Detection of Coronavirus in the Central Nervous System of a Child With Acute Disseminated Encephalomyelitis

Abstract

ABSTRACT. We present a case in which human coronavirus was detected in the cerebrospinal fluid of a child presumed to have acute disseminated encephalomyelitis. In murine models, coronavirus has been found to cause a chronic demyelinating condition that resembles multiple sclerosis. Additionally, there is in vitro evidence of human coronavirus's ability to infect neural cells. This case report provides additional support for the hypothesis that coronavirus may be an important etiologic factor in the pathogenesis of demyelinating disease in humans. Pediatrics 2004;113:e73-e76. URL: http://www.pediatrics. org/cgi/content/full/113/1/e73; coronavirus, HCoV, acute disseminated encephalomyelitis, ADEM, postinfectious encephalitis, demyelination, child.ABBREVIATIONS. ADEM, acute disseminated encephalomyelitis; CNS, central nervous system; MRI, magnetic resonance imaging; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; IgG, immunoglobulin G; RT, reverse transcription; HCoV, human coronavirus; MS, multiple sclerosis.A cute disseminated encephalomyelitis (ADEM) is a monophasic, demyelinating disease of the central nervous system (CNS) that primarily affects children and young adults. It is characterized by high-signal-intensity lesions in the white matter of the brain and spinal cord on T2-weighted magnetic resonance imaging (MRI). These lesions may be independent of the clinical findings. Children may present with diffuse encephalopathy, seizures, optic neuritis, hemiparesis, and/or symptoms suggestive of spinal cord transection.The epidemiology of the condition is unknown. A review of cases presenting to a children's hospital suggested a prevalence of ϳ4.5 cases per 10 000 pediatric hospital admissions, exclusive of newborns. 1 The etiology of the illness is cryptogenic, although the disorder is generally thought to be due to a paraor postinfectious process. Certainly, many case reports in the literature suggest an infectious process before the onset of CNS symptoms, and some have identified specific infectious agents in cases of ADEM. [2][3][4] However, in most cases, a specific etiologic infectious agent is not identified. For example, in a recent retrospective review of cases of ADEM, clinicians were able to identify an infectious agent in only 1 of 18 cases. 1 ADEM has also been described after immunizations. 5,6 Despite reports of the possible association between infection and ADEM, there is no clear understanding of the relationship between the infectious agent and the onset of demyelination. There is experimental evidence in mice for a relationship between coronavirus and CNS demyelination. [7][8][9] Little is known, however, about this virus's relationship to demyelinating disease in humans. Indeed, there have been no case reports of this virus in relation to ADEM. We report a case of demyelinating disease in a child in which cerebrospinal fluid (CSF) and nasopharyngeal specimens were positive for human coronavirus (HCoV) by polymerase chain reaction (PCR) and in whom a fourfold rise in antibody titer ...

Coronavirus Infections in the Central Nervous System and Respiratory Tract Show Distinct Features in Hospitalized Children

“…Human pathogenic CoVs are associated with a wide range of respiratory illnesses, including common colds, pneumonia, and bronchiolitis [7]. Additionally, several studies have described that CoVs are associated with CNS diseases such as acute disseminated encephalomyelitis and multiple sclerosis [8,9,10]. Respiratory tract infection contributes to high morbidity and mortality with a worldwide disease burden estimated at 112,900,000 disability-adjusted life years and 3.5 million deaths [11].…”

“…The effect of CoV infection is influenced by various factors, including environmental factors, genetic factors, and immune-mediated process [10]. Cytokines are widely recognized as important mediators of inflammatory response [13].…”

The OC43 human coronavirus envelope protein is critical for infectious virus production and propagation in neuronal cells and is a determinant of neurovirulence and CNS pathology

“…Coronaviruses also represent a significant public health concern due to the recent zoonotically emerged, highly pathogenic species, SARS corovonavirus (SARS-CoV) (Drosten et al, 2003;Ksiazek et al, 2003Ksiazek et al, ) in 2002Ksiazek et al, -2003Ksiazek et al, and, since 2012, Middle-East respiratory syndrome coronavirus (MERS-CoV) (Zaki et al, 2012), localized to the Arabian Peninsula, but with sporadic travel-related outbreaks worldwide. In addition to their respiratory tropism, human coronaviruses have been detected concurrently with severe and acute neurological symptoms (Arabi et al, 2015;Morfopoulou et al, 2016;Yeh et al, 2004) and shown to naturally infect the central nervous system (CNS) (Arbour et al, 2000;Gu et al, 2005;Xu et al, 2005) with neurons demonstrated as the main target of infection in HCoV-OC43 (Bonavia et al, 1997;Favreau et al, 2012;Jacomy et al, 2006;Jacomy and Talbot, 2003) and SARS-CoV (Gu et al, 2005;Xu et al, 2005).…”

Axonal Transport Enables Neuron-to-Neuron Propagation of Human Coronavirus OC43

“…To circumvent these limitations, we developed a model of HCoV neuropathogenesis by taking advantage of the natural susceptibility of mice to neuroinvasion by the widely circulating HCoV OC43 human strain. Upon infection, mice indeed developed neurological symptoms reminiscent of the afflictions reported in several human patients (10,13,(19)(20)(21), such as encephalitis, transient flaccid paralysis, and long-term persistence in surviving mice (23,24,(30)(31)(32)(33). Knowledge of the paths and underlying mechanisms governing the propagation of the virus from the upper respiratory tract to and within the CNS is currently incomplete, which hinders the elaboration of antiviral countermeasures adapted to this particular host compartment.In our study, we defined the path taken by HCoV OC43 (34, 35) to access and spread to and within the CNS and studied the underlying modes of intercellular propagation to better understand its neuropathogenesis in both humans and mice.…”