Handbook of Clinical Neurology, Vol. 123 (3rd series) Neurovirology A.C. Tselis and J. Booss, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 31

Neurologic complications of hepatic viruses JOHANN SELLNER1,2 AND ISRAEL STEINER3* Department of Neurology, Christian-Doppler-Klinik, Paracelsus Medical University, Salzburg, Austria

1

Department of Neurology, Klinikum rechts der Isar, Technische Universita¨t Munich, Germany

2 3

Department of Neurology, Rabin Medical Center, Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

INTRODUCTION Hepatitis is a collective term for a medical condition defined by an inflammation of the liver. A group of viruses known as the hepatitis viruses are the most common causative agents. There are five main hepatitis viruses, referred to as types A (HAV), B (HBV), C (HCV), D (HDV), and E (HEV). According to the World Health Organization (WHO), one-third of the world´s population has been infected with HBV, and more than 350 million suffer from chronic infection. With regard to HCV, it has been estimated that 170 million persons have chronic infections and that three to four million new cases occur each year. An overview of the nomenclature and clinical features of hepatitis viruses is presented in Table 31.1. Herpes simplex virus type 1 (HSV-1), cytomegalovirus (CMV), and Epstein– Barr virus (EBV) are examples of other viruses that can cause hepatitis (Clemente and Schwarz, 2011). The clinical spectrum of viral hepatitis ranges from asymptomatic and inapparent to fulminant and fatal acute infection (Wender, 2011). The condition is acute when it lasts less than 6 months and chronic when it persists longer. Typical symptoms of acute viral hepatitis include fever, malaise, nausea, vomiting, abdominal discomfort, dark urine, and jaundice ( Jeong and Lee, 2010). Less common symptoms are myalgia, pruritus, diarrhea, arthralgia, and skin rash. Liver enzymes aspartate transaminase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) show a variable increase during the prodromal phase of acute hepatitis and precede the rise of bilirubin. However, acute levels of these enzymes do not correlate with the degree of liver cell damage (Dienstag, 2010). On the other hand, the spectrum of disorders triggered by chronic infections with

hepatic viruses ranges from persistent subclinical to rapidly progressive chronic liver disease with cirrhosis and even hepatocellular carcinoma (HCC) (McGlynn and London, 2011). Both acute and chronic liver dysfunction can lead to hepatic encephalopathy (HE), a brain dysfunction that develops as a result of serious liver disease, such as in fulminant hepatitis or cirrhosis, or a portosystemic shunt (Munoz, 2008; Ramos and Leal, 2011).

THE SPECTRUM OF EXTRAHEPATIC MANIFESTATIONS Viral hepatitis can be accompanied by various extrahepatic manifestations, in both acute and chronic infection. Such complications are observed frequently with HBV during acute hepatic virus infections, less often in acute HCV, and only occasionally in acute HAV infections (Pischke et al., 2007). With regard to chronic infections, clinically important extrahepatic manifestations occur particularly with HCV. Importantly, several extrahepatic disorders contribute significantly to morbidity and mortality. Hepatic viruses have been implicated as an infectious cause or trigger of various disorders of the central and peripheral nervous system (CNS and PNS, respectively). Neurologic manifestations are relatively uncommon (Table 31.2) and can develop either as an isolated complication or in the setting of other extrahepatic manifestations. Alternatively, neurologic signs and symptoms precede hepatitis, develop in the post-acute phase, or occur with anicteric hepatitis. The purpose of this chapter is to review the occurrence and significance of extrahepatic manifestations of hepatic viruses involving the nervous system. HE,

*Correspondence to: Israel Steiner, M.D., Department of Neurology, Rabin Medical Center, Campus Beilinson, 49100 Petach Tikva, Israel. Tel: þ 972-3-9376351, E-mail: [email protected]

648

J. SELLNER AND I. STEINER

Table 31.1 Virologic and clinical features of hepatitis viruses and their worldwide distribution

Genome Classification

Source Incubation period Chronic infection

Vaccine Antiviral treatment Infections worldwide

HAV

HBV

HCV

HEV

7.5 kb RNA Hepatovirus (Picornavirus family) Feces 15–50 days (average 28 days) No

3.2 kb DNA Hepadnavirus family

9.4 kb RNA Hepacivirus (Flavivirus family)

Blood/body fluids 45–160 days (average 120 days)

Blood/body fluids 14–180 days (average 180 days) Yes (in 55–85% of infected persons)

7.4 kb RNA Hepevirus (Calicivirus family) Feces 15–60 days (average 42 days) No

Yes No 1.4 million

Yes (up to 90% of infants infected at birth, in 30% of children infected at age 1–5 years, in up to 6% infected after age 5) Yes Yes 2 billion

No Yes 200–300 million

No No Antibody prevalence up to 26% in endemic regions

HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatis C virus; HEV, hepatitis E virus.

Table 31.2 Frequency of extrahepatic and neurologic complications in acute and chronic hepatitis caused by hepatitis viruses A, B, C, and E

Extrahepatic manifestations Neurologic complications

HAV

HBV

Acute þ þ

Acute þ þ

HCV Chronic þþ þ

Acute þ þ

HEV Chronic þþþ þþþ

Acute þ þ

þ Low; þþmoderate; þþþ high rate.

an important neurologic complication due to hepatic dysfunction, is not covered in this chapter.

HEPATITIS AVIRUS Background Stephen M. Feinstone and his colleagues, Robert H. Purcell and Albert Z. Kapikian, identified the HAV in 1973 by immune electron microscopy and developed the first tests to detect the antibody and the virus (Feinstone et al., 1973). HAV is a non-enveloped small RNA virus in the Hepatovirus genus of the Picornavirus family ( Jeong and Lee, 2010). This family also includes the polio viruses and other enteroviruses capable of inducing neurologic disease, such as ECHO and coxsackieviruses.

Transmission occurs through the fecal–oral route, person-to-person contact, and ingestion of contaminated food and water. HAV infection is usually short-lasting, rarely fatal, and does not increase the risk of HCC. Humans are their only reservoir. Despite the availability of an effective vaccine since the early 1990s, HAV is still a frequent cause of acute viral hepatitis worldwide. While 1.5 million clinical cases are reported by the WHO per year, serologic data point at an asymptomatic infection rate that is more than 10 times higher (Wasley et al., 2006). Clinical manifestations only develop in a subgroup and depend on the age of the host. Indeed, less than one-third of infected young children develop symptoms of the disease, whereas about 80% of adults develop severe acute hepatitis. On rare occasions, atypical courses characterized by fulminant or relapsing hepatitis may develop (Sagnelli et al., 2003; Jeong and Lee, 2010).

NEUROLOGIC COMPLICATIONS OF HEPATIC VIRUSES

Pathogenesis The pathogenetic link between HAV and neurologic disease is a matter of debate. Potential mechanisms of neuroaxonal injury by HAV were proposed (St€ ubgen, 2011a): (1) cell-mediated immunity; (2) neurotropism; and (3) circulating immune complex deposition. The presence of oligoclonally expanded T cells and increased myelin basic protein levels in cerebrospinal fluid (CSF) in a patient with relapsing acute disseminated encephalomyelitis (ADEM) following HAV infection indicates that molecular mimicry-triggered demyelination may also be involved (Oleszak et al., 2001).

Extrahepatic manifestations Among extrahepatic manifestations of HAV are hematologic disorders such as hemolytic anemia, aplastic anemia, and pure cell aplasia (Pischke et al., 2007). Further complications include pleural or pericardial effusion, acute reactive arthritis, and acute pancreatitis. Kidney injury and acalculous cholecystitis aggravating the course have also been reported (Kim et al., 2008a). Neurologic manifestations are rare and concern both the CNS and PNS (Jeong and Lee, 2010). The diagnostic workup of these cases was, however, not comprehensive. Diagnosis is generally based on a temporal relationship with acute HAV infection and a clinical syndrome in combination with pleocytosis and increased protein in CSF but negative viral CSF polymerase chain reaction (PCR) or culture. An exception to this situation is the case of a 5-year-old boy, who presented with nuchal rigidity and seizures, where HAV was detected in his CSF (Cam et al., 2005). Pleocytosis is mostly dominated by lymphocytes (Davoudi et al., 2010). Among the seven cases of HAV-associated acute transverse myelitis (ATM), 3 patients had an increased immunoglobulin G (IgG) index (St€ ubgen, 2011a). Evidence for an intrathecal detection of anti-HAV antibodies beyond Guillain– Barre´ syndrome (GBS) manifestation associated with HAV is rare (Breuer et al., 2001; Kocabas and Yildizdas, 2004; Chitambar et al., 2006; Thapa et al., 2009b). In this regard, a disrupted blood–nerve barrier is most likely responsible for the detection of antiHAV IgM antibodies in the CSF.

CENTRAL NERVOUS SYSTEM There are case studies of encephalitis (Hammond et al., 1982; Parajua et al., 1991; Davis et al., 1993; Hegazi et al., 2011), mono- and multiphasic disseminated encephalomyelitis (Oleszak et al., 2001; Alehan et al., 2004; Unay et al., 2004; Quaranta et al., 2006; El Moutawakil et al., 2008), meningoencephalitis

649

(Bromberg et al., 1982; Nishimura et al., 1987; Matsushima et al., 1992; Davoudi et al., 2010), meningitis (Satou et al., 1989), and ATM (Tyler et al., 1986; Beeri et al., 1995; Breningstall and Belani, 1995; Jouhadi et al., 2004; Khemiri et al., 2007; Kim et al., 2008b; Ficko et al., 2010) in association with HAV infection. There is also a report of a case of HAV-associated parainfectious neuromyelitis optica (Sellner et al., 2010). Optic neuritis has been reported not only with HAV infection but also following HAV vaccination (McKibbin et al., 1995; Huang et al., 2009).

PERIPHERAL NERVOUS SYSTEM PNS manifestations include mononeuritis simplex and multiplex, and different GBS variants (Bae et al., 2007; Kang and Kim, 2007; Thapa et al., 2009b). St€ ubgen (2011b) summarized 17 GBS cases associated with acute HAV infection collected in a literature search. Most patients had clinical evidence of hepatitis for variable periods preceding the onset of GBS. While the majority of patients had demyelinating polyradiculoneuropathy, some showed dominant axonal involvement. A patient tested for HAV RNA copies in the CSF was negative on day 29 of illness (Chitambar et al., 2006). Mononeuropathies occur usually in the preicteric to convalescent phase of hepatitis. Further associations include cranial nerve palsies and idiopathic intracranial hypertension (pseudotumor cerebri) (Thapa et al., 2009a, c, d).

Management and course There is no specific management for neurologic manifestations of HAV infection. Subsequently, emphasis is placed on prevention through immunization and supportive treatment. Passive and active immunization of household members should be considered (Clemente and Schwarz, 2011). General supportive measures include adequate hydration, nutritional support, use of antiemetics and antipyretics. Acetaminophen for control of fever should be used with caution during the symptomatic period of acute hepatitis due to potential aggravation of hepatic failure (Rezende et al., 2003). In fulminant hepatitis, protein intake should be restricted, and oral lactulose or neomycin administered (Dienstag, 2010). The reported spectrum of treatment and outcome among HAV-associated neurologic manifestations is wide. Monophasic ADEM related to HAV infection was associated with death in two out of four cases (Alehan et al., 2004; El Moutawakil et al., 2008), while in other reports recovery was without any residual deficits following treatment with intravenous

650

J. SELLNER AND I. STEINER

immunoglobulins and/or steroids, respectively (Unay et al., 2004; Quaranta et al., 2006). Outcome in HAVassociated ATM seems to be more favorable, similar to what is seen in acute partial transverse myelitis due to autoimmune mechanisms (Sellner et al., 2009). Of seven ATM cases, four recovered (St€ ubgen, 2011a). Among the 17 patients with GBS, two were treated with prednisone, three with plasma exchange, and six with intravenous immunoglobulins (St€ ubgen, 2011b). Prognosis of GBS associated with acute HAV infection is generally good. The course of mononeuropathies associated with acute HAV infection varies from spontaneous resolution to protracted course (St€ ubgen, 2011b). The latter may improve with pulsed steroid treatment.

HEPATITIS B VIRUS Background The identification of HBV by Baruch S. Blumberg is regarded as one of the greatest medical achievements of the 20th century. He not only received the Nobel Prize in 1967 for this accomplishment but also later developed a diagnostic test and vaccine (Blumberg et al., 1965). HBV is a hepatotropic non-cytopathic DNA virus which is transmitted via percutaneous or permucosal exposure to infected fluids, mostly blood, semen, and saliva (Dienstag, 2008). In two-thirds of patients no history of a percutaneous exposure can be identified. The virus is an important worldwide cause of acute and chronic liver disease. About two-thirds of patients with acute HBV infection have a mild, asymptomatic, and subclinical illness (Bertoletti et al., 2007). Up to 10% of infected adults are unable to clear the virus and become chronically infected. Chronic HBV infection is one of the most important causes of hepatic failure and HCC (Sinn et al., 2008; Lehman and Wilson, 2009). In addition, current or past HBV exposure is seen in up to 30% of patients infected with human immunodeficiency virus (HIV) (Ladak et al., 2012).

Pathogenesis HBV proteins and nucleic acids have been found in a number of non-hepatic tissues, including lymph nodes, spleen, bone marrow, kidney, colon, stomach, periadrenal ganglia, skin, thyroid, pancreas, testis, ovaries, brain, heart, and lung tissue (Rong et al., 2007). There are several lines of evidence suggesting that different cell types such as endothelial cells, epithelial cells, neurons, and various cells of the monocyte and leukocyte lineage are permissive for HBV replication in humans (Yoffe et al., 1990; Mason et al., 1993). Most of the extrahepatic manifestations are immune-mediated. There is only

limited evidence for a direct HBV infection within the CNS and most of the data suggests an immune-mediated pathogenesis. Several mechanisms are proposed: (1) deposition of hepatitis B surface antigen (HBsAg)containing circulating immune complexes, followed by activation of the complement cascade (Cacoub and Terrier, 2009); (2) local antibody interaction with viral antigen trapped within tissue (Guignard et al., 1975); (3) reaction of HBV-induced autoantibodies with tissue antigens (Hansen et al., 1995; Kansu et al., 2004); (4) formation and deposition of cryoprecipitates (Levo et al., 1977); and (5) HBV replication in targeted tissues (He et al., 1998; Mason et al., 2005). HBV DNA copies can be found only rarely in CSF by PCR. On some occasions, intrathecal HBsAg can be detected in HBV-associated GBS. Of note, some antivirals for the treatment of chronic HBV infection can trigger myopathies and neuropathies, as well as CNS complications (Fontana, 2009).

Extrahepatic manifestations As many as 20% of patients with HBV infection experience extrahepatic complications (Mason, 2006; Cacoub and Terrier, 2009). These include serum sickness syndrome, arthritis and polyarthralgias, dermatologic manifestations, polyarteritis nodosa, glomerulonephritis, mixed cryoglobulinemia, and Gianotti–Crosti syndrome (Pischke et al., 2007; Chan, 2010).

MUSCLE Muscle disorders with a clinical course reminiscent of polymyositis have been reported following HBV antigenemia (Nojima et al., 2000). The HBV-associated cases are often characterized by subacute and proximal weakness. Muscle biopsy frequently reveals an immune complex-mediated pathology (Capasso et al., 2006).

PERIPHERAL NERVOUS SYSTEM PNS complications include peripheral neuropathies, mononeuropathies, and GBS (Nam et al., 2010). The latter can develop before, during, and after HBsAgpositive hepatitis (Berger et al., 1981; Saiz-Hervas et al., 1995). In mononeuritis simplex or multiplex, motor and sensory deficit occurs suddenly in the distribution of a single or various nerves and is often accompanied by pain (Rumbaugh and Johnson, 2008). HBV-associated GBS can also develop with a relapsing course (Inoue et al., 1987; Tsukada et al., 1987). There are several reports on GBS following vaccination with HBV vaccine preparations (Ribera and Dutka, 1983). The occurrence of peripheral neuropathies is partly linked to the presence of cryoglobulinemia. Biopsy of both nerve and

NEUROLOGIC COMPLICATIONS OF HEPATIC VIRUSES muscle is likely to increase the sensitivity in cases with suspected necrotizing vasculitis (Said et al., 1988). If neuropathies develop secondary to vasculitis, multiple organ systems in addition to the nervous system may be involved.

CENTRAL NERVOUS SYSTEM The CNS can be affected as a consequence of polyarteritis nodosa of cerebral arteries, a severe form of vasculitis that affects small and medium-sized vessels. Interestingly, in the evaluation of a large cohort of Korean HBsAg seropositives, a decreased risk of ischemic stroke and myocardial infarction and an increased risk of hemorrhagic stroke were elucidated (Sung et al., 2007). However, the relationship of cardiovascular disease and HBV was secondary to liver dysfunction in this study. No association between HBV infection and atherosclerosis was identified in a survey among a German cohort (Volzke et al., 2004). In contrast, a potential causal relationship of the carotid and vertebral artery stenoses in a 34-year-old man after 10 years of HBV infection and antiviral treatment was suggested (Kim et al., 2011). Acute and relapsing demyelinating transverse myelitis has been found in association with acute HBV infection (Matsui et al., 1996; Inoue and Yoshino, 1998). Of note, Japanese researchers detected HBV DNA in the CSF of a patient with acute HBV infection and ATM (Inoue et al., 2008). Genomic sequencing revealed that the clones were unique to the CSF, pointing at a causal relationship of virus and myelitis. Patients with chronic HBV infection show a slowly progressive spastic paraparesis, similar to the clinical observation in human T-lymphotropic virus-1-associated myelopathy (Hino et al., 1994). ADEM cases following acute viral hepatitis with HBV as well as vaccination are reported (Hynson et al., 2001). A few studies had reported increased risk for developing MS following vaccination with a certain preparation, whereas others report that vaccination against HBV might even confer a lower risk for developing MS (Mikaeloff et al., 2009; Farez and Correale, 2011).

Antiviral treatment US Food and Drug Administration (FDA)-approved drugs for the treatment of chronic HBV infections include entecavir, lamivudine, adefovir dipivoxil, interferon-a 2b, pegylated interferon-a 2b, tenofovir, and telbivudine. The initial decision regarding which drug to use involves a choice between interferon and nucleoside/nucleotide analogs. Interferons have the advantage that they are administered for a finite duration and are not associated with specific drug-resistant

651

mutations, but have to be administered parenterally. Initial endpoints of therapy are clearance of HBe antigen and HBV DNA in peripheral blood, improvement of liver disease as indicated by normalization of ALT, and a decrease in inflammation determined on liver biopsy.

Side-effects of therapy Myopathy associated with clevudine is characterized by weakness in proximal muscles of the lower extremities with elevated muscle enzymes and presumably caused by mitochondrial toxicity (Tak et al., 2010). Clevudine was also shown to induce polymyositis in 2 patients with chronic HBV infection (Yang et al., 2010). Telbivudine appeared to be associated with accelerated muscle toxicity in a patient with pre-existing muscle damage (Finsterer and Ay, 2010). Pre-existing peripheral neuropathies in patients with cryoglobulinemia may exacerbate following interferon-a treatment (La Civita et al., 1996). Neurovisual impairment may be a potential complication of interferon-a treatment in both chronic HBV and HCV infection. Patients with HBV and older age seemed most susceptible in a Greek study (Manesis et al., 1998). Three HIV patients co-infected with HBV from Serbia and Montenegro developed immune reconstitution inflammatory syndrome (IRIS) under highly active antiretroviral therapy (HAART) ( Jevtovic et al., 2005).

Management and course There are vaccination recommendations for preexposure prophylaxis in the setting of frequent exposure, and post-exposure prophylaxis following potential exposure. Seven drugs are licenced in the United States for the treatment of HBV infection in adults (Dienstag, 2008). Alpha-interferon and lamivudine are the only FDA-approved treatments for children (Clemente and Schwarz, 2011). If HBV is directly involved in the pathogenesis of extrahepatic manifestations, there is a high chance that antiviral therapy will lead to attenuation of the disorder (Pischke et al., 2007). Which antiviral drug combinations, however, are most suitable for treating neurologic complications is unknown. Treatment of HBV-associated neurologic complications beyond symptomatic and supportive treatment (similar to that recommended for HAV) needs to be individualized to the respective manifestation and potential pathogenesis, e.g., direct viral or immune-mediated. Polymyositis associated with hepatitis B was treated with entacavir and only responded when prednisone was added (Wong et al., 2011). There is a report on successful treatment of HBV-associated mononeuritis multiplex with prednisone (Nam et al., 2010). In patients with a potential vasculitic pathogenesis of neuropathy, acute treatment with

652

J. SELLNER AND I. STEINER

prednisone should be followed by long-term immunosuppressive therapies (Gorson, 2006). In cases of parainfectious ADEM, treatment with steroids and, if required, escalation with plasma exchange may be effective (Wender, 2011). Uncontrolled studies indicate that HBV-associated polyarteritis nodosa management should include an antiviral agent, short-term steroids, and plasma exchange (Takeshita et al., 2006; de Menthon and Mahr, 2011). Discontinuation of antiviral treatment in cases of potential CNS and PNS side-effects may lead to complete resolution of symptoms (Manesis et al., 1998; Finsterer and Ay, 2010; Yang et al., 2010).

HEPATITIS C VIRUS Background HCV is a positive-stranded RNA virus classified within the Flaviviridae family as a separate genus (Hepacivirus) (Gremion and Cerny, 2005). HCV accounts for 20% of community-acquired acute viral hepatitis, and is an important cause of chronic hepatitis, cirrhosis, and HCC (Sievert et al., 2011). Although the incidence of HCV infection is lower than that of HBV, chronicity in up to 85% explains its significant burden on healthcare. HCV infection causes acute symptoms in only 15% of cases (Maheshwari et al., 2008). Early identification and initiation of antiviral treatment in patients with acute HCV infection can prevent the development of chronic hepatitis C in approximately 90% of patients (Gerlach et al., 2003). However, both interferon-a and ribavirin therapy are associated with a large variety of side-effects, particularly in the CNS (Manns et al., 2006). In addition, interferon-a was shown to induce or aggravate autoimmune diseases, including autoimmune thyroiditis, diabetes, and hepatitis (Manns et al., 2006). Interferon sparing regimens are now available, see Note added in proof. The routes of transmission are generally similar to those of HBV. Sexual and vertical transmission is less frequent with HCV (Alter, 2011). In up to 40% of cases, no route of acquisition can be identified and non-sexual transmission via oral fluid is most commonly presumed (Ferreiro et al., 2005). Up to 40% of HIV-infected patients are also infected with HCV, whereas HBV and HCV co-infection with HIV is in the range of 5–20% (Dionne-Odom et al., 2009; Sulkowski, 2012).

Pathogenesis HCV copies were detected in CSF and brain tissue in a few cases, providing support for a potential neuroinvasive pathogenesis of complications (Seifert et al., 2008; Wilkinson et al., 2009). Circulating levels of mixed cryoglobulins can be detected in 40–66% of HCV-infected patients, whereas an overt vasculitis develops in less than

10% of cases (Saadoun et al., 2007). Cryoglobulins are single or mixed immunoglobulins that undergo reversible precipitation at low temperatures. There is evidence for CNS injury by HCV-associated mixed cryoglobulinemia. Indeed, cryoglobulinemic vasculitis can lead to endoneural microangiopathy and subsequent neuroaxonal damage. Potential pathomechanisms for noncryoglobulinemic vascular damage were summarized recently, to include (St€ ubgen, 2011a): (1) deposition of HCV RNA-containing immunoglobulins; (2) direct infection of endothelial or mononuclear cells; and (3) HCV-induced B-lymphocyte proliferation with autoantibody production. With regard to CNS dysfunction, it is hypothesized that a direct effect of HCV on the brain and neurotoxic effects of HCV-related systemic inflammation are involved in the pathogenesis (Bokemeyer et al., 2011; Senzolo et al., 2011). Notably, magnetic resonance spectroscopy of brain parenchyma in HCVinfected individuals suggests multiple metabolic derangements, including altered neurotransmission of tryptophan-serotonin metabolism (Forton et al., 2001; Weissenborn et al., 2006; Zignego et al., 2007).

Extrahepatic manifestations HCV can affect organ systems besides the liver. Up to 50% of patients with chronic HCV infection have one or more extrahepatic manifestations (Agnello and De Rosa, 2004; Ramos-Casals and Font, 2005). Three categories of extrahepatic manifestations can be distinguished (Gremion and Cerny, 2005): (1) manifestations clearly linked to HCV; (2) manifestations possibly linked to HCV; and (3) manifestations linked to interferon therapy. Type 1 disorders include mixed cryoglobulinemia, glomerulonephritis, porphyria cutanea tarda, sicca syndrome/Sj€ogren´s syndrome, and excess autoantibody production. Disorders that belong to category 2 include: lymphoproliferative disorders, systemic vasculitispolyarteritis, autoimmune thrombocytopenia, arthralgia and myalgias, and type 2 diabetes.

PERIPHERAL NERVOUS SYSTEM Peripheral neuropathy is considered the most common neurologic complication with HCV infection. In a French cohort of 321 subjects with chronic hepatitis C infection, symptomatic peripheral neuropathy was observed in 9% of cases (Cacoub et al., 2000). Even though the neurologic findings were more frequent among cryoglobulin-positive patients, a significant proportion of cryoglobulin-negative individuals had PNS involvement. Such neuropathies start mostly as sensory abnormalities that affect the distal parts of the PNS and are often asymmetric (Tembl et al., 1999; Lidove et al., 2001a, b; Nemni et al., 2003). Later they are frequently

NEUROLOGIC COMPLICATIONS OF HEPATIC VIRUSES complicated by involvement of motor fibers, particularly of the lower limbs. Electrophysiologic studies mostly reveal axonal involvement. The corresponding finding on biopsy is severe axonal damage associated with vasculitis of small-size vessels and an inflammatory infiltrate. A high frequency of autonomic nervous system dysfunction is observed in patients with HCV-related mixed cryoglobulinemia (Ammendola et al., 2007). A German study evaluated sensory neuropathies in cryoglobulin-negative HCV infection and found a high rate with involvement of small sensory fibers (46.3%) (Yoon et al., 2011). Interestingly, the clinical and electrophysiologic pattern did not differ between different HCV subtypes and among patients with interferon-a therapy and treatment-naı¨ve cases. Other forms of neuropathies observed in HCV infection include demyelinating variants and polyradiculoneuritis (Authier et al., 1993; Nemni et al., 2003). A case of simultaneous PNS and CNS demyelination with a relapsing disease course and negative cryoglobulins is reported (Bezerra et al., 2011). Additional details on mononeuritis and neuropathies secondary to vasculitis are covered in the HBV section.

MUSCLE Polymyositis, dermatomyositis, and inclusion body myositis have been reported in association with hepatitis C infection (Rumbaugh and Johnson, 2008). Occasionally, HCV copies can be detected in muscle fibers of these patients.

CENTRAL NERVOUS SYSTEM CNS involvement by HCV can present with different facets. Well-documented reports on CNS involvement in patients with HCV-associated vasculitis are rare and include mostly cryoglobulin-positive patients (Cacoub et al., 2001; Filippini et al., 2002; Arena et al., 2003). An increased rate of intracranial ischemic and hemorrhagic complications is found among young HCVpositive patients (Raguin et al., 1998). In contrast, overall risk for myocardial infarction and stroke is not higher, and atherosclerotic consequences such as increased carotid intima media thickness, carotid plaques, and stenoses are not raised with HCV seropositivity (Volzke et al., 2004). Choroidal and optic nerve infarction can develop in HCV-associated polyarteritis nodosa (Kostina-O’Neil et al., 2007). Other rare complications include brain hemorrhage and leukencephalopathy (Buccoliero et al., 2006; Erro Aguirre et al., 2008). Moreover, cranial neuropathies, encephalitis, and encephalopathies have been reported (Origgi et al., 1998; Heckmann et al., 1999; Cacoub et al., 2001; Casato et al., 2003). Two patients with HCV developed progressive multifocal

653

leukencephalitis (PML) (Pearce et al., 1993; Bosch et al., 1999). Among hepatic viruses, HCV is most commonly related to the occurrence of inflammatory myelopathies. In this regard, there are 19 reported HCV-associated ATM cases (St€ ubgen, 2011a). Yet, the association needs to be taken with caution since many of the case descriptions evaluated the presence of antibodies or RNA copies in serum. Mostly, patients suffer from a chronic, recurrent myelopathy, and clinical features range from sensory ataxia to paraplegia with neurogenic bladder (Aktipi et al., 2007). Spinal cord magnetic resonance imaging commonly reveals multisegmental abnormalities and serum cryoglobulins are mostly negative. In a study of seven HCV-related myelopathy cases with serologic evidence for HCV infection, 2–5 relapses at intervals ranging from 3 to 12 months were observed (Aktipi et al., 2007). There is also a HCV-positive patient who suffered from optic neuritis before the onset of myelitis (Earnest et al., 2010). The prevalence of fatigue in patients with chronic HCV infection is high; interestingly, no correlation with the degree of hepatitis was established (Forton et al., 2003a, b). Cognitive impairment was detected in almost half of the HCV-infected patients without cirrhosis (Hilsabeck et al., 2002). The rate is even higher in patients with cirrhosis and involves selective impairments of attention, concentration, and psychomotor speed (Sene et al., 2004). Symptoms of depression are found in up to 30% of HCV-infected patients (Carta et al., 2007; Perry et al., 2008).

Antiviral treatment Treatment should be started in patients with active HCV infection and increased risk for cirrhosis. This group is characterized by persistent elevation of ALT, high levels of HCV in peripheral blood, and evidence of early scarring or moderate inflammation and injury of liver cells on biopsy. Also, patients who are co-infected with HIV should be treated. Current treatment is a combination pegylated interferon-alpha and ribavirin for a period of 24 or 48 weeks, depending on the HCV genotype. Treatment endpoints are distinct for the different genotypes. See note added in proof.

Side-effects of therapy More than 20% of patients had side-effects in the major pegylated interferon or ribavirin trials. Frequent neurologic or psychiatric complications were headache (47–62%), myalgia (37–56%), nausea (35–43%), fatigue (48–64%), irritability (24–35%), and depression (22–31%) (Manns et al., 2006). In addition, a case of psychosis potentially related to the combination of

654

J. SELLNER AND I. STEINER

interferon-a and ribavirin therapy is reported (Quarantini et al., 2006). A case of fulminant CNS demyelination following initiation of interferon-a therapy, indicating induction or aggravation of autoimmune CNS disease, is mentioned in the section above (Hö ftberger et al., 2007). Other potential side-effects of the interferon-a and ribavirin therapy include anterior ischemic optic neuropathy (Gupta et al., 2002; Vardizer et al., 2003; Fodor et al., 2008; Kabbaj et al., 2009; Wei et al., 2009; Fraunfelder and Fraunfelder, 2011; Knyazer et al., 2011), retinopathy (Rossi et al., 2010), Bell´s palsy (Ogundipe and Smith, 2000; Hoare et al., 2005; Barut et al., 2009), dystonia (Quarantini et al., 2007), and acute inflammatory demyelinating neuropathy (Khiani et al., 2008). The mechanism of action involved in the pathogenesis of interferon-aassociated complications is unclear. Interferon sparing regimens are now available, see Note added in proof. There is also a well-documented case of fulminant demyelination throughout the brain and the spinal cord associated with HCV infection and following initiation of interferon-a therapy (H€ oftberger et al., 2007). Remarkably, autopsy of this case revealed HCV sequences in florid plaques. Noteworthy is a case of PML following antiviral treatment in an HCV-positive but HIV-negative patient (Lima et al., 2005). Both reports argue that the combination of HCV infection and antiviral treatment might trigger or propagate CNS disease. In this regard, 15 patients under HAART and with HCV co-infection developed IRIS in a cohort of 389 HIV patients (Jevtovic et al., 2005).

Management and course At present, there is no effective vaccine for HCV, neither active nor passive. Hence, prevention takes a major role and comprises behavioral changes and precautions to limit exposures to infected persons. Treatment is focused on achieving a sustained virologic response, defined as an absence of detectable viral RNA 6 months after completion of antiviral therapy (Dienstag, 2010). Once a diagnosis of chronic HCV infection has been confirmed, adherence to treatment algorithms based on the virus genotype, viral load, hepatic function, and ability to tolerate therapy is recommended (EASL, 2011). See note added in proof. The treatment of HCV-associated peripheral neuropathy in mixed cryoglobulin-positive individuals is based on anti-HCV drugs (Pietrogrande et al., 2011). Combination therapy with interferon-a plus ribavirin may induce a complete clinical remission in a significant proportion of patients with HCV-related systemic vasculitis, and consequently, in those with mixed cryoglobulin-related peripheral neuropathy (Ammendola et al., 2005). There are a few case reports showing favorable outcomes in cryoglobulinemic subjects treated with corticosteroids

or interferon-a for CNS involvement (Filippini et al., 2002; Arena et al., 2003). However, such reports cannot support a solid recommendation, especially for those patients with cryoglobulin-negative CNS vasculitis. In addition, it should be emphasized that, for cases of severe cryoglobulinemia-associated vasculitis (such as those with rapidly progressive renal failure or neurologic involvement), it is recommended that antiviral therapy should be delayed for 2–4 months while they are submitted to aggressive therapy with plasma exchange, corticosteroids (intravenous methylprednisolone followed by oral prednisone), and either cyclophosphamide or rituximab (Cai et al., 2006; Cavallo et al., 2009). However, long-term outcome of peripheral neuropathies following treatment is unclear. Data about the safety and efficacy of interferon-based regimens in the treatment of HCVassociated CNS vasculitis are even scarcer. The role of HCV therapy in subjects with cryoglobulin-negative peripheral neuropathy is unclear. Significant neurologic improvement in two cryoglobulin-negative patients treated with interferon-a was reported (Lidove et al., 2001a). With regard to depression, both for HCV-induced and interferon-a-associated cases, psychiatric care and the use of antidepressants, especially serotonin uptake inhibitors, are recommended (Schaefer et al., 2005). A diagnosis of PML is normally made on the basis of distinguishing neurologic features at presentation, characteristic brain magnetic resonance imaging changes, and the presence of JC virus DNA in the CSF. The condition has a 3-month mortality rate of 20–50% and prompt intervention is essential (Brew et al., 2010). Immunomodulatory or immunosuppressive therapy should be stopped and protein-based drugs with long life may be removed by plasma exchange. The hallmark of IRIS is paradoxic worsening of an existing infection or disease process or appearance of a new infection/disease process soon after initiation of therapy. The immunopathogenesis appears to be the result of unbalanced reconstitution of effector and regulatory T cells, leading to exuberant inflammatory response (Barber et al., 2012). Immune restoration, whenever possible, is the cornerstone of treatment. Antiviral treatment is usually continued and therapy for the associated condition optimized (Sharma and Soneja, 2011).

HEPATITIS E VIRUS Background HEV is a RNA virus which is spread by fecally contaminated water in endemic areas (Emerson and Purcell, 2003; Rein et al., 2011). Since the virus was identified in 1983, epidemics have occurred regularly in South and Southeast Asia when seasonal floods have

NEUROLOGIC COMPLICATIONS OF HEPATIC VIRUSES contaminated drinking water supplies and in Africa during humanitarian crises among refugee populations without access to clean water. Person-to-person transmission is uncommon, with rates ranging from 1% to 2% (Hadem and Manns, 2007). There are also reports on vertical transmission from mother to child. HEV infection is usually self-limiting but chronic infections have been seen in immunocompromised patients. The overall case-fatality rate is 0.5–3% (Panda et al., 2007). However, mortality rates of up to 20% have been reported for pregnant women, especially in the third trimester during HEV outbreaks in developing countries (Emerson and Purcell, 2003). HEV has at least two distinct epidemiological profiles: (1) large outbreaks and epidemics in developing countries, usually caused by HEV genotype 1, resulting in high morbidity and mortality among pregnant women and young children; and (2) very few symptomatic cases with HEV genotype 3, most cases without symptoms or clear source(s) of infection (Teshale et al., 2010).

Pathogenesis Recent data indicate that HEV infection is a porcine zoonosis (Panda et al., 2007). HEV infection can manifest as subclinical to fulminant disease in humans but asymptomatic cases are also reported. HEV viremia is usually brief. However, prolonged viremia for more than 3 years has been reported. The pathogenesis of HEV is not well understood, as serologic assays have only recently become available and the pathogenesis of extrahepatic manifestations has not been studied in detail. Most of the reported cases are based on detection of either antibodies or virus in sera. However, there are also sporadic cases with HEV RNA detection in CSF and resolution of neurologic signs and symptoms with clearance of HEV viremia (Kamar et al., 2011).

Extrahepatic manifestations Extrahepatic manifestations among 86 patients with viral hepatitis due to HEV were evaluated (Amarapurkar and Amarapurkar, 2002). Only 1 patient was found to have an extrahepatic manifestation, which was aplastic anemia. Glomerular diseases are frequently present in kidney biopsies from patients with acute and chronic HEV infection (Kamar et al., 2012b). All cases in this study were associated with genotype 3 and included membranoproliferative glomerulonephritis and relapses of IgA nephropathy. Among 126 patients with HEV genotype 3 infection, 7 (5.5%) developed neurologic disorders (Kamar et al., 2011): inflammatory polyradiculopathy (n ¼ 3), GBS (n ¼ 1), bilateral brachial neuritis (n ¼ 1), encephalitis (n ¼ 1), and ataxia/proximal myopathy (n ¼ 1). Four cases occurred in chronic HEV infection

655

and in immunocompromise. HEV was detected in the CSF of the 4 patients with chronic HEV infection, indicating that local viral replication is occurring in the CNS. Neurologic manifestations of HEV infection are likely to be underestimated and patients with liver dysfunction and CNS/PNS disturbances should be tested for HEV serology.

CENTRAL NERVOUS SYSTEM Acute meningoencephalitis and seizures have been reported in a single patient with acute HEV infection (Kejariwal et al., 2001). Two CSF PCR-documented cases of meningitis during acute HEV hepatitis were studied in France (Despierres et al., 2011). Different HEV quasispecies may coexist in serum and CSF in chronic HEV infection, similar to the situation in HIV. Hence, neurologic signs and symptoms can result from de novo infection or emergence of neurotropic HEV variants due to compartmentalization (Kamar et al., 2012a). There is a case report of a patient with both CNS and PNS involvement in chronic HEV infection (Kamar et al., 2012a).

PERIPHERAL NERVOUS SYSTEM There are two cases of neuralgic amyotrophy with serologic evidence of HEV infection or HEV RNA detection in serum, respectively (Fong and Illahi, 2009; Rianthavorn et al., 2011). One case of Bell´s palsy associated with HEV infection is reported (Dixit et al., 2006). In addition, there are several case studies of GBS associated with acute HEV infection (Sood et al., 2000; Kamani et al., 2005; Tse et al., 2012), while there is also a report on GBS in the aftermath of acute HEV infection (Mandal and Chopra, 2006; Loly et al., 2009). There are cases of acute HEV-associated GBS with either GM1 or GM2 antibodies (Cronin et al., 2011; Maurissen et al., 2011). A patient with acute HEV infection and elevated creatine kinase without symptoms of muscle damage was reported (Kitazawa et al., 2003).

Management and course HEV infection control and prevention strategies aim at improving hygienic conditions in endemic areas. In a phase II trial, HEV vaccine was shown to be safe and well tolerated, and effectively prevented clinically overt HEV infection in Nepali volunteers (Shrestha et al., 2007). However, no commercial vaccine is currently available against HEV, and administration of immune serum globulin from endemic areas did not decrease infection rates during epidemics (Khuroo and Dar, 1992; Panda et al., 2007). The concepts for symptomatic and supportive treatment are covered in the section on HAV infection, above. Furthermore, treatment considerations

656

J. SELLNER AND I. STEINER

depending on a potential direct viral or immunemediated pathogenesis may be relevant for the treatment, as discussed in the sections on HBV and HCV, above. Outcomes among the 7 patients with neurologic disorders associated with HEV infection were complete clinical resolution (n ¼ 3), improvement with neurologic deficit (n ¼ 3), and no improvement (n ¼ 1) (Kamar et al., 2011).

OTHER HEPATIC VIRUSES Hepatitis D virus (HDV) depends on HBV to be infective. However, no extrahepatic manifestations have been reported particularly for the double infection. Other viruses which can cause acute and chronic hepatitis are HSV-1, CMV, and EBV. All three viruses are DNA viruses and members of the herpesvirus family. They mostly cause hepatitis in the context of a systemic infection. These viruses can cause CNS and PNS infections per se (Steiner et al., 2010). Liver involvement by these pathogens mostly, but not exclusively, occurs in immunocompromised individuals and in children (Williams and Riordan, 2000; Steiner et al., 2010; Steiner, 2011).

CONCLUSION Acute and chronic viral hepatitis are associated with, and may trigger or exacerbate, a wide range of extrahepatic complications. Neurologic manifestations resulting from infection with hepatic viruses are relatively uncommon and develop mostly in the context of multiple extrahepatic manifestations. Knowledge of most neurologic complications in this context is scarce and it is of key importance to consider the spectrum of potential manifestations in patients infected with hepatic viruses. On the other hand, the potential cause of CNS or PNS disease by hepatic viruses should be taken into account in the workup of these conditions. Several potential pathogenetic mechanisms involved in CNS and PNS manifestations are proposed. Nevertheless, many questions about the potential neurotropism and the immunopathogenesis of neurologic complications due to hepatic viruses remain unclear. An individualized strategy is required for the treatment of neurologic complications of hepatic virus infections. Antivirals should be applied if available, and direct virus-induced damage or by immune complexes containing viral particles is presumed. In this regard, potential side-effects of antiviral therapy, including PNS and PNS involvement, need to be considered. Moreover, there is only limited knowledge on the efficacy of different antivirals, newer drug developments, and their combinations for the treatment of neurologic complications caused by hepatic virus infections.

In contrast, if a pathologic immune-mediated process is likely to be involved, an individualized immunosuppressive or immunomodulatory therapy is recommended. Nevertheless, the efficacy of a single drug and drug combinations for the therapy of neurologic complications, as well as optimal treatment duration, remain to be determined. Eventually, it can be anticipated that clinical situations occur in which both antiviral and immunosuppressive therapy is applied.

DEDICATION This chapter is dedicated to the memory of Professor Itzchak Wirguin.

Note added in proof The field of anti-HCV therapy is going through a period of rapid evolution, as various highly effective directacting anti-viral drugs (DAA) become available. DAAs are molecules that target specific non-structural proteins of the virus and result in disruption of viral replication and infection. The first-generation DAAs included telaprevir and boceprevir which were added to the non-specific agents interferon (pegylated interferon a2a and 2b) and ribarvirin. Among the second-generation DAAs are sofosbuvir, simprevir, faldaprevir and others in development. These drugs are generally well-tolerated and have a more favorable safety profile than first-generation DAAs. Indeed, the combination of DAAs of two or more classes with non-overlapping resistance profiles has shown sustained virological response rates exceeding 90%. Such a regimen is likely to achieve high cure rates and freedom of dependence on interferon. Yet, cost effectiveness and affordability currently limit their global usage.

REFERENCES Agnello V, De Rosa FG (2004). Extrahepatic disease manifestations of HCV infection: some current issues. J Hepatol 40: 341–352. Aktipi KM, Ravaglia S, Ceroni M et al. (2007). Severe recurrent myelitis in patients with hepatitis C virus infection. Neurology 68: 468–469. Alehan FK, Kahveci S, Uslu Y et al. (2004). Acute disseminated encephalomyelitis associated with hepatitis A virus infection. Ann Trop Paediatr 24: 141–144. Alter MJ (2011). HCV routes of transmission: what goes around comes around. Semin Liver Dis 31: 340–346. Amarapurkar DN, Amarapurkar AD (2002). Extrahepatic manifestations of viral hepatitis. Ann Hepatol 1: 192–195. Ammendola A, Sampaolo S, Ambrosone L et al. (2005). Peripheral neuropathy in hepatitis-related mixed cryoglobulinemia: electrophysiologic follow-up study. Muscle Nerve 31: 382–385.

NEUROLOGIC COMPLICATIONS OF HEPATIC VIRUSES Ammendola A, Sampaolo S, Migliaresi S et al. (2007). Autonomic neuropathy in mixed cryoglobulinemia. J Neurol 254: 215–219. Arena MG, Ferlazzo E, Bonanno D et al. (2003). Cerebral vasculitis in a patient with HCV-related type II mixed cryoglobulinemia. J Invest Allergol Clin Immunol 13: 135–136. Authier FJ, Pawlotsky JM, Viard JP et al. (1993). High incidence of hepatitis C virus infection in patients with cryoglobulinemic neuropathy. Ann Neurol 34: 749–750. Bae YJ, Kim KM, Kim KK et al. (2007). A case of acute hepatitis a complicated by Guillain–Barre´ syndrome. Korean J Hepatol 13: 228–233. Barber DL, Andrade BB, Sereti I et al. (2012). Immune reconstitution inflammatory syndrome: the trouble with immunity when you had none. Nat Rev Microbiol 10: 150–156. Barut S, Karaer H, Oksuz E et al. (2009). Bell’s palsy and choreiform movements during peginterferon alpha and ribavirin therapy. World J Gastroenterol 15: 3694–3696. Beeri R, Golan G, Newman D et al. (1995). Transverse myelitis heralding hepatitis A. J Clin Gastroenterol 20: 262–263. Berger JR, Ayyar R, Sheremata WA (1981). Guillain–Barre´ syndrome complicating acute hepatitis B. A case with detailed electrophysiological and immunological studies. Arch Neurol 38: 366–368. Bertoletti A, Kennedy P, Gehring AJ (2007). Role of the immune response in hepatitis B. In: ME Gershwin, JM Vierling, MP Manns (Eds.), Liver immunology: principles and practice. Humana Press, Totowa, NJ, pp. 179–191. Bezerra ML, Harumi JA, Shinosaki JS et al. (2011). Hepatitis C virus: a rare manifestation – remitting relapsing central and peripheral demyelination. Neurol India 59: 114–116. Blumberg BS, Alter HJ, Visnich S (1965). A “new” antigen in leukemia sera. JAMA 191: 541–546. Bokemeyer M, Ding XQ, Goldbecker A et al. (2011). Evidence for neuroinflammation and neuroprotection in HCV infection-associated encephalopathy. Gut 60: 370–377. Bosch J, Sumalla J, Mauleon A et al. (1999). Progressive multifocal leukoencephalopathy in elderly immunocompetent patients. Report of 2 cases. Rev Neurol 29: 133–137. Breningstall GN, Belani KK (1995). Acute transverse myelitis and brainstem encephalitis associated with hepatitis A infection. Pediatr Neurol 12: 169–171. Breuer GS, Morali G, Finkelstein Y et al. (2001). A pregnant woman with hepatitis A and Guillain–Barre´. J Clin Gastroenterol 32: 179–180. Brew BJ, Davies NW, Cinque P et al. (2010). Progressive multifocal leukoencephalopathy and other forms of JC virus disease. Nat Rev Neurol 6: 667–679. Bromberg K, Newhall DN, Peter G (1982). Hepatitis A and meningoencephalitis. JAMA 247: 815. Buccoliero R, Gambelli S, Sicurelli F et al. (2006). Leukoencephalopathy as a rare complication of hepatitis C infection. Neurol Sci 27: 360–363. Cacoub P, Terrier B (2009). Hepatitis B-related autoimmune manifestations. Rheum Dis Clin North Am 35: 125–137. Cacoub P, Renou C, Rosenthal E et al. (2000). Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. The GERMIVIC. Groupe d’Etude et de Recherche en

657

Medecine Interne et Maladies Infectieuses sur le Virus de l’Hepatite C. Medicine (Baltimore) 79: 47–56. Cacoub P, Maisonobe T, Thibault V et al. (2001). Systemic vasculitis in patients with hepatitis C. J Rheumatol 28: 109–118. Cai FZ, Ahern M, Smith M (2006). Treatment of cryoglobulinemia associated peripheral neuropathy with rituximab. J Rheumatol 33: 1197–1198. Cam S, Ertem D, Koroglu OA et al. (2005). Hepatitis A virus infection presenting with seizures. Pediatr Infect Dis J 24: 652–653. Capasso M, Di Muzio A, Comar M et al. (2006). The association of chronic hepatitis B and myopathy. Neurology 67: 1467–1469. Carta MG, Hardoy MC, Garofalo A et al. (2007). Association of chronic hepatitis C with major depressive disorders: irrespective of interferon-alpha therapy. Clin Pract Epidemiol Ment Health 3: 22. Casato M, Lilli D, Donato G et al. (2003). Occult hepatitis C virus infection in type II mixed cryoglobulinaemia. J Viral Hepat 10: 455–459. Cavallo R, Roccatello D, Menegatti E et al. (2009). Rituximab in cryoglobulinemic peripheral neuropathy. J Neurol 256: 1076–1082. Chan TM (2010). Hepatitis B and renal disease. Curr Hepat Rep 9: 99–105. Chitambar SD, Fadnis RS, Joshi MS et al. (2006). Case report: Hepatitis A preceding Guillain–Barre´ syndrome. J Med Virol 78: 1011–1014. Clemente MG, Schwarz K (2011). Hepatitis: general principles. Pediatr Rev 32: 333–340. Cronin S, McNicholas R, Kavanagh E et al. (2011). Antiglycolipid GM2-positive Guillain–Barre´ syndrome due to hepatitis E infection. Ir J Med Sci 180: 255–257. Davis LE, Brown JE, Robertson BH et al. (1993). Hepatitis A post-viral encephalitis. Acta Neurol Scand 87: 67–69. Davoudi S, Soudbakhsh A, Emadikouchak H et al. (2010). Meningoencephalitis associated with hepatitis A infection: a case report and review of literature. Trop Doct 40: 176–177. de Menthon M, Mahr A (2011). Treating polyarteritis nodosa: current state of the art. Clin Exp Rheumatol 29: S110–S116. Despierres LA, Kaphan E, Attarian S et al. (2011). Neurologic disorders and hepatitis E, France, 2010. Emerg Infect Dis 17: 1510–1512. Dienstag JL (2008). Hepatitis B virus infection. N Engl J Med 359: 1486–1500. Dienstag JL (2010). Acute viral hepatitis. In: DL Longo, A Fauci (Eds.), Harrison’s gastroenterology and hepatology. McGraw-Hill, Totowa, New Jersey, United States, pp. 349–377. Dionne-Odom J, Osborn MK, Radziewicz H et al. (2009). Acute hepatitis C and HIV coinfection. Lancet Infect Dis 9: 775–783. Dixit VK, Abhilash VB, Kate MP et al. (2006). Hepatitis E infection with Bell’s palsy. J Assoc Physicians India 54: 418. Earnest BS, Men LC, Sukvinder Kaur G et al. (2010). Chronic hepatitis C infection associated with neuromyelitis optica and antinuclear antibodies. J Assoc Physicians India 58: 118–120.

658

J. SELLNER AND I. STEINER

EASL (2011). Clinical practice guidelines: management of hepatitis C virus infection. J Hepatol 55: 245–264. El Moutawakil B, Bourezgui M, Rafai MA et al. (2008). Acute disseminated encephalomyelitis associated with hepatitis A virus infection. Rev Neurol (Paris) 164: 852–854. Emerson SU, Purcell RH (2003). Hepatitis E virus. Rev Med Virol 13: 145–154. Erro Aguirre ME, Ayuso Blanco T, Tun˜o´n Alvarez T et al. (2008). Brain hemorrhage as a complication of chronic hepatitis C virus-related vasculitis. J Neurol Neurosurg Psychiatry 255: 944–945. Farez MF, Correale J (2011). Immunizations and risk of multiple sclerosis: systematic review and meta-analysis. J Neurol 258: 1197–1206. Feinstone SM, Kapikian AZ, Purceli RH (1973). Hepatitis A: detection by immune electron microscopy of a viruslike antigen associated with acute illness. Science 182: 1026–1028. Ferreiro MC, Dios PD, Scully C (2005). Transmission of hepatitis C virus by saliva? Oral Dis 11: 230–235. Ficko C, Imbert P, Mechai F et al. (2010). Acute myelitis related to hepatitis A after travel to Senegal. Med Trop (Mars) 70: 7–8. Filippini D, Colombo F, Jann S et al. (2002). Central nervous system involvement in patients with HCV-related cryoglobulinemia: literature review and a case report. Reumatismo 54: 150–155. Finsterer J, Ay L (2010). Myotoxicity of telbivudine in preexisting muscle damage. Virol J 7: 323. Fodor M, Nagy V, Berta A et al. (2008). Hepatitis C virus presumably associated bilateral consecutive anterior ischemic optic neuropathy. Eur J Ophthalmol 18: 313–315. Fong F, Illahi M (2009). Neuralgic amyotrophy associated with hepatitis E virus. Clin Neurol Neurosurg 111: 193–195. Fontana RJ (2009). Side effects of long-term oral antiviral therapy for hepatitis B. Hepatology 49: S185–S195. Forton DM, Allsop JM, Main J et al. (2001). Evidence for a cerebral effect of the hepatitis C virus. Lancet 358: 38–39. Forton DM, Taylor-Robinson SD, Thomas HC (2003a). Cerebral dysfunction in chronic hepatitis C infection. J Viral Hepat 10: 81–86. Forton DM, Thomas HC, Taylor-Robinson SD (2003b). Quality of life and cognitive function in chronic hepatitis C – what to measure? J Hepatol 39: 272–274. Fraunfelder FW, Fraunfelder FT (2011). Interferon alfaassociated anterior ischemic optic neuropathy. Ophthalmology 118 (408–411): e401–e402. Gerlach JT, Diepolder HM, Zachoval R et al. (2003). Acute hepatitis C: high rate of both spontaneous and treatmentinduced viral clearance. Gastroenterology 125: 80–88. Gorson KC (2006). Therapy for vasculitic neuropathies. Curr Treat Options Neurol 8: 105–117. Gremion C, Cerny A (2005). Hepatitis C virus and the immune system: a concise review. Rev Med Virol 15: 235–268. Guignard D, Nydegger U, Lambert PH et al. (1975). Physiopathology of hepatitis B virus infection. Schweiz Med Wochenschr 105: 1033–1040. Gupta R, Singh S, Tang R et al. (2002). Anterior ischemic optic neuropathy caused by interferon alpha therapy. Am J Med 112: 683–684.

Hadem J, Manns MP (2007). Immune response to hepatitis A and E viruses. In: ME Gershwin, JM Vierling, MP Manns (Eds.), Liver immunology: principles and practice. Humana Press, Totowa, NJ, pp. 163–177. Hammond GW, MacDougall BK, Plummer F et al. (1982). Encephalitis during the prodromal stage of acute hepatitis A. Can Med Assoc J 126: 269–270. Hansen HL, Andersen PL, Brandt L et al. (1995). Antibodies against hepatitis viruses in merchant seamen. Scand J Infect Dis 27: 191–194. He XY, Fang LJ, Zhang YE et al. (1998). In situ hybridization of hepatitis B DNA in hepatitis B-associated glomerulonephritis. Pediatr Nephrol 12: 117–120. Heckmann JG, Kayser C, Heuss D et al. (1999). Neurological manifestations of chronic hepatitis C. J Neurol 246: 486–491. Hegazi MA, Mansor I, Rahman FA et al. (2011). Hepatitis A virus presenting as fatal encephalitis in a child. Pediatr Infect Dis J 30: 1012. Hilsabeck RC, Perry W, Hassanein TI (2002). Neuropsychological impairment in patients with chronic hepatitis C. Hepatology 35: 440–446. Hino H, Ayabe M, Honda J et al. (1994). Hepatitis B virus antibody positive spastic paraparesis. Rinsho Shinkeigaku 34: 691–695. Hoare M, Woodall T, Alexander GJ (2005). Bell’s palsy associated with IFN-alpha and ribavirin therapy for hepatitis C virus infection. J Interferon Cytokine Res 25: 174–176. H€ oftberger R, Garzuly F, Dienes HP et al. (2007). Fulminant central nervous system demyelination associated with interferon-alpha therapy and hepatitis C virus infection. Mult Scler 13: 1100–1106. Huang EH, Lim SA, Lim PL et al. (2009). Retrobulbar optic neuritis after hepatitis A vaccination in a HIV-infected patient. Eye (Lond) 23: 2267–2271. Hynson JL, Kornberg AJ, Coleman LT et al. (2001). Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children. Neurology 56: 1308–1312. Inoue Y, Yoshino H (1998). Acute transverse myelitis presenting with syrinx formation associated with anti-sulfated glucuronyl lactosaminyl paragloboside antibody and anticardiolipin antibody. No To Shinkei 50: 181–185. Inoue A, Tsukada N, Koh CS et al. (1987). Chronic relapsing demyelinating polyneuropathy associated with hepatitis B infection. Neurology 37: 1663–1666. Inoue J, Ueno Y, Kogure T et al. (2008). Analysis of the fulllength genome of hepatitis B virus in the serum and cerebrospinal fluid of a patient with acute hepatitis B and transverse myelitis. J Clin Virol 41: 301–304. Jeong SH, Lee HS (2010). Hepatitis A: clinical manifestations and management. Intervirology 53: 15–19. Jevtovic DJ, Salemovic D, Ranin J et al. (2005). The prevalence and risk of immune restoration disease in HIVinfected patients treated with highly active antiretroviral therapy. HIV Med 6: 140–143. Jouhadi Z, Ouazzani I, Abid A et al. (2004). Devic’s optic neuromyelitis and viral hepatitis type A. A paediatric case report. Rev Neurol (Paris) 160: 1198–1202. Kabbaj N, Sentissi S, Mohammadi M et al. (2009). Anterior ischemic optic neuropathy complicating interferon alpha

NEUROLOGIC COMPLICATIONS OF HEPATIC VIRUSES and ribavirin therapy in patients with chronic hepatitis C. Gastroenterol Clin Biol 33: 115–117. Kamani P, Baijal R, Amarapurkar D et al. (2005). Guillain– Barre´ syndrome associated with acute hepatitis E. Indian J Gastroenterol 24: 216. Kamar N, Bendall RP, Peron JM et al. (2011). Hepatitis E virus and neurologic disorders. Emerg Infect Dis 17: 173–179. Kamar N, Izopet J, Cintas P et al. (2012a). Hepatitis E virusinduced neurological symptoms in a kidney-transplant patient with chronic hepatitis. Am J Transplant 10: 1321–1324. Kamar N, Weclawiak H, Guilbeau-Frugier C et al. (2012b). Hepatitis E virus and the kidney in solid-organ transplant patients. Transplantation 93: 617–623. Kang BH, Kim KK (2007). Fulminant Guillain–Barre´ syndrome mimicking cerebral death following acute viral hepatitis A. J Clin Neurol 3: 105–107. Kansu A, Kuloglu Z, Demirceken F et al. (2004). Autoantibodies in children with chronic hepatitis B infection and the influence of interferon alpha. Turk J Gastroenterol 15: 213–218. Kejariwal D, Roy S, Sarkar N (2001). Seizure associated with acute hepatitis E. Neurology 57: 1935. Khemiri M, Ouederni M, Barsaoui S (2007). A new case of acute transverse myelitis following hepatitis A virus infection. Med Mal Infect 37: 237–239. Khiani V, Kelly T, Shibli A et al. (2008). Acute inflammatory demyelinating polyneuropathy associated with pegylated interferon alpha 2a therapy for chronic hepatitis C virus infection. World J Gastroenterol 14: 318–321. Khuroo MS, Dar MY (1992). Hepatitis E: evidence for personto-person transmission and inability of low dose immune serum globulin from an Indian source to prevent it. Indian J Gastroenterol 11: 113–116. Kim HW, Yu MH, Lee JH et al. (2008a). Experiences with acute kidney injury complicating non-fulminant hepatitis A. Nephrology (Carlton) 13: 451–458. Kim SY, Kim MG, Choi WC (2008b). Acute transverse myelitis after acute hepatitis a: findings on magnetic resonance imaging. Clin Gastroenterol Hepatol 6: xxviii- e1. Kim JT, Park MS, Nam TS et al. (2011). Multiple cerebral arterial stenosis associated with hepatitis B virus infection. J Clin Neurol 7: 40–42. Kitazawa T, Ota Y, Suzuki M et al. (2003). Acute hepatitis E with elevated creatine phosphokinase. Intern Med 42: 899–902. Knyazer B, Lifshitz T, Marcus M et al. (2011). Anterior ischemic optic neuropathy in a patient with hepatitis C treated with interferon-alpha and ribavirin. Isr Med Assoc J 13: 251–253. Kocabas E, Yildizdas Y (2004). A child with Guillain–Barre´ syndrome caused by acute hepatitis A infection. Indian Pediatr 41: 92–93. Kostina-O’Neil Y, Jirawuthiworavong GV, Podell DN et al. (2007). Choroidal and optic nerve infarction in hepatitis C-associated polyarteritis nodosa. J Neuroophthalmol 27: 184–188. La Civita L, Zignego AL, Lombardini F et al. (1996). Exacerbation of peripheral neuropathy during alphainterferon therapy in a patient with mixed cryoglobulinemia and hepatitis B virus infection. J Rheumatol 23: 1641–1643.

659

Ladak F, Gjelsvik A, Feller E et al. (2012). Hepatitis B in the United States: ongoing missed opportunities for hepatitis B vaccination, evidence from the Behavioral Risk Factor Surveillance Survey, 2007. Infection 40: 405–413. Lehman EM, Wilson ML (2009). Epidemiology of hepatitis viruses among hepatocellular carcinoma cases and healthy people in Egypt: a systematic review and meta-analysis. Int J Cancer 124: 690–697. Levo Y, Gorevic PD, Kassab HJ et al. (1977). Association between hepatitis B virus and essential mixed cryoglobulinemia. N Engl J Med 296: 1501–1504. Lidove O, Cacoub P, Maisonobe T et al. (2001a). Hepatitis C virus infection with peripheral neuropathy is not always associated with cryoglobulinaemia. Ann Rheum Dis 60: 290–292. Lidove O, Maisonobe T, Servan J et al. (2001b). Peripheral neuropathy and hepatitis C virus infection: more than cryoglobulinemia. Rev Med Interne 22: 939–947. Lima MA, Auriel E, Wuthrich C et al. (2005). Progressive multifocal leukoencephalopathy as a complication of hepatitis C virus treatment in an HIV-negative patient. Clin Infect Dis 41: 417–419. Loly JP, Rikir E, Seivert M et al. (2009). Guillain–Barre´ syndrome following hepatitis E. World J Gastroenterol 15: 1645–1647. Maheshwari A, Ray S, Thuluvath PJ (2008). Acute hepatitis C. Lancet 372: 321–332. Mandal K, Chopra N (2006). Acute transverse myelitis following hepatitis E virus infection. Indian Pediatr 43: 365–366. Manesis EK, Moschos M, Brouzas D et al. (1998). Neurovisual impairment: a frequent complication of alpha-interferon treatment in chronic viral hepatitis. Hepatology 27: 1421–1427. Manns MP, Wedemeyer H, Cornberg M (2006). Treating viral hepatitis C: efficacy, side effects, and complications. Gut 55: 1350–1359. Mason A (2006). Role of viral replication in extrahepatic syndromes related to hepatitis B virus infection. Minerva Gastroenterol Dietol 52: 53–66. Mason A, Wick M, White H et al. (1993). Hepatitis B virus replication in diverse cell types during chronic hepatitis B virus infection. Hepatology 18: 781–789. Mason A, Theal J, Bain V et al. (2005). Hepatitis B virus replication in damaged endothelial tissues of patients with extrahepatic disease. Am J Gastroenterol 100: 972–976. Matsui M, Kakigi R, Watanabe S et al. (1996). Recurrent demyelinating transverse myelitis in a high titer HBsantigen carrier. J Neurol Sci 139: 235–237. Matsushima K, Niwa K, Fujita H et al. (1992). Acute hepatitis A (HA) presenting findings of meningoencephalitis. Rinsho Shinkeigaku 32: 441–443. Maurissen I, Jeurissen A, Strauven T et al. (2011). First case of anti-ganglioside GM1-positive Guillain–Barre´ syndrome due to hepatitis E virus infection. Infection 40: 323–326. McGlynn KA, London WT (2011). The global epidemiology of hepatocellular carcinoma: present and future. Clin Liver Dis 15: 223–243, vii-x.

660

J. SELLNER AND I. STEINER

McKibbin M, Cleland PG, Morgan SJ (1995). Bilateral optic neuritis after hepatitis A. J Neurol Neurosurg Psychiatry 58: 508. Mikaeloff Y, Caridade G, Suissa S et al. (2009). Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood. Neurology 72: 873–880. Munoz SJ (2008). Hepatic encephalopathy. Med Clin North Am 92: 795–812, viii. Nam TS, Lee SH, Park MS et al. (2010). Mononeuropathy multiplex in a patient with chronic active hepatitis B. J Clin Neurol 6: 156–158. Nemni R, Sanvito L, Quattrini A et al. (2003). Peripheral neuropathy in hepatitis C virus infection with and without cryoglobulinaemia. J Neurol Neurosurg Psychiatry 74: 1267–1271. Nishimura M, Shigemoto R, Matsubayashi K et al. (1987). Meningoencephalitis during the pre-icteric phase of hepatitis A – a case report. Rinsho Shinkeigaku 27: 1441–1444. Nojima T, Hirakata M, Sato S et al. (2000). A case of polymyositis associated with hepatitis B infection. Clin Exp Rheumatol 18: 86–88. Ogundipe O, Smith M (2000). Bell’s palsy during interferon therapy for chronic hepatitis C infection in patients with haemorrhagic disorders. Haemophilia 6: 110–112. Oleszak EL, Lin WL, Legido A et al. (2001). Presence of oligoclonal T cells in cerebrospinal fluid of a child with multiphasic disseminated encephalomyelitis following hepatitis A virus infection. Clin Diagn Lab Immunol 8: 984–992. Origgi L, Vanoli M, Carbone A et al. (1998). Central nervous system involvement in patients with HCV-related cryoglobulinemia. Am J Med Sci 315: 208–210. Panda SK, Thakral D, Rehman S (2007). Hepatitis E virus. Rev Med Virol 17: 151–180. Parajua JL, Riera M, Garcia MJ (1991). Hepatitis A virus encephalitis. Med Clin (Barc) 97: 279. Pearce DA, Wong V, Miloszewski KJ (1993). Hepatitis C: a novel cause of progressive multifocal leucoencephalopathy. Br J Hosp Med 50: 193. Perry W, Hilsabeck RC, Hassanein TI (2008). Cognitive dysfunction in chronic hepatitis C: a review. Dig Dis Sci 53: 307–321. Pietrogrande M, De Vita S, Zignego AL et al. (2011). Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients. Autoimmun Rev 10: 444–454. Pischke S, Vogel A, Jaeckel E et al. (2007). Immunopathogenesis of extrahepatic manifestations in HAV, HBV, and HCV infections. In: ME Gershwin, JM Vierling, MP Manns (Eds.), Liver immunology: principles and practice. NJ, Humana Press, Totowa, pp. 209–217. Quaranta L, Batocchi AP, Sabatelli M et al. (2006). Monophasic demyelinating disease of the central nervous system associated with hepatitis A infection. J Neurol 253: 944–945. Quarantini LC, Cruz SC, Batista-Neves SC et al. (2006). Psychosis during peginterferon-alpha 2a and ribavirin therapy: case report. Braz J Infect Dis 10: 406–407. Quarantini LC, Miranda-Scippa A, Parana R et al. (2007). Acute dystonia after injection of pegylated interferon alpha-2b. Mov Disord 22: 747–748.

Raguin G, Rosenthal E, Cacoub P et al. (1998). Hepatitis C in France: a national survey in the Departments of Internal Medicine and Infectious Diseases. The GERMIVIC (Joint Study Group on Hepatitis C virus of the French National Society of Internal Medicine and the French Society of Infectious Diseases). Eur J Epidemiol 14: 545–548. Ramos JF, Leal CR (2011). Review of the final report of the 1998 Working Party on definition, nomenclature and diagnosis of hepatic encephalopathy. Ann Hepatol 10 (Suppl 2): S6–S9. Ramos-Casals M, Font J (2005). Extrahepatic manifestations in patients with chronic hepatitis C virus infection. Curr Opin Rheumatol 17: 447–455. Rein DB, Stevens G, Theaker J et al. (2011). The global burden of hepatitis E virus. Hepatology 55: 988–997. Rezende G, Roque-Afonso AM, Samuel D et al. (2003). Viral and clinical factors associated with the fulminant course of hepatitis A infection. Hepatology 38: 613–618. Rianthavorn P, Thongmee C, Limpaphayom N et al. (2011). The entire genome sequence of hepatitis E virus genotype 3 isolated from a patient with neuralgic amyotrophy. Scand J Infect Dis 42: 395–400. Ribera EF, Dutka AJ (1983). Polyneuropathy associated with administration of hepatitis B vaccine. N Engl J Med 309: 614–615. Rong Q, Huang J, Su E et al. (2007). Infection of hepatitis B virus in extrahepatic endothelial tissues mediated by endothelial progenitor cells. Virol J 4: 36. Rossi C, Scotton PG, Farina F et al. (2010). Retinopathy in chronic hepatitis C patients during interferon treatment: a case report. Infez Med 18: 267–269. Rumbaugh JA, Johnson RT (2008). Hepatitis viruses: neurologic complications. Available online at www.medlink.com. Saadoun D, Landau DA, Calabrese LH et al. (2007). Hepatitis C-associated mixed cryoglobulinaemia: a crossroad between autoimmunity and lymphoproliferation. Rheumatology 46: 1234–1242. Sagnelli E, Coppola N, Marrocco C et al. (2003). HAV replication in acute hepatitis with typical and atypical clinical course. J Med Virol 71: 1–6. Said G, Lacroix-Ciaudo C, Fujimura H et al. (1988). The peripheral neuropathy of necrotizing arteritis: a clinicopathological study. Ann Neurol 23: 461–465. Saiz-Hervas E, Jimenez-Jimenez FJ, Vaquero A et al. (1995). Peripheral neuropathy, first manifestation of hepatitis B virus infection. Presse Med 24: 548. Satou J, Andou Y, Kubo K et al. (1989). A case of viral hepatitis type A associated with aseptic meningitis. Nihon Shokakibyo Gakkai Zasshi 86: 2587–2591. Schaefer M, Schwaiger M, Garkisch AS et al. (2005). Prevention of interferon-alpha associated depression in psychiatric risk patients with chronic hepatitis C. J Hepatol 42: 793–798. Seifert F, Struffert T, Hildebrandt M et al. (2008). In vivo detection of hepatitis C virus (HCV) RNA in the brain in a case of encephalitis: evidence for HCV neuroinvasion. Eur J Neurol 15: 214–218. Sellner J, L€ uthi N, Sch€ upbach WM et al. (2009). Diagnostic workup of patients with acute transverse myelitis: spectrum

NEUROLOGIC COMPLICATIONS OF HEPATIC VIRUSES of clinical presentation, neuroimaging and laboratory findings. Spinal Cord 47: 312–317. Sellner J, Hemmer B, Muhlau M (2010). The clinical spectrum and immunobiology of parainfectious neuromyelitis optica (Devic) syndromes. J Autoimmun 34: 371–379. Sene D, Limal N, Cacoub P (2004). Hepatitis C virusassociated extrahepatic manifestations: a review. Metab Brain Dis 19: 357–381. Senzolo M, Schiff S, D’Aloiso CM et al. (2011). Neuropsychological alterations in hepatitis C infection: the role of inflammation. World J Gastroenterol 17: 3369–3374. Sharma SK, Soneja M (2011). HIV & immune reconstitution inflammatory syndrome (IRIS). Indian J Med Res 134: 866–877. Shrestha MP, Scott RM, Joshi DM et al. (2007). Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med 356: 895–903. Sievert W, Altraif I, Razavi HA et al. (2011). A systematic review of hepatitis C virus epidemiology in Asia, Australia and Egypt. Liver Int 31 (Suppl 2): 61–80. Sinn DH, Paik SW, Kang P et al. (2008). Disease progression and the risk factor analysis for chronic hepatitis C. Liver Int 28: 1363–1369. Sood A, Midha V, Sood N (2000). Guillain–Barre´ syndrome with acute hepatitis E. Am J Gastroenterol 95: 3667–3668. Steiner I (2011). Herpes simplex virus encephalitis: new infection or reactivation? Curr Opin Neurol 24: 268–274. Steiner I, Budka H, Chaudhuri A et al. (2010). Viral meningoencephalitis: a review of diagnostic methods and guidelines for management. Eur J Neurol 17: 999–e57. St€ ubgen JP (2011a). Immune-mediated myelitis associated with hepatitis virus infections. J Neuroimmunol 239: 21–27. St€ ubgen JP (2011b). Neuromuscular complications of hepatitis A virus infection and vaccines. J Neurol Sci 300: 2–8. Sulkowski MS (2012). Hepatitis C virus-human immunodeficiency virus coinfection. Liver Int 32 (Suppl 1): 129–134. Sung J, Song YM, Choi YH et al. (2007). Hepatitis B virus seropositivity and the risk of stroke and myocardial infarction. Stroke 38: 1436–1441. Tak WY, Park SY, Cho CM et al. (2010). Clinical, biochemical, and pathological characteristics of clevudineassociated myopathy. J Hepatol 53: 261–266. Takeshita S, Nakamura H, Kawakami A et al. (2006). Hepatitis B-related polyarteritis nodosa presenting necrotizing vasculitis in the hepatobiliary system successfully treated with lamivudine, plasmapheresis and glucocorticoid. Intern Med 45: 145–149. Tembl JI, Ferrer JM, Sevilla MT et al. (1999). Neurologic complications associated with hepatitis C virus infection. Neurology 53: 861–864. Teshale EH, Hu DJ, Holmberg SD (2010). The two faces of hepatitis E virus. Clin Infect Dis 51: 328–334. Thapa R, Biswas B, Ghosh A et al. (2009a). Unilateral palatal and abducens palsy in childhood hepatitis A virus infection. J Child Neurol 24: 628–629. Thapa R, Biswas B, Mallick D et al. (2009b). Pharyngealcervical-brachial variant of pediatric Guillain–Barre´ syndrome with antecedent acute hepatitis A virus infection. J Child Neurol 24: 865–867.

661

Thapa R, Ghosh A, Mukherjee S (2009c). Childhood hepatitis A virus infection complicated by pseudotumor cerebri. South Med J 102: 204–205. Thapa R, Mallick D, Biswas B et al. (2009d). Childhood hepatitis A virus infection complicated by Bell’s palsy. Clin Pediatr (Phila) 48: 427–428. Tse AC, Cheung RT, Ho SL et al. (2012). Guillain–Barre´ syndrome associated with acute hepatitis E infection. J Clin Neurosci 19: 607–608. Tsukada N, Koh CS, Inoue A et al. (1987). Demyelinating neuropathy associated with hepatitis B virus infection. Detection of immune complexes composed of hepatitis B virus surface antigen. J Neurol Sci 77: 203–216. Tyler KL, Gross RA, Cascino GD (1986). Unusual viral causes of transverse myelitis: hepatitis A virus and cytomegalovirus. Neurology 36: 855–858. Unay B, Sarici SU, Bulakbasi N et al. (2004). Intravenous immunoglobulin therapy in acute disseminated encephalomyelitis associated with hepatitis A infection. Pediatr Int 46: 171–173. Vardizer Y, Linhart Y, Loewenstein A et al. (2003). Interferonalpha-associated bilateral simultaneous ischemic optic neuropathy. J Neuroophthalmol 23: 256–259. Volzke H, Schwahn C, Wolff B et al. (2004). Hepatitis B and C virus infection and the risk of atherosclerosis in a general population. Atherosclerosis 174: 99–103. Wasley A, Fiore A, Bell BP (2006). Hepatitis A in the era of vaccination. Epidemiol Rev 28: 101–111. Wei YH, Wang IH, Woung LC et al. (2009). Anterior ischemic optic neuropathy associated with pegylated interferon therapy for chronic hepatitis C. Ocul Immunol Inflamm 17: 191–194. Weissenborn K, Ennen JC, Bokemeyer M et al. (2006). Monoaminergic neurotransmission is altered in hepatitis C virus infected patients with chronic fatigue and cognitive impairment. Gut 55: 1624–1630. Wender M (2011). Acute disseminated encephalomyelitis (ADEM). J Neuroimmunol 231: 92–99. Wilkinson J, Radkowski M, Laskus T (2009). Hepatitis C virus neuroinvasion: identification of infected cells. J Virol 83: 1312–1319. Williams R, Riordan SM (2000). Acute liver failure: established and putative hepatitis viruses and therapeutic implications. J Gastroenterol Hepatol 15 (Suppl): G17–G25. Wong MH, Sockalingam S, Zain A (2011). Polymyositis associated with hepatitis B: management with entacavir and prednisolone. Int J Rheum Dis 14: e38–e41. Yang CY, Park SA, Kim HS et al. (2010). Polymyositis in patients taking antiviral clevudine therapy: a report of two cases. NeuroRehabilitation 26: 159–162. Yoffe B, Burns DK, Bhatt HS et al. (1990). Extrahepatic hepatitis B virus DNA sequences in patients with acute hepatitis B infection. Hepatology 12: 187–192. Yoon MS, Obermann M, Dockweiler C et al. (2011). Sensory neuropathy in patients with cryoglobulin negative hepatitis-C infection. J Neurol 258: 80–88. Zignego AL, Cozzi A, Carpenedo R et al. (2007). HCV patients, psychopathology and tryptophan metabolism: analysis of the effects of pegylated interferon plus ribavirin treatment. Dig Liver Dis 39 (Suppl 1): S107–S111.