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A century ago when Guillain, Barré, and Strohl described the acute inflammatory polyneuropathic syndrome (GuillainBarré syndrome [GBS]) for which they are still eponymously remembered, they noted that, “The pathogenesis of this radiculoneuropathic syndrome cannot be precisely defined. Although an infection or toxic insult should be considered, we have found no supporting evidence for either.”1(p316) Many patients with GBS have signs or symptoms consistent with an antecedent infection, generally involving the respiratory and/or gastrointestinal tracts.2,3 In about 50% of cases of GBS with a suspected infectious precipitant, a specific pathogen can be identified as a potential trigger of a presumably postinfectious immune-mediated process leading to disease. The strongest associations, based on epidemiological studies, involve bacteria (Camplylobacter jejuni and Haemophilus influenzae), mycoplasma (Mycoplasma pneumoniae), and viruses (cytomegalovirus [CMV] and Epstein-Barr virus [EBV]).2,3 A far larger list of pathogens may be involved in the pathogenesis of sporadic cases or produce clusters of GBS during outbreaks or epidemics, as recently suggested for the Zika virus.4 In this issue of JAMA Neurology, Stevens and colleagues5 provide additional evidence that the hepatitis E virus (HEV) should be added to the list of viruses associated with GBS. Their study and others6,7 indicate that acute HEV infection may be associated with 5% to 11% of sporadic cases of GBS in developed countries. Hepatitis E virus belongs to the Orthohepevirus genus of the family Hepeviridae8 and is a nonenveloped, singlestrand, positive-sense, RNA virus that infects mammals, including humans. Infection is ubiquitous in feral and commercially farmed pigs, and ingestion of contaminated pig meat is likely responsible for zoonotic transmission of infection in developed countries.8 Cases of HEV infection in humans were previously included in the clinical category of enteric non-A non-B hepatitis. Serologic and nucleic acid amplification techniques now allow identification of hepatitis E as a distinct pathogenic agent.8 Molecular analysis of HEV strains allows them to be grouped into 4 major genotypes. Viruses in the developed world typically belong to genotype 3 and less commonly 4, while genotypes 1 and 2 are more prevalent in developing countries. Hepatitis E virus is the most common cause of acute viral hepatitis in many developing countries, accounting for 25% to 70% of cases in the Indian subcontinent, China, and Egypt. In these areas, infection commonly results from ingestion of drinking water contaminated with fecal matter. By contrast, symptomatic HEV infection, including hepatitis, is significantly less common in the developed world, and transmission appears to be predominantly zoonotic (owing to ingestion of contaminated pig products or infected game, including boar, deer, rabbits, or infected shellfish) or, in some cases, from blood transfusion.8 The data presented by Stevens and colleagues5 are best considered in the context of related studies from the Netherlands6 and Japan.7 Although diagnostic criteria differed among the 3 studies, in general, acute HEV infection was defined by the presence of anti-HEV IgM antibodies using enzyme-linked immunosorbent assay testing, sometimes with or without IgG antibodies, and supplemented in some patients by the associated detection of HEV RNA by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in serum or stool samples. Using these criteria, acute HEV infection was associated with approximately 5% to 8% of cases of GBS,5-7 a figure generally similar to the estimate of 11% reported from Bangladesh.9 Some antecedent infections, as exemplified by those caused by specific strains of C jejuni, may be associated with particular clinical or electrophysiological subtypes of GBS, such as acute motor axonal neuropathy or Miller-Fisher syndrome.2,3 In 3 series of cases of GBS associated with HEV from the developed world,5-7 approximately half of the patients presented clinically and electrophysiologically with acute inflammatory demyelinating polyneuropathy, with the remainder including several variants, such as acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, and the pharyngeal-cervical-brachial variant. Almost all the reported cases have an albuminocytological dissociation, as exemplified by the 6 patients described by Stevens et al,5 who had cerebrospinal fluid protein levels between 296 and 1028 mg/L, with 5 of the 6 patients also having 6 cells per microliter or less. No significant features in terms of patient age, sex, severity or duration of illness, electrophysiological findings, or response to therapy (typically intravenous immunoglobulin) seem to distinguish HEV-associated cases of GBS from those that are not associated with GBS.5-7 One possible indicator of the presence of HEV infection may be elevated liver enzymes, including alanine or aspartate aminotransferase, which occurred in approximately 75% of patients in the combined series.5-7 These abnormalities are not, however, likely to be either sensitive or specific for HEV infection, as they occur among patients with GBS associated with CMV and GBS associated with EBV. The mechanism by which most antecedent infections trigger GBS remains speculative. In C jejuni infection, lipooligosaccharides present in the bacterial cell wall resemble GM1, GD1a, and/or GQ1b gangliosides present on peripheral nerves (known as molecular mimicry), and the host response against Related article Opinion