Follow-Up of an Infant With Posterior Cerebral Artery Stroke

In this article, we present the case of a full-term female infant who was admitted to the neonatal neurocritical care unit with neonatal encephalopathy (NE). Postrewarming brain magnetic resonance imaging (MRI) revealed a perinatal arterial ischemic stroke (PAIS) affecting the left posterior cerebral artery (PCA) territory. Following initial treatment, the infant received ongoing multidisciplinary care through the combined stroke and neonatal neurodevelopmental follow-up clinic. This case details the important aspects of follow-up care for neonates with PAIS.The infant was born to a 25-year-old primigravida woman with normal prenatal laboratory tests. Antenatal ultrasonography scans were unremarkable with normal glucose challenge test. A cell-free DNA test was not obtained. The pregnancy was complicated by maternal hypertension requiring labetalol, with no significant family history. She was admitted to the hospital with elevated blood pressures at 38 weeks' gestation, and because of a nonreassuring fetal heart rate with fetal decelerations, an emergency cesarean section was performed. The arterial cord gas pH was 6.91 with a base excess of −22 mmol/L, and the venous cord gas pH was 6.99 with a base excess of −20 mmol/L.After delivery, the female infant required continuous positive airway pressure because of increased work of breathing, with a positive end-expiratory pressure of 6 cmH2O and a fractional inspired oxygen of 0.25; this was later discontinued on postnatal day 3. Her Apgar score was 6 and 7 at 1 and 5 minutes of age, respectively. The infant was brought to the neonatal intensive care unit for further care. Her birth weight was 2820 g (thirtieth percentile). The infant had a decreased level of consciousness with lethargy and reduced spontaneous activity and muscle tone with a weak suck and gag and an absent Moro reflex. The initial Sarnat score at 1 hour of age demonstrated moderate NE with a Thompson score of 7. Umbilical lines were placed. Laboratory and clinical criteria for therapeutic hypothermia were met, and the infant reached the target temperature at 5 hours of age. Empirical ampicillin and tobramycin were started as per the therapeutic hypothermia protocol, and the placenta was sent for pathological investigation.The infant was then transferred to the neonatal neurocritical care unit for further management. Cranial ultrasonography showed mildly increased echogenicity in the white matter, especially in the left posterior parietal region. Some asymmetry was noted in the echogenicity of the posterior white matter regions (Figure 1). During the rewarming process on postnatal day 3, electrographic seizures were noted on amplitude-integrated electroencephalogram (EEG) without any clinical signs. The infant received 2 doses of lorazepam and a loading dose of phenobarbital. Continuous video-integrated EEG did not reveal any further seizures; however, the background activity was of low amplitude with excessive discontinuity for age, with intermittent bilateral independent multifocal sharp wave discharges seen over the temporal and parietal regions.An abdominal ultrasonography was obtained on postnatal day 4 because of persistent thrombocytopenia. A nonobstructive thrombus in the left internal iliac artery was detected and thought most likely to be secondary to umbilical artery catheterization. Prothrombotic workup revealed a slightly low level of protein C, normal protein S level, normal homocysteine level, and high antithrombin and fibrinogen levels; the team did not recommend anticoagulation. A postnatal echocardiogram to assess for a mass was obtained on postnatal day 4, which was notable for normal biventricular systolic function with a small patent foramen ovale shunting left-to-right; no obvious intracardiac mass or vegetation was seen.Postrewarming brain MRI obtained on postnatal day 4 revealed diffusion restriction in the left occipital and parietal lobes, in keeping with acute infarction within the left PCA distribution, with associated pre-Wallerian degeneration in the left optic radiation and splenium of the corpus callosum. An additional smaller infarction of the medial left thalamus with a few tiny foci of white matter injury were noted. MR-angiography showed patency of major arteries of anterior and posterior circulation (Figure 2). These findings were consistent with PAIS in the left PCA territory. There was no family history of stroke, myocardial infarction, aneurysms, pulmonary embolism, systemic thrombosis, multiple recurrent miscarriages, or other clotting or bleeding disorders.Following the brain MRI, the neonatal neurology team convened with the pediatric stroke team to reach a consensus on the potential neurodevelopmental outcome trajectories. Subsequently, a family meeting took place to disclose the findings. The team explained that the primary area that was involved was responsible for the function of vision. They discussed that their daughter was at an increased risk of developing a visual defect, with the possibility of right-sided visual field deficits. Additionally, it was noted that there was a mildly increased risk of postneonatal seizure development because of cortical involvement. Given the intact motor areas and limited brain injury, favorable prognoses were anticipated for motor skills, cognitive abilities, and language development. The importance of close monitoring of neurodevelopmental outcomes was emphasized. The results of the placental pathology were also discussed with the parents; the pathology showed features suggestive of fetal vascular malperfusion and stem villous thromboses with a hypercoiled umbilical cord showing eccentric insertion. The cord coiling index was 1.5 with a normal index ranging between 0.2 and 0.3. The features of fetal vascular malperfusion were most likely secondary to the hypercoiled umbilical cord. The etiology of PAIS was thought to be placental embolism; thus, no medication was started for secondary stroke prevention. However, the infant was started on phenobarbital maintenance. Visual evoked potentials and automated auditory brainstem response hearing screen were obtained on postnatal day 8 and were normal. The infant was discharged from the neonatal neurocritical care unit at 39 2/7 weeks' gestation of postmenstrual age with appropriate oral feeding and on maintenance phenobarbital. Follow-up was arranged with the combined stroke and neonatal neurodevelopmental follow-up clinic.The infant's first neurodevelopmental follow-up occurred at 4 months of age. She was cared for at home by her parents, who were very engaged in her care and development. The infant appeared well and showed appropriate growth with a weight of 5.9 kg (twelfth percentile), a length of 61 cm (tenth percentile), and a head circumference of 41 cm (thirty-eighth percentile). Her head was normally shaped with no signs of plagiocephaly, and her anterior fontanelle was open. Visual fixation was normal, and she tracked objects appropriately both horizontally and vertically. She was also visually attentive to faces and objects. There were no signs of strabismus or nystagmus. Her axial and appendicular tone, muscle bulk, and deep tendon reflexes were all within normal ranges. The pediatric stroke outcome score was 0 (ie, normal). Her gross motor skills, assessed with the Alberta Infant Motor Scale, were at the fiftieth percentile. She demonstrated age-appropriate fine motor development by swiping at toys, reaching for objects symmetrically against gravity with both hands, and bringing her hands to her mouth. Additionally, she was cooing, which was consistent with age-appropriate language development. Given her neuroimaging findings demonstrating an ischemic stroke that may have compromised the left optic radiation and primary visual cortex, she was referred to the ophthalmology clinic to further monitor her vision.The infant's parents were provided with anticipatory guidance together with information pamphlets about age-appropriate play activities and speech and language activities over the next several months. The infant had a repeat EEG at 4 months of age, which showed intermittent focal slowing recorded in sleep over the left posterior region, expected for a remote ischemic event, with no epileptiform activity. She was weaned off phenobarbital over the following weeks. The genotype for factor V Leiden and factor II revealed normal factor V (1691 G>A) and normal prothrombin (20210 G>A).The infant's routine 8-month neurodevelopmental follow-up was conducted virtually at 9.5 months because of COVID-19 hospital restrictions. Since her previous clinic visit, she had remained healthy, with no infections or seizures since discontinuing her maintenance phenobarbital. Her immunizations were up-to-date, and there were no concerns about her vision or hearing. She was able to fix and follow objects both horizontally and vertically. She was consuming a variety of thick pureed foods 3 times daily and drinking between 750 and 850 mL of infant milk formula daily. She was also finger-feeding and using utensils. There were no concerns regarding her temperament, sleep patterns, or behavior, and she appeared to be making age-appropriate progress across all developmental domains. The parents were counselled to keep her well hydrated and avoid iron deficiency as part of the general stroke prevention strategies. Parents received anticipatory guidance and recommendations on age-appropriate play activities, speech and language activities, and expected developmental progress over the next 6 months. They were also directed to our institutional parent resources for general neurodevelopmental recommendations.The subsequent neurodevelopmental follow-up was at 12 months of age. She had been healthy in the interim. There was no concern about her vision or hearing. She was fixing and following appropriately without any signs of strabismus or visual field deficits. She was eating all types and textures of food in 3 meals daily with snacks and was drinking 480 to 600 mL of homogenized cow's milk daily. Parents reported no concerns about temperament and sleep patterns. Physical examination revealed an alert, responsive, healthy-appearing child. Her weight at 8.39 kg was in the nineteenth percentile, her length at 71.2 cm was in the fourth percentile, and her head circumference at 45.9 cm was in the sixty-sixth percentile. Her growth velocity was steady, and she had normal axial tone with normal deep tendon reflexes. Assessment of the gross motor development using the Alberta Infant Motor Scale showed age-appropriate gross motor functioning on the ninetieth percentile. She had been walking independently since 10.5 months of age. She had a symmetrical, 4-point reciprocal crawl and transitioned from 4-point to sitting with ease. She also transitioned into and out of a variety of sitting positions. She squatted to play and transitioned up into standing from the floor. Assessment of her fine motor development using the Posture and Fine Motor Assessment of Infants scale also showed age-appropriate fine motor functioning. She was reaching symmetrically against gravity with both arms and hands, showing a 3-jaw chuck grasp for blocks and a superior pincer grasp for small objects. She was able to transfer objects at the midline, stack blocks, and have a voluntary release without external support. The quality of her gross and fine motor movements was normal. Assessment of speech and language development using the Communication and Symbolic Behavior Scale Developmental Profile Infant-Toddler Checklist showed typically developing speech and language skills. There was no concern about her socioadaptive behavior, and she was imitating baby games as expected for her age.At the 18-month clinic visit, she presented as a curious and playful infant and adapted well to the novel testing environment. She warmed up to the examiner and was observed to smile in response to social stimulations. She was alert and interested in exploring toys and the environment. She sat well in her chair and was attentive and motivated by the tasks presented. She followed verbal instructions well during the assessment. She was able to express herself and indicate her needs using gestures, combined with vocalizations that had a great deal of intonation resembling actual speech, and a handful of single words. Her parents completed the Ages and Stages Questionnaire-3 to better understand the developmental progress observed at home and did not report any concerns for her development (Table 1). The Bayley Scales of Infants and Toddler Development, third edition (Bayley-III) assessment revealed age-appropriate developmental progress across all domains, with a high average score in expressive language (Table 2). Parental rating on the Modified Checklist for Autism in Toddlers revealed a score of 0 with no concerns about her social interaction skills. On the visual reception scale of the Mullen Scales of Early Learning, which measures visual discrimination, she scored slightly below age expectations. On the Child Behavior Checklist, a questionnaire addressing characteristic behavior and emotional regulation, the infant's parents did not identify any areas of concern and reported typical emotional and behavioral development as compared with other female infants her age.At the 36-month clinic visit, the child's Bayley-III assessment once again revealed age-appropriate developmental progress across all domains with a high average score in expressive language (Table 3). Her parents did not report any concerns on Ages and Stages Questionnaire-3 and were happy with her developmental progress (Table 4). Her neurological examination was normal with normal muscle tone, strength, and deep tendon reflexes. There were also no concerns with her visual assessment. The infant was discharged from the neonatal neurodevelopmental follow-up program; however, as infants with a history of PAIS are at an increased likelihood of learning and executive functioning challenges at school age, a referral was made for a school-aged neuropsychological assessment by the stroke team, and she continued with ophthalmology follow-up.At her most recent visit at 5 years of age in the Stroke Clinic, conducted via virtual assessment, her parents reported no seizures or other neurological symptoms. They expressed no concerns regarding her neurodevelopment. She was capable of walking independently, running, jumping, hopping on 1 foot, swimming, and moving her limbs symmetrically. She was able to feed herself with cutlery, drink from a cup, and dress independently, although she needed help tying her shoes. She demonstrated bilateral pincer grasp, could hold a pen, and scribble. She responded to her name, followed instructions, counted to 10, and recognized basic colors and shapes. She was attending daycare full-time, where she was reported to be shy occasionally but was able to make friends. Her parents also reported no concerns about her vision or hearing. She will continue to be seen by the Stroke Clinic until the end of her high school years.NE has been described by the American College of Obstetricians and Gynecologists and American Academy of Pediatrics as a clinical syndrome of disturbed neurologic function in a neonate born at or beyond 35 weeks' gestation, manifested by an abnormal level of consciousness or seizures, often accompanied by difficulty with initiating and maintaining respiration and depression of tone and reflexes.1 NE can occur because of numerous underlying causes, of which hypoxic-ischemic encephalopathy (HIE) is a common etiology and represents approximately half of cases. However, many nonasphyxial factors in the perinatal period can also cause or contribute to NE either as a sole etiology or, more commonly, as a contributing factor, including systemic infections or infections of the central nervous system, intracranial hemorrhage, perinatal stroke, and genetic or neurometabolic conditions.2Because the established treatment of NE is therapeutic hypothermia, which is most effective if initiated within the first 6 hours after birth, treatment decisions must be made immediately. Therefore, there is an urgent need for a descriptive working diagnosis based on rapid clinical assessment. Later, a final diagnosis is required, incorporating information from subsequent diagnostic procedures, record reviews, and neuroimaging modalities. It is proposed that NE should be the initial working diagnosis, to be refined to NE because of a more specific cause as investigations progress. The presented case highlights the importance of this approach because the infant initially presented with NE, received timely therapeutic hypothermia for possible HIE, and was later diagnosed with PAIS as the underlying cause.PAIS has an incidence of 1 in 1000 live births and is the main cause of hemiparetic cerebral palsy in childhood.3,4 Affected infants present acutely in the first week after birth with signs of NE and seizures, with the insult presumed to occur in utero or peripartum.5 Focal motor seizures occur 12 to 72 hours after birth in over 70% of affected infants, with a low risk of recurrence because the majority of PAIS events occur because of placental embolism.6 PAIS can involve 1 or more vascular territories in the brain with the posterior artery affected in less than 10% of infants.7If a PAIS is suspected, a brain MRI should be obtained, along with MR-angiography and/or MR-venography, and acute infarction areas are most effectively visualized using diffusion-weighted imaging sequences.8 The diagnostic accuracy of cranial ultrasonography scans is inferior to brain MRI for PAIS, and for optimal prognostic information, infants with clinical histories suggestive of PAIS should have a brain MRI as the gold standard assessment.9 The infant presented in this case showed asymmetric ultrasonographic echogenicities suggestive of PAIS; however, the definitive diagnosis could only be made after obtaining the brain MRI. In a recent study of 473 infants with moderate and severe encephalopathy, PAIS was diagnosed in 21 (4%) infants, most of whom (16 of 21; 76%) also had concurrent HIE patterns of brain injury.10 In contrast, the infant in this case presented with isolated PAIS with focal ischemic infarcts within an arterial distribution.Many risk factors for the development of PAIS in newborns have been described.11 Placental histology is important when considering the underlying etiology of PAIS. Fetal vascular malperfusion is a term used to describe varying degrees of placental abnormalities at the histological level, including reduced or absent perfusion.12 Although not clearly understood, the 3 factors involved in Virchow's triad, endothelial injury, venous stasis, and presence of hypercoagulable state, are often quoted.12 Fetal vascular malperfusion has also been associated with intrauterine growth restriction and adverse perinatal outcome.13 Hypercoiling of the umbilical cord, defined as greater than 3 coils per every 10 cm of cord, has been associated with the adverse perinatal outcomes of umbilical artery acidosis, fetal placental thrombosis, and chronic fetal hypoxia.14 The umbilical cord coiling index is calculated by dividing the total number of coils by the umbilical cord length (cm), and the normal index is 0.17 (±0.009).15 Features of fetal vascular malperfusion in the current case were most likely secondary to the hypercoiled umbilical cord, and PAIS was thought to be placental in origin; therefore, the recurrence risk was deemed very low.Because of the highly neuroplastic capacity of the developing brain, the prognosis of PAIS can be favorable, with up to 40% of infants affected having a completely normal neurological examination and age-appropriate neurodevelopment at follow-up. However, the majority of infants with PAIS may experience neurodevelopmental impairment, with outcomes varying based on the size and location of the lesion. By examining the long-term outcomes of children with PAIS until 13 years of age, the Canadian Pediatric Ischemic Stroke Registry reported that 40% of affected children had typical outcomes, 33% had mild deficits, and 27% had moderate-to-severe deficits.16It is important to note that the arterial distribution of PAIS is a key factor in predicting outcomes. The middle cerebral artery is the most commonly affected arterial territory, and strokes in this region are generally associated with an increased likelihood of motor impairment, cerebral palsy, cognitive impairment, visual field defects, and epilepsy.17 Strokes in the PCA are linked to visual field defects and epilepsy, whereas those in the anterior cerebral artery, although less common, can result in motor and cognitive impairments.17–19 Perforator strokes not involving the posterior limb of the internal capsule generally have favorable outcomes. Multifocal strokes, often caused by placental emboli, have outcomes that depend on the size and location of the lesions. Strokes involving the posterior limb of the internal capsule, cerebral peduncles, or basal ganglia are associated with motor impairment and cerebral palsy. Mild cognitive impairment has been reported in children with a history of PAIS, with more significant impairment observed in strokes affecting the frontal lobe.8,17 Baak et al reported in a systematic review and meta-analysis that corticospinal tract assessment on brain MRI and standardized motor assessments are best to predict cerebral palsy after PAIS.19 This underscores the importance of obtaining a brain MRI for more accurate prognostication and close monitoring of the affected infant with standardized motor assessments during the early childhood years.When communicating prognosis with parents, it is important to acknowledge some prognostic uncertainty and the element of neuroplasticity of the developing brain and present expected outcomes in terms of likelihood using the most up-to-date literature.8 Often, for parents, it is not the generic prognosis, which is important, but the functional neurodevelopmental outcomes. Parents often ask questions such as "Will my child be able to walk and talk like other children?""Will my child be able to play with friends?""How will my child be able to interact with the world around them?""What will my child be able to achieve at school?"Because of the close association among PAIS involving the PCA territory and visual field deficits, the infant presented in this case requires regular ophthalmological examinations until childhood. However, a motor disability including cerebral palsy was unlikely in this infant, and the likelihood of cognitive and language delays was only mildly elevated.17 It has been consistently reported that parental education and socioeconomic status often influence neurodevelopmental outcomes after perinatal brain injury. The infant presented here had well-educated parents who were highly engaged in her care, and she was at home with her mother until 12 months of age, after which she was cared for by her paternal grandparents during the day and attended early infant socialization services provided by the local government. These programs help strengthen adult-child relationships, support parent education, and foster healthy child development, which may have played a role in this infant's optimal development. Notably, she did not require any rehabilitation services such as occupational therapy and physiotherapy; however, because of the PAIS diagnosis, continued observation until school age with standardized neurodevelopmental testing is essential.NE can result from various pathologies, with HIE being a significant underlying condition that necessitates prompt management with therapeutic hypothermia.Brain MRI plays a crucial role in identifying the underlying cause of NE and is essential for confirming the diagnosis. PAIS is an important cause of NE in the neonatal period and some affected infants may present with NE, meeting the criteria for therapeutic hypothermia. Routine placental pathology examination should be conducted in all NE cases to help determine the underlying etiology.Infants with PAIS involving the PCA territory are especially at increased likelihood of visual deficits and postneonatal epilepsy and require close neurodevelopmental follow-up. Ongoing neurodevelopmental monitoring with standardized tests into school age is essential for infants with all types of PAIS to monitor and address cognitive and behavioral challenges that may manifest at school age.We would like to express sincere thanks and gratitude to this infant's family for their willingness to share their story and the journey of their daughter with the wider neonatal community. Furthermore, we acknowledge the high level of compassion and care delivered by the neonatal neurocritical care service, the pediatric stroke team, and the neonatal neurodevelopmental programs at The Hospital for Sick Children in Toronto, Canada.