NeoQuest December 2022: Abnormal Brain MRI Findings in a Term Infant with Feeding Difficulties

An infant with a history of bilateral ventriculomegaly noted on a third trimester prenatal sonogram was delivered at 37 weeks’ gestation via cesarean section. The physical exam was notable for mild distal flexion of the extremities, uncoordinated suck reflex, and a head circumference in the 40^th percentile. During her hospitalization, she required nasogastric tube feedings due to disorganized feeding. Brain magnetic resonance imaging was obtained with findings shown below.

Figure 1: Axial (left) and parasagittal (right) views of the infant’s brain magnetic resonance imaging (MRI) obtained at 5 days of age. From: Nataraj P, Rajderkar D, de la Cruz D, Weiss MD. Early term infant with prenatal brain abnormalities and decreased oral intake. Neoreviews. 2022;23(12):e856–e860. 10.1542/neo.23-12-e856

What lab finding was most likely present on her initial work-up?

1. Elevated nucleated red blood cell count
2. Metabolic acidosis
3. Pleocytosis in cerebrospinal fluid
4. Thrombocytopenia

Answer: A. Elevated nucleated red blood cell count

Explanation:

The brain MRI findings for the patient in this vignette demonstrated right-sided subependymal blood products (yellow arrow in Figure 1A), periventricular cystic encephalomalacia (white arrow in Figure 1B), and bilateral ventriculomegaly consistent with sequelae following a perinatal stroke (Figure 1A–B).^1,2

Perinatal strokes generally occur between 20 weeks’ gestation and 28 days’ postnatal age and can involve either the arterial or venous circulation, leading to ischemic and/or hemorrhagic injury notable on neuroimaging.^2,3 There are six major types of perinatal stroke, classified based on the mechanism of injury. Neonatal arterial ischemic stroke (NAIS) represents more than 80% of all cases, most commonly affecting the territory supplied by the middle cerebral artery (Figure 2).² The majority of infants with a NAIS present with a focal motor seizure between 12 and 72 hours after birth.²

Figure 2: Axial diffusion-weighted brain MRI in infant with a neonatal arterial ischemic stroke involving the territory supplied by the left middle cerebral artery (white arrow). From: Srivastava R, Kirston A. Perinatal stroke: a practical approach to diagnosis and management. Neoreviews. 2021;22(3):e16

The stroke subtype for this patient was most consistent with an arterial presumed perinatal ischemic stroke (APPIS) as a result of an in utero hypoxic event.^2,3 Infants with an APPIS are usually asymptomatic at birth but can develop focal neurologic deficits such as spastic hemiparesis during the first year of age.^2,3 On brain MRI, an APPIS appears as a chronic infarction with associated cystic encephalomalacia with or without hemorrhagic transformation (Figure 3).² Although neuroimaging is the gold standard to diagnose a perinatal stroke, an initial complete blood count at birth may show evidence of an elevated nucleated red blood cell (nRBC) count (Option A) depending on the timing of the hypoxic event. A high concentration of nRBCs in the circulation noted immediately after birth has previously been described as a potential biomarker for fetal tissue hypoxia.⁴ The mechanism involves the upregulation of hypoxia-inducible factors, which leads to increased fetal erythropoietin production and subsequent release of immature erythrocytes from the bone marrow and the liver into the bloodstream.⁴ Studies have evaluated the “emergence time” of nRBCs and have determined nRBC elevation occurs after at least 24 hours have passed from any initial hypoxic insult.⁴ In contrast, levels are usually normal in a neonate with an acute hypoxic event immediately surrounding delivery (eg, placental abruption or umbilical cord compression) because the bone marrow has not had enough time to synthesize nRBCs in response to increased circulating erythropoietin.^4,5 Our patient had an elevated nRBC count on her initial complete blood count obtained soon after birth, which was consistent with evidence of chronic ischemia and hemorrhagic changes on her postnatal brain MRI from an injury that likely occurred in utero.

Figure 3: Axial fluid-attenuated inversion recovery sequence from a brain MRI in an infant with arterial presumed perinatal ischemic stroke (APPIS) with encephalomalacia involving the left cerebral hemisphere (white arrow). From: Srivastava R, Kirston A. Perinatal stroke: a practical approach to diagnosis and management. Neoreviews. 2021;22(3):e165

Metabolic acidosis (Option B) can be seen in infants with hypoxic-ischemic encephalopathy (HIE), which is the most common cause of neonatal encephalopathy. HIE occurs as a direct result of a sentinel hypoxia-inducing event surrounding delivery.⁶ The evolution of HIE starts with an initial insult that leads to global hypoperfusion and compromised gas exchange. This is followed by a cascade of events that results in a switch to anaerobic metabolism, which is evident by metabolic acidosis and lactic acid accumulation.⁶ It is of critical importance that cord blood gas measurements are evaluated in a newborn with suspected HIE. Large clinical trials have reported that a base deficit greater than 14 mEq/L has over 70% sensitivity and 82% specificity for predicting moderate to severe HIE and is part of the diagnostic evaluation to help clinicians identify which infants should undergo therapeutic hypothermia.⁷ Clinical history indicating the occurrence of a sentinel event, combined with metabolic acidosis reflected on cord blood gas, low Apgar scores, and abnormal physical exam findings using the Sarnat Grading Scale for Neonatal Encephalopathy, are all important factors to consider in the diagnosis of HIE.⁷ Studies have demonstrated that nRBC counts are most often normal in infants with HIE because not enough time has lapsed between the acute intrapartum event, erythropoietin surge, and production of nascent nRBCs in response to the sentinel event.^4,5 Brain MRI findings in infants with HIE include watershed infarctions involving both the cortical gray matter and subcortical white matter as well as injury to vital structures such as the basal ganglia and thalamus (Figure 4).⁶ Our patient did not have an intrapartum sentinel event, and her neurologic examination following delivery and neuroimaging were not consistent with neonatal encephalopathy.

Figure 4: Axial view from a brain MRI in a term infant with diffuse hypoxic-ischemic injury involving the deep gray nuclei (yellow arrows) and cortex (blue arrows) bilaterally. From: Russ JB, Simmons R, Glass HC. Neonatal encephalopathy: beyond hypoxic-ischemic encephalopathy. Neoreviews. 2021;22(3):e152

Pleocytosis in cerebrospinal fluid (CSF) (Option C) can be seen in infants with bacterial meningitis, which carries high rates of neurologic mortality and morbidity.⁸ The two most common causative organisms for neonatal bacterial meningitis include Group B Streptococcus and Escherichia coli, which can both easily penetrate the blood-brain barrier, particularly after a primary bloodstream infection.⁸ Clinical presentations in infants can be quite nonspecific, ranging from lethargy and temperature instability to new-onset seizures.⁸ A blood culture, complete blood count, and inflammatory markers are often the first lab evaluations undertaken in a neonatal sepsis evaluation. However, bacterial meningitis can occur even without a positive blood culture, and inflammatory markers (eg, C-reactive protein, procalcitonin) can lack specificity.^9,10 A cerebrospinal fluid culture is the gold standard for diagnosing meningitis. Gram stain may demonstrate the presence of bacteria and help guide initial antimicrobial therapy, while findings of pleocytosis, low glucose, and elevated protein concentrations can also support a diagnosis of meningitis.⁸ Neuroimaging can be used as supportive evidence of meningitis, with findings such as ventriculitis or cerebral abscesses, and can assist in guiding the duration of antimicrobial therapy. However, it is not diagnostic for meningitis.⁸ Bacterial meningitis can also predispose infants to coagulopathy and increased risk of developing cerebral sinus venous thrombosis involving the superficial or deep veins, usually within the first 28 days after birth (Figure 5).² Our infant had evidence of brain injury that began in utero and thus is not consistent with venous thrombosis or bacterial meningitis.

Figure 5: Brain computed topography (CT) imaging without contrast (A) and with contrast (B) in an infant who initially presented with seizures. Findings revealed a cerebral sinovenous thrombosis involving the superior sagittal sinus (SSS), straight sinus (SS), internal cerebral veins (ICV) and the left transverse sinus (TS), as evidenced by the white arrows. From: Poisson KE, Thomas CW, Leach JL. A 2-week-old infant presenting with seizures. Neoreviews. 2020;21(9):e63

Thrombocytopenia (Option D) can occur in newborns, and neonatal alloimmune thrombocytopenia (NAIT) is the most common cause of severe thrombocytopenia in an otherwise healthy neonate.¹¹ In NAIT, maternal antibodies destroy fetal platelets that express a paternally-inherited human platelet antigen (HPA), leading to platelet destruction and subsequent thrombocytopenia with platelet levels typically below 50 x 10³/mcL.^11,12 Unlike other hemolytic diseases of the newborn (eg, anti-D alloimmunization), NAIT can occur during the first pregnancy of an at-risk couple with HPA mismatch. NAIT tends to recur with greater severity of thrombocytopenia in subsequent pregnancies.^11,13 Infants can be asymptomatic at birth or have evidence of petechiae, bruising, or severe intracranial hemorrhage (ICH), which can occur in up to 20% of infants. Of infants affected by ICH secondary to NAIT, approximately 50% of cases have occurred in utero (Figure 6).^11,13 Cranial ultrasound is often the initial imaging of choice used to screen for ICH. Brain MRI, with and without contrast, is the gold standard for identifying and delineating the location and extent of an ICH.^12,13 Our infant’s brain MRI was most consistent with the sequelae associated with a perinatal stroke instead of a large intraparenchymal bleed, which is more consistent with NAIT.

Figure 6: Axial view from a contrast-enhanced brain MRI in an infant with neonatal alloimmune thrombocytopenia. A large brain bleed was first discovered in utero involving the left hemisphere (white arrow) with mass effect. From: Griffin M, Brennan B, Paes BA. Fetal intracerebral mass with major perinatal implications. Neoreviews. 2012;13(4):e251

Did you know?
In utero cerebral venous thromboembolism is a direct result of a clot passing from the placenta to the fetus. In the fetal circulation, blood is preferentially directed to the cerebral vasculature, resulting in an increased risk of perinatal stroke. In cases of perinatal stroke, routine examination of placental pathology should be strongly considered to elucidate potential etiologies.³

Should anticoagulation be routinely used to treat a cerebral venous sinus thrombosis?
To find the answer, please refer to the following article: Poisson KE, Thomas CW, Leach JL. A 2-week-old infant presenting with seizures. Neoreviews. 2020;21(9):e631–635

NeoQuest December Authors
Faith Kim, MD, Columbia University Medical Center/NewYork-Presbyterian Children’s Hospital 
Anisha Bhatia, MD, Northeast Ohio Medical University

References

1. Nataraj P, Rajderkar D, de la Cruz D, Weiss M. Early term infant with prenatal brain abnormalities and decreased oral intake. Neoreviews. 2022;23(12):e856–e860. 10.1542/neo.23-12-e856
2. Srivastava R, Kirton A. Perinatal stroke: a practical approach to diagnosis and management. Neoreviews. 2021;22(3):e163–176
3. Roach GD. Perinatal arterial ischemic stroke. Neoreviews. 2020;21(11):e741–748
4. Christensen RD, Lambert DK, Richards DS. Estimating the nucleated red blood cell ‘emergence time’ in neonates. J Perinatol. 2014;34(2):116–119
5. Bahr TM, Ohls RK, Baserga MC, Lawrence SM, Winter SL, Christensen RD. Implications of an elevated nucleated red blood cell count in neonates with moderate to severe hypoxic-ischemic encephalopathy. J Pediatr. 2022;246:12–18.e2
6. Russ JB, Simmons R, Glass HC. Neonatal encephalopathy: beyond hypoxic-ischemic encephalopathy. Neoreviews. 2021;22(3):e148–162
7. Dysart, KC. Diagnosing neonatal encephalopathy as hypoxic-ischemic encephalopathy: interpreting test results in real time. Neoreviews. 2017;18(12):e703–711
8. Kim KS. Neonatal bacterial meningitis. Neoreviews. 2015;16(9):e535–543
9. Bhatti M, Chu A, Hageman JR, Schreiber M, Alexander K. Future directions in the evaluation and management of neonatal sepsis. Neoreviews. 2012;13(2):e103–110
10. Hooven TA, Polin RA. Neonatal bacterial infections. In: Martin GI, Rosenfeld W, ed. Common Problems in the Newborn Nursery: An Evidence and Case-Based Guide. Switzerland: Springer International Publishing; 2019. p. 71–80
11. Morrone K. Thrombocytopenia in the newborn. Neoreviews. 2018;19(1):e34–41
12. Sillers L, Van Slambrouck C, Lapping-Carr G. Neonatal thrombocytopenia: etiology and diagnosis. Pediatr Ann. 2015;44(7):e175–180
13. Griffin M, Brennan B, Paes BA. Fetal intracerebral mass with major perinatal implications. Neoreviews. 2021;13(4):e251–253