Infectious Disorders

Updated 11.06.2023
Released 02.08.2015
Expires For CME 11.06.2026

Hepatitis viruses: neurologic complications

Authors: Sergio Monteiro de Almeida MD PhD, Maria Lucia Alves Pedroso MD PhD

Editor: Christina M Marra MD

Introduction

Overview

Viral hepatitis has emerged as a major public health problem worldwide, affecting several hundreds of millions of people. It is a cause of considerable morbidity and mortality in the human population, both from acute infection and chronic sequelae. Hepatitis viruses encompass a range of diverse and unrelated groups of viruses from different families, with the common characteristics of hepatotropism, hepatovirulence, and hepatotoxicity. The hepatitis viruses of neurologic interest primarily comprise RNA viruses, hepatitis A, C, and E viruses (HAV, HCV, and HEV, respectively), and a DNA virus, hepatitis B virus (HBV). This article provides a broad overview of the neurologic manifestations and complications of acute and chronic viral hepatitis.

Key points

	• The most common hepatitis viruses with nervous system involvement are hepatitis C virus and hepatitis B virus.
	• Hepatitis viruses can affect the entire nervous system, including the brain, spinal cord, motor neurons, peripheral nerves, and muscles.
	• The most common neurologic manifestation of hepatitis C virus and hepatitis B virus is peripheral neuropathy.
	• A significant proportion of patients with chronic hepatitis C virus experience cognitive impairment in the absence of advanced liver disease.
	• Neurologists should be aware of the specific neurologic complications of hepatitis viruses.

Historical note and terminology

There were several key milestones in the history of hepatitis viruses during the 20th century. From 1942 to 1950, a series of independent experiments in Europe and the United States confirmed the transmissibility of viral hepatitis A and B and defined their clinical-epidemiological characteristics. However, the individualization of hepatitis viruses only emerged after World War II. In 1947, MacCallum classified viral hepatitis into two types, hepatitis A and B. In 1965, Baruch Blumberg identified the hepatitis B surface antigen (HBsAg). Blumberg was awarded the Nobel Prize in Medicine in 1976 for both the description of hepatitis B virus and the notion of the revolutionary first-generation hepatitis B virus vaccine. In 1973, Stephen Mark Feinstone identified the hepatitis A virus using immune-electron microscopy. In 1974, Prince and Feinstone independently described several cases of posttransfusion hepatitis, HBsAg negative, named non-A non-B hepatitis. However, it was only in 1989 that hepatitis C virus, responsible for 80% to 90% of posttransfusion hepatitis, was identified. The Nobel Prize in Medicine in 2020 was awarded to Harvey J. Alter, Michael Houghton, and Charles M. Rice for the discovery of hepatitis C virus, which started a new era as it was the first virus identified using a direct molecular approach (76). Hepatitis E virus was identified in 1990 by Reyes (138). The neurologic history of hepatitis viruses started in 1943, when Arthur Hurst reported the first case of acute polyneuropathy secondary to hepatitis. Hepatitis C virus sequences in the brain were first reported in 1996 by Bolay and associates (02). In the beginning of the 21st century, evidence of a brain effect of hepatitis C virus was shown for the first time (36; 37).

Clinical manifestations

Presentation and course

	• Viral hepatitis can be accompanied by various extrahepatic manifestations in both acute and chronic infections.
	• Hepatitis viruses can affect the central nervous system (CNS) and peripheral nervous system.
	• Hepatitis C virus and hepatitis B virus are the most frequent hepatitis viruses with nervous system involvement.
	• Nervous system involvement has also been described with hepatitis A and E viruses, with lesser frequency.

Table 1. Neurologic Complications of Hepatitis Viruses

Hepatitis virus	A	B	C	E
Central nervous system
Meningitis	+
Encephalitis	+		+	+
Cognitive impairment		?	+
Acute disseminated encephalomyelitis	+	+	+
Optic neuritis	+		+
Myelitis	+	+	+	+
Recurrent myelitis		+	+
Pseudotumor	+			+
Ataxia				+
Vasculitis		+	+
Major depression			+
Parkinson disease		+	+
Restless legs syndrome			+
Fatigue			+
Risk of stroke increased			+	+
Leukoencephalopathy			+

Peripheral nervous system
Guillain-Barre syndrome	+	+	+	+
Chronic inflammatory demyelinating polyneuropathy			+
Polyneuropathy	+	+	+	+
Mononeuropathy	+	+	+	+
Myositis		+	+	+
Polymyositis/dermatomyositis		+	+

Hepatitis C virus. The extrahepatic manifestations of hepatitis C virus are independent of the severity of the underlying chronic liver disease and hepatic encephalopathy. Neurologic complications of hepatitis C virus occur mainly in chronic infections but can also occur in acute cases. Nervous system impairment occurs in more than 50% of chronically infected hepatitis C virus individuals (51; 87). Hepatitis C virus affects mainly neurons responsible for motor function, memory, and concentration (84). Although the incidence of hepatitis C virus infection is lower than that of hepatitis B virus, chronicity occurs in up to 85% of cases (123); this could explain the high frequency of neurologic complications.

Peripheral nervous system. Peripheral nervous system complications in patients with hepatitis C virus include peripheral neuropathy, which is the most common neurologic complication among individuals with chronic hepatitis C virus infection (03). Hepatitis C virus infection is known to cause motor, sensory, and sensorimotor mononeuropathy, mononeuropathy multiplex, or polyneuropathy (03). Symptomatic peripheral neuropathy was observed in 9% of cases (11). In contrast to the brain, there is currently no evidence of hepatitis C virus replication in peripheral nerves (03). Peripheral neuropathy associated with hepatitis C virus is usually associated with cryoglobulinemia and is mainly characterized by axonal damage. It was postulated that nerve damage is secondary to epineural vessel changes caused by occlusion or vasculitis induced by longstanding cryoglobulin precipitation with complement fixation and rheumatoid factor deposition. The vasculitis or vascular occlusion causes fascicular ischemia, leading to axonal degeneration (93).

Guillain-Barre syndrome associated with hepatitis C virus infection is rare (20). The mechanism of Guillain-Barre syndrome is based on autoimmune-induced demyelination of peripheral nerves that often occurs after an infectious episode (144). Chronic inflammatory demyelinating polyneuropathy associated with hepatitis C virus has also been described (33).

Cognitive impairment. A significant proportion of patients with chronic hepatitis C virus experience cognitive impairment, hepatitis C virus neurocognitive disorder, in the absence of advanced liver disease, which may interfere with activities of daily living and quality of life (26). The rates of cognitive impairment vary widely across studies (0% to 82%), reflecting differences in comorbidities and ascertainment methods (47). Several studies have investigated domain-specific cognitive impairments in patients infected with hepatitis C virus and found deficits in attention, concentration, working memory, executive function, and psychomotor speed (26). Cognitive impairment was not correlated with detection of hepatitis C virus RNA in the peripheral blood or cerebrospinal fluid, or the presence of cirrhosis (22; 26), and was not dependent on the hepatitis C virus subtype (84; 26).

Myelitis during hepatitis C virus infection is rare and is anecdotally reported (05). Sensory ataxia in myelopathy with chronic hepatitis C virus infection has also been described (96).

Other neurologic complications. Other neurologic complications in patients with hepatitis C virus infection include restless legs syndrome, optic neuritis, cerebral ischemia, leukoencephalopathy, acute disseminated encephalomyelitis (ADEM), and progressive encephalomyelitis (11). The association of Parkinson disease with hepatitis C virus infection is still controversial (01; 102; 41). A study showed the rates of Parkinson disease were increased following hepatitis C virus infection (standardized rate ratio [RR] 1.51; 95% confidence interval [CI] 1.18–1.9; P < 0.001) (102).

Hepatitis C virus is recognized as an independent risk factor for stroke; the hazard ratio (HR) for newly detected stroke was 1.23 (95% CI: 1.06–1.42; P = 0.008) for subjects with hepatitis C virus compared to the age- and sex-matched subjects without hepatitis C virus (46). Chronic hepatitis C virus infection increases the risk of ischemic stroke through several mechanisms. It accelerates atherosclerosis through a number of mechanisms including colonization and replication within arterial walls, chronic inflammation, oxidative stress, endotoxemia, hyperhomocysteinemia, hypoadiponectinemia, insulin resistance, and diabetes (04). Other factors that predispose patients to stroke in the setting of hepatitis C virus infection are the presence of mixed cryoglobulinemia, antiphospholipid, and antineutrophil cytoplasmic antibodies (46; 33).

Hepatitis B virus. Approximately 20% of patients with hepatitis B virus develop extrahepatic disease manifestations, including nervous system involvement. The most common are sensorimotor neuropathies (5%), myalgia (3%), arthralgia (3%), Sjögren syndrome (3%), glomerulonephritis (3%), uveitis (2%), Raynaud syndrome (2%), psoriasis (1%), and pruritus (1%). The most severe are the polyarteritis nodosa form of vasculitis and glomerulonephritis (12).

Peripheral nervous system. Peripheral nervous system complications usually develop in patients with chronic hepatitis B virus infection and rarely during acute infection (92). They include peripheral neuropathies, mononeuropathies, and Guillain-Barre syndrome (92). The pathogenesis of various hepatitis B virus-associated neuropathy syndromes possibly involves the deposition of immune complexes in the nerves or blood vessel walls. Direct viral infection of the nerves has not been demonstrated (129). There are several reports of Guillain-Barre syndrome following vaccination with hepatitis B virus vaccine preparations (114).

Cognitive impairment. Cognitive impairment in patients infected with hepatitis B virus has been described (112), although there are few such studies. The neurocognitive profiles of hepatitis B virus differ from those of hepatitis C virus. The cognitive domains affected in hepatitis B virus are the same as in hepatitis C virus; however, patients infected with hepatitis B virus performed significantly better than those with hepatitis C virus on visuospatial memory, alertness, and working memory (112; 28).

Other neurologic complications. Rare cases of muscle disease, mostly subacute inflammatory myopathy, have been associated with hepatitis B virus infection. Presumably, hepatitis B virus-associated antigens trigger immune mechanisms directed against muscle tissue components. Thus, muscle biopsy frequently reveals an immune complex-mediated pathology (15), although no evidence of a replicative virus infecting the muscle fibers exists. Management of hepatitis B virus-associated muscle disease entails immunomodulatory treatment, occasionally with anti-hepatitis B virus therapy (130).

In the same study that investigated rates of Parkinson disease after hepatitis C virus infection, the rates were also increased following hepatitis B virus infection (RR: 1.76; 95% CI: 1.28–2.37; P < 0.001), with higher rates than after hepatitis C virus infection (102).

Acute disseminated encephalomyelitis cases following acute hepatitis B, as well as vaccination, have been reported (48). Acute and relapsing demyelinating transverse myelitis has been described in association with acute hepatitis B virus infection (50). However, the evidence is currently inadequate to establish a causal relationship between hepatitis B virus vaccine and these neurologic syndromes (128).

Hepatitis A, E, and D virus. Hepatitis A virus and hepatitis E virus are associated with neurologic diseases; their pathophysiology is unknown (108; 82). There is evidence of neurologic disease in 5.5% to 30% of patients with acute or chronic hepatitis E virus infection (57; 104; 115; 53). Dual infection with hepatitis A and E virus presenting with aseptic meningitis has been described (90). The neurologic complications of hepatitis A virus and hepatitis E virus infection are listed in Table 1.

Hepatitis D virus is an incomplete RNA virus that requires the hepatitis B virus envelope for transmission and, therefore, infects only hepatitis B virus surface antigen (HBsAg)-positive patients or simultaneously infects with hepatitis B virus. No extrahepatic manifestations, including in the nervous system, have been reported for the dual infection of hepatitis B virus and hepatitis D virus (80).

Clinical vignette

A 60-year-old, Caucasian man infected with hepatitis C subtype 1a diagnosed 90 months before presented with shock-like pain episodes followed by continuous paresthesias in stocking-glove distribution in hands and feet. He also experienced limb petechiae, rash, bruising, joint pain, and Raynaud phenomenon. He developed right fibular nerve distribution weakness with footdrop and continuous, severe, symmetric pain in the distal third. Concomitantly, the patient complained of fatigue, lassitude, and impaired concentration and memory, which interfered with his ability to perform daily life activities.

On neurologic examination, muscle strength was 2/5 in right foot extension and flexion, 3/5 on right knee extension with abolished Achilles and patella reflexes in this same limb. Muscle strength was 3/5 on left foot extension and flexion and left knee flexion and extension. Left lower extremity reflexes were globally diminished (1+/2+). He had hypoesthesia over the distal one-third lateral and medial surface of the right lower limb and medial surface of left lower limb, anesthesia on lateral surface of right lower limb, and preserved deep sensitivity.

Laboratory profile. Aspartate aminotransferase to platelet ratio index (APRI): 0.37 (normal); fibrosis 4 score (FIB-4): 1.13 (normal), both showing no hepatic fibrosis.

Log plasma and CSF hepatitis C virus RNA (quantified by RealTime HCV) were 5.9 and 1.1, respectively. The patient was not coinfected with hepatitis A virus, hepatitis B virus, hepatitis D virus, hepatitis E virus, HIV, or syphilis.

Investigation of peripheral neuropathy. Screening for cryoglobulinemia was positive followed with protein electrophoresis and immunofixation testing that showed type 2 mixed cryoglobulinemia (which consists of a mixture of monoclonal and polyclonal immunoglobulins; this type is often seen in hepatitis C virus or other viral infections).

Electromyography showed an axonal sensory-motor polyneuropathy; no electrophysiological signs of demyelination or cranial nerve involvement were found.

Biopsy of sural nerve showed perivascular inflammatory infiltrates, occluded arteries and neoformation of epineural arterioles, loss of large and small myelinated fibers within fascicles, little axonal degeneration or regeneration, confirming the diagnosis of peripheral nervous system vasculitis.

Investigation of cognitive impairment. Conventional brain magnetic resonance imaging was normal for age. CSF cytology and biochemistry were normal. Neuropsychologic evaluation (Table 2) showed significant deficits in executive function, attention, speed of information processing, and visuospatial memory.

Table 2. Suggested Neuropsychological Test Battery to Investigate Hepatitis Viruses Associated with Neurocognitive Disorder

Ability domains	Neuropsychological test
Executive function	Color Trails Test 2, Wisconsin Card Sorting Test-64 perseverative errors, Stroop Color word
Motor performance	Grooved pegboard test-dominant hand and non-dominant hand
Verbal fluency	Phonemic: controlled oral word association test (COWAT), category: animals and actions
Attention/working memory	Wechsler Memory Scale (WMS)-III spatial span
Learning and memory	Brief visuospatial memory test-revised (BVMT-R) learning and delayed recall, Hopkins Verbal Learning Test-Revised (HVLT-R) learning and delayed recall
Speed of information processing	Wechsler Adult Intelligence Scale (WAIS)-III digit symbol and symbol search, Trail Making Test A, Color Trails Test 1, Stroop Color Naming
Adapted from: (59; 26)

The patient’s neurologic diagnosis was neuropathic pain secondary to peripheral nervous system vasculitis induced by cryoglobulinemia and hepatitis C virus-associated neurocognitive disorder.

The peripheral neuropathy was treated with opioid analgesics, pulse steroid therapy, gabapentin (900 mg/day), and daily rehabilitation with total resolution of pain. Treatment of hepatitis C virus with sofosbuvir + daclatasvir led to sustained virological response at 12 weeks after the end of treatment, which could be responsible for the resolution of neuropathic pain. There was partial improvement in cognitive impairment.

Biological basis

Etiology and pathogenesis

Hepatitis C virus. Hepatitis C virus is an enveloped single-stranded RNA virus that belongs to the Flaviviridae family and Hepacivirus genus. The Flaviviridae family encompasses several viruses with a worldwide distribution and well-described neurotropism. Some members of this family include the Zika virus (143), Dengue virus, West Nile virus, Saint Louis encephalitis virus, Murray Valley virus, tick-borne encephalitis virus, and the Japanese encephalitis virus (127). All of these are arboviruses except for hepatitis C virus. There are seven hepatitis C virus genotypes and 67 subtypes.

The receptors for hepatitis C virus expressed in CNS cells are scavenger receptor class B member 1 (SR-B1), low-density lipoprotein receptor (LDL-R), tetraspanin CD81, claudin-1, and occludin (34; 72). The CNS cells potentially infected by hepatitis C virus are microglia, astrocytes (nonproductive infection), and the endothelial cells of the microvasculature. It is unknown if neurons are directly infected by hepatitis C virus (34; 72).

Table 3. Central Nervous System Cells Potentially Infected by Hepatitis Viruses

SNC cells	HCV					HBV/HDV?		HAV	HEV
	SR B1	CD 81	CLDN-1	OCC	LDL-R	NTCP	EGFR	HAVCR-1	INTG- α3
Microglia	+	+	?	?	-	-	-	-	-
Astrocyte	+	+	+	+	-	-	+	-	-
Oligodendrocytes	-	-	-	-	-	-	-	-	-
Neurons	-	-	-	-	-	-	+	+	+
Endothelial cells	+	+	+	+	+	-	-	-	-
Ependymal	-	-	-	-	-	-	+	-	-
Choroid plexus	-	-	-	-	-	+	-	-	-
The second row of the table refers to the cellular receptors: SR B1, scavenger receptor class B member 1; CD 81, tetraspanin; CLDN-1, claudin-1; OCC, occludin; LDL-R, low-density lipoprotein receptor; NTCP, sodium taurocholate cotransporting polypeptide; EGFR, epidermal growth factor receptor; HAVCR-1, Hepatitis A virus cellular receptor 1; INTG, integrin (137; 34; 73; 119; 72; 49; 141; 71; 52; 124)

Hepatitis C virus is a noncytopathic virus; much of its pathogenesis is due to the activation of the immune response (64). Hepatitis C virus RNA has been detected in the CSF and brain tissue in a few cases (122), although neuronal infection by hepatitis C virus is less probable because of the lack of specific cell receptors for this virus. The pathogenic mechanisms more probable to explain neurologic disorders in chronic hepatitis C virus infection include: (1) the derangement of metabolic pathways in infected cells; (2) impairment in neurotransmitter circuits; (3) immune-mediated impairment by cryoglobulins and autoimmunity induced by hepatitis C virus; and (4) cerebral or systemic inflammation (10; 129; 03). Additionally, exposure of neurons to hepatitis C virus core protein causes neuronal injury through suppression of neuronal autophagy in addition to neuroimmune activation (145). Neuronal autophagy is a natural process in brain cells employed for eliminating toxic proteins, and suppression of autophagy can result in the accumulation of these proteins (145).

Several hypotheses have been proposed to explain the occurrence of cognitive impairment in hepatitis C virus infections. Microglia and astrocytes in the CNS express receptors associated with hepatitis C virus cell entry (Table 3) and may be particularly vulnerable to infection. Hepatitis C virus has been detected in human brain tissues indicating that blood-derived hepatitis C virus-infected cells or free virus can migrate to the brain to incite CNS dysfunction (88). Another potential contributor to cognitive impairment in chronic hepatitis C virus is the indirect perpetuation of neurotoxic inflammatory pathways caused by hepatitis C virus activation of cytokines (23; 113), which is also likely mediated by hepatitis C virus viral load (132). Additionally, there is speculation that brain injury in neurologic and psychiatric disorders might result from interactions between recreational drug use and hepatitis at multiple levels (03).

Hepatitis B virus. Hepatitis B virus is a partially double-stranded DNA virus and a member of the Hepadnaviridae family and Orthohepadnavirus genus. There are 10 hepatitis B virus genotypes, identified as A to J. Each genotype is associated with distinct geographic distributions, transmission modes, rates of disease progression, and response to therapy with pegylated interferon-alfa (97).

Hepatitis B virus is a noncytopathic virus, causing little or no damage to the host cell. Much of its pathogenesis appears to be related to the host immune responses. Various lines of evidence indicate that hepatitis B virus infection also imposes metabolic-related physiological stress (71).

The cellular receptor for hepatitis B virus and its satellite, hepatitis D virus, is a liver-specific bile acid transporter named the sodium taurocholate cotransporting polypeptide (NTCP) (71) (Table 3). NTCP is present on the apical side of the choroid plexus cells in the brain; however, it is not expressed in neuronal cells, endothelial cells, glial cells, or neuropils (141). The expression of NTCP alone is not sufficient for efficient hepatitis B virus internalization into hepatocytes; the epidermal growth factor receptor (Table 3) acts as a host factor that interacts with NTCP and mediates hepatitis B virus internalization (52). In the brain, reactive astrocytes, ependymal cells, and many types of nerve cells (cerebral cortical pyramidal cells, pyramidal and granular hippocampal cells, Purkinje cells, cerebellar granular cells, and neurons in the molecular layer of the cerebellum) express epidermal growth factor receptor, whereas small neurons and normal glial cells do not express epidermal growth factor receptor (137).

Hepatitis B virus proteins and nucleic acids are identified in non-hepatic tissues including the brain. Although there is only limited evidence for direct hepatitis B virus infection of the CNS, most of these data suggest an immune-mediated pathogenesis. Several mechanisms have been proposed: (1) the deposition of hepatitis B virus surface antigen (HBsAg), containing circulating immune complexes, followed by the activation of the complement cascade (12); (2) local antibody interaction with viral antigens trapped within tissues (42); (3) the reaction of hepatitis B virus-induced autoantibodies with tissue antigens (60); (4) and formation and deposition of cryoprecipitate (70). Hepatitis B virus DNA can be found only rarely in CSF. Occasionally, intrathecal HBsAg can be detected in hepatitis B virus-associated Guillain-Barre syndrome (148).

Hepatitis A virus. Hepatitis A virus is a small, unenveloped RNA virus, classified as a hepatovirus, sharing many characteristics with members of the Picornaviridae family. This family is the same as that of the polioviruses and other enteroviruses, which are important etiological agents of neurologic diseases (123). There are seven hepatitis A virus genotypes, which vary according to the geographic region (110; 111).

To enter the cell, hepatitis A virus interacts with the hepatitis A virus cellular receptor 1 (HAVCR-1) (73), a significant allergy and autoimmunity determinant in humans (39) (Table 3). In the brain, hepatitis A virus cellular receptor 1 is expressed in low concentrations on neuronal cells in the cortex and hippocampus and it is not detected in glial, endothelial cells, and neuropil (Table 3) (141). Hepatitis A virus does not result in chronic infection and rarely causes fulminant hepatitis, although it may induce a temporary shut-off of CD4+ regulatory T-cells (Treg) function (105) and induce autoantibodies synthesis (85). The virtual absence of a chronic hepatitis A virus-infected state likely explains the rare occurrence of extrahepatic immune-mediated diseases (131).

The replication of hepatitis A virus occurs chiefly within the cytoplasm of the hepatocyte, where the virus causes a noncytopathic infection. The pathogenetic link between hepatitis A virus and neurologic disease is a matter of debate; the proposed potential mechanisms of neuroaxonal injury by hepatitis A virus are through: (1) cell-mediated immunity, (2) neurotropism, and (3) circulating immune complex deposition (129). The presence of oligoclonal expanded T-cells and elevated myelin basic protein levels in CSF in a patient with relapsing acute disseminated encephalomyelitis following hepatitis A virus infection indicates that molecular mimicry-triggered demyelination may also be involved (99). A structural protein of hepatitis A virus (VP3) shares seven common tripeptides with myelin basic protein, so hepatitis A virus could trigger a demyelinating disease on the basis of molecular mimicry between viral antigens and host proteins (142). Other associated pathogenic mechanisms involve excessive systemic host responses to severe hepatitis in which the immune reaction against hepatitis A virus may damage the CNS (129).

Hepatitis E virus. Hepatitis E virus is a member of the Hepeviridae family and is classified under the genus Orthohepevirus. Hepatitis E virus is a single-stranded RNA virus with an enveloped (env) and a nonenveloped (nenv) form. It shares many biophysical and biochemical features with Caliciviruses (89). There are eight genotypes of hepatitis E virus; genotypes 1 and 2 are found only in humans whereas genotypes 3 and 4 are found in humans and other species and can be transmitted to humans through the consumption of undercooked meats. Hepatitis E virus is the only hepatitis virus with animal reservoirs, primarily pigs (94; 14). The pathogenesis of hepatitis E virus is not well understood. Most of the reported cases with extrahepatic manifestations are based on detection of either antibodies or virus in sera. However, there are also sporadic cases where hepatitis E virus RNA is detected in the CSF and neurologic signs and symptoms resolve with the clearance of hepatitis E viremia (57). The host factors involved in infection, including receptors (see Table 3), remain to be elucidated.

The pathophysiological mechanisms by which hepatitis E virus can induce extrahepatic manifestations, including neurologic injury, are largely unknown but may be caused either by: (1) direct viral effects due to hepatitis E virus replication in affected tissues; (2) indirectly by various immune-mediated mechanisms; or (3) the deposition of hepatitis E virus-antigens/antibody-immune-complexes (108). Cross-reactivity between viral epitopes and self-antigens (molecular mimicry) might induce autoimmunity, as has been shown for many other viruses. However, molecular mimicry for hepatitis E virus has not been demonstrated. Neurotropic hepatitis E virus quasispecies have been described (56). In cases with hepatitis E virus meningitis, hepatitis E virus in the CSF (24; 25) and hepatitis E virus replication in neuronal cells have been detected (31). Hepatitis E virus replication has been demonstrated in the brain and CSF of experimentally infected gerbils (125; 108). Hepatitis E virus infects brain microvascular endothelial cells, crosses the blood–brain barrier, and invades the CNS (136).

Epidemiology

• Hepatitis B virus and hepatitis C virus infection are the two most common chronic viral infections in the world.

Hepatitis B virus and hepatitis C virus infection are the two most common chronic viral infections in the world (66). The epidemiologic, clinical, and viral characteristics of the four hepatitis viruses of neurologic interest are shown in Table 4.

Table 4. Epidemiologic, Clinical, and Viral Characteristics of the Hepatitis Viruses with Neurologic Importance

Virus	Genome	Virus family	Envelope	Transmission	Chronic carriers	Incubation period (days)	Onset	Illness	Age	Neurologic manifestations	Laboratory test usually used for diagnosis
HAV	ssRNA	Picornavirus	No	fecal-oral, person to person	No	10-50	Abrupt	Mild, low mortality	Children	+	IgM HAV
HBV	Partially dsDNA	Hepadnavirus	Yes	BBF, sexual, vertical	Yes	30-180	Insidious	Risk of chronic hepatitis and cirrhosis³	Any age	+++	HBsAg, IgM HBcAb, total HBcAb, HBV DNA
HCV	ssRNA	Flavivirus	Yes	BBF, sexual¹, vertical²	Yes	15-160	Insidious	Fluctuating, significant risk of chronic hepatitis and cirrhosis	Any age	++++	HCV Ab, HCV RNA
HEV	ssRNA	Calicivirus	enveloped and non-enveloped forms	fecal-oral, vertical, BBF, food, animal	Unlikely	10-60	Abrupt	High mortality in pregnancy, risk of chronic hepatitis and cirrhosis⁴	Any age	++	HEV Ab HEV RNA
Notes: ss-single stranded; ds-double stranded; BBF-blood and body fluid; [1] sexual transmission likely but poorly documented; [2] if HIV coinfection; [3] significant risk among those who acquire HBV infection during childhood; [4] In immunocompromised individuals; [5] raw or undercooked meat

Hepatitis C virus. The typical transmission route of hepatitis C virus is via percutaneous exposure to infected blood, for example, following unsafe injections. Sexual and vertical transmission are less frequent for hepatitis C virus (135). Hepatitis C virus genotype distribution varies by geographic location; genotype 1 is globally predominant, followed by genotypes 3 and 4 (67). Regarding different hepatitis C virus genotypes, 1b and 2a are more often associated with cryoglobulinemia; however, patients with genotypes 1b and 3 have more peripheral nervous system involvement than those with genotypes 2a and the mixed genotype 2a/c (100). Hepatitis C virus-associated neurocognitive disorder occurs independent of hepatitis C virus genotype (84; 26).

Hepatitis B virus. Hepatitis B virus is an important worldwide cause of acute and chronic liver disease. It is endemic in the human population and hyperendemic in countries in which it was not possible to implement hepatitis B virus vaccination programs, particularly in the rural areas. Hepatitis B virus infection is hyperendemic [> 8% of hepatitis B surface antigen (HBsAg) chronic carriers in the general population] in some sub-Saharan countries, such as Nigeria, Namibia, Gabon, Cameroon, and Burkina Faso. Other countries like Kenya, Zambia, The Ivory Coast, Liberia, Sierra Leone, and Senegal are considered areas of intermediate endemicity (2% to 8%) (150). It is transmitted via percutaneous or permucosal exposure to infected fluids, mostly blood, semen, or saliva. The risk of chronicity is high among those who acquire the infection during childhood and is low among adults (138). Current or past hepatitis B virus exposure is seen in up to 30% of persons living with HIV (65).

High-risk groups for hepatitis B virus infection are health care providers and emergency responders; sexually active individuals (more than one partner in the past 6 months); men who have sex with men (MSM); individuals diagnosed with a sexually transmitted disease; Illicit drug users (injecting, inhaling, snorting, pill popping); sexual partners or those living in close household contact with an infected person; individuals born in countries where hepatitis B virus is common (Asia, Africa, South America, Pacific Islands, Eastern Europe, and the Middle East); individuals born to parents who have emigrated from countries where hepatitis B virus is common; children adopted from countries where hepatitis B is common; adoptive families of children from countries where hepatitis B virus is common; anyone diagnosed with cancer prior to initiation of anticancer treatment, kidney dialysis patients, and those in early kidney (renal) failure; inmates and staff of a correctional facility; residents and staff of facilities for developmentally disabled persons; all pregnant women (17).

Hepatitis A virus. Hepatitis A virus transmission occurs through the fecal-oral route, person-to-person contact, and ingestion of contaminated food or water. Hepatitis A virus infection is usually short-lasting, and rarely fatal. Humans are the only hepatitis A virus reservoir. Poor sanitation measures have made the disease more prevalent in developing regions and in susceptible adult populations (69). High endemic areas for hepatitis A virus are those in which 90% or more of children have been infected by 10 years of age and include much of sub-Saharan Africa and parts of South Asia. Hepatitis A is considered a traveler's disease as it is the most frequently occurring, vaccine-preventable infection in travelers. People at increased risk for hepatitis A are international travelers; MSM; people who use or inject drugs (all those who use illegal drugs); people with occupational risk for exposure; people who anticipate close personal contact with an international adoptee; and people experiencing homelessness. People at increased risk for severe disease from hepatitis A infection are people with chronic liver disease, including hepatitis B and hepatitis C, and people with HIV (17).

Hepatitis E virus. Hepatitis E virus is one of the most common causes of acute and fulminant hepatitis worldwide (124). It is mainly fecal-oral transmitted; person-to-person transmission is uncommon, with rates ranging from 1% to 2% (44). There are also reports on vertical transmission from mother to child, and transmission through blood transfusion. Moreover, possible foodborne transmission of hepatitis E virus via pigs and other production animals has been described (61).

Prevention

Methods of preventing hepatitis C virus infection include the routine use of disposable needles and syringes for patient care and implementation of community-based prevention programs for people who inject drugs, such as medication-assisted treatment and syringe services programs. The risk of sexual transmission of hepatitis C virus is considered to be low; avoiding unprotected sexual exposure reduces the chance of sexually transmitted hepatitis C virus infections.

Great advances have been made in the prevention and treatment of chronic hepatitis C virus; however, to date there is no vaccine against hepatitis C virus. More potent interventions are needed to meet the World Health Organization’s 2030 goal, which is to achieve a 90% reduction in new hepatitis C virus infections (08; 45).

Hepatitis B virus vaccination [hepatitis A and hepatitis B (recombinant) vaccine (TWINRIX), GlaxoSmithKline Biologicals (Rixensart, Belgium)] is highly effective in preventing hepatitis B virus infection and transmission. The World Health Organization recommends three doses of the hepatitis B virus vaccine for all children worldwide (the first dose within 24 hours of birth); and as soon as possible for persons unvaccinated, mainly those at high risk of hepatitis B virus infection and older age groups. Temporary immunity may be obtained by administering hepatitis B immune globulin for postexposure prophylaxis (97). The hepatitis B virus vaccine also prevents hepatitis D virus infection (63).

The vaccines against hepatitis A virus are highly effective. They are inactivated, single-antigen vaccine, HAVRIX (SmithKline Beecham Biologicals, Rixensart, Belgium) and VAQTA (Merck and Co, Inc, West Point, PA, USA), which can be given in combination with hepatitis B vaccine. It is recommended for children 12 months or older and for adults who are at increased risk for hepatitis A virus infection. The CDC recommends vaccination for healthy nonimmune contacts within 2 weeks of hepatitis A virus exposure. Passive immunization with immunoglobulin for intramuscular administration is reserved for groups where vaccination is contraindicated or the risks of severe disease are high (30). Improvements in sanitation are essential for the prevention hepatitis A virus.

Hepatitis E virus prevention efforts have focused on sanitation and on vaccination. Hecolin (Xiamen Innovax Biotech, China), a protein-based hepatitis E virus vaccine eliciting anticapsid antibodies, is currently licensed only in China for individuals 16 years of age and older (94; 27).

Adverse effects of hepatitis vaccines are extremely rare. Guillain-Barre syndrome or acute disseminated encephalomyelitis have been described after vaccination against hepatitis A virus or hepatitis B virus (68), although the evidence is currently inadequate to establish a causal relationship between hepatitis A virus or hepatitis B virus vaccine and these neurologic syndromes (128).

Diagnostic workup

	• The diagnostic evaluation of the patient with neurologic complications potentially associated with viral hepatitis includes the confirmation of hepatitis virus infection as well as the exclusion of other potential etiologies endemic to the region where the patient lives or has traveled.
	• Clinical, epidemiological, and laboratory data must be taken into consideration when contemplating possible complications of infection with hepatitis viruses.

It is important to consider hepatitis viruses in the differential diagnosis of neurologic syndromes in people with an appropriate travel history or who emigrated from endemic areas. The frequently anicteric nature of some hepatitis viral infections, such as seen with hepatitis A virus, causes a low index of suspicion that could hinder the identification of such cases, lowering the apparent incidence of such disease.

The neurologic complications associated with hepatitis virus infections usually develop in the presence of other extrahepatic complications. It is important to be suspicious of a viral hepatitis etiology when a patient with neurologic symptoms has abnormal liver function tests, mainly in cases with acute hepatitis (54; 108; 29). However, in most chronic hepatitis cases, the neurologic manifestations are independent of the severity of the underlying chronic liver disease, which sometimes makes the diagnosis challenging. Meningoencephalitis is reported as an initial manifestation of hepatitis A virus infection preceding the liver injury, with normal liver function at admission (43). The diagnosis requires confirming the etiology of viral hepatitis.

The diagnosis of specific viral hepatitis is done by traditional serology and viral RNA or DNA quantification in serum (110). In the case of hepatitis C virus, the diagnosis is made when anti-hepatitis C virus antibody (anti-HCV) is detected in serum and viral RNA is detected in blood. The anti-hepatitis C virus antibody may persist after the infection has been cured but does not confer immunity due to the high variability of hepatitis C virus (146). Guidelines for the diagnosis and management of hepatitis C virus infection were released jointly by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America in 2014 (www.hcvguidelines.org). For hepatitis B virus, hepatitis B surface antigen (HBsAg) is the hallmark of serological markers for infection. During acute infection, hepatitis B core antibody (anti-HBc) IgM appears after HBsAg, and both last for months; however, only anti-HBc IgG persists for many years after the infection. The presence of antibodies to hepatitis B virus surface antigen (anti-HBs) represents immunity to hepatitis B virus after previous hepatitis B virus exposure, through either infection or vaccination. Hepatitis Be antigen (HBeAg) and anti-HBe have been used to demonstrate viral replication, although currently this information is most accurately quantified using hepatitis B virus DNA testing (138; 133). Concerning hepatitis A virus, diagnostic confirmation is made by a positive test for anti-hepatitis A virus IgM, which is later replaced by anti-HAV IgG, conferring lifetime viral immunity (110). For hepatitis E virus, the diagnosis of acute hepatitis E virus infection can be made with a positive anti-hepatitis E virus IgM antibody and also by the detection of hepatitis E virus RNA. Anti-hepatitis E virus IgG remains detectable after the infection has been cured (14; 27).

Neuroimaging tests are important tools for the investigation of acute or chronic complications of hepatitis virus infection of the CNS, although the findings are not specific (101). The main MRI features of acute or fulminant hepatitis caused by viral infections are associated with encephalitis. Encephalitis shows signal changes in brain areas, mainly in fluid-attenuated inversion recovery/T2 (T2/FLAIR) sequences, and diffusion restriction together with edema with or without the presence of infarction or herniation. The affected areas of the brain and spinal cord are not specific for hepatitis virus infection (118).

The MRI findings of hepatitis C virus-induced vasculitis are generally associated with the presence of infarcts in various stages of development in several areas of the brain, characterized mainly by areas of high signals on T2/FLAIR and restricted diffusion (16). Hepatitis C virus is associated with increased oxidative stress and chronic inflammation of the CNS, especially with the development of cryoglobulinemia, which is an independent risk factor for stroke in nonspecific arterial territories in the brain (79).

Regarding hepatitis C virus-associated neurocognitive disorder, the clinical manifestations typically occur in the absence of structural brain damage or signal abnormalities on conventional brain MRI (84). Although in some cases, nonspecific findings such as global or asymmetric atrophy, especially in the parietal lobes, or atrophy and morphological changes of hippocampus can be seen (134). Metabolic and microstructural changes or chronic inflammation can be detected by in vivo proton magnetic resonance spectroscopy and perfusion-weighted and diffusion tensor MRI (84; 134). The regional distribution of proton magnetic resonance spectroscopy abnormalities suggests that only cortical and subcortical telencephalon areas, but not the thalamus or posterior fossa structures, are involved in hepatitis C virus-associated neurocognitive disorder (84). Diffusion imaging on hepatitis C virus-associated neurocognitive disorder shows evidence of structural injury in the axonal fibers of white matter tracts associated with temporal and frontal cortices (06).

There are reports of parkinsonism after hepatitis B and C virus infection, especially in young patients, with nonspecific imaging findings (01; 102).

The peripheral nervous system manifestations of hepatitis are mostly related to neuropathy or Guillain-Barre syndrome. A high signal on T2-weighted MRI in peripheral nerves and plexus and an increase in the caliber of peripheral nerves are seen in neuropathies (75). Spinal MR in patients with Guillain-Barre syndrome may show surface thickening and contrast enhancement of the nerve roots of the cauda equina and the conus medullaris (68; 75).

The MRI findings associated with acute disseminated encephalomyelitis after hepatitis virus treatment or vaccine are high signal on T2 and edema in subcortical areas, as well as in the brainstem and thalamus; some of these lesions can present with restricted diffusion as well as peripheral contrast enhancement (68).

CSF studies in individuals with viral hepatitis are scarce and usually limited to case reports. CSF findings are usually consistent with the fully described characteristic of these neurologic syndromes, ie, acute inflammatory demyelinating polyneuropathy usually shows albuminocytologic dissociation; cases with chronic inflammatory demyelinating polyneuropathy present with increased CSF total protein concentration and normal white blood cell count; and cases with meningoencephalitis usually show lymphocytic pleocytosis associated with total protein increase, although normal CSF can be found. During hepatitis A virus encephalitis, CSF pleocytosis, with or without total protein increase, is often observed, but not in all cases (54). CSF hepatitis B virus DNA may be identified in patients with meningoencephalitis (106). Detection of CSF hepatitis A virus DNA was reported in a case of hepatitis A virus encephalitis in which CSF cell and protein concentrations were normal. CSF polymerase chain reaction results are often negative in the early stages of encephalitis. Hepatitis E virus RNA is detected in the CSF of some individuals with acute and chronic hepatitis E virus infection (108). Genetic compartmentalization of hepatitis C virus in the CSF was seen in cognitively impaired patients, consistent with CNS replication or sequestration (140).

Studies on CSF inflammatory biomarkers in hepatitis C virus are rare. Elevated serum cytokine levels in hepatitis C virus-infected patients with cognitive dysfunction reveal a distinct profile that may be related to cognitive impairment or to viral penetration into the CNS (140). Serum brain-derived neurotrophic factor (BDNF) level may represent a useful marker of cognitive dysfunction in patients with hepatitis C virus infection and a useful index for assessing the effect of treatment (74).

Management

• The treatment of the neurologic complications of viral hepatitis should be directed toward viral eradication, as well as directed to the underlying neurologic syndrome.

An attempt at viral eradication should be considered as a first-line therapeutic option for all the nervous system complications associated with hepatitis viruses, including cryoglobulinemic syndromes (77).

Great advances have been made in the treatment of chronic hepatitis C virus (110; 135; 146). A new era of hepatitis C virus therapy has been heralded with the emergence of oral pan-genotypic direct-acting antiviral agents (DAAs). In comparison to the lack of specificity of IFN-based therapy, direct-acting antiviral agents directly block various nonstructural proteins involved in the hepatitis C virus replication pathways. There are four classes of direct-acting antiviral agents: NS3/4A protease inhibitors, nucleoside and nucleotide NS5B polymerase inhibitors, NS5A inhibitors, and nonnucleoside NS5B polymerase inhibitors. Direct-acting antiviral agents are typically used in combinations (109).

Treatment of hepatitis C virus-related neuropathy may differ depending upon how the nerve damage occurred, such as whether or not there is cryoglobulinemia. The best way to treat hepatitis C virus-related neuropathy has not been established (09). Several treatment modalities have been used for hepatitis C virus infection associated with cryoglobulinemic vasculitis. These modalities include corticosteroids, immunosuppressants, plasmapheresis, interferon-alpha, ribavirin, and direct-acting antiviral agents (126). Immunosuppression is still considered the first-line therapeutic approach in cryoglobulinemic vasculitis (107). Rituximab treatment is proposed for patients with severe mixed cryoglobulinemia and is preferred over other more conventional treatments such as glucocorticoids, immunosuppressants, or plasmapheresis (116). There is a report of improvement of peripheral neuropathy associated with cryoglobulinemia after the use of direct-acting antiviral therapy (77). Treatment with oxcarbazepine showed discrete relief of cryoglobulinemic polyneuropathic signs in some patients, without consistent side effects (86).

The available antiviral treatments for hepatitis B virus are pegylated interferon (Peg-IFN) (133), although good results were achieved only in select patient groups, and nucleotide analogs. Currently, entecavir or tenofovir monotherapy are preferred because they have potent antiviral activity and a high barrier to antiviral resistance. All these treatments inhibit hepatitis B virus replication, but they do not eradicate hepatitis B virus (97). The management of hepatitis B virus neuropathy entails antivirals, immunomodulatory treatments as clinically indicated, and supportive care (130).

The treatment for hepatitis E virus encompasses supportive care, and monotherapy treatment with the nucleoside analog, ribavirin, is a therapeutic option for patients with chronic hepatitis E infection (58). Ribavirin and steroids have been used in some patients with extrahepatic manifestations with apparent success, but the efficacy of these drugs still needs to be verified in larger studies (108). No specific antiviral treatment for hepatitis A virus is available.

Outcomes

Direct-acting antiviral agents for the treatment of hepatitis C virus have allowed almost 100% cure rates, regardless of the presence of cirrhosis, hepatitis C virus genotype, or comorbid conditions. Complete viral eradication is usually confirmed with a negative plasma hepatitis C virus RNA test 12 weeks after the last dose of treatment (78). However, in chronic infection, hepatitis C virus may replicate in extrahepatic cells such as peripheral blood mononuclear cells and gastrointestinal mucosa; these cells can act as an extrahepatic reservoir for viral recurrence and persistence (117; 149).

Severe adverse effects of direct-acting antivirals, including those related to the nervous system, are not frequent; typical adverse effects include headache, fatigue, insomnia, and depression (109; 120). Anecdotal reports of ischemic or hemorrhagic stroke have been described after direct-acting antiviral treatment (83).

Regarding peripheral neuropathy due to hepatitis C virus-associated cryoglobulinemic vasculitis, there was partial response in 73% after IFN-free direct-acting antiviral treatment. The improvement was evaluated clinically (visual analogue scales, muscle testing) or electrophysiologically or using both modalities (13). A severe form of hepatitis C virus cryoglobulinemic vasculitic peripheral neuropathy has a poorer response to direct-acting antivirals (13).

The role of direct-acting antivirals in treatment of neurocognitive impairment in hepatitis C virus infection remains unclear (02). Some studies showed cognitive improvements in several domains measured by standard neuropsychological testing after treatment (62; 40). Although the penetration of the direct-acting antivirals through the blood-brain barrier and their effectiveness in the CNS has not been adequately studied, the improvement in cognitive impairment after the use of direct-acting antivirals is probably due to reduction in systemic hepatitis C virus viral load and peripheral inflammatory response, and not to reduction of viral load in the CNS. The positive effects of direct antiviral therapy on cognitive impairment are likely to be more significant when treatment is instituted before involvement of multiple domains and an early cognitive screening in all patients with hepatitis C virus infection may be indicated (95).

Some antivirals for the treatment of chronic hepatitis B virus infection, such as tenofovir or lamivudine, which are oral nucleoside analogs, can trigger myopathies and neuropathies as well as CNS complications. These side effects are due to reduction in intracellular mitochondrial DNA levels that can lead to varying clinical manifestations of mitochondrial toxicity (35). Nonetheless, neurologic side effects are rarely reported on hepatitis B virus treatment.

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Hepatitis viruses: neurologic complications

Differential Diagnosis

HIV
Epstein-Barr virus
cytomegalovirus
leptospirosis
brucellosis
- enterovirus
- mumps
- measles
- influenza
- Toxoplasma
- Legionella
- lymphocytic choriomeningitis virus
- amyotrophic lateral sclerosis
- multiple sclerosis
- paraneoplastic effect
- radiation myelopathy
- human T-lymphotropic virus type 1–associated myelopathy
- vascular spinal cord disease
- severe acute respiratory syndrome coronavirus-2

Hepatitis viruses: neurologic complications

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Neurologic Complications of Hepatitis Viruses

Clinical vignette

Table 2. Suggested Neuropsychological Test Battery to Investigate Hepatitis Viruses Associated with Neurocognitive Disorder

Biological basis

Etiology and pathogenesis

Table 3. Central Nervous System Cells Potentially Infected by Hepatitis Viruses

Epidemiology

Table 4. Epidemiologic, Clinical, and Viral Characteristics of the Hepatitis Viruses with Neurologic Importance

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Immunocompromised patients

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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