Hepatitis E and Neuropathy

By Michael Rubin, MD

Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: In this prospective case-control study of patents with neuralgic amyotrophy, Guillain-Barré syndrome, and Bell’s palsy, an association with acute hepatitis E infection was demonstrated only with neuralgic amyotrophy.

SOURCE: Ripellino P, Lascano AM, Scheidegger O, et al. Neuropathies related to hepatitis E virus infection: A prospective, matched case-control study. Eur J Neurol 2023; Aug 7. doi: 10.1111/ene.16030. [Online ahead of print].

Hepatitis E virus (HEV), the most common yet least diagnosed cause of acute viral hepatitis, is a single-stranded ribonucleic acid (RNA) virus with global distribution, with its highest prevalence in Asia and Africa, causing 20 million new infections, more than 3 million cases of acute hepatitis, and more than 55,000 deaths annually. Transmission is through contaminated food and water, blood transfusions, and from mother to child, with an overall seroprevalence of 6.1% in the United States between 2009 and 2016, down from 21% between 1998 and 1994. Most patients with acute HEV infection are asymptomatic or mildly symptomatic, but neurologic complications, including neuropathy, have been reported. A lack of prospective case-controlled studies makes any association between HEV infection and dysimmune neuropathy unclear. This review addresses the conundrum.

Between September 2019 and October 2022, among 11 Swiss neuromuscular centers, patients with neuralgic amyotrophy (NA), Guillain-Barré syndrome (GBS), or Bell’s palsy were prospectively enrolled in an observational, case-control study, and matched with healthy controls with respect to age, gender, geographic location, and timing of blood collection. Patients were enrolled within one month of symptom onset, with follow-up at three months. Alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) testing was performed on all patients. GBS patients underwent lumbar puncture, and GBS and NA patients underwent electrodiagnostic studies (EDX). HEV was diagnosed by serum anti-HEV immunoglobulin M (IgM) and immunoglobulin G (IgG) assays and/or HEV detected by polymerase chain reaction (PCR), NA was diagnosed by standard clinical criteria confirmed by EDX, and GBS was diagnosed using National Institute of Neurological Disorders and Stroke (NINDS) criteria, confirmed by EDX. Bell’s palsy required isolated lower motor neuron facial weakness, without other cranial neuropathy. Statistical analysis comprised chi-square or Fisher’s exact test, using Cramer’s V as a measure of association, with significance placed at P < 0.05.

Among 184 eligible patients, four patients with Bell’s palsy declined to participate, leaving 51 NA patients, 59 GBS patients, and 70 Bell’s palsy patients, with controls and patients equally distributed with respect to age (50 and 51 years, respectively) and gender. Acute HEV was detected in six NA patients, but in none of the matched controls, a statistically significant association, with P = 0.027. All NA patients were treated with a two-week tapering dose of prednisone and by three months had resolution of pain and improved arm muscle strength.

Four of the six patients had bilateral brachial plexus involvement with increased ALT and GGT, indicating concomitant acute hepatitis. HEV was detected in two GBS cases (not statistically significant) and in no cases of Bell’s palsy. Of the two GBS cases, one had a diarrheal illness four weeks prior, developed subacute tetraparesis, areflexia, and glove-stocking hypesthesia, and was treated with intravenous immunoglobulin (IVIG). At three months, he continued to have gait difficulties. Miller Fisher syndrome was diagnosed in the second patient, with positive anti-GQ1b IgG antibodies. The patient experienced full recovery by one month. In this study, acute HEV infection was associated with NA but not with GBS or Bell’s palsy.

COMMENTARY

About 12.5% of the worldwide population is infected with HEV during their lifetime. Four main genotypes of HEV are identified, with genotypes 1 and 2 being common in developing countries and transmitted by contaminated water from a fecal-oral route, and with genotypes 3 and 4 common in developed countries, and resulting in occasional transmission to humans by undercooked meat.

Although most patients are asymptomatic and have spontaneous viral clearance without treatment, HEV1 and HEV3 can cause fulminant hepatitis, with HEV3 leading to chronic hepatitis and cirrhosis in the immunocompromised host. Neurologic complications may include encephalitis and myelitis, with both reported in small case series in the United States, Europe, and Asia. No specific treatment is required for acute HEV, and none is approved for chronic HEV. However, ribavarin, an antiviral agent used for hepatitis C, is recommended for chronic HEV infection, with pegylated interferon alpha offered to patients refractory to ribavirin. No Food and Drug Administration-approved vaccine is available.¹

REFERENCE

1. Songtanin B, Molehin AJ, Brittan K, et al. Hepatitis E virus infections: Epidemiology, genetic diversity, and clinical considerations. Viruses 2023;15:1389.