Case Report
Daniel T. Kashima, MD, PhD1,2,3; Steven M. Leber, MD, PhD1,2, Angad Kochar, MD1; Taryn Surtees, MD1
AUTHOR AFFILIATIONS
1 Department of Pediatrics, Michigan Medicine, Ann Arbor, MI, USA.
2 Department of Neurology, Michigan Medicine, Ann Arbor, MI, USA.
3 Current affiliation: Division of Pediatric Neurology, Ann & Robert H. Lurie Children’s Hospital, Chicago, IL, USA
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Abstract
Background.
SARS-CoV-2 (COVID-19) infections may be associated with a variety of neurologic pathologies. Neonatal COVID-19 infections have been associated with diffusion impedance on brain magnetic resonance imaging (MRI), although persistent clinical deficits have not been reported.
Clinical presentation.
We describe a 5-week-old boy born at 30-weeks, 5-days gestation who developed focal status epilepticus, respiratory failure, and widespread diffusion impedance of cerebral white matter on MRI in the setting of a COVID-19 infection without cerebral spinal fluid pleocytosis, meningoencephalitis, or genetic etiology. Repeat imaging showed cystic changes consistent with encephalomalacia. The distribution and timing of injury was not consistent with typical patterns of ischemia. Residual neurologic deficits were noted during follow-up evaluation at 4 months (2-months corrected gestational age) and at most recent appointment at 11 months (9-months corrected gestational age).
Conclusion.
Neonatal/infantile COVID-19 infection in absence of meningoencephalitis may cause widespread supratentorial white matter diffusion impedance with evolution to cystic changes and lasting clinical deficits.
Introduction
Since the advent of the SARS-CoV-2 (COVID-19) global pandemic, there has been increased recognition for the virus causing dysfunction of the nervous system1,2. Proposed mechanisms include direct invasion of the brain parenchyma or secondary injury such as through systemic inflammation, endothelial injury, or a hypercoagulable state leading to stroke1,3. Autopsy studies in adult patients suggest neuronal damage from COVID-19 stems from secondary injury rather than direct viral invasion4. In neonates, COVID-19 infection has been associated with diffusion impedance on brain magnetic resonance imaging (MRI)2,3,5,6. Similar patterns have been seen with other viral infections including parechovirus, enterovirus, and rotavirus7. Although diffusion impedance warrants consideration of ischemic stroke with possibility of permanent injury8, long-term neurologic deficits have not previously been reported even when MRI abnormalities have been documented in cases of neonatal COVID-195,6.
Here we present a case of focal status epilepticus in a preterm infant found to have widespread supratentorial white matter diffusion impedance in the setting of COVID-19. Repeat imaging and outpatient follow-up was consistent with permanent neurologic deficits.
Case Report
A newborn boy was born at 30-weeks, 5-days gestation via vaginal delivery due to early placental detachment. Delivery room resuscitation included drying, stimulation, and suctioning. Apgars were 7 and 9 at 1 minute and 5 minutes, respectively. Initial cord gases were reassuring against acidemia (arterial pH 7.38, venous pH 7.45). Continuous positive airway pressure was initiated for reduced respiratory effort and an orogastric tube was placed for decompression prior to transfer to the neonatal intensive care unit. Serial cranial ultrasounds performed on day of life (DOL) 3, 7, and 14 did not show evidence of hemorrhage. He was discharged from the hospital at DOL 31. The newborn screen was drawn at DOL 2 with repeat on DOL 30. These were normal.
On DOL 39, he developed a cough and nasal congestion in the setting of multiple family members having symptomatic COVID-19 infections. He subsequently had reduced oral intake, lethargy, and developed episodes of eye and leg twitching leading to presentation to the emergency department on day of life 40. There, vital signs included temperature of 35.9° C, heart rate of 135/min., respiratory rate of 53/min., and 100% oxygen saturation on room air. He then had recurrent episodes of apnea associated with perioral cyanosis and desaturations down to 18% for which he was intubated and placed on a warmer. Initial venous blood gas was notable for a respiratory acidosis with pH 7.27, pCO2 64mm Hg, and HCO3 28.5mmol/L. Lactate was 1.4mmol/L (within normal limits). Repeat venous blood gas following mechanical ventilation showed improvement in acidosis with pH 7.33, pCO2 55, and HCO3 28.3. Infectious workup was positive for COVID-19 on a respiratory virus panel. Chest x-ray showed mild peripheral airway disease without consolidation. Diagnostic workup also included a lumbar puncture on corrected gestational age (CGA) 36-weeks, 4-days with 0 white blood cells, protein of 122mg/dL, and glucose of 47mg/dL (serum glucose was 80mg/dL). A cerebral spinal fluid (CSF) meningitis panel including enterovirus and parechovirus was negative. He developed multi-focal status epilepticus that was aborted with a 20mg/kg phenobarbital load and continuous midazolam infusion up to 600mcg/kg/hr. Midazolam infusion was weaned off after 3 days without evidence of additional seizures during long-term electroencephalogram monitoring. The initial brain MRI obtained at CGA 36-weeks, 5-days showed widespread diffusion impedance of cerebral white matter (Figure 1). The imaging raised concern for a genetic/metabolic etiology; whole genome sequencing was obtained and was without causal findings. He received a 5-day course of 30mg/kg methylprednisolone given suspicion for an inflammatory process contributing to the presentation. A repeat brain MRI performed 9 days later (CGA 38-weeks, 0-days) showed new cystic T1 and T2 FLAIR hypointensities involving the deep cerebral white matter consistent with encephalomalacia as well as persistent diffusion impedance of the corpus callosum (Figure 2). There was an absence of associated contrast enhancement. He was discharged from the hospital without additional clinical concerns for ongoing seizure or infection. He was not on any antiseizure medications at time of discharge.
On follow-up outpatient examination at 4-months of age (CGA 2-months) , the patient’s neurologic exam was notable for increased left lower extremity tone, poor visual tracking, and intermittent dysconjugate gaze consistent with residual deficits. He was again seen at 11-months of age (CGA 9-months). At that time, there was gross motor delay evidenced by inability to sit unsupported as well as a possible fine motor delay with ongoing raking grasp. Neurologic exam was notable for poor visual tracking as well as axial, appendicular, and facial hypotonia (drooling and open-mouth resting face). He otherwise had normal muscle bulk, strength, and reflexes. The hypotonia was suspected to be secondary to white matter injury and contributing to the patient’s motor delays. There were no concerns for ongoing seizures. He continues to be followed in our neurology clinic.
Discussion
We describe a preterm infant with widespread diffusion impedance of supratentorial white matter followed by cystic changes consistent with encephalomalacia in the setting of systemic COVID-19 infection without meningoencephalitis. Similar patterns of diffusion impedance have been seen with parechovirus, enterovirus, and rotavirus7. Following the global SARS-CoV-2 pandemic, several publications demonstrated that COVID-19 may also cause white matter injury in newborns3,5,6, however, follow-up imaging was not performed and neurologic development was reported to be normal at time of outpatient follow-up at >2 months of age5,6. Other reports of neonatal COVID-19-associated brain parenchyma injury demonstrated imaging findings concerning for lasting injury but were without clinical follow-up2,9. In our patient, follow-up brain MRI demonstrated cystic changes concerning for irreversible injury which was corroborated by deficits on neurologic exam during outpatient follow-up. To our knowledge, this is the first report clinically correlating follow-up radiographic injury with COVID-19-associated white matter diffusion impedance in a newborn/infant.
Although the pathophysiology of COVID-19-associated white matter injury in neonates/infants is unknown3,5, proposed mechanisms leading to brain injury include direct viral invasion of the brain parenchyma, secondary effect of systemic inflammation, virus-induced autoimmune response, metabolic injury, hypercoagulability and ischemia, as well as hypoxic injury1–3. CSF testing for COVID-19 was not performed although an otherwise bland CSF profile and lack of contrast enhancement suggests direct viral invasion was unlikely the primary cause/mechanism of injury. Although hypoxia and hypercoagulability with ischemia may have contributed to our patient’s overall clinical course, the pattern of widespread supratentorial white matter diffusion restriction does not clearly align with typical patterns seen in term neonatal hypoxic-ischemic injury10 and the severity of imaging findings was out of proportion to the initial blood gases obtained. Finally, given the transient nature of diffusion restriction with strong apparent diffusion coefficient correlate coupled with non-concerning serial cranial ultrasounds during the perinatal period, the imaging abnormalities seen in our patient were also unlikely from a remote in-utero or perinatal injury. An underlying genetic predisposition to parenchymal injury was also not identified. Although confirmatory brain biopsy was not pursued, secondary effect of systemic inflammation or para-infectious immune response remained as likely possibilities for which a steroid course was administered.
In addition to cystic changes, follow-up imaging for our patient was notable for persistent diffusion impedance of the corpus callosum. This fits under the radiographic umbrella of cytotoxic lesion of the corpus callosum (CLOCC). Although COVID-19 has been associated with CLOCC, the finding is non-specific and may be caused by a variety of pathologies including trauma, medication/drugs, other infections, metabolic disorders, and cancer11.
Taken together, this case highlights that COVID-19-associated white matter changes can lead to permanent injury and neurologic deficits.
Conclusion
Neonatal/infantile COVID-19 infection in absence of meningoencephalitis may cause widespread supratentorial white matter diffusion impedance with evolution to cystic changes and lasting clinical deficits.
References
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Figure Legends
Figure 1. Initial brain MRI
Axial images obtained as part of initial workup at corrected gestational age 36-weeks, 5-days shows diffusion restriction throughout supratentorial white matter (A, B) with corresponding apparent diffusion coefficient signaling (C,D) with minimal changes on T1 or T2 imaging (E, F, respectively).
Figure 2. Follow-up brain MRI
Axial images obtained with brain MRI repeated 9 days after initial imaging (Figure 1), at corrected gestational age 38-weeks, 0-days shows improvement in diffusion restriction (A, B) but new cystic hypointensities in deep cerebral white matter on T1 and T2 FLAIR imaging concerning for encephalomalacia (C, D, respectively). There were no additional findings on T1 post-contrast or T2 (E, F, respectively).
Neonatal COVID-19 Infection Diffusion Impedance
