Introduction
Most cases of Hepatitis E virus (HEV) infection in humans are asymptomatic, whereas some lead to acute hepatitis and only a minority to extrahepatic manifestations. Interestingly, the most common extrahepatic features of HEV infection are neurologic diseases, mostly involving the peripheral nervous system (i.e. amyotrophic neuralgia, Guillain Barrè syndrome, meningo-encephalitis and cranial nerves neuropathies). Facial nerve palsy is the most common cranial nerve disorder. The etiology is frequently unknown, although associations with viral or bacterial infection and autoimmune diseases has been demonstrated in a subset of patients.
Objectives
The aim of this prospective, pilot study is to investigate the occurrence of HEV infection in idiopathic facial nerve palsy, whose etiology and pathopsysiology is still debated. We would also like to study its clinical, serological, epidemiologic, neurophysiologic and radiologic features.
Study design
Patient clinically diagnosed of peripheral facial nerve palsy with will be enrolled in the study. All patient will undergo a complete neurological examination, a serum screening and a brain TC scan. The grading of facial palsy will be assessed by the House-Brackmann facial nerve grading system (HBS) at baseline visit, after one and 6 months from the clinical onset. At the same timepoints, we will collect serum for testing viral RNA and for anti-HEV IgM and IgG assessment, as weel as a specimen of saliva, that will be analyzed for HEV RNA too. Neurophysiological study will be performed to assess the facial nerve prognosis. We would also like to study all patients with a functional magnetic resonance imaging (fMRI) by examining functional connectivity (FC) at rest, and through the analysis of both the amplitude and the fractional amplitude of low-frequency fluctuation (ALFF, fALFF). Finally, we will investigate habits and lifestyle factors associated with HEV infection through specific questionnaires.
Studies reporting the extra-hepatic manifestations of HEV infection, both acute and chronic, explain a link mainly due to the temporal association between the infection and other symptoms onset, after excluding the other possible etiologies that may cause the manifestations (2).
In vitro studies have demonstrated a direct neurotropism of HEV, with the ability to infect neurologic tissues (7,20). This is supported by the fact that HEV RNA had been isolated from the cerebrospinal fluid (CSF) of affected patients, and it was found to be different from the ones seen in the serum at the same time point, suggesting the presence of certain neurotropic variants (21). A second hypothesis could be the ability of the virus to acquire host RNA sequences, thereby the property to infect multiple cell types including neurons (7). However, Guillain-Barrè syndrome and neuralgic amyotrophy, whose association with HEV has been proved, are thought to be dysimmune entities, even when associated to other known infectious agent. Some strains of HEV seem to have the property to produce certain antigens which in turn leads to autoimmune inflammatory polyneuropathy via molecular mimicry (21,22).
On the other hand, facial nerve palsy is frequently idiopathic, and when symptomatic may be caused by latent herpes viruses (herpes simplex, herpes zoster) reactivated from cranial nerve ganglia, or associated with bacterial infection (Borrelia Brurgdorferi), or with autoimmune diseases with a supposed cell-mediated autoimmune mechanism against myelin basic protein.
Both mechanism could be the basis of the association of HEV infection and facial nerve palsy.
Understanding pathophysiology underling the disease could be important for many aspects: the variability of the disease, association with particular environmental factors, possible predisposition features, prognosis and recovery. Moreover, the viral hypothesis concerning the etiology of idiopathic peripheral facial nerve palsy, implies that combined treatment with a glucocorticoid drug and a virostatic drug might be beneficial.
References
20. Kamar N., Abravanel F., Lhomme S., Rostaing L., Izopet J. Hepatitis E virus: Chronic infection, extra-hepatic manifestations, and treatment. Clin. Res. Hepatol Gastroenterol. 2014;39:1-8.
21. Kamar N., Izopet J., Cintas P., Garrouste C., Uro-Coste E., Cointault O., Rostaing L. Hepatitis e virus-induced neurological symptoms in a kidney-transplant patient with chronic hepatitis: Case report. Am. J. Transpl. 2010;10:1321-1324
22. McLean B.N., Gulliver J., Dalton H.R. Hepatitis E virus and neurological disorders. Pr. Neurol. 2017;17:282-288.