Acute flaccid myelitis: an emerging clinical entity

Abstract

Acute flaccid myelitis (AFM) is a recently defined clinical entity associated with outbreaks of enterovirus D68 (EV-D68) infections. AFM was first recognized in the United States in 2014 and has subsequently been reported in Europe, Australia, Japan, and South Africa, indicating a worldwide spread. A case definition of AFM has been proposed by the US Centers for Disease Control and Prevention. However, the detailed clinical aspects of AFM remain poorly understood. As AFM associated with EV-D68 or other viral infections is an emerging threat among children after eradication of poliomyelitis, vigorous studies of AFM are warranted. Gordon-Lipkin et al. described serial neuroimaging findings and their relationships to the outcomes of 16 children with AFM. Although the key neuroimaging feature of AFM is longitudinally extensive hyperintensity of grey matter evident on T2-weighted images, the authors emphasized that white matter involvement was also apparent during the acute period. This is important not only to prohibit erroneous exclusion of AFM but also regarding AFM pathobiology. As the authors stated, the fact that AFM onset is infection-associated suggests two possible pathomechanisms: primary neurotropic infection or a secondary immune response/infection susceptibility. Experimentally, EV-D68 inoculation via several different routes (intracerebral, intranasal, and intraperitoneal) was followed by limb paralysis with the appearance of viral ribonucleic acid in the spinal cords of affected animals. Although the experimental studies support a primary neurotropic infection, the data may be inconsistent with the fact that EV-D68 ribonucleic acid was not detected in most patients with AFM associated with virologically proven EV-D68 infections. Further studies are necessary to elucidate the AFM pathomechanism. The outcomes of children with AFM are inadequately known. In their case series, Kirolos et al. reported the 18month outcomes of five children with AFM associated with virologically proven EV-D68 infections. Despite continuing improvements in motor function, the most severely affected children required home ventilation and tracheostomy. Proximal limb weakness was evident in most patients, consistent with the persistence of spinal lesions during convalescence, as reported by Gordon-Lipkin et al., although lesions evident in spinal magnetic resonance imaging improved over time. Currently, outcomes of AFM are poor; the threat to childhood well-being cannot be ignored, although only small numbers of children are affected. These studies indicate that there are several issues to be solved regarding AFM among children. At first, it remains unclear whether EV-D68 is the causative AFM pathogen. The clear temporal association between an epidemiological increase in EV-D68 detection and AFM clustering strongly implies a causal relationship. However, virological evidence of EV-D68 infection has been obtained from only a few children with AFM. Establishment of a surveillance system is essential to clarify the contribution made by EV-D68 (or other viruses) to AFM; appropriate specimens must be collected and analyzed. Second, an effective treatment for AFM is lacking. Steroids and intravenous immunoglobulins are commonly administered to children with AFM, and plasma exchange may have been performed in some patients. Unfortunately, no such treatment is yet of proven efficacy. To rationalize such work, the pathomechanism of AFM must be clarified; antiviral treatment will be useful if the etiology is a direct infection, whereas anti-inflammatory treatment will be required if the etiology is parainfectious.