Rotavirus infection-associated central nervous system complications: clinicoradiological features and potential mechanisms

Abstract

Despite the introduction of vaccines in 2006, rotavirus remains one of the most common causes of pediatric gastroenteritis worldwide. While many studies have conclusively shown that rotavirus infection causes gastroenteritis and is associated with various extra-intestinal manifestations including central nervous system (CNS) complications, extra-intestinal manifestations due to rotavirus infection have been relatively overlooked. Rotavirus infectionassociated CNS complications are common in children and present with diverse clinicoradiological features. Rotavirus infection-associated CNS complications can be classified based on clinical features and brain magnetic resonance imaging findings, particularly lesion location on diffusion-weighted imaging. Common clinicoradiological features of rotavirus infection-associated CNS complications include: (1) benign convulsions with mild gastroenteritis; (2) acute encephalopathies/encephalitis, such as mild encephalopathy with a reversible splenial lesion, acute encephalopathy with biphasic seizures and late reduced diffusion, and acute necrotizing encephalopathy; (3) acute cerebellitis; and (4) neonatal rotavirus-associated leukoencephalopathy. The precise mechanism underlying the development of these complications remains unknown despite a number of clinical and laboratory studies. Here we review the diverse clinicoradiological features of rotavirus infection-associated CNS complications and propose a hypothesis of their pathophysiology.

Increasing our understanding of rotavirus-induced central nervous system manifestations

“…4) Rotavirus infection shows a wide spectrum of central nervous system (CNS) manifestations, including benign convulsions with mild gastroenteritis (CwG), acute meningoencephalitis, white matter injuries, and lethal encephalitis/encephalopathies. 4,5) However, although it has not yet been clearly identified as a risk factor for rotavirusrelated CNS complications, regional or racial differences are suspected, as it is reported more often in East Asia than in Europe or the United States. 6) CwG is the most commonly encountered CNS complication, occurring in previously healthy infants and children aged 6 months to 3 years.…”

“…7) In addition to CwG, diverse clinicoradiological features related to rotavirus infection in the brain have been re ported, as various brain MRI protocols, such as fluid attenuated inversion recovery and diffusionweighted imaging, have been widely and early applied in clinical settings. 5) Rotavirusinduced CNS complications primarily involve acute encephalopathy with transient and reversible changes rather than acute encephalitis with destructive lesions on MRI. These include white matter injuries in neonates, mild encephalopathy with a reversible splenial lesion, acute encephalopathy with biphasic seizures and reduced diffusion, and posterior reversible encephalopathy syndrome.…”

“…1). 5) First, CNSdriven symptoms such as vomiting, sickness, loss of appetite, and malaise are considered braingut communication in rotavirus infection. 2,11) This includes activating the vagal nerves that project to regions of the brain via enterotoxin nonstructural viral protein 4dependent 5hydroxy tryptamine release.…”

“…11) Second, previously described CNS com plications are explained as direct CNS effects, although rotavirus antigen and ribonucleic acid are rarely detected in the CSF. 5) Po tential mechanisms by which the pathogen causes these diverse CNS complications are: (1) direct viral invasion into the CNS;…”

“…(2) CNS entry of deleterious braindamaging mediators; and (3) CNS entry of activated circulating leukocytes. 5) The most likely mechanism is that the bloodborne rotavirus enters the brain via disrupted and increased vascular permeability of the blood brain barrier (BBB); thus, the direct viral infection of neuronal cells induces cytopathic results. 2,11) Various circulating mediators produced during rotavirus infection can damage BBB integrity and induce hypothalamic dysregulation.…”