The results suggest that children with severe EV71 infection are fever and/or skin rash, easy convulsion, and lethargy. Some patients are with abnormal neurological magnetic resonance imaging. The white blood cell count in the cerebrospinal fluid of children with EV71 infection may increase with the increase in the ratio of peripheral blood neutrophils within the first 3 days of illness. The results may provide a deeper understanding of the clinical characteristics of the disease.
This study found that fever and rash tended to appear earlier in the course of EV71 infection, followed by susceptibility and lethargy, which might be related to the infection mechanism. Indeed, EV71 enters the human body through the mouth, initially replicates in the pharynx (tonsils) or intestinal tract, and then multiplies in the regional lymph nodes, which can cause mild viremia [18–20]. The illness of most infected people can be controlled at this stage. In a small number of infected people, the virus continues to invade the reticuloendothelial tissue, deep lymph nodes, liver, spleen, bone marrow, skin, mucous membranes, central nervous system, and heart, and further proliferate and cause corresponding lesions [21]. Generally, the symptoms of systemic viremia, such as fever and rash, appear first after reproduction through the respiratory tract or gastrointestinal tract. If the disease continues to progress, the nervous system can be impaired, leading to susceptibility and lethargy.
In this study, susceptibility usually appeared on the 1st to 4th day, especially on the 2nd or 3rd day. The essence of susceptibility is myoclonus, which is divided into myoclonus from the corticothalamic axis and subcutaneous non-epileptic myoclonus originating from the back of the pons. Considering the fact that no epilepsy waves were found in the scalp EEG of the included children and MRI lesions were more common in dorsal pons, it is possible that susceptibility is from myoclonus caused by the release of 5-HT from the dorsal pons (predominant raphe nucleus) [22]. Lethargy mostly occurred after the fever subsided and the end of susceptibility, mainly on the 3rd or 4th day, and lasted for 1–2 days. Impairment of the cortical or ascending reticular activation system can reduce the level of consciousness [23–25]. Still, most of the children had normal EEG without obvious cognitive dysfunction during the recovery period, suggesting that it is likely that the non-specific projection system damage of the ascending reticular activation system in the upper pons or lower part of the midbrain led to lethargy.
Among the 101 children included, two died. None of the remaining children entered the stage of cardiopulmonary failure or pre-cardiopulmonary failure. Nevertheless, the frequencies of susceptibility and lethargy were 69.3% and 55.4%, respectively, suggesting that susceptibility and lethargy are common clinical manifestations of central nervous system involvement in most children with EV71 infection. In recent years, with the use of immunoglobulin, the number of cases of limb weakness has decreased compared with early studies. Limb weakness mostly occurred after the 4th day and resulted from the anterior horn of the spinal cord being invaded by the virus. The two cases of death due to cardiopulmonary failure occurred in the first 3 days of the course of the disease, mostly without skin rash. Considering that the lesions involved the dorsal nucleus of the vagus nerve and the nucleus of the solitary tract, or the inner acceleration center or vasoconstriction center of the reticular structure [26, 27], it is possible that the lesions are caused by sympathetic excitation.
MRI was performed on 32 patients in this study. The lesions involved pontine tegmentum (43.8%), medulla oblongata (34.3%), midbrain (28.1%), cerebellum and dentate nucleus (25.0%), basal ganglia (12.5%), cortex (12.5%), spinal cord (9.3%), and meninges (3.1%), consistent with that reported by Lee et al. [28]. In this study, the incidence of radiographic infection sites was consistent with the incidence of corresponding clinical manifestations in children: susceptibility (raphe nucleus), lethargy (ascending reticular activation system), ataxia (cerebellum and dental nucleus), limb weakness (anterior horn of the spinal cord), seizures (cortical) and meningeal irritation (meningeal).
Sixty-three patients underwent CSF examination within 3 days of the onset of the disease. The proportion of neutrophils was positively correlated with the white blood cell count in CSF within 3 days of the onset of disease, suggesting that with the increase of the proportion, the white blood cell count in the cerebrospinal fluid has a gradually increasing trend, which has not been reported and has certain significance for guiding the clinical cerebrospinal fluid examination of children with EV71 infection.
There was some limitations. Only one center was involved, leading to a small sample size. In addition, the numbers of patients with EV71 infection in the third and fourth stages were small. The retrospective nature of the study limited the data to those available in the charts. The mechanism of the EV71 virus invading the nervous system and the relationship between different mechanisms and the speed and severity of disease progression are not fully understood, and further research is needed.