Hepatitis viruses: neurologic complications

Christopher Hill (Mr. Hill of Indiana University School of Medicine has no relevant financial relationships to disclose.)
Karen L Roos MD FAAN (Dr. Roos of Indiana University School of Medicine has no relevant financial relationships to disclose.)
Originally released February 8, 2015; last updated August 28, 2018; expires August 28, 2021

Historical note and terminology

In the first descriptions of viral hepatitis in the third millennium B.C., the etiological agent was thought to be a devil named Ahhazu who attacked the liver (Payen 2002; Payen and Rongieres 2002). Hippocrates later described the first clinical features of epidemic jaundice, and reports have since occurred throughout history (Oon 2012). In 1947, MacCallum classified viral hepatitis into 2 types: hepatitis A and B (MacCallum 1947). In 1965, Blumberg discovered the Australia antigen (later named the hepatitis B surface antigen, or HBsAg) in aborigines (Blumberg et al 1967). In 1968, Prince and Okochi isolated the Australia antigen in hepatitis B patients, and, using this information along with the discovery of the Dane particle in 1970, the first vaccine for hepatitis B was produced in 1981 and licensed as "Heptavax" (Okochi and Murakami 1968; Prince 1968).

In 1974, it was noted that most cases of post-transfusion hepatitis were HBs negative and were, therefore, neither hepatitis A virus (HAV) nor hepatitis B virus (HBV) infections, initially called non-A non-B hepatitis (Prince et al 1974; Feinstone et al 1975). It was not until 1989 that the hepatitis C virus (HCV) was isolated, and in 1992, a blood test was marketed that allowed screening for HCV in blood donations. Prior to the screening of the blood supply for hepatitis C, approximately 300,000 Americans contracted hepatitis C through blood transfusions or blood products.

In 1977, while studying immunohistological patterns of Italian patients infected with HBV, Rizetto identified a new nuclear antigen distinct from the hepatitis B core (HBc) antigen, known as the delta antigen (Rizzetto et al 1977). Although it was always restricted to HBV carriers, this marker was associated with specific clinical forms of the disease and was later found to be caused by a different hepatitis virus, hepatitis D virus (HDV) (Purcell 1993).

Studies of large epidemics in India and China suggested the existence of a waterborne hepatitis with a short incubation period that was not HAV, HBV, or HCV. One of the clinical hallmarks of this form of hepatitis was the high mortality, particularly in pregnant women. In 1955, the Russian virologist Mikhail Balayan performed a self-inoculation test after an outbreak. After ingesting stool extracts, Balayan developed acute hepatitis and used his own feces to look for the virus by immune electron microscopy. He observed 27 to 32 virus-like particles (Balayan et al 1983). Later, using the same technique used for identifying HCV, the Centers for Disease Control and Prevention identified the hepatitis E virus (HEV) (Krawczynski and Bradley 1989).

Neurologic manifestations of hepatitis were first described during World War I when Hurst reported the first case of acute polyneuropathy complicating hepatitis (Hurst 1943). Although cases of myelopathy following liver disease had been reported earlier, it wasn't until the identification of the Australia antigen in 1965 that the association of neurologic symptoms with hepatitis was confirmed (Leigh and Card 1949; Pant et al 1963). Meningoencephalitis in patients infected with HAV was first described by Bromberg in 1982, and the first case of sensory neuronopathy associated with autoimmune chronic active hepatitis was reported in 1993 (Bromberg et al 1982; Merchut et al 1993).

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