NeoQuest June 2023: A Term Infant with Abnormal Movements

A 6-week-old nondysmorphic term infant presents to the emergency department after multiple episodes of new-onset clonic movements of the left arm and leg. The infant is appropriate for gestational age for all growth parameters, afebrile and hemodynamically stable, but lethargic with intermittent apnea, requiring emergent intubation. A complete blood count with differential, electrolytes, liver function panel, and coagulation studies are normal. Cerebrospinal fluid (CSF) studies are significant for total cell count 997/μL (47.2% polymorphonuclear white blood cells), total protein 1.34 g/L, glucose 64 mg/dL, and red blood cells 100,000/μL in the setting of a normal CSF infectious polymerase chain reaction panel. An electroencephalogram (EEG) demonstrates repetitive ictal discharges from the right side. Computed tomography imaging of the brain is obtained (Figure 1).

Figure 1: Computed tomography of the brain in a 6-week-old infant with lethargy, acute respiratory failure associated with apnea, and new-onset clonic movements that demonstrates bilateral frontal and parieto-occipital subdural hemorrhages (arrows) without skull fracture. Image from: Fontoura-Matias J, Pereira-Nunes J, Vicente-Ferreira M, Sampaio L, Vilan A. Newborn with left-sided clonic movements. Neoreviews. 2023;24(6):e393–e398¹

Which of the following additional features is most likely associated with this condition?

1. Retinal hemorrhages
2. Single maxillary central incisor
3. Vacuum-assisted vaginal delivery
4. Vesicular rash
5. Widening of the Sylvian fissures and pretemporal subarachnoid spaces

Answer: A. Retinal hemorrhages

Explanation:

This 6-week-old term infant acutely presents with bilateral frontal and parieto-occipital subdural hemorrhages (Figure 1) in the setting of lethargy, acute respiratory failure associated with apnea, and new-onset seizures, a constellation of symptoms concerning for abusive head trauma (AHT). Subdural hemorrhage occurs under the dura mater, typically due to rupture of the bridging veins in the subdural space. Although the differential diagnosis for infantile subdural hematoma can be vast (Table).

Table: Differential diagnosis of infantile subdural hemorrhages categorized by etiology.^2–4

AHT is one of the most common causes seen in children with subdural hemorrhages under two years of age.^2–4 Because the diagnosis of AHT can be challenging, it requires a multidisciplinary approach focused on obtaining a thorough history, performing a complete physical exam, and completing an extensive laboratory and radiologic evaluation.^2,3 Of note, a family history of child abuse is associated with AHT and should be inquired about tactfully if evidence suggests.^2,3 However, families may not readily provide this type of information to the medical team. Many cases of AHT will also lack a clear history of events that can explain the presence of subdural hemorrhages and other symptoms of abuse. The presence of the classic triad of clinical findings for AHT—subdural hematomas, retinal hemorrhages (Option A), and neurologic sequelae such as encephalopathy, seizures, and ictal apnea—in the setting of a negative infectious and hematologic evaluation, can help establish the diagnosis of abuse.^2,3 Although not pathognomonic for AHT, bilateral retinal hemorrhages (Figure 2) are present in up to 85% of AHT cases.^2,3

Figure 2: Ophthalmological examination demonstrating retinal hemorrhages (white arrows) across the posterior pole of the retina, Roth spots (black arrows), and retinal edema (dashed circle). Image from: Fontoura-Matias J, Pereira-Nunes J, Vicente-Ferreira M, Sampaio L, Vilan A. Newborn with left-sided clonic movements. Neoreviews. 2023;24(6):e393–e398 ¹

Severe congenital brain malformations such as holoprosencephaly can be associated with seizures and neurologic deficits seen in the infant in this vignette. Due to incomplete midline cleavage of the forebrain, holoprosencephaly presents with a spectrum of midline cranial, facial, neurologic, and endocrine defects that vary in severity depending on the degree of nonseparation.⁵ Mild craniofacial features include microcephaly, hypotelorism, and a single maxillary central incisor (Option B).⁵ In this particular case, the seizing infant is normocephalic and nondysmorphic and has a brain computed tomography scan exhibiting grossly normal midline neuroanatomy, findings that are not consistent with the diagnosis of holoprosencephaly.⁵

Subdural hemorrhage may also occur secondary to traumatic birth injury with a higher incidence in infants delivered vaginally compared to cesarean section.⁶ The incidence of birth-related subdural hemorrhage nearly triples with instrumentation (eg, vacuum and forceps) (Option C).⁷ Birth-related subdural hemorrhage can present with altered mental status, irritability, seizures, apnea, and neurological deficits classically within the first 48 hours after birth.⁷ In this patient, the onset of clinical symptoms at 6 weeks of age points against birth trauma as the direct cause of this infant’s acute neurologic decompensation. 

Similar to AHT, infants with herpes simplex virus (HSV) can present with acute encephalopathy, seizures, and intracranial hemorrhage.^2,8 HSV encephalitis is a common, severe viral cause of encephalopathy in the neonatal period. The average age of neonatal patients who present with seizures from HSV ranges from 15 to 20 days.⁸ The classic vesicular rash is only present in approximately 60% of infants (Option D).⁸ While red blood cells in the CSF are a feature of HSV with central nervous system (CNS) manifestations, it is a distractor in this case. In neonatal seizures caused by HSV encephalitis, diffuse brain abnormalities are seen on neuroimaging, which were not present in this patient. Infants with CNS disease from HSV frequently have involvement of the thalamus, corticospinal tract, and posterior limb of the internal capsule.⁹ The typical EEG findings for seizures caused by HSV infection include periodic sharp discharges in the frontal and temporal regions, which were also not demonstrated in this patient.⁸

An evaluation for AHT must exclude medical conditions that can mimic AHT, such as glutaric aciduria type 1 (GA1).  GA1 is an autosomal recessive organic acidemia caused by a deficiency of the enzyme glutaryl-CoA dehydrogenase, impacting the metabolism of lysine, hydroxylysine, and tryptophan.¹⁰ As a result, toxic metabolites from this metabolic pathway can accumulate, causing brain atrophy and bilateral striatal neurodegeneration.¹⁰ Neonates with GA1 may develop progressive macrocephaly and hypotonia by late infancy. If GA1 is not appropriately diagnosed and treated early in life, acute encephalopathy, seizures, loss of motor skills, and extrapyramidal manifestations can occur.¹⁰ Pathognomonic neuroimaging findings of GA1 consist of frontotemporal cerebral atrophy and widening of the Sylvian fissures and pretemporal subarachnoid spaces (Option E) (Figure 3).¹¹ Timely diagnosis and the initiation of metabolic treatment (ie, low lysine diet, carnitine supplementation, and intensified emergency treatment during acute illness) are critical in preventing neurological disease and improving overall prognosis.¹⁰

Figure 3: Axial T2 brain magnetic resonance imaging scan illustrating frontotemporal atrophy, prominent pretemporal subarachnoid spaces, and widened sylvian fissures in a patient with glutaric acidemia type 1. Image from: Kaur S, Pappas K. Genetic etiologies of neonatal seizures. Neoreviews. 2020;21(10):e663–e672

Did you know?

• Retinal hemorrhages are not pathognomonic for AHT and can be seen in various conditions (eg, Terson syndrome, leukemia, chronic anemias, vaginal delivery, and post-cardiopulmonary resuscitation).¹¹
• Terson syndrome, which consists of intraocular hemorrhage associated with intracranial hemorrhage, can masquerade as AHT due to similar overlapping ophthalmic and neurological findings.¹¹

The accumulation of what metabolite is associated with prenatal hiccups and neonatal symptoms of lethargy, hypotonia, hiccups, and intractable seizures?

To find the answer, please read the following article:

• Kaur S, Pappas K. Genetic etiologies of neonatal seizures. Neoreviews. 2020;21(10):e663–e672

NeoQuest June 2023 Authors:

Allison N. J. Lyle, MD, MA, University of Washington
Neena Jube-Desai, MD, University of Maryland

References:

1. Fontoura-Matias J, Pereira-Nunes J, Vicente-Ferreira M, Sampaio L, Vilan A. Newborn with left-sided clonic movements. Neoreviews. 2023;24(6):e393–e398
2. Kemp AM. Investigating subdural haemorrhage in infants. Arch Dis Child. 2002;86(2):98–102
3. Choudhary AK, Servaes S, Slovis TL, et al. Consensus statement on abusive head trauma in infants and young children. Pediatr Radiol. 2018;48(8):1048–1065
4. Carpenter S, Abshire T, Anderst J, et al. Evaluating for suspected child abuse: conditions that predispose to bleeding. Pediatrics. 2013;131(4):e1357–e1373
5. Raam MS, Solomon BD, Muenke M. Holoprosencephaly: a guide to diagnosis and clinical management. Indian Pediatr. 2011;48(6):457–466
6. Nikam RM, Kandula VV, Yue X, et al. Birth-related subdural hemorrhage: prevalence and imaging morphology. Pediatr Radiol. 2021;51(6):939–946
7. Sims M. Legal briefs: 3 vacuum-assisted deliveries, 3 bad outcomes. Neoreviews. 2018;19(9):e551–e554
8. Hahn J, Olson D. Etiology of neonatal seizures. Neoreviews. 2004;5(8):e327–e335
9. Bajaj M, Mody S, Natarajan G. Clinical and neuroimaging findings in neonatal herpes simplex virus infection. J Pediatr. 2014;165:404–407
10. Hartley LM, Khwaja OS, Verity CM. Glutaric aciduria type 1 and nonaccidental head injury. Pediatrics. 2001;107(1):174–175
11. Kaur S, Pappas K. Genetic etiologies of neonatal seizures. Neoreviews. 2020;21(10):e663–e672
12. Thanos A, Yonekawa Y, Yomogida K, Bloom DA, Trese MT, Drenser KA. Retinal findings in abusive head trauma. Retina Today. 2016;11(3):57–59