplatelet agents or anticoagulation are generally also not recommended, except in neonates with an identified ongoing risk factor, such as congenital heart disease or thrombophilia. Our patient’s heterozygous variant in factor V Leiden was considered not to be an ongoing risk factor for recurrent AIS, so a multidisciplinary decision was made to continue to monitor off antithrombotic therapy.Mortality after NAIS is low (approximately 1%-2%),24 and recurrence rates are also low (approximately 1%),4,25 except in children with congenital heart disease.26 Unfortunately, most perinatal AIS (PAIS; NAIS + APPIS) survivors experience life-long morbidity, with deficits in motor, cognitive, and/or behavioral function, although in some studies up to approximately one-third of PAIS survivors are reported to have a normal neurodevelopmental outcome.27 PAIS survivors are also at increased risk of epilepsy. The severity of the long-term sequelae can vary widely, but severe disabilities are rare28 and most often seen in patients with bilateral injury.29 Regardless, the lifetime costs of pediatric stroke greatly exceed that of adult stroke because most children with stroke have a normal or near normal life expectancy, resulting in decades of neurologic disability.30Motor deficits are the most common long-term sequela of NAIS and most commonly manifest as spastic hemiparetic CP,27,31 as seen in our patient. In a study of 111 children with perinatal stroke (n = 67 NAIS, n = 44 APPIS), 76 (68%) were diagnosed with CP.32 Similarly, in a cohort of 100 children from Switzerland, 39% of NAIS survivors were diagnosed with CP by age 2 years.33 Patients with a complete MCA territory stroke, as seen in our patient, a stroke involving the cerebral peduncle (including Wallerian degeneration), or a stroke involving any part of the corticospinal tract have the highest risk of motor impairment.24,33 Upper extremity impairment is more common than lower extremity impairment after PAIS,8,24 and most children with PAIS are able to walk independently, at least in indoor settings.24Motor impairment is best addressed through a rehabilitation program by an team of occupational and physical and speech and language However, the most effective rehabilitation to be as the for There is extensive rehabilitation for patients with however, it is unclear whether these are for pediatric patients with stroke. Moreover, there is a of despite several and studies rehabilitation for pediatric stroke. As pediatric stroke rehabilitation but not or rehabilitation focus on structural and of the body, for although may be if not than PAIS survivors have a outcome with approximately of patients with PAIS manifesting children with AIS have scores in the to is generally with left hemisphere although in and language may In children with perinatal stroke and language or should undergo EEG to include sleep to for an deficits can also be including and with and and and with stroke have an increased risk of and their function and are typically It is important to note that and deficits may not apparent a when the on their functioning and it will be important to continue to our patient time to for and outcome measures may also not subtle and indeed, among children who undergo evaluation years after stroke onset, more than a or This is in with that suggest that with and behavioral and are more common among pediatric stroke survivors than the and indeed, parents of children with stroke identify mental as a concern in their on rehabilitation after pediatric stroke is generally focus on in the use of alternative or of the and or of involving have generally shown only impact and poor the study motor rehabilitation including therapy, the of the upper extremity is to in of the affected upper extremity, have been shown to in children with This may motor a to function and noted many patients with PAIS present with seizures, and approximately on to develop There is also an increased risk of occurring in of children with infarct is associated with an increased risk of and PAIS survivors with are at increased risk of other types of epilepsy later is no evidence to suggest that maintenance ASMs prevent the of epilepsy in neonates with AIS, and they should only be started a patient has presented with a seizure and the criteria for the diagnosis of epilepsy. Unfortunately, the of epilepsy after PAIS has been associated with neurodevelopmental in PAIS survivors can also and for epilepsy should given the presence of a focal many PAIS survivors are should the patient to include the parents and other family of the after perinatal stroke is not and is associated with mental outcomes the Similarly, the and functioning of children with CP with A recent of the of interventions (ie, and on patients with neonatal brain injury found positive of the in of suggesting that including may impact outcomes for neonatal brain injury patient did not undergo brain MRI scans after the diagnosis of his stroke. or not to imaging in a patient with NAIS is the low risk of recurrence in those without congenital heart the of routine follow-up imaging is not and be the risk of for most commonly with neonatal etiology of neonatal stroke often remains but likely interactions among the infant, the patient, and intrapartum/placental care focuses on including seizure neonatal stroke survivors develop motor most commonly hemiparetic This typically the upper extremity more so than the lower extremity, and most neonatal stroke survivors walk outcomes are although patients should continue to be followed long-term to for is the of long-term however, there is a of on which to base of neurologic disorders in the the for care for patients with neurologic disorders in the neonatal care