EXPERIENCE AND REASON |


* Departments of Neurology
Microbiology
Pediatrics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York
| ABSTRACT |
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Key Words: 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
Acute 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 childrens hospital suggested a prevalence of
4.5 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 para- or 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.24 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.79 Little is known, however, about this viruss 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 was documented. All other testing for infectious agents was negative.
| CASE PRESENTATION |
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1 day before admission. He also reported clumsiness in his right hand. His mother noted increased irritability. The patient and his mother denied visual changes, seizure, headache, mental status changes, bowel or bladder dysfunction, or speech or language difficulties. There was no history of toxin ingestion. There was a history of an upper respiratory tract illness
1 week before his first symptom. His brother had experienced a sore throat 1 to 2 weeks before the hospitalization. The patients developmental milestones were normal, and he was an honor student at school. He was, however, enrolled in a special behavioral class. He was employed part-time as a bus boy at a local restaurant and lived with his mother and brother. There were three pet dogs, one of which was a puppy, in the home. The patients father was not involved in the family. All family members were reported to be healthy, although little was known about the fathers medical history.
The patients general physical examination was unremarkable. His vital signs were stable, and he was afebrile. He was alert, oriented, and cooperative. Speech was fluent. His neurologic examination revealed normal optic discs and cranial nerve function. Sphincter tone was normal. Reflexes were present and symmetric in all extremities. Plantar reflexes were normal. There was mild distal weakness in the right hand and foot (4/5 in the finger extensors and extensor hallucis longus and 4 /5 in the remainder of the upper and lower right limb). Sensory function above T10 was normal. There was patchy loss of vibration and temperature sensation below T10. Proprioception and pinprick sensation were normal below T10. Cerebellar testing revealed mild dysmetria of the left hand. Heel-to-toe walking was poor. The patients gait was antalgic, likely due to discomfort associated with his sensory dysfunction. The Romberg test was negative. The patients symptoms resolved over several weeks without any therapeutic intervention.
An MRI of the brain and spinal cord was performed the morning after admission. It demonstrated lesions on T2-weighted imaging at C4C5 and at T7T8. The spinal cord lesions were nonenhancing. The MRI of the brain revealed patchy areas of hyperintensity in the white matter tracts, particularly in the centrum semiovale (Fig 1). There was an area of hyperintensity in the left cerebellum adjacent to the superior aspect of the left brachium pontes (Fig 2). There was enhancement of some lesions, including that in the left centrum semiovale.
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A follow-up MRI of the brain
6 weeks after the onset of symptoms showed improvement of the lesions in the brain and cerebellum. However, a follow-up MRI performed 3 months after the onset of symptoms showed a possible new lesion in the left hemisphere of the cerebellum. The periventricular lesion in the right cerebral hemisphere appeared brighter and larger. There was no gadolinium enhancement of the lesions. The spinal cord lesions had resolved. Despite these changes, the patient had not complained of additional symptoms.
| LABORATORY METHODS |
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Immunofluorescence
Adherent rhabdomyosarcoma (ATCC CCL136) cells were infected with 0.3 mL of viral suspension providing a multiplicity of infection of 0.1 and incubated for 2 hours at 37°C with periodic agitation. Cell monolayers were washed with phosphate-buffered saline and incubated for 24 hours at 33°C and fixed in acetone at 20°C. The uninfected control cells were fixed in acetone immediately after the 2-hour adsorption period. For viral antigen control, the primary antibody, monoclonal antibody 4B-6.2, reacting with HCoV-OC43 nucleocapsid antigen at 1:500 dilution was used on infected cells. Fluorescein-conjugated goat anti-mouse F(ab')2(Cappel, Durham, NC) at 1:20 dilution was used as a secondary antibody.14
Fc receptors were blocked with normal goat serum before incubation with primary antibodies. Acute (January 22, 2003) and convalescent (February 11, 2003) sera were diluted twofold 1:401:1280, and each dilution was incubated on infected cells for 1 hour at 37°C. After washing, fluorescein-conjugated rabbit anti-human IgG F(ab')2 (Dako, Carpinteria, CA) at 1:20 dilution was used as a secondary antibody. The test was validated with human serum having a neutralizing antibody titer to HCoV OC43 of 320 by plaque assay in MRC-5 cells and a titer of 1:200 in the immunofluorescence assay. For the negative control, IgG-deficient (134 mg/dL) human serum at a dilution of 1:40 was used. Fluorescence was observed on a Leitz (Leitz, Germany) epifluorescence microscope at x40 magnification.
| DISCUSSION |
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ADEM is presumed to be the result of a post- or parainfectious process. Approximately 75% of patients are reported as having had a recent upper respiratory tract infection or vaccination before the onset of ADEM.1,1517 Some studies have shown seasonal variation, with the majority of cases occurring in the winter and spring, suggesting a seasonal respiratory virus.1 Although associations with numerous infectious agents have been reported, a specific etiologic agent has not been identified, nor has the pathogenesis been clarified.
Coronaviruses are common causes of upper respiratory tract infections in adults and children and generally produce mild disease. Most recently, a newly described variant of coronavirus has been associated with severe acute respiratory syndrome (SARS).18 Coronaviruses are distributed worldwide. They are RNA viruses, enveloped with lipid-soluble coats, and are pleomorphic. Outbreaks tend to occur in winter and spring, with young children having the highest infection rates. These viruses are difficult to diagnose because they cannot be cultured easily.
In a murine model, the coronavirus mouse hepatitis virus has been associated with demyelination in the CNS. It produces a chronic demyelinating condition that resembles MS. This disorder is thought to be the outcome of an immune-mediated process.79
HCoV has been examined as a possible contributing factor in the pathogenesis of MS. HCoV RNA has been detected in the CSF of MS patients and in the brains of MS patients on autopsy.1921
In vitro, this virus has been shown to cause acute and persistent infections in human neural cell lines. The astrocytoma cell lines U-87 MG, U-373 MG, and GL-15 as well as neuroblastoma SK-N-SH, neuroglioma H4, and oligodendrocytic MO3.13 have been found to be susceptible to acute infection by HCoV OC43 and 229E. CHME-5 immortalized fetal microglial cell lines have also been found to be susceptible to acute infection by HCoV 043. Persistent infection by HCoV 229E and 043 has been observed in the MO 3.13 and H4 cell lines. HCoV 043 also has been linked to persistent infections in the U-87 MG and U-373 MG cell lines.10,2224
Thus far, clinical studies have not shown a direct relationship between human demyelinating disease and HCoV. A recent study of patients with acute, monosymptomatic optic neuritis, for example, showed only 4 of 37 patients with this disorder with a positive CSF PCR for HCoV 229E, with 1 of the 15 controls testing positive.25 Similarly, in an autopsy study, patients with MS were no more likely to have HCoV RNA than controls without neurologic disease.26
| CONCLUSIONS |
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Does coronavirus play a role in the pathogenesis of ADEM or MS? What is the mechanism by which demyelination might occur after infection with coronavirus? The etiology of ADEM and other demyelinating disorders, of course, is probably multifactorial, with both environmental and genetic factors playing important roles. Certainly, in the case of demyelination associated with MS, multiple factors including human leukocyte antigen types, T-cell-mediated mechanisms, and myelin basic protein have been implicated as etiologic factors. Controlled studies are needed to clarify the role of coronavirus in demyelinating disease and, additionally, to explore which qualities distinguish ADEM, a self-limited disorder, from MS.
| ACKNOWLEDGMENTS |
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| FOOTNOTES |
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Address correspondence to E. Ann Yeh, MD, MA, Womens and Childrens Hospital of Buffalo, Department of Neurology, 219 Bryant St, Buffalo, NY 14222. E-mail: ann.yeh{at}sympatico.ca
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E. Marchioni, S. Ravaglia, G. Piccolo, M. Furione, E. Zardini, D. Franciotta, E. Alfonsi, L. Minoli, A. Romani, A. Todeschini, et al. Postinfectious inflammatory disorders: Subgroups based on prospective follow-up Neurology, October 11, 2005; 65(7): 1057 - 1065. [Abstract] [Full Text] [PDF] |
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