key: cord-0890730-rw9m43u2 authors: Singer, Timothy G.; Evankovich, Karen D.; Fisher, Kristen; Demmler-Harrison, Gail J.; Risen, Sarah R. title: Coronavirus Infections in the Nervous System of Children: A Scoping Review Making the Case for Long-Term Neurodevelopmental Surveillance date: 2021-01-29 journal: Pediatr Neurol DOI: 10.1016/j.pediatrneurol.2021.01.007 sha: 47a502787d26ad1ca05c5994038a8ff91fd78104 doc_id: 890730 cord_uid: rw9m43u2 BACKGROUND: The objective of this study was to describe the case literature of human coronavirus infections in the nervous system of children, including from SARS-CoV-2, and to provide guidance to pediatric providers for managing the potential long-term effects on neurodevelopment of human coronavirus infections in the nervous system. METHODS: Using a structured strategy, the PubMed and Ovid:Embase databases were queried for articles about the clinical presentation and pathophysiology of coronavirus infections in the nervous system of children and young adults, aged 0 to 24 years. RESULTS: Of 2302 articles reviewed, 31 described SARS-CoV-2 infections in the nervous system of children and 21 described other human coronaviruses: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1. Excepting MERS-CoV, we found cases of neurological disease in children from each human coronavirus. Children with non-SARS-CoV-2 infections have suffered acute flaccid paralysis, acute disseminated encephalomyelitis, encephalitis, and seizures. In addition, cases of ischemic, hemorrhagic, and microvascular strokes have occurred in children with SARS-CoV-2. Patients with multisystem inflammatory syndrome in children have suffered encephalitis, stroke, pseudotumor cerebri syndrome, and cytotoxic lesions of deep brain structures. Despite these reports, few articles evaluated the impact of human coronavirus infections on long-term neurodevelopmental domains including cognitive, language, academic, motor, and psychosocial outcomes. CONCLUSIONS: Neurological manifestations of human coronavirus infections can cause severe disease in children. The case literature suggests a critical gap in knowledge of the long-term effects on child neurodevelopment of these infections. As the current SARS-CoV-2 pandemic continues, this gap must be filled to facilitate optimal outcomes in recovering children. Although they primarily target the respiratory and enteric systems, six of the seven human coronaviruses (HCoV), including the novel SARS-CoV-2 virus, have been associated with severe neurological diseases in children. [1] [2] [3] [4] The seventh, the Middle East respiratory syndrome coronavirus (MERS-CoV), has been identified in neurological diseases in adults. 5 Whether affected by direct HCoV infections or secondary neurological insults due to systemic illnesses, children are uniquely vulnerable to long-term cognitive or behavioral sequelae as a consequence of injury during critical stages of neurodevelopment. 6, 7 These sequelae can range from mild neuromotor deficits to profound cognitive impairments following severe disease affecting the central nervous system (CNS). Resulting neurodevelopmental impairments, especially those more subtle, may not be apparent initially following infection and appear later with increasing demands or when a child reaches an age where a particular skill is expected to develop. However, even seemingly mild deficits can have a detrimental impact on a child's quality of life, academic achievement, mental health, and social interactions. 7 Given the relative rarity of neurological illnesses associated with HCoVs in children, there is a paucity of information on potential neurodevelopmental sequelae. This knowledge gap hinders the ability of providers to facilitate evaluation and management strategies for optimal outcomes in recovering children. As cases of neurological disease associated with SARS-CoV-2 infections in children continue to mount, such clinical guidance is urgently needed. In this scoping review we evaluate the case literature describing primary and secondary neurological insults associated with HCoV infections in children for insights into the potential neurodevelopmental sequelae of similar SARS-CoV-2 infections in children. Drawing on past reports, we suggest clinical neurodevelopmental guidance for pediatric providers treating children with SARS-CoV-2 infections with neurological manifestations. Coronaviruses are enveloped, single-stranded RNA viruses that typically enter cells via interaction between their spike protein and tissue-specific cell surface receptors. 8 Within human neurons, the spike proteins of both SARS-CoV-1 and SARS-CoV-2 recognize the angiotensin-converting enzyme 2 protein, which is also widely expressed in the airways and gastrointestinal tract. 9 HCoVs disseminate through the nervous system in two ways. Hematogenous spread occurs when circulating monocytes take up HCoV virions and subsequently express chemokines, increasing permeability of the blood-brain barrier. The virions then traverse the blood-brain barrier resulting in CNS disease. 1 Alternatively, following intranasal infection, HCoV virions cross the cribriform plate and infect the olfactory bulbs. Thereafter, neuron-to-neuron spread occurs via exocytosis/endocytosis of membrane-enclosed virions across synapses. 1 In addition to direct infection, HCoVs sometimes trigger secondary disease processes that result in neurological illness. For example, in the peripheral nervous system, multiple case reports have described Guillain-Barr e syndrome (GBS), the post-infectious demyelinating process associated with macrophage hyperactivity, following coronavirus infections in children. And, in the CNS, the recently described Kawasaki disease (KD)-like "multisystem inflammatory syndrome in children" (MIS-C) following SARS-CoV-2 infection appears to be associated with an acute, neuroinflammatory response, which predisposes children to cerebral edema, hemorrhage, stroke, and aseptic meningitis. 10 Neurological manifestations of SARS-CoV-2 such as encephalopathy, seizures, or peripheral nerve palsies have been reported in only a small fraction of children infected with SARS-CoV-2, perhaps as few as 1% of cases. 11 Notably, a recent case series of adults observed neurological complications including headache, altered mental status, and acute cerebrovascular events in 36% of patients. 12 The most severe neurological manifestations of SARS-CoV-2 infections in children have been associated with children suffering from MIS-C. 13 For example, a case review of 187 children with MIS-C found that 34% had suffered neurological involvement, with the vast predominance being central, rather than peripheral, manifestations. 10 Neurodevelopmental implications of severe neurological disease The rare occurrence of HCoV-related severe neurological illness in children underscores the need to better understand the potential neurodevelopmental sequalae associated with these infections. Until more evidence is gathered about the pathogenesis of SARS-CoV-2 in the nervous system of children, case reports from other HCoVs and viruses causing neurological manifestations can help us anticipate and manage the neurodevelopmental effects of pediatric SARS-CoV-2 infections. Our scoping review was conducted according to the guidelines from the Joanna Brigs Institute Reviewers Manual Criteria and the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews checklist. 14, 15 Inclusion criteria Included articles explored the clinical presentation and pathophysiology of HCoVs in the nervous system in children and young adults, aged 0 to 24 years. Only human clinical studies were included. Questions about inclusion were resolved by consensus among the authors. Two electronic databases, PubMed and Ovid:Embase, were searched. First, we identified pediatric HCoV studies (Supplementary Table 1 ). The same terms were used for each database. The second search used index terms specific to the HCoV infections of the nervous system identified in the first search. Articles returned in multiple searches were analyzed and counted once. Finally, the reference lists of all included articles were reviewed for additional articles. Three searches were performed; April 21, 2020; April 28, 2020; and during revision of the manuscript on November 1, 2020. Eligibility criteria for inclusion were peer-reviewed articles, including articles in press, published between 1949 to November 1, 2020, as the first characterization of HCoV CNS infections was reported in an animal model in 1949. 1 All languages and geographic areas were included. Articles were evaluated for clinical data of patient presentation, chronic conditions, laboratory test results and imaging evaluation, and outcomes, including neurodevelopmental. Articles were included if they discussed a nervous system manifestation of HCoV infections in children. Articles were categorized as non-SARS-CoV-2 HCoVs and SARS-CoV-2 infections. Included articles were organized by article type, including case reports, case series, cohort studies, and review papers. Articles were excluded if there was no mention of a clinical presentation of a nervous system manifestation associated with an HCoV infection in a child. Articles were excluded if patients were adults, defined as older than 24 years. Conference abstracts and articles wherein full manuscript text was not available were excluded. Nonhuman studies were utilized only for understanding the pathophysiology. Studies that had possible neurological symptoms but where a neurological cause was ruled out were excluded. The reasons for excluding all articles were tabulated (Supplementary Tables 2-4) . In total 2,302 articles were evaluated. Search 1 yielded 1,004 articles, 184 (18.3%) from Ovid:Embase and 820 (81.7%) from PubMed. Search 2 yielded 91 additional articles, 54 (59.3%) from Ovid:Embase and 37 (40.7%) from PubMed. Search 3 yielded 12 articles, seven of which were excluded because they were nonpediatric but were useful for understanding the pathophysiology of HCoV nervous system infections (Fig) . We identified 31 articles describing SARS-CoV-2 infections in the nervous system of children and 21 nervous system infections from other HCoVs. Within the SARS-CoV-2 studies, eight were cases of MIS-C with neurological involvement in children. There were 2,250 excluded articles. Among the non-SARS-CoV-2 articles, five were case reports and 16 were case series (Table 1) . Among the case reports, there were four infections from HCoV-OC43 and one child with both HCoV-OC43 and HCoV-229E. Case series were identified for HCoV-229E, HCoV-OC43, HCoV-HKU1, HCoV-NL63, and SARS-CoV-1 infections. No case series were identified for MERS-CoV. Clinical presentations of children due to these non-SARS-CoV-2 infections included acute flaccid paralysis (AFP), acute disseminated encephalomyelitis (ADEM), cranial nerve palsies, encephalitis, encephalopathy, febrile seizures, and weakness. Among the 31 SARS-CoV-2 articles, there were 27 cases reports and four case series. In children without MIS-C, neurological presentations including peripheral and central etiologies of AFP (GBS and transverse myelitis), ADEM, encephalitis, and seizures, as well as cases of ischemic, hemorrhagic, and microvascular strokes ( Table 2) . Eight case reports detailed nervous system illness in patients with MIS-C including encephalitis, stroke, pseudotumor cerebri syndrome, and cytotoxic lesions of deep brain structures including the thalami and corpus callosum (Table 3) . Importantly, other than diagnoses based on pathologic specimens, these cases present only an association between coronavirus infection and neurological symptoms. However, in the literature where a definitive diagnosis was not made, each of the study authors reported that extensive evaluation for other etiologies was negative. Further, in instances of postinfectious neurological manifestations, the time course of symptom onset was within an accepted range for the reported disease processes. In addition, each of the HCoV-associated neurological manifestations discussed here in children has also been reported in adults with HCoVs, suggesting a common association between the virus and neurological symptoms. 38 Given the severity of these clinical courses for patients, the World Health Organization (WHO) recently authored a provisional case definition for the association of SARS-CoV-2 with neurological diseases. Importantly, the preceding infection is more challenging in children given the increased propensity for asymptomatic infection in this population. Although the WHO case definition is based on adult presentations, these definitions were considered during evaluation and discussion of pediatric cases included in this review. 38 A summary of pediatric case presentations, evaluation, and clinical outcomes follows here. Acute flaccid paralysis Multiple case reports described children with clinical features and laboratory studies consistent with the broad category of AFP including the more specific diagnosis of GBS, the postinfectious immune-mediated polyradiculoneuropathy. Notably, these cases were each consistent with the WHO provisional case definitions where HCoVs were "probably associated" with the child's neurological condition, including symptom onset within six weeks of suspected acute infection, RNA or antibody evidence of infection, and absence of other probable etiology on evaluation. Turgay et al. reported the case of a previously healthy threeyear-old female in Turkey who presented with one day of dyspnea and inability to walk shortly after onset of fever, cough, and rhinorrhea. 17 Her neurological examination showed bulbar paralysis characterized by inability to chew, speak, or swallow; reduced motor strength (0/5); and absent deep tendon reflexes. She rapidly progressed to respiratory failure requiring intubation. Her initial evaluation was negative, including blood, urine, and CSF studies, as well as electromyography and magnetic resonance imaging (MRI) of the brain and spinal cord. The only positive finding was coinfection of HCoV-229E and HCoV-OC43 on a nasopharyngeal swab detected by reverse transcription-polymerase chain reaction (RT-PCR). The authors suspected GBS, one of several etiologies of AFP. After empirical treatment with intravenous immunoglobulin (IVIG), she made gains over three days but thereafter had persistent motor weakness. Surprisingly, repeat CSF and electromyography studies three weeks after presentation were again normal, leading the authors to conclude that her presentation was more consistent with the less-specific diagnosis of AFP secondary to coronavirus infection given the known neurotrophic, neuroinvasive, and neuroinflammatory potential of the coronaviruses. In another case, a five-year-old male presented with unilateral facial nerve palsy, progressive lower extremity weakness, and areflexia two weeks after having fever and nasal congestion. 19 The patient developed bulbar palsy characterized by dysphagia with drooling, a weak cough, and respiratory distress but did not require intubation. Diagnostic evaluation was consistent with GBS including CSF with albuminocytologic dissociation. MRI of the brain and spine demonstrated enhancement of the left bulbar nerve complex and anterior and posterior cervical nerve roots. Microbiology evaluation was negative except HCoV-OC43 by RT-PCR of the patient's blood. Following IVIG his respiratory status and bulbar palsy improved over a week. Similarly, GBS has been reported in a child with SARS-CoV2. 26 An 11-year-old male in Saudi Arabia presented with onset of symmetrical leg weakness and loss of deep tendon reflexes three weeks after a fever and upper respiratory tract infection. In addition, the patient had lower extremity tingling and impaired sensation to pain, light touch, and proprioception. Supporting a diagnosis of GBS, CSF studies showed albuminocytologic dissociation, MRI of the spine demonstrated enhancement of the cauda equina nerve roots, and nerve conduction studies were consistent with a demyelinating process. Initially the authors evaluated the child for infectious pathogens more commonly associated with GBS-like presentations, all of which were found to be negative; this prompted a nasopharyngeal swab for SARS-CoV-2, which was positive approximately 22 days after symptom onset. He was treated with IVIG for GBS and then later received a week-long course of hydroxychloroquine. Over a two-week period, the patient regained the ability to ambulate, which was further reflected in improvement in nerve conduction studies repeated one week after discharge. In all three cases, the patients made general recoveries, but weeks after presentation they had not yet regained full motor strength. Long-term neurodevelopmental outcomes were not reported. A central cause of AFP, transverse myelitis (TM), was reported in a child with otherwise asymptomatic SARS-CoV-2 infection. 29 Three weeks following upper respiratory tract symptoms in multiple household family members, all of whom ultimately proved to have SARS-CoV-2 infection, a three-year-old girl presented with progressive weakness and decreased sensation in her extremities. She rapidly declined to flaccid quadriparesis and respiratory failure requiring intubation. MRI of the spine revealed spinal cord edema with a longitudinally extensive lesion involving most of the transverse spinal cord from the lower medulla to the midthoracic level. CSF studies revealed pleocytosis and mildly elevated protein. Extensive evaluation for possible infectious, rheumatologic, and autoimmune etiologies was negative other than positive SARS-CoV-2 RT-PCR from nasopharyngeal swab. Given the persistence of flaccid paresis, treatment of her TM escalated to plasmapheresis. Unfortunately, her examination eight days after presentation remained unchanged, and long-term outcome was not reported. Central demyelination due to ADEM has also been reported in children with coronaviruses. Yeh et al. cared for a 15-year-old male, previously healthy, who had one day of irritability, right hand clumsiness, and difficulty walking. 16 Abnormalities on neurological examination included distal weakness in his upper and lower extremities, left hand dysmetria, antalgic gait, and diminished vibration and temperature sensation below T10. MRI of the brain and spinal cord revealed hyperintensity in the white matter of the right centrum semiovale and left cerebellum and non-enhancing spinal lesions at the cervical and thoracic levels, all consistent with a diagnosis of ADEM. HCoV-OC43 was detected in nasopharyngeal secretions, and evaluation for more common pathogens was negative. Symptoms resolved over several weeks without therapeutic intervention. Follow-up MRI at three months showed a new demyelinating lesion in the left cerebellum and increased size of the right cerebral lesion. Despite these imaging changes, he did not report additional symptoms. Similarly, a previously healthy 12-year-old female presented with five days of fever, headache, and rash followed by acute, progressive, bilateral, symmetrical upper and lower extremity weakness. 21 On the second hospital day, she developed respiratory failure requiring intubation with loss of several brainstem reflexes, inability to follow commands, and onset of profound flaccid quadriparesis and absence of deep tendon reflexes. As with the prior case, all infectious studies were negative, including CSF studies, except for a positive nasopharyngeal RT-PCR for SARS-CoV-2. Consistent with ADEM, MRI of the brain showed extensive bilateral restricted diffusion involving the subcortical and deep white matter and corpus callosum. Similarly, MRI of the cervical spine showed longitudinally extensive myelopathy involving both white and gray matter. Unlike the patient reported by Yeh et al. who recovered, more than two months after initial presentation, this patient had only begun to regain strength and motor control. She had persistent spastic quadriparesis with her maximal extremity strength being that she was able to move against gravity but not against resistance. The patient could sit with support and reach for objects nearby but had global hyperreflexia and incomplete sphincter control. These cases illustrate the potential for persistent subclinical and severe clinical deficits following ADEM in children associated with coronavirus infections. Seizures, especially simple febrile seizures, were the most common neurological presentation associated with all coronavirus infections among the cases evaluated. Simple febrile seizures are characterized by brief (less than 15 minutes) generalized seizures that occur in the absence of intracranial infection, metabolic disorders, or history of afebrile seizures. Simple febrile seizures are not associated with increased risk of epilepsy or neurodevelopmental disorders. 39 In particular, multiple case series reported the predominance of HCoV-associated simple febrile seizures in children younger than one year. Laurent et al. found that HCoV-OC43 infections occurred more frequently than influenza viruses in this age group. [40] [41] [42] Children with HCoV-related febrile seizures appear to recover well. 42, 43 No studies included discussion of long-term neurodevelopmental outcomes following febrile seizures due to HCoV infections. Encephalitis was the second most common neurological presentation of children with SARS-CoV-2 and other HCoVs. In both the non-SARS-CoV-2 encephalitis case reports, the patients were younger than one year, immunocompromised, and infected by HCoV-OC43. In 2016, Morfopoulou et al. reported an 11-month-old boy with fatal encephalitis and severe combined immunodeficiency deficiency. 18 The patient had undergone an unconditioned cord blood transplant with successful T cell engraftment. Unfortunately, one and a half months post-transplant he developed encephalitis and died. The patient had negative microbiology results on RT-PCR. However, RNA sequencing of the brain biopsy detected HCoV-OC43. Similarly, Nilsson et al. reported the case of a ninemonth-old male with pre-B acute lymphoblastic leukemia who tested positive for HCoV-OC43 on a respiratory swab five months after diagnosis. 20 At the time, all evaluation was otherwise negative, including CSF for HCoV-OC43. An additional four months later, the patient was admitted with altered behavior and abdominal myoclonic seizures. Electroencephalography showed general slowing and MRI of the brain demonstrated increased T2 signal bilaterally in the white matter tracts adjacent to the lateral ventricles and in the thalami and pons. As the patient deteriorated, deep sequencing analysis of a brain biopsy sample was done and found to be positive for HCoV-OC43. An experimental trial of lopinavir, the human immunodeficiency virus protease inhibitor, was attempted, but the patient died shortly thereafter. In addition to these case reports, Li et al. and Dominguez et al. found HCoV antibodies in the CSF of 22 of 183 (12%) and five of 63 (8%) of their respective cohorts of children with acute encephalitislike presentations (seizure, headache, vomiting). The relative frequency of HCoV antibodies in these patients suggests that HCoV CNS infections may be underreported in children. 48, 49 We identified six cases of encephalitis in children with SARS-CoV-2; however, the patient described by Freij 25 In this case, a previously healthy five-year-old girl presented following six days of fever and severe headache. Notably, she had a normal head computed tomography (CT) on day 9 of illness, which was obtained due to persistence of her initial headaches. She was discharged on day 10, only to be readmitted later that day following onset of confusion and a two-minute seizure. Her course waxed and waned until day 15 when she became lethargic and had asymmetric pupils followed by ongoing neurological and overall clinical deterioration. She was intubated on day 17. CSF studies were negative for infectious etiology including SARS-CoV-2. MRI of the brain showed extensive progression of meningoencephalitis of the cerebellum and corpus callosum, with leptomeningeal enhancement especially over the surface of the brainstem and into the auditory canals. As her clinical case worsened, she underwent a midline suboccipital craniectomy and C1 laminectomy on day 30. The cerebellum was necrotic and edematous and herniated out of the surgical defect. Sadly, she died on day 32 of illness. Despite previously negative infectious studies, cerebellar brain biopsy was positive for SARS-CoV-2 RNA as well as for Mycobacterium tuberculosis complex DNA. Tracheal aspirates grew M. tuberculosis weeks after the patient's death. Freji and colleagues hypothesized that their patient was asymptomatically infected with M. tuberculosis but that eventually the host immune system could not concurrently respond to the SARS-CoV-2 virus and continue to suppress M. tuberculosis proliferation within macrophages. These three cases are notable among multiple reports of encephalitis for their illustration of the role coronavirus infections may play in dysregulating the immune system or exacerbating underlying immunocompromise. Despite the prospect of lifethreatening encephalitis, none of the cases identified included description of the neurodevelopmental outcomes. Cerebrovascular events were only reported in association with SARS-CoV-2 infections. Similar to the case presented by Freji et al., Essajee and colleagues in Cape Town, South Africa, reported concurrence of active M. tuberculosis infection and SARS-CoV-2 in a previously healthy 2.5-year-old girl. 28 Upon presentation, the patient had acute onset of lethargy (Glasgow Coma Scale: 11), right pupillary dilatation with right ptosis, left sided weakness (arm > leg), globally brisk deep tendon reflexes, and bilateral extensor plantar responses. In addition, she had progressively enlarging cervical lymphadenopathy and decreased appetite. Nasopharyngeal swab for SARS-CoV-2 was positive, and an emergency head CT showed pan-hydrocephalus, basal meningeal enhancement, and infarction involving the anterior limb of the right internal capsule, lentiform nucleus, and thalamus. Cerebral sinus venous thrombosis was seen on postcontrast images as multiple filling defects in the venous system, mainly superior sagittal and transverse sinuses. Gastric aspirate was sent for Gen-eXpert MTB/RIF testing and found to be positive and rifampicin sensitive. Blood cultures also grew M. tuberculosis. Notably, she was coagulopathic on presentation with an international normalized ratio of 1.63, elevated prothrombin time, normal activated partial thromboplastin time, and elevated fibrinogen and D-dimer. Like Freji and colleagues, Essajee et al. postulated that SARS-CoV-2 likely caused a cytokine storm, which exhausted the patient's capacity to immunologically respond to both the virus and M. tuberculosis infections. In addition, the hyperinflammatory response is suspected to have resulted in endothelial damage, which exacerbated her coagulopathy and stroke risk. This patient survived and following one month of intensive neurorehabilitation had regained the ability to feed orally, but she still had residual left hemiparesis. No mention is made in the report of her potential for long-term neurodevelopmental deficits. Two additional case reports describe focal cerebral arteriopathy characterized by narrowing and banding of the left middle cerebral artery with acute infarctions of the left insula and basal ganglia in children with positive SARS-CoV-2 testing. 50, 51 In both cases, additional etiologic evaluation was unremarkable. Based on current evidence from the adult population, the authors hypothesize that these strokes were secondary to SARS-CoV-2 cytokine storm resulting in inflammation-induced focal vasculitis. Notably, neither presentation met the diagnostic criteria of MIS-C. The WHO characterized MIS-C according to a six-part definition, which includes pediatric age, persistence of fever, laboratory evidence of inflammation, signs or symptoms of organ dysfunction, lack of an alternative diagnosis, and a close temporal onset with SARS-CoV-2 infection or exposure. 52 In our review, there were eight articles that reported neurological signs and symptoms in the setting of MIS-C including encephalitis, acute hemiparesis following cerebrovascular events, altered mental status associated with microinfarcts in deep brain structures, acute-onset neuropsychiatric symptoms including confusion and agitation, and cranial nerve palsies associated with elevated intracerebral pressure. Among patients suffering from cerebrovascular disease, children with MIS-C appeared to have more evidence of microvascular infarcts in deep brain structures compared with cerebrovascular manifestations in patients without MIS-C. Regev et al. reported a 16-year-old male, previously healthy, who experienced fever, sore throat, fatigue, and abdominal pain three weeks following SARS-CoV-2 exposure. 30 He had headache and nuchal rigidity at presentation, and on the third day of hospitalization he developed warm shock requiring intubation. Initially nasopharyngeal swabs for SARS-CoV-2 were negative, but following clinical decompensation he had a positive nasopharyngeal swab and associated serologic confirmation of past SARS-CoV-2 infection with positive IgG and IgA antibodies. Initial head CT was negative, but brain MRI/ magnetic resonance angiography showed diffuse small low-signal foci of hemosiderosis in subcortical white matter of both hemispheres and the corpus callosum suggestive of an inflammatory process of the cerebral microvasculature. The patient generally recovered from MIS-C without obvious cognitive deficits, although he was noted to have persistent weakness. Similarly, Gaur et al. reported two cases in males, nine and 12 years old, who had onset of fever and altered mental status. In both cases MRI of the brain revealed restricted diffusion lesions throughout the corpus callosum. 33 Both patients were diagnosed with MIS-C and had a rapid response to immunotherapy. In the nine-year-old patient, repeat MRI showed near-complete resolution of the corpus callosum lesions, indicating that the suspected microinfarcts were likely secondary to an inflammatory, possibly cytokine-mediated, mechanism. In addition to cerebrovascular lesions, atypical neurological presentations of other neurological disorders were observed in children with MIS-C. Secondary pseudotumor cerebri was reported in a 14-year-old who presented after five days of fever, headache, rash, diarrhea, and dyspnea that progressed to septic shock requiring mechanical ventilation. 31 Following extubation, he had an apparent new righteye abducens nerve palsy. Dilated fundoscopic examination revealed bilateral papilledema and left-disk hemorrhages with the remainder of his neurological examination otherwise normal. Brain MRI/magnetic resonance venography revealed signs of increased intracranial pressure consistent with secondary pseudotumor cerebri syndrome. Two months after discharge the patient has resolution of papilledema, disk hemorrhages, and abducens nerve palsy. Neurobehavioral manifestations are exemplified by the case report of a 14-year-old previously healthy male who had acute onset of fever, abdominal pain, truncal rash, and altered mental status including disorientation, delusions, and aggression. 36 Initial evaluation included echocardiography, which found a diminished left ventricular ejection fraction of 58% and mild coronary artery dilation (z score < 2.5). He was begun at admission on a course of methylprednisolone, and he met the diagnostic criteria for atypical KD and received a course of IVIG. Early in the course, his neuropsychiatric status continued to deteriorate, eventually requiring sedation with dexmedetomidine. Notably, an MRI of the brain on day 3 was unremarkable and no CSF studies were done. Nasopharyngeal swab for SARS-CoV-2 was negative, but testing for SARS-CoV-2 IgG was positive one week following initial presentation. When his sedation was successfully discontinued, his neurological examination showed him to be sleepy, inattentive, and unable to follow multistep commands with an otherwise intact neurological examination. Gradually he regained his cognitive baseline including normal speech, attention, concentration, and short-term memory based on bedside examination and neurologist assessment. Formal measures of cognitive and behavioral function were not completed, and postdischarge neurocognitive assessment was not reported. The authors note confounding variables and likely multifactorial etiology contributing to severe agitation in a child in the pediatric intensive care unit (PICU). However, the consistency of this presentation to reported neuropsychiatric manifestations in KD lends weight to the role of cytokine storm-induced inflammation as one important contributor. In this scoping review we evaluated the case literature of HCoV infections in the nervous system in children to gain insight into the anticipated neurodevelopmental effects of pediatric SARS-CoV-2 infections. Six of the seven HCoVs, excepting MERS-CoV, have been associated with either primary or secondary neurological insults in children. In the most severe form, cases of HCoV infections were associated with AFP, ADEM, encephalitis, status epilepticus, and stroke. Particularly notable were CNS lesions associated with MIS-C secondary to SARS-CoV-2 infections, which included major vessel and microvascular cerebral infarcts, secondary pseudotumor cerebri, and acute-onset severe neuropsychiatric distress in previously healthy children. Fatalities have been reported in multiple children with neurological insults following MIS-C. In less-severe presentations, HCoV infections were associated with febrile seizures, particularly among infants, and focal nerve palsies. Taken together these reports illustrate the rare but established ability for HCoVs to cause severe neurological disease resulting in ongoing functional impairments. Further, among the articles excluded for absence of neurological manifestations, there is an extensive body of literature demonstrating the potential of HCoVs to cause severe systemic illness requiring critical care, a risk factor itself for neurodevelopmental deficits. However, among all articles reviewed, we identified only brief exploration of the neurodevelopmental implications of HCoV infections. Given the risk to long-term child neurodevelopment of HCoV infections, greater guidance for neurodevelopmental monitoring is needed. Neurodevelopmental monitoring may be intuitive for many of these diagnoses in many child neurology clinical practices. However, there is variability in the duration of monitoring, the extent of evaluation, and the availability of testing options. Rapid global recovery of skills may mask more subtle long-term yet impairing deficits, some of which may appear years later when a child is expected to develop a specific skill. Many of these deficits are either not readily apparent before discharge from neurological clinical care or are not specifically queried in clinic and thereafter may persist without additional evaluation. Furthermore, the role of the neurologist in managing developmental and behavioral sequelae is not standardized, with some providers preferring to refer learning-, behavior-, and motor function-related deficits to colleagues in developmental and behavioral pediatrics, psychiatry, and physical medicine and rehabilitation, respectively. Therefore, at out institution, we have developed the practice that children with direct neurological involvement or critical illness and factors associated with increased risk for developmental and behavioral sequelae are followed by neurodevelopment and, when needed, neuropsychology specialists. However, given that such specialty care is not always easily accessed, primary care providers must be familiar with the common, age-related signs of potential neurodevelopmental impairment following acquired brain injury. Guidance by age is provided in Table 4 . Although some parents or the child may express concerns about neurodevelopmental changes following illness, physicians often need to inquire specifically about each area of neurological function to comprehensively address sequelae. Asking in depth about skills outlined in Table 4 provides a cognitive construct that can guide providers in eliciting further standardized evaluation. For example, when asked if their child remembers to do their chores or turn in their homework, a parent may acknowledge that their child is "not remembering anything," which could represent a working memory deficit, inattention, mood interference, or a more global injury affecting memory. Although the specific tests used may vary across clinical practices, neuropsychologists are able to administer standardized testing to help better understand the underlying cognitive deficit to guide targeted management. The overarching goals of neurodevelopmental monitoring are to anticipate and mitigate functionally disruptive symptoms, to optimally transition into home, school, and community, and to maximize outcome through timely therapeutic and medical interventions. From our review, it is apparent that a knowledge gap exists about the long-term neurodevelopmental sequelae of HCoV infections in children and particularly SARS-CoV-2. Until more robust clinical evidence is available, the sequalae associated with other pathogens causing similar clinical presentations are useful case studies for anticipating the neurodevelopmental effects of pediatric SARS-CoV-2 infections. Acute flaccid paralysis GBS primarily affects the peripheral nerves, whereas both acute flaccid myelitis (AFM) and TM are immune-mediated conditions affecting the CNS, especially the spinal cord. Under the category of AFP, GBS, AFM, and TM present with substantial weakness and potentially respiratory depression. 53, 54 Despite the consistency of weakness at onset, reported outcomes reveal a great deal of variability in long-term motor strength and function for all three pathologies. Data from several pediatric GBS cohorts suggest full motor recovery in 66% to 94% patients. However, one-fourth of the children report adverse effects on schoolwork and quality of life. 54 Followup studies of adults who had GBS during childhood have shown that many patients experience residual pain, unsteadiness, and fatigue in their daily lives. 55 A recent review of pediatric TM discusses the variability in reported outcomes. 56 Overall, nearly half of the children make a complete recovery, although individuals with ongoing weakness can experience substantial functional Slower or lack of self-help skills; slower than peers to learn (e.g., rules of game, colors, shapes); inattention Needs longer time to process and/or repetition when learning or completing tasks; forgetfulness (e.g, "not remembering anything"); inattention; executive dysfunction (e.g., poor organization and planning) Language Delay in expressive and receptive language milestones (e.g., pointing to identify; novel 2word sentences; concept of "one") Does not ask or understand "Why" questions; difficulty with prepositions, word-finding, and/or following conversation impairment. In addition, there is a high frequency of ongoing sensory disturbance and bladder dysfunction. Data on the longterm outcomes of the recent United States AFM outbreak from 2012 to 2016, which was associated primarily with Enterovirus D68, indicate that the majority of children make notable functional gains, such as the ability to walk short distances, over several months. Yet, 75% to 95% may still have residual weakness and significant functional impairments with a minority remaining technology dependent and severely disabled. 53, 57 Children presenting with AFP of any etiology, including GBS, TM, and AFM, associated with SARS-CoV-2 should receive long-term neurodevelopmental surveillance. Children generally do well and do not typically develop major neurodevelopmental sequelae following febrile seizures. However, one large population-based prospective study reported a 20% to 35% increase in the diagnosis of attention-deficit/hyperactivity disorder in children with febrile seizures that followed into adulthood compared with the general population. 58 In addition, both febrile status epilepticus and recurrent febrile seizures have been associated with long-term neurodevelopmental difficulties including weaker motor development and expressive and receptive language delays. 59, 60 The association between more severe febrile seizures and developmental delays does not imply causality as children with neurodevelopmental disorders are already at increased risk for epilepsy. The history and severity of febrile seizures should guide referral for neurodevelopmental follow-up. In addition to febrile seizures, our review included multiple cases of children in whom an afebrile seizure concurrent with HCoV infection unmasked a potential genetic predisposition to seizure disorders. In the case presented by Garcia-Howard and colleagues, the authors used whole exome sequencing to identify a mutation in the PRRT2 gene that has been associated with benign familial infantile convulsions. 45 Although this finding does not carry the neurodevelopmental risk of more severe genetic-associated causes of epilepsy, it is a notable given that four cases in our review report that status epilepticus was the presenting symptom of SARS-CoV-2 infection without exploration of the underlying genetic etiology of seizures in the patients. For children experiencing status epilepticus, the risk of developing epilepsy is high, with estimates ranging from 20% to 40%. 61 And, with this comes the associated risks to neurodevelopmental outcomes in children including motor and intellectual disability, educational difficulties, and decline in quality of life as described widely including in the recent review by Sculier and colleagues and an eight-year prospective follow-up study of more than 200 children who presented with convulsive status epilepticus by Pujar and colleagues. 61, 62 Therefore, children presenting with febrile seizures should be evaluated routinely by their primary care providers for general signs and symptoms of neurodevelopmental consequences following SARS-CoV-2 infections. Those who experience severe symptoms, including status epilepticus, should receive appropriate neurodevelopmental and neuropsychologic follow-up. ADEM is a predominantly monophasic immune-mediated inflammatory demyelinating disorder of the CNS that typically occurs after a viral infection. A recent meta-analysis indicated that global neurocognitive sequelae (i.e., intellectual disability) are not observed following ADEM. 63 However, a sizable subset of children, 20% to 43%, demonstrate specific but persistent impairments in sustained attention and processing speed. The adolescent patients described by Yeh et al. and de Miranda Henriques-Souza et al. infected with HCoV-OC43 and SARS-CoV-2, respectively, would ideally receive ongoing neurodevelopmental and neuropsychologic monitoring. Survivors of pediatric encephalitis demonstrate long-term neurological sequelae ranging from neurocognitive impairments and related learning challenges to behavioral and personality changes. [64] [65] [66] A 2016 meta-analysis found that a nearly half of the children who recover from viral encephalitis demonstrate ongoing neurodevelopmental impairments. 7 Long-term sequelae included developmental delay (35%), behavior problems (18%), intellectual impairments (17.6%), and motor deficits (18%). 7 Importantly, neurocognitive sequelae may be less obvious in infants and young children as their functional skills are more globally, versus specifically, assessed at this age. For instance, discharge outcome measures studied by Britton et al. indicated that the majority of infants with parechovirus encephalitis had a "good outcome." 67 However, specific developmental testing 12 months after hospital discharge showed that 50% had developmental concerns and nearly onefourth had severe developmental delay. 67 Similar findings were reported by Michaeli et al. who observed high rates of attentiondeficit/hyperactivity disorder and learning disabilities in children who survived encephalitis. 66 In our review multiple cases of encephalitis were identified including in the setting of MIS-C following SARS-CoV-2 as reported by Abel et al. 34 Any cases of SARS-CoV-2 encephalitis will require neurodevelopmental surveillance. Cerebrovascular events were associated with SARS-CoV-2 infections among the case literature we reviewed. Among these, all were in children beyond the perinatal period (less than one month old). In the cases presented, children suffered a breadth of stroke etiologies. Mirazee et al. and Gulko et al. reported cases of focal cerebral arteriopathy involving the left cerebral artery causing damage to the basal ganglia. 50,51 Kihira et al. reported a large right anterior and middle cerebral artery infarction with subarachnoid hemorrhage in the left hemisphere in the setting of MIS-C. 35 Even more extensively, Tiwari et al. reported extensive bilateral lesions in a nine-year-old girl with MIS-C and SARS-CoV-2 including smooth stenosis of both internal carotid arteries, both A2 segments of the anterior cerebral arteries, and diffuse narrowing of the M2 and M3 of both middle cerebral arteries. 37 The unifying risk factor cited by multiple cases of stroke in children with SARS-CoV-2 infections appears to be a severe acute, neuroinflammatory response. 32 To date, however, clinical evidence for neuroprotective measures in children infected with SARS-CoV-2 is scarce, and further understanding remains urgently needed. Outcomes following stroke in children are more nuanced than a localization-based understanding of neuroanatomy as pediatric stroke recovery occurs in the contexts of innate brain developmental processes which vary by age, neuroplasticity, and the sequence of brain injury recovery. In addition, long-term functional deficits following pediatric stroke vary by mechanism of insult and extent of injury. Large vessel strokes typically result in corresponding impairments of function controlled by that region, whereas microhemorrhages may result in more subtle cognitive or behavioral deficits that are difficult to predict. However, with all etiologies of pediatric stroke there is a great of variability in the extent of these deficits in the existing literature. 68 Therefore, in the absence of current clinical knowledge of pediatric recovery following SARS-CoV-2 stroke, consideration of the extent of injury and a child's early clinical course can guide aggressiveness of rehabilitation. However, even if major deficits are not present, children with cerebrovascular disease associated with HCoV infections should undergo neurodevelopmental follow-up for evaluation of deficits resulting from minor disruptions in neural connectivity. Multisystem inflammatory syndrome in children, or MIS-C, is now an established manifestation of SARS-CoV-2 infection seen in the pediatric population. 69 As a hyperinflammatory syndrome, MIS-C has been compared with KD, the pediatric vasculitis that most notably can result in coronary artery aneurysms and also can lead to other neurological and neurodevelopmental sequelae. Of note, previous associations between KD and HCoV-229E have been established. 70 The most commonly reported neurological presentations of KD include aseptic meningitis (up to 50% patients), hemiplegia, facial palsy, and encephalopathy. 71 Patients with KD have been shown to experience long-term behavioral impairments including internalizing behaviors, attention, and social interactions. 72 The main differences between KD and MIS-C include the age of onset, with older children and adolescents presenting with MIS-C, and increased cardiovascular involvement in MIS-C. 73 Of 186 children with MIS-C across 26 states, a majority of children had involvement of four or more organs and required admission to intensive care. 73 Unfortunately, neurological outcomes are not reported in this population. Given the neurocognitive and behavioral sequelae in KD, high frequency of severe illness in children with MIS-C, and lack of knowledge on potential short-and long-term neurodevelopmental deficits, neurodevelopmental monitoring is highly recommended to support optimal outcomes. In addition to MIS-C, our literature search demonstrated that HCoVs can cause critical illness, whether associated with neurological manifestations of disease or not, and especially in young children and those with immunodeficiencies. This potential is well illustrated by a recent report of 48 children with SARS-CoV-2 admitted to the PICU. 74 In this study, 68% children were categorized as "severe-critical," 38% required mechanical ventilation, 25% needed vasoactive support, and the average length of PICU admission was greater than 2.5 days. Children with critical illness, even without neurological injury, are at high risk for acquired functional deficits following PICU discharge. Up to 81.5% experience a decline in one or more functional domains six months following PICU admission and functional disability increases over time postdischarge. 75, 76 Therefore, children admitted to the PICU due to SARS-CoV-2 should receive neurodevelopmental follow-up regardless of infectious presentation. Studies of children enduring viral encephalitis, ADEM, and KD have demonstrated a severe psychosocial effect on patients and their families including an increase in internalizing symptoms such as anxiety and depression even when neurocognitive outcomes are generally positive. 63, 64, 77 In addition to neurodevelopmental sequelae, PICU admissions are associated with an alarming risk of post-traumatic stress disorder and anxiety for both children and their parents. 75, 78 The tremendous stress and trauma of severe illness courses can have chronic consequences for quality of life. Neurodevelopmental surveillance can play a critical role in reducing these effects. Our review is not exhaustive in capturing all articles on HCoV nervous system infections in children. Notably, the full text of 84 articles (3.7%) was not available through our databases. Many of the cases also present only an association between HCoVs and neurological manifestations. It is important to acknowledge that association in chronicity between infections and symptoms is not diagnostic of causality, particularly in instances where study authors transparently report that the presence of an HCoV was effectively the only notable positive finding after a thorough diagnostic evaluation, and therefore the "favored" diagnosis. Further, the exclusion of adult studies may limit our understanding of the pathophysiology and additional clinical manifestations of HCoV in the nervous system, although the presented pediatric neurological manifestations have also been reported in adults. 37 In addition, we did not identify evidence of long-term neurodevelopmental sequelae in adults who had severe HCoV infections as children. Finally, our study is limited, inherently, by the novel nature of the SARS-CoV-2 pandemic. In this scoping review we evaluated the rare but serious neurological manifestations that HCoVs, including the novel SARS-CoV-2 virus, can cause in children and the threat that such serious illnesses may pose to long-term neurodevelopmental outcomes. Although awareness of and testing for coronaviruses is heightened in the current pandemic, prior reports suggest that pediatric HCoV infections may have been underdetected, especially as a cause of febrile seizures and encephalitis. SARS-CoV-2 and other coronaviruses should be ruled out in children with acute onset of neurological disease who have likely risk factors, including age less than one year and immunocompromise. Current literature provides insufficient evidence on long-term function in children with neurological manifestations or critical illness from HCoVs. However, evidence from other etiologies suggests a high likelihood of impairing neurodevelopmental sequelae that should be deliberately queried in clinical follow-up. Altogether, to achieve optimal functional outcomes and quality of life, children who experience severe neurological illness due to coronaviruses, including all those who require intensive care, should receive longitudinal neurodevelopmental monitoring to detect overt and subtle deficits and guide therapy. 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