In contrast to adults, neonates and infants with coronavirus disease 2019 (COVID-19) infection have milder symptoms and are less likely to require hospitalization. However, some neonates with COVID-19 can present with significant symptoms. Recent evidence suggests that neurologic manifestations of neonatal COVID-19 infection may be higher than initially thought. In this comprehensive review of the current literature, we summarize the clinical, laboratory, and radiologic findings, as well as potential management strategies for COVID-19–related neurologic illness in neonates. Although the growing brain may be affected by neurologic disease associated with COVID-19 infection, the few published studies on the long-term outcomes after COVID-19 infection in neonates and infants provide conflicting results. Larger collaborative clinical studies are needed to determine whether COVID-19 infection in neonates has long-term neurodevelopmental outcomes.
Education Gaps
Potentially devastating neurologic complications of acute COVID-19 infection in the adult population have been reported extensively in the literature. However, data on the neurologic impact of COVID-19 on neonates are limited.
Objectives
After completing this review, readers should be able to:
Describe the spectrum of acute neurologic manifestations that have been reported in neonates with COVID-19, along with the suggested pathophysiologic mechanisms.
Summarize the laboratory, imaging, and electroencephalographic findings in neonates with neurologic symptoms in the setting of COVID-19 infection.
Describe the potential effect of COVID-19 infection on long-term neurodevelopmental outcomes.
Background
Our lives have not been the same since the world was impacted by the deadly severe acute respiratory syndrome–coronavirus 2 infection (SARS-CoV-2, also referred to as coronavirus disease 2019 [COVID-19]) with postpartum infection being the most common mode of neonatal acquisition. (1) Affected neonates are either asymptomatic or present with a mild illness, with the most common reported symptoms including fever, vomiting, diarrhea, cough, respiratory distress, and lethargy. (2)(3)(4) Our understanding of the disease in the neonatal period is evolving. Rare reports of neonates with COVID-19 infection leading to multisystem involvement with neurologic symptoms have been published (Table 1). The aim of this review is to describe the reported findings of neurologic complications associated with SARS-CoV-2 among neonates and advocate for further large-scale collaborative research to study the potential long-term impact of this infection on neurodevelopmental outcomes.
Summary of Clinical, Laboratory, and Radiographic Findings of Reported Cases of Neonates with COVID-19 and Neurologic Manifestations
| Authors, Country of Origin | Source | Population | Neonatal Clinical Presentation | Laboratory Results | Neuroimaging |
|---|---|---|---|---|---|
| Fragoso et al, (11) Brazil | Case report | Term male tested positive for COVID-19 at 3 days of age | Clonic seizures, lethargy, hypotonia, brisk tendon reflexes, no primitive reflexes at 5 days of age, required intubation | Lymphopenia, thrombocytopenia CSF analysis normal EEG–persistent electrographic seizures | Brain MRI at 15 days of age–bilateral white matter abnormalities, restricted diffusion in corpus callosum Follow-up MRI at 31 days of age–cystic cavitations |
| Kumar et al, (12) India | Case report | Late preterm with perinatal COVID infection | Persistent pneumonia, difficulty in weaning from ventilator Encephalopathy with seizure at 42 days of age Symptoms improved over 8 weeks | Thrombocytosis, lymphocytic leukocytosis EEG normal | MRI brain at 42 days of age- subcortical volume loss, cystic changes, tiny hemorrhages, loss of myelination at the posterior limb of the internal capsule |
| Lorenz et al, (15) Germany | Letter to the editor | Term female with COVID-positive mother NP and rectal swabs positive for SARS-CoV-2 | Lethargy and fever 24 hours after birth, progressed to encephalitis at 3 days of age Double-peaked course of respiratory symptoms (distress followed by hypopnea) | CSF negative for SARS-CoV-2 | Head ultrasound scan without abnormalities |
| Alvarado-Socarras et al, (14) Colombia | Case report | Term male neonate | Hyperthermia and transient neurologic symptoms at 21 days of age (drowsiness, poor feeding, hypotonia) | Leukopenia EEG normal | Head ultrasound scan without abnormalities |
| Tetsuhara et al, (21) Japan | Case report | Term male NP and rectal swabs positive for SARS-CoV-2 | Recurrent apnea at 29 days of age due to nonconvulsive status epilepticus requiring mechanical ventilation | Normal cell counts and inflammatory markers CSF normal and negative for SARS-CoV-2 EEG–rhythmic spike and wave complex of 1.5–2 Hz in the left hemisphere | MRI brain–T2 hyperintensity, FLAIR sequence hypointensity in the deep and subcortical white matter, diffusion restriction in the corpus callosum Follow-up MRI on day 45–multiple cystic cavitations |
| Chacón-Aguilar et al, (13) Spain | Scientific letter | 26-day-old male infant NP swab for SARS-CoV-2 was positive | 2 paroxysmal episodes associated with altered tone and posture, fever of 12 hours, with nasal discharge, vomiting, irritability, watery stools | Leukopenia Increased CPK and LDH CRP and metabolic panel normal Blood, urine, CSF, and stool cultures negative EEG normal | Cranial ultrasound scan normal |
| Brum et al, (22) Argentina | Case report | 17-day-old term male newborn Acquired postnatally | Fever, seizures, and lethargy | Neutropenia, mildly elevated CRP, consumption coagulopathy CSF normal with negative RT-PCR | MRI–2 small focal lesions in left frontal white matter with diffusion restriction suggestive of ischemic lesions |
| Raschetti et al, (8) France | Systematic review | 176 published cases 70% postnatal acquisition 30% vertical transmission | 18% neurologic symptoms | Elevated inflammatory markers (CRP, procalcitonin) 15.5% | Abnormal lung imaging–64% MRI brain–gliosis of periventricular and subcortical white matter |
| Dhir et al, (1) India | Systematic review | 58 neonates with SARS-CoV-2 Mother tested positive in 91% of these neonates | 50% respiratory symptoms 38% ICU admission 15.5% fever 5.2% lethargy & poor feeding 17% ventilated | Not analyzed | Not mentioned |
| Gale et al, (23) United Kingdom | Prospective national cohort study | 66 neonates with SARS-CoV-2 Average age at diagnosis 9 days 26% perinatal 52% postnatal | Most common symptoms: Fever, poor feeding, or vomiting | 55% increased lactate (>2 mmol/L) 29% elevated CRP (>5 mg/L) 9% leukopenia | No abnormalities detected on cranial ultrasound |
| de Moraes et al, (16) Brazil | Literature review (45 articles and case reports) | 87 newborns with a positive RT-PCR test | 23% asymptomatic 46% respiratory distress 26% neurologic features 3 premature neonates with respiratory distress died | Not analyzed | Authors concluded that the occurrence of long-term neuropsychiatric sequelae is unknown |
| Authors, Country of Origin | Source | Population | Neonatal Clinical Presentation | Laboratory Results | Neuroimaging |
|---|---|---|---|---|---|
| Fragoso et al, (11) Brazil | Case report | Term male tested positive for COVID-19 at 3 days of age | Clonic seizures, lethargy, hypotonia, brisk tendon reflexes, no primitive reflexes at 5 days of age, required intubation | Lymphopenia, thrombocytopenia CSF analysis normal EEG–persistent electrographic seizures | Brain MRI at 15 days of age–bilateral white matter abnormalities, restricted diffusion in corpus callosum Follow-up MRI at 31 days of age–cystic cavitations |
| Kumar et al, (12) India | Case report | Late preterm with perinatal COVID infection | Persistent pneumonia, difficulty in weaning from ventilator Encephalopathy with seizure at 42 days of age Symptoms improved over 8 weeks | Thrombocytosis, lymphocytic leukocytosis EEG normal | MRI brain at 42 days of age- subcortical volume loss, cystic changes, tiny hemorrhages, loss of myelination at the posterior limb of the internal capsule |
| Lorenz et al, (15) Germany | Letter to the editor | Term female with COVID-positive mother NP and rectal swabs positive for SARS-CoV-2 | Lethargy and fever 24 hours after birth, progressed to encephalitis at 3 days of age Double-peaked course of respiratory symptoms (distress followed by hypopnea) | CSF negative for SARS-CoV-2 | Head ultrasound scan without abnormalities |
| Alvarado-Socarras et al, (14) Colombia | Case report | Term male neonate | Hyperthermia and transient neurologic symptoms at 21 days of age (drowsiness, poor feeding, hypotonia) | Leukopenia EEG normal | Head ultrasound scan without abnormalities |
| Tetsuhara et al, (21) Japan | Case report | Term male NP and rectal swabs positive for SARS-CoV-2 | Recurrent apnea at 29 days of age due to nonconvulsive status epilepticus requiring mechanical ventilation | Normal cell counts and inflammatory markers CSF normal and negative for SARS-CoV-2 EEG–rhythmic spike and wave complex of 1.5–2 Hz in the left hemisphere | MRI brain–T2 hyperintensity, FLAIR sequence hypointensity in the deep and subcortical white matter, diffusion restriction in the corpus callosum Follow-up MRI on day 45–multiple cystic cavitations |
| Chacón-Aguilar et al, (13) Spain | Scientific letter | 26-day-old male infant NP swab for SARS-CoV-2 was positive | 2 paroxysmal episodes associated with altered tone and posture, fever of 12 hours, with nasal discharge, vomiting, irritability, watery stools | Leukopenia Increased CPK and LDH CRP and metabolic panel normal Blood, urine, CSF, and stool cultures negative EEG normal | Cranial ultrasound scan normal |
| Brum et al, (22) Argentina | Case report | 17-day-old term male newborn Acquired postnatally | Fever, seizures, and lethargy | Neutropenia, mildly elevated CRP, consumption coagulopathy CSF normal with negative RT-PCR | MRI–2 small focal lesions in left frontal white matter with diffusion restriction suggestive of ischemic lesions |
| Raschetti et al, (8) France | Systematic review | 176 published cases 70% postnatal acquisition 30% vertical transmission | 18% neurologic symptoms | Elevated inflammatory markers (CRP, procalcitonin) 15.5% | Abnormal lung imaging–64% MRI brain–gliosis of periventricular and subcortical white matter |
| Dhir et al, (1) India | Systematic review | 58 neonates with SARS-CoV-2 Mother tested positive in 91% of these neonates | 50% respiratory symptoms 38% ICU admission 15.5% fever 5.2% lethargy & poor feeding 17% ventilated | Not analyzed | Not mentioned |
| Gale et al, (23) United Kingdom | Prospective national cohort study | 66 neonates with SARS-CoV-2 Average age at diagnosis 9 days 26% perinatal 52% postnatal | Most common symptoms: Fever, poor feeding, or vomiting | 55% increased lactate (>2 mmol/L) 29% elevated CRP (>5 mg/L) 9% leukopenia | No abnormalities detected on cranial ultrasound |
| de Moraes et al, (16) Brazil | Literature review (45 articles and case reports) | 87 newborns with a positive RT-PCR test | 23% asymptomatic 46% respiratory distress 26% neurologic features 3 premature neonates with respiratory distress died | Not analyzed | Authors concluded that the occurrence of long-term neuropsychiatric sequelae is unknown |
CRP=C-reactive protein, CPK=creatine phosphokinase, CSF=cerebrospinal fluid; EEG=electroencephalogram; ICU=intensive care unit, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging; NP=nasopharyngeal, RT-PCR=reverse transcriptase polymerase chain reaction, SARS-COVID-19=severe acute respiratory syndrome–coronavirus 19.
Neurologic Presentation in Neonatal COVID-19 Infection
Central nervous system (CNS) complications of acute COVID-19 are well-described in the adult population. (5) Children have not been spared from these symptoms, and the risk is unpredictable, ranging from 5% to 57% across various reports. (6)(7) Neonatal data on neurologic manifestations associated with COVID-19 are extremely limited, with most reported evidence coming from isolated case reports that have limited inferential value. Globally, there are knowledge gaps in the epidemiology, neurologic manifestations, and long-term outcomes of SARS-CoV-2 infection among neonates.
Although there are many systematic reviews on COVID-19 infection in younger children and adolescents, only a few focus on neonates. (1)(4)(8) Neonates typically acquire COVID-19 infection postnatally from infected care providers. Vertical transmission can occur in neonates born to COVID-19–positive pregnant persons, though the risk is small. (9)(10) In some cases, it is difficult to determine whether vertical or horizontal transmission has occurred. Transplacentally acquired COVID-19 infection is considered more severe because of the in utero fetal inflammatory process, (3)(8) and thus, affected neonates are more likely to present with more severe systemic symptoms, and potentially be at increased risk for long-term neurologic sequelae similar to other intrauterine viral infections. However, these long-term potential effects remain speculative as they have not been scientifically proven. (9)
Recent evidence suggests that neurologic manifestations from neonatal COVID-19 infections may be more significant than previously thought. (1)(7)(8)(11)(12)(13)(14)(15) A systematic review by Raschetti et al reported neurologic manifestations in 18.6% of symptomatic neonates with SARS-CoV-2 (n=18/97). (8) A literature review by de Moraes from Brazil noted neurologic features in 26.4% of affected neonates. (16) Further data are needed to clarify the neurologic impact of COVID-19 infections in neonates.
Pathophysiology of Neurologic Involvement in Neonates with COVID-19
There are several mechanisms by which CNS involvement may occur in association with COVID-19 infection in neonates. The postulated mechanisms of brain injury (Figure) include coronavirus-related neuronal damage (ie, neuroinvasive), direct neurotoxic effects causing endothelial injury, resulting in apoptosis and necrosis, postinfectious autoantibody-mediated (including antineuronal and antiglial antibodies), and parainfectious brain injury as a result of cytokine storm. (3)(7)(17)(18)(19) Pulmonary involvement also affects the neurologic system indirectly through the hypothesized concept of brain-lung cross talk via ventilation-perfusion mismatch, hypoxia, hypercarbia, oxidative stress, the Bohr effect, and lung inflammation. (18)(19) Both direct invasion of the CNS as well as hyperinflammation can cause vascular endothelial damage, leading to vasculitis and stroke. It is likely that there is an overlap of various pathophysiologic neurologic mechanisms of neonatal COVID-19 infection.
Potential pathophysiology of neurological manifestations in neonates with perinatally and postnatally acquired COVID infection.
Potential pathophysiology of neurological manifestations in neonates with perinatally and postnatally acquired COVID infection.
Neurologic Manifestations in Neonates with COVID-19
Table 1 provides a summary of published clinical, laboratory, and radiologic findings of reported cases of neonates with COVID-19 infection and neurologic involvement. Among newborns with COVID-19 infection who exhibit neurologic manifestations, clinical findings can be quite varied, potentially involving the entire neuraxis. (20)(21)(22)(23) The most common neurologic symptom reported in neonates with COVID-19 infection is lethargy. (16) However, lethargy and tone abnormalities can be found in the setting of various nonencephalitic, infectious, and metabolic processes in neonates, even in the absence of specific CNS findings and do not address the localization of the disease process or its mechanism. Neurologic symptoms can be divided into nonspecific and specific symptoms as described in Table 2. Neonates can have neurologic manifestations similar to the multisystem inflammatory syndrome in children (MIS-C), which is reported in less than 5% of affected neonates. (3) There are a few reports of a perinatally acquired COVID-19 infection giving rise to neonatal stroke as a result of ischemia and cerebral venous sinus thrombosis. (24)(25)(26) However, there is no substantial evidence to support the causation except for circumstantial evidence, with COVID-19 being the only temporal association found.
Spectrum of Neurologic Symptoms in Neonatal COVID-19
| Nonspecific Symptoms | Specific Symptoms |
|---|---|
| Lethargy Irritability, high-pitched cry Hypotonia Apnea | Febrile seizure, nonfebrile seizure, nonconvulsive status epilepticus Altered sensorium, encephalopathy, encephalitis Meningitis Stroke |
| Nonspecific Symptoms | Specific Symptoms |
|---|---|
| Lethargy Irritability, high-pitched cry Hypotonia Apnea | Febrile seizure, nonfebrile seizure, nonconvulsive status epilepticus Altered sensorium, encephalopathy, encephalitis Meningitis Stroke |
Laboratory and Radiologic Findings in COVID-19–Infected Neonates with Neurologic Manifestations
Various laboratory abnormalities have been published in clinical cases of neonates with COVID-19 infection including abnormal cell count, increased inflammatory markers, increased liver function tests, and abnormal electrolytes. The most reported abnormalities have been leukopenia, neutropenia, and thrombocytopenia. (3)(11)(12)(22) Contrary to what would be expected, inflammatory markers were mostly reported as normal. (8)(12)(13) In a systematic review, inflammatory markers were increased in only 15% of neonates with COVID-19. (8) Elevated C-reactive protein and procalcitonin levels were found in a few cases. (8)(11) Measurement of cytokine levels (such as interleukin 6) and proinflammatory markers (like ferritin, D-dimer, lactate dehydrogenase, and pro–brain natriuretic peptide) and qualitative antibody detection tests could not be done in most cases due to logistical constraints.
Most clinical studies in neonates with COVID-19 infection have reported unremarkable cerebrospinal fluid (CSF) findings. Even in those with severe neurologic symptoms, CSF studies, including cytology, biochemistry, and culture, were normal. COVID-19 virus could not be identified with reverse transcriptase polymerase chain reaction (RT-PCR) in any of the case reports in neonates, supporting the symptom profile to be vascular or inflammatory in origin. Although the sensitivity as well as the validity of CSF testing for COVID-19 RT-PCR is unknown, all CSF studies that have been reported in neonates, infants, and children were negative. (7)(14)(15) Antineuronal and antiglial autoantibodies seen with immune-mediated postinfectious diseases have not been tested in CSF specimens of neonates with COVID-19 with neurologic symptoms. Appropriate CSF studies seem to be lacking to establish the diagnosis of COVID-19–related neurologic disorders, and neurologic involvement from COVID-19 should be considered even in the absence of CSF pleocytosis or other CSF abnormalities.
Neonates with profound neurologic presentations would be anticipated to develop alterations in electroencephalography (EEG) findings and neuroimaging. EEG studies have been reported in only a few neonates with COVID-19–related neurologic manifestations, with findings including normal studies, abnormal background, ictal spikes, nonconvulsive electrographic status epilepticus, and asymmetric rhythmic spike-wave patterns (Table 1).
Magnetic resonance imaging (MRI) with MR spectroscopy (MRS) of the brain is the most studied neuroimaging parameter in COVID-19–infected neonates with neurologic illness. There is no specific pattern of brain injury in neonates with neurologic manifestations associated with COVID-19 infections. Normal CNS imaging has been reported by many, (14)(15) whereas a few studies found pronounced abnormalities including white matter injury, demyelination, multiple foci of restricted diffusion, ischemic stroke, and cavitation. (11)(12)(21)(22)(24)
Management Strategies for COVID-19–Infected Neonates with Neurologic Findings
There are no standard treatment guidelines for the management of neonatal COVID-19–related neurologic manifestations. Clinicians have used antibiotics, inhaled steroids, systemic steroids, and antiviral agents as well as intravenous immunoglobulin. There is no role for antiviral medications such as lopinavir, ritonavir, remdesivir, or specific medications like chloroquine or hydroxychloroquine in the management of neonatal COVID-19 infection, irrespective of the mode of transmission or symptom profile. (27)(28) In a population-based cohort study from the United Kingdom, 3% of neonates received antiviral agents, 3% received corticosteroids, and 2% received pooled immunoglobulin. (23) However, the overall number of patients was very small (n=66) and no improvement in outcome was documented. (23) Nebulized steroids, along with a course of azithromycin, have been used in cases with postinfectious viral pneumonia as an immunomodulator. (12)(13) However, their role in neonates remains unclear. The use of intravenous immunoglobulin for the treatment of severe COVID-19–associated neurologic disease has been extrapolated from adult trials and is based on the assumption of neurologic symptoms being a part of a MIS-C (9)(29); although there is no evidence to support or refute the use of intravenous immunoglobulin in neonates. Neonates and children have been treated with various steroid regimens (high-dose methylprednisolone, low-dose prednisolone, dexamethasone) in isolated case reports, based on the hypothesis that acute COVID-19 infection leads to multisystem inflammation and dysfunction of the immune system. We could not find any scientific evidence to suggest routine use of steroids in COVID-19–associated neurologic disease, especially when the long-term implications remain questionable.
Impact of Acute Neonatal COVID-19 Infection with Neurologic Symptoms on Long-term Neurodevelopment
Early life, especially the first 1,000 days, is a critically important and vulnerable period for long-term neurodevelopment, as it is characterized by rapid neuronal growth and maturation, which lays the foundation for lifelong brain architecture. (30)(31) There are only a few published studies (with a few more ongoing) that have examined the neurodevelopmental outcomes of neonates with COVID-19 and neurologic symptoms. Rapidly accumulating evidence suggests that neonates with early transient neurologic symptoms make a complete recovery, though the impact of the COVID-19 pandemic on the growing brain is not completely known. Ayed et al from Kuwait enrolled 58 neonates diagnosed with SARS-CoV-2 infection prospectively using their national registry and assessed their 18-month neurodevelopmental outcomes using Bayley Scales of Infant and Toddler Development, 3rd Edition. (32) Although they reported no difference in the neurodevelopmental outcomes compared with controls, the authors acknowledged the need for longer follow-up. (32) Aldrete-Cortez et al from Mexico concluded that infants prenatally exposed to SARS-CoV-2 (n=56) had absence of fidgety movements between 3 to 5 months of age and were at higher risk for serious neurologic disorders. (33) A multicenter observational study conducted in China on neonates born to women with COVID-19 infections reported abnormal brain MRI findings in 3 of 5 infected neonates; these findings included delayed myelination, brain dysplasia, and abnormal signal in the periventricular white matter but normal physical growth at 44 weeks’ postmenstrual age. (34) Hessami et al conducted a systematic review of infants delivered during the COVID-19 pandemic and found that their neurodevelopment in the first year of age was not altered by perinatal exposure to SARS-CoV-2. (35) However, the infants in this study had significant risks of communication delay, regardless of maternal infection. (35) Shuffrey and colleagues reported that infants born during the pandemic (independent of maternal COVID infection) had differences in neurodevelopment at age 6 months with significantly lower scores in gross motor, fine motor, and personal social subdomains, which was assessed using the Ages and Stages Questionnaire, 3rd edition. (36) These preliminary conflicting results should not make researchers and clinicians complacent; good-quality data are still insufficient to draw unbiased conclusions.
Conclusion
It is evident from scientific publications that neonates with COVID-19 infection can present with primary neurologic manifestations, though the mechanism is uncertain. Pediatric specialists, neonatologists, and pediatric neurologists should be aware of possible neurologic involvement associated with novel coronavirus in neonates and infants and its possible potential to cause long-term neurodevelopmental consequences. Larger collaborative clinical studies are needed to understand the long-term neurodevelopmental implications of COVID-19 infection in neonates.
Take Home Message
The spectrum of neurologic manifestations in neonates with COVID-19 is variable, with lethargy being the most commonly reported symptom.
The postulated mechanisms of brain injury in acute neonatal COVID infection include neuroinvasion, direct neurotoxicity, brain-lung cross talk, and immune-mediated neurotoxicity.
There is no scientific evidence to support the routine use of antivirals, steroids, or any other specific medication in the neonatal age group to treat COVID-19 infections (including those with neurologic manifestations) and thus, management should be symptomatic and supportive.
Potential long-term neurodevelopmental impact of neonatal COVID-19 infection on the growing brain cannot be disregarded.
Know the normal CSF counts and chemistries in preterm and term neonates and changes with infection.
AUTHOR DISCLOSURES
Dr Soraisham is the cochair of the Canadian Pediatric Society’s NRP Committee. Dr Chopra has attended meetings with the support of Kepler Pharma. Drs Rustogi and Saxena have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.
- CNS
central nervous system
- COVID-19
coronavirus disease 2019
- CSF
cerebrospinal fluid
- EEG
electroencephalography
- MIS-C
multisystem inflammatory syndrome in children
- MRI
magnetic resonance imaging
- RT-PCR
reverse transcriptase polymerase chain reaction
- SARS- CoV-2
severe acute respiratory syndrome–coronavirus 2 infection
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