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Central Nervous System Involvement in Hepatitis C Virus Infection

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Abstract

Hepatic encephalopathy is the most obvious neurological consequence of chronic hepatitis C virus (HCV) infection. There are also case reports of HCV-associated cerebral vasculitis. This review is concerned with the possibility of an effect of HCV on cerebral dysfunction, occurring at an early stage of chronic infection, prior to the development of cirrhosis and unrelated to vasculitis. There is emerging evidence of mild, but significant neurocognitive impairment in HCV infection, which cannot be attributed to substance abuse, coexistent depression, or hepatic encephalopathy. In vivo magnetic resonance spectroscopy and neurophysiological studies have suggested that a biological mechanism may underlie these cognitive findings. The recent detection of HCV genetic sequences in postmortem brain tissue raises the intriguing possibility that HCV infection of the central nervous system may be related to the reported neuropsychological symptoms and cognitive impairment.

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REFERENCES

  • Afonso, A.M., Jiang, J., Penin, F., Tareau, C., Samuel, D., Petit, M.A., Bismuth, H., Dussaix, E., and Feray, C. (1999). Nonrandom distribution of hepatitis C virus quasispecies in plasma and peripheral blood mononuclear cell subsets. J. Virol. 73:9213–9221.

    PubMed  Google Scholar 

  • Alter, M.J., Margolis, H.S., Krawczynski, K., Judson, F.N., Mares, A., Alexander, W.J., Hu, P.Y., Miller, J.K., Gerber, M.A., and Sampliner, R.E. (1992). The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N. Engl. J. Med. 327:1899–1905.

    Google Scholar 

  • Back-Madruga, C., Fontana, R., and Bieliauskas, L. (2003). Predictors of cognitive impairment in chronic hepatitis C patients entering the HALT-C trial. J. Int. Neuropsychol. Soc. 9:245–246.

    Google Scholar 

  • Barkhuizen, A., Rosen, H.R., Wolf, S., Flora, K., Benner, K., and Bennett, R.M. (1999). Musculoskeletal pain and fatigue are associated with chronic hepatitis C: A report of 239 hepatology clinic patients. Am. J. Gastroenterol. 94:1355–1360.

    PubMed  Google Scholar 

  • Bonfoco, E., Krainc, D., Ankarcrona, M., Nicotera, P., and Lipton, S.A. (1995). Apoptosis and necrosis: Two distinct events induced, respectively, by mild and intense insults with N-methyl-d-aspartate or nitric ox-ide/ superoxide in cortical cell cultures. Proc. Natl. Acad. Sci. U.S.A. 92:7162–7166.

    PubMed  Google Scholar 

  • Bonkovsky, H.L., and Woolley, J.M. (1999). Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy. The Consensus Interferon Study Group. Hepatology 29:264–270.

    Article  PubMed  Google Scholar 

  • Cacoub, P., Ratziu, V., Myers, R.P., Ghillani, P., Piette, J.C., Moussalli, J., and Poynard, T. (2002). Impact of treatment on extra hepatic manifestations in patients with chronic hepatitis C. J. Hepatol. 36:812–818.

    PubMed  Google Scholar 

  • Cacoub, P., Sbai, A., Hausfater, P., Papo, T., Gatel, A., and Piette, J.C. (1998). Central nervous system involvement in hepatitis C virus infection. Gastroenterol. Clin. Biol. 22:631–633.

    PubMed  Google Scholar 

  • Carithers, R.L., Jr., Sugano, D., and Bayliss, M. (1996). Health assessment for chronic HCV infection: Results of quality of life. Dig. Dis. Sci. 41:75S–80S.

    Google Scholar 

  • Cordoba, J., Flavia, M., Jacas, C., Sauleda, S., Esteban, J., Vargas, V., Esteban, R., and Guardia, J. (2003a). Quality of life and cognitive function in hepatitis C at different stages of liver disease. J. Hepatol. 39:231–238.

    PubMed  Google Scholar 

  • Cordoba, J., Reyes, J., Esteban, J.I., and Hernandez, J.M. (2003b). Labeling may be an important cause of reduced quality of life in chronic hepatitis C. Am. J. Gastroenterol. 98:226–227.

    PubMed  Google Scholar 

  • Davis, G.L., Balart, L.A., Schiff, E.R., Lindsay, K., Bodenheimer, H.C., Jr., Perrillo, R.P., Carey, W., Jacobson, I.M., Payne, J., and Dienstag, J.L. (1994). Assessing health-related quality of life in chronic hepatitis C using the Sickness Impact Profile. Clin. Ther. 16:334–343.

    PubMed  Google Scholar 

  • Dwight, M.M., Kowdley, K.V., Russo, J.E., Ciechanowski, P.S., Larson, A.M., and Katon, W.J. (2000). Depression, fatigue, and functional disability in patients with chronic hepatitis C. J. Psychosom. Res. 49:311–317.

    PubMed  Google Scholar 

  • Ferenci, P., Lockwood, A., Mullen, K., Tarter, R., Weissenborn, K., and Blei, A.T. (2002). Hepatic encephalopathy—definition, nomenclature, diagnosis, and quantification: Final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 35:716–721.

    PubMed  Google Scholar 

  • Fiala, M., Looney, D.J., Stins, M., Way, D.D., Zhang, L., Gan, X., Chiappelli, F., Schweitzer, E.S., Shapshak, P., Weinand, M., and Graves, M.C. (1997). TNF-alpha opens a paracellular route for HIV-1 invasion across the blood–brain barrier. Mol. Med. 3:553–564.

    PubMed  Google Scholar 

  • Filippini, D., Colombo, F., Jann, S., Cornero, R., and Canesi, B. (2002). Central nervous system involvement in patients with HCV-related cryoglobulinemia: Literature review and a case report. Reumatismo 54:150–155.

    PubMed  Google Scholar 

  • Flugel, A., Bradl, M., Kreutzberg, G.W., and Graeber, M.B. (2001). Transformation of donor-derived bone marrow precursors into host microglia during autoimmune CNS inflammation and during the retrograde response to axotomy. J. Neurosci. Res. 66:74–82.

    PubMed  Google Scholar 

  • Fontana, R.J., Hussain, K.B., Schwartz, S.M., Moyer, C.A., Su, G.L., and Lok, A.S. (2002). Emotional distress in chronic hepatitis C patients not receiving antiviral therapy. J. Hepatol. 36:401–407.

    PubMed  Google Scholar 

  • Forton, D.M., Allsop, J.M., Main, J., Foster, G.R., Thomas, H.C., and Taylor-Robinson, S.D. (2001). Evidence for a cerebral effect of the hepatitis C virus. Lancet 358:38–39.

    PubMed  Google Scholar 

  • Forton, D.M., Thomas, H.C., Murphy, C.A., Allsop, J.M., Foster, G.R., Main, J., Wesnes, K.A., and Taylor-Robinson, S.D. (2002). Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology 35:433–439.

    PubMed  Google Scholar 

  • Forton, D.M., Thomas, H.C., and Taylor-Robinson, S.D. (2003). Quality of life and cognitive function in chronic hepatitis C—what to measure? J. Hepatol. 39:272–274.

    PubMed  Google Scholar 

  • Forton, D.M., Karayiannis, P., Mahmud, N., Taylor-Robinson, S.D., and Thomas, H.C. (2004). Identification of unique hepatitis C virus quasispecies in the central nervous system and comparative analysis of internal translational efficiency of brain, liver, and serum variants. J. Virol. 78:5170–5183.

    PubMed  Google Scholar 

  • Foster, G.R., Goldin, R.D., and Thomas, H.C. (1998). Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis. Hepatology 27:209–212

    Article  PubMed  Google Scholar 

  • Gershon, A.S., Margulies, M., Gorczynski, R.M., and Heathcote, E.J. (2000). Serum cytokine values and fatigue in chronic hepatitis C infection. J. Viral Hepat. 7:397–402.

    PubMed  Google Scholar 

  • Gil, R., Breux, J.P., Neau, J.P., and Becq-Giraudon, B. (1992). Cognitive evoked potentials and HIV infection. Neurophysiol. Clin. 22:385–391.

    PubMed  Google Scholar 

  • Goh, J., Coughlan, B., Quinn, J., O'Keane, J.C., and Crowe, J. (1999). Fatigue does not correlate with the degree of hepatitis or the presence of autoimmune disorders in chronic hepatitis C infection. Eur. J. Gastroenterol. Hepatol. 11:833–838.

    PubMed  Google Scholar 

  • Goulding, C., O'Connell, P., and Murray, F.E. (2001). Prevalence of fibromyalgia, anxiety and depression in chronic hepatitis C virus infection: Relationship to RT-PCR status and mode of acquisition. Eur. J. Gastroenterol. Hepatol. 13:507–511.

    PubMed  Google Scholar 

  • Gowans, E.J. (2000). Distribution of markers of hepatitis C virus infection throughout the body. Semin. Liver Dis. 20:85–102.

    PubMed  Google Scholar 

  • Grassi, L., Mondardini, D., Pavanati, M., Sighinolfi, L., Serra, A., and Ghinelli, F. (2001). Suicide probability and psychological morbidity secondary to HIV infection: A control study of HIV-seropositive, hepatitis C virus (HCV)-seropositive and HIV/HCV-seronegative injecting drug users. J. Affect. Disord. 64:195–202.

    PubMed  Google Scholar 

  • Heaton, R.K., Grant, I., Butters, N., White, D.A., Kirson, D., Atkinson, J.H., McCutchan, J.A., Taylor, M.J., Kelly, M.D., and Ellis, R.J. (1995). The HNRC 500—neuropsychology of HIV infection at different disease stages. HIV Neurobehavioral Research Center. J. Int. Neuropsychol. Soc. 1:231–251.

    PubMed  Google Scholar 

  • Heckmann, J.G., Kayser, C., Heuss, D., Manger, B., Blum, H.E., and Neundorfer, B. (1999). Neurological manifestations of chronic hepatitis C. J. Neurol. 246:486–491.

    PubMed  Google Scholar 

  • Hilsabeck, R.C., Perry, W., and Hassanein, T.I. (2002). Neuropsychological impairment in patients with chronic hepatitis C. Hepatology 35:440–446.

    PubMed  Google Scholar 

  • Johnson, M.E., Fisher, D.G., Fenaughty, A., and Theno, S.A. (1998). Hepatitis C virus and depression in drug users. Am. J. Gastroenterol. 93:785–789.

    PubMed  Google Scholar 

  • Kenny-Walsh, E. (1999). Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. N.Engl.J.Med. 340:1228–1233.

    PubMed  Google Scholar 

  • Kramer, L., Bauer, E., Funk, G., Hofer, H., Jessner, W., Steindl-Munda, P., Wrba, F., Madl, C., Gangl, A., and Ferenci, P. (2002). Subclinical impairment of brain function in chronic hepatitis C infection. J. Hepatol. 37:349–354.

    PubMed  Google Scholar 

  • Kraus, M.R., Schafer, A., Csef, H., Faller, H., Mork, H., and Scheurlen, M. (2001). Compliance with therapy in patients with chronic hepatitis C: Associations with psychiatric symptoms, interpersonal problems, and mode of acquisition. Dig. Dis. Sci. 46:2060–2065.

    PubMed  Google Scholar 

  • Kraus, M.R., Schafer, A., Csef, H., Scheurlen, M., and Faller, H. (2000). Emotional state, coping styles, and somatic variables in patients with chronic hepatitis C. Psychosomatics 41:377–384.

    PubMed  Google Scholar 

  • Krause, J., Schuler, A., Ennen, J.C., Ahl, B., Bokemeyer, M., Boeker, K.H.W., Hecker, H., Manns, M.P., and Weissenborn, K. (2001). Cerebral function in hepatitis C patients with normal liver function. J. Hepatol. 34:156–156.

    PubMed  Google Scholar 

  • Kronfol, Z., and Remick, D.G. (2000). Cytokines and the brain: Implications for clinical psychiatry. Am. J. Psychiatry 157:683–694.

    PubMed  Google Scholar 

  • Laskus, T., Radkowski, M., Bednarska, A., Wilkinson, J., Adair, D., Nowicki, M., Nikolopoulou, G.B., Vargas, H., and Rakela, J. (2002). Detection and analysis of hepatitis C virus sequences in cerebrospinal fluid. J. Virol. 76:10064–10068.

    PubMed  Google Scholar 

  • Laskus, T., Radkowski, M., Wang, L.F., Nowicki, M., and Rakela, J. (2000). Uneven distribution of hepatitis C virus quasispecies in tissues from subjects with end-stage liver disease: Confounding effect of viral adsorption and mounting evidence for the presence of low-level extrahepatic replication. J. Virol. 74:1014–1017.

    PubMed  Google Scholar 

  • Lee, D.H., Jamal, H., Regenstein, F.G., and Perrillo, R.P. (1997). Morbidity of chronic hepatitis C as seen in a tertiary care medical center. Dig. Dis. Sci. 42:186–191.

    PubMed  Google Scholar 

  • Lerat, H., Rumin, S., Habersetzer, F., Berby, F., Trabaud, M.A., Trepo, C., and Inchauspe, G. (1998). In vivo tropism of hepatitis C virus genomic sequences in hematopoietic cells: Influence of viral load, viral genotype, and cell phenotype. Blood 91:3841–3849.

    PubMed  Google Scholar 

  • Maisonobe, T., Leger, J.M., Musset, L., and Cacoub, P. (2002). Neurological manifestations in cryoglobulinemia. Rev. Neurol. (Paris) 158:920–924.

    Google Scholar 

  • Marcellin, P., Boyer, N., Gervais, A., Martinot, M., Pouteau, M., Castelnau, C., Kilani, A., Areias, J., Auperin, A., Benhamou, J.P., and Degott, C. (1997). Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann. Int. Med. 127:875–881.

    PubMed  Google Scholar 

  • Marcus, C.D., Taylor-Robinson, S.D., Sargentoni, J., Ainsworth, J.G., Frize, G., Easterbrook, P.J., Shaunak, S., and Bryant, D.J. (1998). 1 H MR spectroscopy of the brain in HIV-1-seropositive subjects: Evidence for diffuse metabolic abnormalities. Metab. Brain Dis. 13:123–136.

    PubMed  Google Scholar 

  • McDonald, J., Jayasuriya, J., Bindley, P., Gonsalvez, C., and Gluseska, S. (2002). Fatigue and psychological disorders in chronic hepatitis C. J. Gastroenterol. Hepatol. 17:171–176

    PubMed  Google Scholar 

  • McHutchison, J.G., Ware, J.E., Jr., Bayliss, M.S., Pianko, S., Albrecht, J.K., Cort, S., Yang, I., and Neary, M.P. (2001). The effects of interferon alpha-2b in combination with ribavirin on health related quality of life and work productivity. J. Hepatol. 34:140–147.

    PubMed  Google Scholar 

  • Meyerhoff, D.J., Bloomer, C., Cardenas, V., Norman, D., Weiner, M.W., and Fein, G. (1999). Elevated subcortical choline metabolites in cognitively and clinically asymptomatic HIV +patients. Neurology 52:995–1003.

    PubMed  Google Scholar 

  • Middleton, F.A., and Strick, P.L. (2000). Basal ganglia output and cognition: Evidence from anatomical, behavioral, and clinical studies. Brain Cogn. 42:183–200.

    PubMed  Google Scholar 

  • Norenberg, M.D., Itzhak, Y., and Bender, A.S. (1997). The peripheral benzodiazepine receptor and neurosteroids in hepatic encephalopathy. Adv. Exp. Med. Biol. 420:95–111.

    PubMed  Google Scholar 

  • Obhrai, J., Hall, Y., and Anand, B.S. (2001). Assessment of fatigue and psychologic disturbances in patients with hepatitis C virus infection. J. Clin. Gastroenterol. 32:413–417.

    PubMed  Google Scholar 

  • Okuda, M., Hino, K., Korenaga, M., Yamaguchi, Y., Katoh, Y., and Okita, K. (1999). Differences in hypervariable region 1 quasispecies of hepatitis C virus in human serum, peripheral blood mononuclear cells, and liver. Hepatology 29:217–222.

    PubMed  Google Scholar 

  • Origgi, L., Vanoli, M., Carbone, A., Grasso, M., and Scorza, R. (1998). Central nervous system involvement in patients with HCV-related cryoglobulinemia. Am.J.Med.Sci. 315:208–210.

    PubMed  Google Scholar 

  • Pavol, M.A., Meyers, C.A., Rexer, J.L., Valentine, A.D., Mattis, P.J., and Talpaz, M. (1995). Pattern of neurobe-havioral deficits associated with interferon alfa therapy for leukemia. Neurology 45:947–950.

    PubMed  Google Scholar 

  • Peterson, P.K., Hu, S., Salak-Johnson, J., Molitor, T.W., and Chao, C.C. (1997). Differential production of and migratory response to beta chemokines by human microglia and astrocytes. J. Infect. Dis. 175:478–481.

    PubMed  Google Scholar 

  • Radkowski, M., Wilkinson, J., Nowicki, M., Adair, D., Vargas, H., Ingui, C., Rakela, J., and Laskus, T. (2002). Search for hepatitis C virus negative-strand RNA sequences and analysis of viral sequences in the central nervous system: Evidence of replication. J. Virol. 76:600–608.

    PubMed  Google Scholar 

  • Rodger, A.J., Jolley, D., Thompson, S.C., Lanigan, A., and Crofts, N. (1999). The impact of diagnosis of hepatitis C virus on quality of life. Hepatology 30:1299–1301.

    PubMed  Google Scholar 

  • Roudot-Thoraval, F., Abergel, A., Allaert, F., Bourliere, M., Desmorat, H., Fagnani, F., Fontanges, T., Hanana, A., Pol, S., Zarski, J.P., and Rousseaux, C. (2001). Hepavir: The first observational study of patients treated with alpha 2-a interferon for chronic hepatitis C: Evaluation of asthenia and its social consequences. Gastroenterol. Clin. Biol. 25:1061–1066.

    PubMed  Google Scholar 

  • Takyar, S.T., Li, D., Wang, Y., Trowbridge, R., and Gowans, E.J. (2000). Specific detection of minus-strand hepatitis C virus RNA by reverse-transcription polymerase chain reaction on PolyA(+)-purified RNA. Hepatology 32:382–387.

    PubMed  Google Scholar 

  • Thomas, H.C., Torok, M.E., Forton, D.M., and Taylor-Robinson, S.D. (1999). Possible mechanisms of action and reasons for failure of antiviral therapy in chronic hepatitis C. J. Hepatol. 31(Suppl. 1):152–159.

    PubMed  Google Scholar 

  • Tong, M.J., el Farra, N.S., Reikes, A.R., and Co, R.L. (1995). Clinical outcomes after transfusion-associated hepatitis C. N. Engl. J. Med. 332:1463–1466.

    PubMed  Google Scholar 

  • Ware, J.E.J., Bayliss, M.S., Mannocchia, M., and Davis, G.L. (1999). Health-related quality of life in chronic hepatitis C: Impact of disease and treatment response. The Interventional Therapy Group. Hepatology 30:550–555.

    Article  PubMed  Google Scholar 

  • Wessely, S., and Pariante, C. (2002). Fatigue, depression and chronic hepatitis C infection. Psychol. Med. 32:1–10.

    PubMed  Google Scholar 

  • Xiao, B.G., and Link, H. (1998). Immune regulation within the central nervous system. J. Neurol. Sci. 157:1–12.

    PubMed  Google Scholar 

  • Zdilar, D., Franco-Bronson, K., Buchler, N., Locala, J.A., and Younossi, Z.M. (2000). Hepatitis C, interferon alfa, and depression. Hepatology 31:1207–1211.

    PubMed  Google Scholar 

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  1. Hepatology Section, Division of Medicine A, Faculty of Medicine, Imperial College, London, United Kingdom

    Daniel M. Forton, Howard C. Thomas & Simon D. Taylor-Robinson

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  1. Daniel M. Forton
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Forton, D.M., Thomas, H.C. & Taylor-Robinson, S.D. Central Nervous System Involvement in Hepatitis C Virus Infection. Metab Brain Dis 19, 383–391 (2004). https://doi.org/10.1023/B:MEBR.0000043983.42843.ac

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