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Pawłowski T, Radkowski M, Perlejewski K, Szymańska B, Berak H, Horban A, Laskus T. Direct-acting antivirals (DAA) positively affect depression and cognitive function in patients with chronic hepatitis C. PLoS One 2025; 20:e0320221. [PMID: 40184345 PMCID: PMC11970650 DOI: 10.1371/journal.pone.0320221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 02/16/2025] [Indexed: 04/06/2025] Open
Abstract
The aim of the study was to determine how depression and cognitive dysfunction in patients with chronic hepatitis C virus (HCV) infection are affected by treatment with direct-acting antivirals (DAA). Fifty-two chronic hepatitis C patients underwent neurocognitive and psychological evaluation before therapy and 5-6 months later. Depression was measured by Beck Depression Inventory (BDI), anxiety by State-Trait Anxiety inventory (STAI), neuroticism by Eysenck Personality Inventory (N/EPO-R), while Ruff Figural Fluency Test (RFFT), Wisconsin Card Sorting Test (WCST), The Grooved Pegboard Test (GPT), and California Verbal Learning Test (CVLT) were used to assess neurocognitive function. There was significant positive change in BDI scores (8.8 ± 6.6 vs 6.1 ± 6.1; p < 0.0001) while the most striking improvement in cognitive tests was observed for CVLT sum of immediate recall from Trial-1 to Trial-5 (50.9 ± 10.0 to 54.1 ± 10.0; p = 0.0005) and RFFT, where the number of unique designs increased from 77.2 ± 21.0 to 86.1 ± 28.3 (p < 0.0001). These differences remained significant when patients with advanced (METAVIR grade F3/F4) and those with mild (grade F0/F1/F2) liver disease were analyzed separately, although in general the improvements were more pronounced in the former group. In conclusion, in chronic HCV infection the brain function is markedly improved by DAA treatment.
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Affiliation(s)
- Tomasz Pawłowski
- Department of Psychiatry, Wrocław Medical University, Wrocław, Poland
| | - Marek Radkowski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Karol Perlejewski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Bogna Szymańska
- Outpatient Clinic, Warsaw Hospital for Infectious Diseases, Warsaw, Poland
| | - Hanna Berak
- Outpatient Clinic, Warsaw Hospital for Infectious Diseases, Warsaw, Poland
| | - Andrzej Horban
- Department of Adult Infectious Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Tomasz Laskus
- Department of Adult Infectious Diseases, Medical University of Warsaw, Warsaw, Poland
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Zahr N, Sullivan E, Pfefferbaum A. [WITHDRAWN] Serum biomarkers of liver fibrosis identify changes in striatal metabolite levels. RESEARCH SQUARE 2024:rs.3.rs-2729490. [PMID: 37034697 PMCID: PMC10081358 DOI: 10.21203/rs.3.rs-2729490/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
The full text of this preprint has been withdrawn by the authors due to author disagreement with the posting of the preprint. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.
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Radkowski M, Kryczka T, Szymańska-Kotwica B, Berak H, Horban A, Pawłowski T, Perlejewski K, Laskus T. Depression and Cognitive Dysfunction in Patients with Chronic Hepatitis C: Correlation with Viral Replication in the Peripheral Blood Mononuclear Cells and Cytokines in Serum. Int J Mol Sci 2023; 24:15351. [PMID: 37895030 PMCID: PMC10607636 DOI: 10.3390/ijms242015351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 10/13/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is commonly associated with depression and cognitive dysfunction, the cause of which could be related to the HCV neuroinvasion and/or state of chronic inflammation. Viral sequences and proteins were previously detected in the brain and since blood leukocytes can cross the blood-brain barrier, they could provide viral access to the CNS. Eighty chronic hepatitis C patients were tested for viral replication in PBMCs (detection of the HCV RNA-negative strand) and serum cytokines. Depression was assessed by the Beck Depression Inventory (BDI), neuroticism by the Eysenck Personality Inventory (N/EPO-R), and anxiety by the State-Trait Anxiety Inventory (STAI) while neurocognitive testing included the Wisconsin Card Sorting Test (WCST), Ruff Figural Fluency Test (RFFT), California Verbal Learning Test (CVLT), and Grooved Pegboard Test (GPT). The HCV RNA-negative strand was detected in PBMCs from 24 (30%) patients and these patients had significantly higher BDI scores (median 12.5 [IQR] 6.3-20.5 vs. median 8.00 [IQR] 3-12; p = 0.013). Both depression and anxiety correlated positively with IL-8 while cognitive flexibility, executive function, problem-solving skills, memory, and motor functioning correlated negatively with some proinflammatory cytokines. Our findings suggest that due to chronic HCV infection, the brain function is negatively affected by both viral replication in PBMCs and by the immune activation state.
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Affiliation(s)
- Marek Radkowski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 02-106 Warsaw, Poland; (M.R.); (K.P.)
| | - Tomasz Kryczka
- Department of Development of Nursing and Social and Medical Sciences, Medical University of Warsaw, 01-445 Warsaw, Poland;
| | - Bogna Szymańska-Kotwica
- Outpatient Clinic, Warsaw Hospital for Infectious Diseases, 01-201 Warsaw, Poland; (B.S.-K.); (H.B.)
| | - Hanna Berak
- Outpatient Clinic, Warsaw Hospital for Infectious Diseases, 01-201 Warsaw, Poland; (B.S.-K.); (H.B.)
| | - Andrzej Horban
- Department of Adult Infectious Diseases, Medical University of Warsaw, 01-201 Warsaw, Poland
| | - Tomasz Pawłowski
- Department of Psychiatry, Wroclaw Medical University, 50-367 Wroclaw, Poland;
| | - Karol Perlejewski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 02-106 Warsaw, Poland; (M.R.); (K.P.)
| | - Tomasz Laskus
- Department of Adult Infectious Diseases, Medical University of Warsaw, 01-201 Warsaw, Poland
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Fang Y, Chen CY, Yu HC, Lin PC. Neuropsychiatric disorders in chronic hepatitis C patients after receiving interferon or direct-acting antivirals: a nationwide cohort study. Front Pharmacol 2023; 14:1191843. [PMID: 37538181 PMCID: PMC10394649 DOI: 10.3389/fphar.2023.1191843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 07/03/2023] [Indexed: 08/05/2023] Open
Abstract
Background: Data on the neuropsychological outcomes after receiving direct-acting antivirals (DAAs) among chronic hepatitis C (CHC) patients have not been well-documented. Aim: This study aimed to evaluate the difference in incidence of neuropsychological disorders (NPDs) after treatment completion between CHC patients receiving interferon (IFN) therapy and DAA therapy. Methods: A nationwide retrospective cohort study was performed using Taiwan's National Health Insurance Research Database (NHIRD) between 2010 and 2018. CHC patients without pre-existing mental disorders were included and divided into the treatment (Tx)-naïve DAA group, retreatment (re-Tx) DAA group, and Tx-naïve IFN group based on their HCV therapy. Propensity score matching was used to balance baseline differences between groups. The primary outcome was the incidence of NPDs during 6 months after completion of therapy. Results: After one-to-one matching, there were 6,461 pairs of patients selected from the Tx-naïve DAA group and Tx-naïve IFN group and 3,792 pairs from the re-Tx DAA group and Tx-naïve IFN group. A lower incidence of NPDs was observed in the Tx-naïve DAA group than in the Tx-naïve IFN group (HR = 0.72, 95% CI = 0.55-0.94, and p = 0.017). The risk of NPDs did not differ between the re-Tx DAA group and the Tx-naïve IFN group (HR = 0.74, 95% CI: 0.52-1.05, and p = 0.092). Conclusion: DAA therapy was associated with lower risk of NPDs when compared with IFN therapy among Tx-naïve CHC patients in a 6-month period after treatment completion, especially among the patients less than 65 years, male gender, and cirrhosis.
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Affiliation(s)
- Yu Fang
- Master Program in Clinical Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pharmacy, Pingtung Veterans General Hospital, Pingtung, Taiwan
| | - Chung-Yu Chen
- Master Program in Clinical Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Hsien-Chung Yu
- Health Management Center, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
- Department of Business Management, Institute of Health Care Management, National Sun Yat-sen University, Kaohsiung, Taiwan
- Department of Nursing, Meiho Institute of Technology, Ping-Tung, Taiwan
| | - Pei-Chin Lin
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
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Mukerjee N, Chaudhari SY, Jha S, Sinha S, Jadhav SB, Dhar R, Rathod VD, Nanaware RB, Chakole RD, Sharma D, Sharma PP, Pawar SD, Ghosh A. Emerging hepatitis C virus and neuron-allied neuroviral intertwine and its therapeutic approaches. Int J Surg 2023; 109:1810-1812. [PMID: 36906766 PMCID: PMC10389473 DOI: 10.1097/js9.0000000000000074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 11/20/2022] [Indexed: 03/13/2023]
Affiliation(s)
- Nobendu Mukerjee
- Department of Microbiology, West Bengal State University, Barasat, Kolkata, West Bengal, India
- Department of Health Sciences, Novel Global Community Educational Foundation, Sydney, New South Wales, Australia
| | | | - Swastika Jha
- Symbiosis School of Biological Sciences, SIU, Pune, Maharashtra
| | - Shweta Sinha
- Manuh Solutions India Private Limited, Bangalore, Karnataka
| | | | - Rajib Dhar
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu
| | - Vivek D. Rathod
- Department of Chemical Technology, Dr Babasaheb Ambedkar Marathwada University, Aurangabad
| | - Rajesh B. Nanaware
- School of Pharmacy, Dr. Vishwanath Karad MIT-World Peace University, Pune
| | | | - Devesh Sharma
- ICMR – National JALMA Institute for Leprosy & Other Mycobacterial Diseases, Agra, Uttar Pradesh
| | - Prince Prashant Sharma
- Department of Pharmaceutical Sciences, Gurukula Kangri (Deemed to be University), Haridwar, Uttarakhand
| | - Sonali D. Pawar
- MGV’s SPH College of Pharmacy, Loknete Vyankatrao Hiray Marg, Malegaon Camp, Malegaon, Nasik, Maharashtra
| | - Arabinda Ghosh
- Department of Botany, Microbiology Division, Gauhati University, Guwahati, Assam, India
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Gutiérrez-Rojas L, de la Gándara Martín JJ, García Buey L, Uriz Otano JI, Mena Á, Roncero C. Patients with severe mental illness and hepatitis C virus infection benefit from new pangenotypic direct-acting antivirals: Results of a literature review. GASTROENTEROLOGIA Y HEPATOLOGIA 2023; 46:382-396. [PMID: 35718017 DOI: 10.1016/j.gastrohep.2022.06.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 05/25/2022] [Accepted: 06/07/2022] [Indexed: 05/09/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) infection is a global health problem that can results in cirrhosis, hepatocellular carcinoma and even death. HCV infection is 3-20-fold more prevalent among patients with versus without severe mental illness (SMI), such as major depressive disorder, personality disorder, bipolar disorder and schizophrenia. Treatment options for HCV were formerly based on pegylated interferon alpha, which is associated with neuropsychiatric adverse events, and this contributed to the exclusion of patients with SMI from HCV treatment, elimination programmes, and clinical trials. Moreover, the assumption of poor adherence, scant access to healthcare and the stigma and vulnerability of this population emerged as barriers and contributed to the low rates of treatment and efficacy. METHODS This paper reviews the literature published between December 2010 and December 2020 exploring the epidemiology of HCV in patients with SMI, and vice versa, the effect of HCV infection, barriers to the management of illness in these patients, and benefits of new therapeutic options with pangenotypic direct antiviral agents (DAAs). RESULTS The approval of DAAs has changed the paradigm of HCV infection treatment. DAAs have proven to be an equally efficacious and safe option that improves quality of life (QoL) in patients SMI. CONCLUSIONS Knowledge of the consequences of the HCV infection and the benefits of treatment with new pangenotypic DAAs among psychiatrists can increase screening, referral and treatment of HCV infection in patients with SMI.
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Affiliation(s)
| | | | - Luisa García Buey
- Gastroenterology Department, Liver Unit, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, Madrid, Spain
| | - Juan I Uriz Otano
- Gastroenterology Department, Liver Unit, Complejo Hospitalario de Navarra, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | - Álvaro Mena
- Infectious Diseases Unit, Internal Medicine Service, Clinical Virology Group, Instituto de Investigación Biomédica de A Coruña (INIBIC)-Complejo Hospitalario Universitario de A Coruña (CHUAC), Universidade da Coruña, Coruña, Spain
| | - Carlos Roncero
- Psychiatry Service, University of Salamanca Health Care Complex and Psychiatric Unit, School of Medicine, Institute of Biomedicine, University of Salamanca, Salamanca, Spain
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Danilescu CM, Ionescu M, Sandulescu DL, Pirlog MC, Streba CT, Rogoveanu I. Perceived Stress in Hepatitis C Virus Infected Patients under the DAA-Based Therapy. Diagnostics (Basel) 2022; 12:1177. [PMID: 35626332 PMCID: PMC9139880 DOI: 10.3390/diagnostics12051177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/29/2022] [Accepted: 05/06/2022] [Indexed: 02/06/2023] Open
Abstract
The Hepatitis C Virus (HCV) infection often associates medical and mental health conditions which lead to increased levels of distress. Our study aimed at assessing the level of perceived stress on a sample of 90 HCV infected patients treated with Direct-Acting Antiviral (DAA) agents for 12 weeks, and its possible correlations with clinical and evolutionary elements. The evaluation was conducted in three phases: before administration of the DAAs (BSL), at the End of the Treatment (EOT), and 24 weeks after the BSL (Sustained Viral Response—SVR). The perceived stress was measured using the Perceived Stress Scale (PSS). The efficiency of the DAA treatment reduced the levels of stress (98.99% moderate and high stress at BSL to 70.00% at SVR). It was observed, for the entire study period (BSL to SVR), that the decrease in the perceived stress severity was significantly associated with demographic items such as gender (p < 0.01), urban environment (p < 0.001), the age of the subjects (p < 0.05), and clinical data such as F4 degree of fibrosis (p = 0.001) and overweight or obesity class II (p < 0.01). The perceived stress is directly associated with the severity of the HCV infection, and it could be significantly lowered by an efficient therapeutic approach, as DAAs are nowadays.
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Affiliation(s)
| | - Mihaela Ionescu
- Department of Medical Informatics and Biostatistics, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Daniela Larisa Sandulescu
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Mihail Cristian Pirlog
- Department of Medical Sociology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Costin Teodor Streba
- Department of Scientific Research Methodology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Ion Rogoveanu
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
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8
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Reichardt JL, Dirks M, Wirries AK, Pflugrad H, Nösel P, Haag K, Lanfermann H, Wedemeyer H, Potthoff A, Weissenborn K, Ding XQ. Brain metabolic and microstructural alterations associated with hepatitis C virus infection, autoimmune hepatitis and primary biliary cholangitis. Liver Int 2022; 42:842-852. [PMID: 34719118 DOI: 10.1111/liv.15093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 10/24/2021] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Neuropsychiatric symptoms in hepatitis C (HCV) patients resemble those of patients with autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC), whilst the mechanisms behind them are unknown. Here we looked for cerebral metabolic and/or microstructural alterations in patients with HCV, AIH or PBC as possible causes behind these symptoms. METHODS Patients with HCV infection (n = 17), AIH (n = 14) or PBC (n = 11) and age-adjusted healthy controls (n = 18) underwent brain magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and psychometric assessment of memory and attention. Brain relative proton density (PD) and T2 relaxation time (T2) were determined in 17 regions of interest (ROIs), as were the concentrations of N-acetyl-aspartate, choline, creatine, myo-inositol and glutamine + glutamate in frontal- (fWM) and parietal white matter (pWM). One-way analysis of variance and Kruskal-Wallis tests were used for group comparison. Correlations between altered neuropsychological findings and MRI/MRS observations were estimated with the Spearman ρ test. RESULTS HCV, AIH and PBC patients revealed similar alterations in brain PD and metabolites compared to controls: significantly decreased PD in 7/17 ROIs in the HCV group, 16/17 ROIs in the PBC group and 14/17 ROIs in the AIH group, significantly increased N-acetyl-aspartate in fWM in all patients, significantly increased choline in the PBC group in both fWM and pWM, in the AIH group only in pWM and with a trend in the HCV group in pWM. Correlation analysis did not reveal significant associations between MRI/MRS alterations and neuropsychological dysfunction. CONCLUSION The findings suggest similar pathophysiological mechanisms behind neuropsychiatric symptoms associated with HCV infection, AIH and PBC.
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Affiliation(s)
- Jan-Luca Reichardt
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Meike Dirks
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | | | - Henning Pflugrad
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Patrick Nösel
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Kim Haag
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Heinrich Lanfermann
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Andrej Potthoff
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - Xiao-Qi Ding
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
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9
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Wirth S. Chronic Viral Hepatitis B and C. TEXTBOOK OF PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY AND NUTRITION 2022:833-842. [DOI: 10.1007/978-3-030-80068-0_63] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Moretti R, Giuffrè M, Merli N, Caruso P, Di Bella S, Tiribelli C, Crocè LS. Hepatitis C Virus-Related Central and Peripheral Nervous System Disorders. Brain Sci 2021; 11:1569. [PMID: 34942871 PMCID: PMC8699483 DOI: 10.3390/brainsci11121569] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatitis C Virus (HCV), despite being a hepatotropic virus, is the causative agent of many systemic disorders, such as vasculitis, autoimmune diseases, lymphoproliferative disorders, and a broad spectrum of neurological and psychiatric manifestations. Although symptoms have been misdiagnosed or underdiagnosed, only recently, evidence of direct (inflammatory) or indirect (immune-mediated) HCV-dependent cerebral effects has been established. HCV infection can promote acute inflammatory response, pro-coagulative status and ischemic disorders, and neurodegeneration. These effects rely on cerebral HCV replication, possibly mediated by blood-brain barrier alterations. Further study is needed to better understand the HCV-related mechanisms of brain damage.
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Affiliation(s)
- Rita Moretti
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Mauro Giuffrè
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Nicola Merli
- Department Neurological Sciences, University of Ferrara, 44121 Ferrara, Italy;
| | - Paola Caruso
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | - Stefano Di Bella
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
| | | | - Lory Saveria Crocè
- Department Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (R.M.); (P.C.); (S.D.B.); (L.S.C.)
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Faccioli J, Nardelli S, Gioia S, Riggio O, Ridola L. Neurological and psychiatric effects of hepatitis C virus infection. World J Gastroenterol 2021; 27:4846-4861. [PMID: 34447230 PMCID: PMC8371503 DOI: 10.3748/wjg.v27.i29.4846] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/07/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is widespread and affects 71 million people worldwide. Although hepatic manifestations are the most frequent, ranging from chronic hepatitis to cirrhosis and hepatocellular carcinoma, it is also associated with several extrahepatic manifestations. Infected patients may present non-specific neurological symptoms, regardless of the presence of liver cirrhosis. Several pathogenetic mechanisms underlying neurological symptoms have been hypothesized: neuroinvasion, immune-mediated damage, neurotransmitter alterations and cryoglobulinemia. Alterations of the central nervous system include cerebral vasculopathy, acute or subacute encephalopathy and inflammatory disorders. HCV infection may be responsible for neuropathies, of which the most frequent form is symmetrical axonal sensory or sensory-motor polyneuropathy which causes loss of leg sensitivity and weakness. Up to 50% of patients with HCV infection may experience cognitive decline and psychological disorders, such as depression and fatigue. HCV associated neurocognitive disorder is independent of the presence of liver cirrhosis and affects different domains than in patients with hepatic encephalopathy. It can be studied using specific tests that mainly explore executive functions, verbal learning and verbal recall. These disorders significantly reduce the quality of life. The new antiviral therapies improve the extrahepatic symptoms of HCV infection and their success depends on the achievement of sustained virological response. However, the effect of therapy may differ depending on the type of organ involved; neurological symptoms can be irreversible if there is organic liver damage. The aim of this review is to provide a critical overview of physiopathological mechanisms, diagnostic and therapeutic strategies of the neurological and psychiatric effects of HCV infection.
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Affiliation(s)
- Jessica Faccioli
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Silvia Nardelli
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Stefania Gioia
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Oliviero Riggio
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Lorenzo Ridola
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
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12
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Zahr NM, Pohl KM, Kwong AJ, Sullivan EV, Pfefferbaum A. Preliminary Evidence for a Relationship between Elevated Plasma TNFα and Smaller Subcortical White Matter Volume in HCV Infection Irrespective of HIV or AUD Comorbidity. Int J Mol Sci 2021; 22:ijms22094953. [PMID: 34067023 PMCID: PMC8124321 DOI: 10.3390/ijms22094953] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 02/08/2023] Open
Abstract
Classical inflammation in response to bacterial, parasitic, or viral infections such as HIV includes local recruitment of neutrophils and macrophages and the production of proinflammatory cytokines and chemokines. Proposed biomarkers of organ integrity in Alcohol Use Disorders (AUD) include elevations in peripheral plasma levels of proinflammatory proteins. In testing this proposal, previous work included a group of human immunodeficiency virus (HIV)-infected individuals as positive controls and identified elevations in the soluble proteins TNFα and IP10; these cytokines were only elevated in AUD individuals seropositive for hepatitis C infection (HCV). The current observational, cross-sectional study evaluated whether higher levels of these proinflammatory cytokines would be associated with compromised brain integrity. Soluble protein levels were quantified in 86 healthy controls, 132 individuals with AUD, 54 individuals seropositive for HIV, and 49 individuals with AUD and HIV. Among the patient groups, HCV was present in 24 of the individuals with AUD, 13 individuals with HIV, and 20 of the individuals in the comorbid AUD and HIV group. Soluble protein levels were correlated to regional brain volumes as quantified with structural magnetic resonance imaging (MRI). In addition to higher levels of TNFα and IP10 in the 2 HIV groups and the HCV-seropositive AUD group, this study identified lower levels of IL1β in the 3 patient groups relative to the control group. Only TNFα, however, showed a relationship with brain integrity: in HCV or HIV infection, higher peripheral levels of TNFα correlated with smaller subcortical white matter volume. These preliminary results highlight the privileged status of TNFα on brain integrity in the context of infection.
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Affiliation(s)
- Natalie M. Zahr
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; (K.M.P.); (A.P.)
- Neuroscience Program, SRI International, Menlo Park, CA 94025, USA;
- Correspondence: ; Tel.: +1-650-859-5243
| | - Kilian M. Pohl
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; (K.M.P.); (A.P.)
- Neuroscience Program, SRI International, Menlo Park, CA 94025, USA;
| | - Allison J. Kwong
- Gastroenterology and Hepatology Medicine, Stanford University School of Medicine, Stanford, CA 94350, USA;
| | | | - Adolf Pfefferbaum
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; (K.M.P.); (A.P.)
- Neuroscience Program, SRI International, Menlo Park, CA 94025, USA;
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13
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Plotogea OM, Ilie M, Bungau S, Chiotoroiu AL, Stanescu AMA, Diaconu CC. Comprehensive Overview of Sleep Disorders in Patients with Chronic Liver Disease. Brain Sci 2021; 11:142. [PMID: 33499194 PMCID: PMC7911845 DOI: 10.3390/brainsci11020142] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/16/2021] [Accepted: 01/19/2021] [Indexed: 12/12/2022] Open
Abstract
The impact of sleep disorders (SDs) on patients with chronic liver diseases (CLD) is tremendous. SDs are frequently encountered among these patients and interfere with their quality of life. This review aims to present the data available so far about the prevalence, phenotypes, and proposed pathophysiological mechanisms of SDs in CLD. Moreover, we proposed to search the literature regarding the most reliable methods to assess SDs and the possible therapeutic options in patients with CLD. The main results of this review show that when it comes to prevalence, the percentages reported vary widely between studies performed among populations from the USA or Europe and those coming from Asian countries. Furthermore, it has been proven that SDs may also be present in the absence of neurocognitive disorders attributable to hepatic encephalopathy (HE), which contradicts traditional suppositions where SDs were considered part of the clinical scenario of HE. Currently, there are no specific recommendations or protocols to assess SDs in CLD patients and data about the therapeutic management are limited. Taking into consideration their impact, a protocol for diagnosing and managing SDs should be developed and included in the daily practice of hepatologists.
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Affiliation(s)
- Oana-Mihaela Plotogea
- Department 5, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Madalina Ilie
- Department 5, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania;
| | | | | | - Camelia Cristina Diaconu
- Department 5, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Department of Internal Medicine, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
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14
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Intrinsic Brain Abnormalities in Patients with Hepatitis C Virus Infection with Cognitive Impairment: A Preliminary Resting-State fMRI Study. BIOMED RESEARCH INTERNATIONAL 2020; 2020:1693043. [PMID: 33204682 PMCID: PMC7655249 DOI: 10.1155/2020/1693043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/22/2020] [Accepted: 10/24/2020] [Indexed: 11/17/2022]
Abstract
Purpose Patients with a hepatitis C virus (HCV) infection frequently exhibit various neuropsychiatric complications such as cognitive decline. This study is aimed at investigating alterations in regional and network-level neural function in patients with HCV infection and examining the association between these alterations and patients' cognition dysfunction. Methods The study included 17 patients with HCV infection and 17 healthy controls. These individuals had undergone resting-state functional magnetic resonance imaging as well as cognitive assessment using a battery of tests that were collectively called the "psychometric hepatic encephalopathy score (PHES)" examination. Analyses of amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity (FC) were conducted to assess, respectively, regional neural function and functional integration. Results HCV-infected patients performed significantly worse in cognitive tests. In the HCV group, ALFF decreased in Region 1 (left medial frontal gyrus and bilateral anterior cingulate gyrus) and Region 2 (right middle and superior frontal gyrus). The HCV group showed lower FC between Region 1 and right middle frontal gyrus, whereas they presented an increase in FC between Region 2 and the left supramarginal gyrus/superior temporal gyrus and right supramarginal gyrus. No significant correlation was observed between ALFF/FC measurements and PHES result. Conclusion This preliminary study presents additional evidence that HCV infection affects brain function, including local intrinsic neural activity and global functional integration.
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15
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Kleefeld F, Arendt G, Neuen-Jacob E, Maschke M, Husstedt I, Obermann M, Schmidt H, Hahn K. [Neurological complications of hepatitis C infections]. DER NERVENARZT 2020; 92:144-149. [PMID: 33001263 PMCID: PMC7873080 DOI: 10.1007/s00115-020-00999-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 08/03/2020] [Indexed: 12/26/2022]
Abstract
Die chronische Hepatitis-C-Virus(HCV)-Infektion ist eine hochprävalente Systemerkrankung, die verschiedene neurologische Komplikationen verursachen kann. Es lassen sich HCV-assoziierte Symptome im zentralen und peripheren Nervensystem sowie der Muskulatur unterscheiden. Wichtige Pathomechanismen sind die HCV-assoziierte Autoimmunität (z. B. gemischte Kryoglobulinämie mit Polyneuropathie) und direkte Neurotoxizität (z. B. bei HCV-assoziierten kognitiven Defiziten). Die häufigsten neurologischen Komplikationen sind distal-symmetrische Polyneuropathien, Small-fiber-Neuropathien und kognitive Defizite. Die HCV-Infektion stellt außerdem einen Risikofaktor für ischämische und hämorrhagische Schlaganfälle sowie den Morbus Parkinson dar. Die frühe Identifikation und antivirale Behandlung HCV-positiver Patienten steht im Zentrum der Behandlung. Durch neue antivirale Therapien können >90 % der Patienten dauerhaft von der HCV-Infektion geheilt werden.
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Affiliation(s)
- Felix Kleefeld
- Klinik für Neurologie, Universitätsmedizin Charité, Charitéplatz 1, 10117, Berlin, Deutschland
| | - Gabriele Arendt
- Neurologie, Neuro-Centrum Düsseldorf, Hohenzollernstr. 5, 40211, Düsseldorf, Deutschland
| | - Eva Neuen-Jacob
- Institut für Neuropathologie, Universitätsklinikum Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Deutschland
| | - Matthias Maschke
- Klinik für Neurologie, Krankenhaus der Barmherzigen Brüder, Nordallee 1, 54292, Trier, Deutschland
| | - Ingo Husstedt
- Praxis an der Klinik Maria Frieden, Am Krankenhaus 1, 48291, Telgte/Münster, Deutschland
| | - Mark Obermann
- Klinik für Neurologie, Asklepios Kliniken Schildautal, Karl-Herold-Str. 1, 38723, Seesen, Deutschland
| | - Holger Schmidt
- Klinik für Neurologie, Elbe-Kliniken Stade, Bremervörder Str. 111, 21682, Stade, Deutschland
| | - Katrin Hahn
- Klinik für Neurologie, Universitätsmedizin Charité, Charitéplatz 1, 10117, Berlin, Deutschland.
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16
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Direct antivirals and cognitive impairment in hepatitis C: a clinical-neurophysiologic study. J Neurovirol 2020; 26:870-879. [PMID: 32910431 PMCID: PMC7716927 DOI: 10.1007/s13365-020-00904-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/05/2020] [Accepted: 08/26/2020] [Indexed: 12/26/2022]
Abstract
Cognition was assessed in hepatitis C virus (HCV) patients, who did not meet the criteria for a minimal hepatic encephalopathy. Their liver function was compensated. We then disentangled potential cognitive changes associated with a sustained virologic response at 12 weeks (SVR-12), following treatment with direct antiviral agents (DAAs). We studied 23 selected HCV patients with a battery of standard neuropsychological tests, and with recordings of the P300 wave, a cerebral potential of “cognitive” significance. There was a baseline evaluation (T0) and a second one 6 months later (T1). We had 2 control groups of comparable age and sex, i.e., 15 patients suffering from non-alcoholic fatty liver disease (NAFLD) and 15 healthy subjects. At T0, we detected a significant (p < 0.05) cognitive impairment in the HCV group, which involved episodic and working memory, attention, visuospatial and verbal abilities, executive functions, and logic reasoning. The P300 latency was significantly (p < 0.05) delayed in the group. At T1, we observed some significant (p < 0.05) HCV recovery in given test domains, e.g., memory, executive functions, and reasoning. Accordingly, the P300 latency shortened significantly (p < 0.05). HCV patients exhibited subtle cognitive defects, somehow independent of their liver condition, possibly linked to direct or indirect brain involvement by the virus. These defects partly recovered following the SVR-12, as achieved through DAAs. The P300 wave was a valid neurophysiologic counterpart of these changes. DAAs can have a role in the early preservation of cognition in HCVs.
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17
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Neuroimaging Findings in Chronic Hepatitis C Virus Infection: Correlation with Neurocognitive and Neuropsychiatric Manifestations. Int J Mol Sci 2020; 21:ijms21072478. [PMID: 32252497 PMCID: PMC7177498 DOI: 10.3390/ijms21072478] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/26/2020] [Accepted: 03/31/2020] [Indexed: 01/18/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is commonly associated with neurocognitive dysfunction, altered neuropsychological performance and neuropsychiatric symptoms. Quantifiable neuropsychological changes in sustained attention, working memory, executive function, verbal learning and recall are the hallmark of HCV-associated neurocognitive disorder (HCV-AND). This constellation is at variance with the neuropsychological complex that is seen in minimal hepatic encephalopathy, which is typified by an array of alterations in psychomotor speed, selective attention and visuo-constructive function. Noncognitive symptoms, including sleep disturbances, depression, anxiety and fatigue, which are less easily quantifiable, are frequently encountered and can dominate the clinical picture and the clinical course of patients with chronic HCV infection. More recently, an increased vulnerability to Parkinson’s disease among HCV-infected patients has also been reported. The degree to which neurocognitive and neuropsychiatric changes are due to HCV replication within brain tissues or HCV-triggered peripheral immune activation remain to be determined. Without absolute evidence that clearly exonerates or indicts HCV, our understanding of the so-called “HCV brain syndrome”, relies primarily on clinical and neuropsychological assessments, although other comorbidities and substance abuse may impact on neurocognitive function, thus confounding an appropriate recognition. In recent years, a number of functional and structural brain imaging studies have been of help in recognizing possible biological markers of HCV-AND, thus providing a rationale for guiding and justifying antiviral therapy in selected cases. Here, we review clinical, neuroradiological, and therapeutic responses to interferon-based and interferon-free regimens in HCV-related cognitive and neuropsychiatric disorder.
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18
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The Many Difficulties and Subtleties in the Cognitive Assessment of Chronic Hepatitis C Infection. Int J Hepatol 2020; 2020:9675235. [PMID: 32257447 PMCID: PMC7106929 DOI: 10.1155/2020/9675235] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 02/27/2020] [Accepted: 03/10/2020] [Indexed: 12/30/2022] Open
Abstract
Since the discovery of HCV in 1989, several diseases have been related to chronic infection by this virus. Often, patients with hepatitis C virus (HCV) complain of cognitive impairment even before the development of hepatic cirrhosis, which they described as "brain fog." Several studies have proposed a link between chronic HCV infection and the development of cognitive alterations, but the inclusion of confounding factors in their samples significantly limits the analysis of the results. In this article, we will give an overview about cognitive dysfunction in patients with HCV.
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19
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Modification of Serum Brain-Derived Neurotrophic Factor Levels Following Anti-HCV Therapy with Direct Antiviral Agents: A New Marker of Neurocognitive Disorders. HEPATITIS MONTHLY 2020. [DOI: 10.5812/hepatmon.95101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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20
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Fortini I, Arouca EMG, Tengam FM, Nitrini R. Chronic HCV infection and neuropsychiatric dysfunction. eNeurologicalSci 2019; 17:100206. [PMID: 31656863 PMCID: PMC6806448 DOI: 10.1016/j.ensci.2019.100206] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 08/23/2019] [Accepted: 09/03/2019] [Indexed: 02/06/2023] Open
Abstract
•Cognitive impairment may contribute to the morbidity of chronic HCV infection.•Deficits in memory recall can be found in chronic HCV patients.•There is a lack of correlation between virus genotypes, viral load and cognitive performance.•Minimal hepatic encephalopathy may be present in HCV patients with cognitive impairment.
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Affiliation(s)
- Ida Fortini
- Department of Neurology, University of São Paulo School of Medicine, Avenida Dr. Eneas de Carvalho Aguiar 155, Room n° 5140, 5th floor, ZIP code: 05403-000 Cerqueira César, São Paulo, Brazil
| | - Eustáquio Martins Gomes Arouca
- Department of Neurology, University of São Paulo School of Medicine, Avenida Dr. Eneas de Carvalho Aguiar 155, Room n° 5140, 5th floor, ZIP code: 05403-000 Cerqueira César, São Paulo, Brazil
| | - Fatima Mitiko Tengam
- Hepatitis C Outpatient Clinic, Department of Infectious and Parasitic Diseases, University of São Paulo School of Medicine, Avenida Dr. Eneas de Carvalho Aguiar 155, 4th floor, Cerqueira César, ZIP code: 05403-000 São Paulo, São Paulo, Brazil
| | - Ricardo Nitrini
- Department of Neurology, University of São Paulo School of Medicine, Avenida Dr. Eneas de Carvalho Aguiar 155, Room n° 5140, 5th floor, ZIP code: 05403-000 Cerqueira César, São Paulo, Brazil
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21
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Amirsardari Z, Rahmani F, Rezaei N. Cognitive impairments in HCV infection: From pathogenesis to neuroimaging. J Clin Exp Neuropsychol 2019; 41:987-1000. [PMID: 31405320 DOI: 10.1080/13803395.2019.1652728] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Extrahepatic manifestations of hepatitis C virus (HCV) infection, in particular cognitive impairments, can be present in the absence of clinical liver dysfunction. Executive memory, attention, and concentration are cognitive domains that are most frequently affected. Microstructural and functional changes in cortical gray matter and basal ganglia associate these neuropsychiatric changes in early HCV infection. No study has covered the relationship between imaging features of HCV-related cognitive impairment and HCV pathology. Herein we summarize evidence suggesting a direct pathology of HCV in microglia, astrocytes, and microvascular endothelial cells, and a neuroinflammatory response in HCV-related cognitive decline. Lipoproteins and their receptors mediate HCV infectivity in the central nervous system and confer susceptibility to HCV-related cognitive decline. Magnetic resonance spectroscopy has revealed changes compatible with reactive gliosis and microglial activation in basal ganglia, frontal and occipital white matter, in the absence of cirrhosis or hepatic encephalopathy. Similarly, diffusion imaging shows evidence of structural disintegrity in the axonal fibers of white matter tracts associated with temporal and frontal cortices. We also discuss the cognitive benefits and side-effects of the two most popular therapeutic protocols interferon-based therapy and interferon-free therapy using direct acting anti-virals. Evidences support a network-based pattern of disruption in functional connectivity in HCV patients and a common neuronal substrate for HCV-related and interferon-therapy-associated cognitive decline. These evidences might help identify patients who benefit from either interferon-based or interferon-free treatment regimen.
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Affiliation(s)
- Zahra Amirsardari
- Student's Scientific Research Center (SSRC), Tehran University of Medical Sciences , Tehran , Iran.,NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN) , Tehran , Iran
| | - Farzaneh Rahmani
- Student's Scientific Research Center (SSRC), Tehran University of Medical Sciences , Tehran , Iran.,NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN) , Tehran , Iran
| | - Nima Rezaei
- NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN) , Tehran , Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences , Tehran , Iran
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22
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Limphaibool N, Iwanowski P, Holstad MJV, Kobylarek D, Kozubski W. Infectious Etiologies of Parkinsonism: Pathomechanisms and Clinical Implications. Front Neurol 2019; 10:652. [PMID: 31275235 PMCID: PMC6593078 DOI: 10.3389/fneur.2019.00652] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 06/04/2019] [Indexed: 12/13/2022] Open
Abstract
Extensive research in recent decades has expanded our insights into the pathogenesis of Parkinson's disease (PD), though the underlying cause remains incompletely understood. Neuroinflammation have become a point of interest in the interconnecting areas of neurodegeneration and infectious diseases. The hypothesis concerning an infectious origin in PD stems from the observation of Parkinson-like symptoms in individuals infected with the influenza virus who then developed encephalitis lethargica. The implications of infectious pathogens have later been studied in neuronal pathways leading to the development of Parkinsonism and PD, through both a direct association and through synergistic effects of infectious pathogens in inducing neuroinflammation. This review explores the relationship between important infectious pathogens and Parkinsonism, including symptoms of Parkinsonism following infectious etiologies, infectious contributions to neuroinflammation and neurodegenerative processes associated with Parkinsonism, and the epidemiologic correlations between infectious pathogens and idiopathic PD.
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Affiliation(s)
| | - Piotr Iwanowski
- Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland
| | | | - Dominik Kobylarek
- Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland
| | - Wojciech Kozubski
- Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland
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23
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Goldstein L, Fogel-Grinvald H, Steiner I. Hepatitis B and C virus infection as a risk factor for Parkinson's disease in Israel-A nationwide cohort study. J Neurol Sci 2019; 398:138-141. [PMID: 30710864 DOI: 10.1016/j.jns.2019.01.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 01/04/2019] [Accepted: 01/10/2019] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To study the association between hepatitis C and B viruses and Parkinson's disease (PD) in Israel. METHODS A retrospective cohort study was performed by analyzing the computerized database of Clalit Healthcare Service in Israel. Cohorts of people with hepatitis C virus (HCV) infection, hepatitis B virus (HBV) infection and nonalcoholic steatohepatitis (NASH) were constructed and compared to a reference cohort for prevalence of PD. RESULTS The prevalence of PD in Israel was found to be 0.5% in the general population. The M-H (Mantel-Haenszel) odds ratio (OR) of PD for HBV-positive patients was 1.08 (95% CI: 1.00-1.16). The M-H OR of PD for HCV-positive patients was 1.18 (95% CI: 1.04-1.35). The M-H OR of PD for patients infected with both hepatitis C and B was 1.13 (95% CI: 0.87-1.47). The M-H OR of PD for patients diagnosed with nonalcoholic steatohepatitis (NASH) was 1.13 (95% CI: 1.08-1.19). CONCLUSIONS We report evidence supporting a minor increased risk for PD in patients with HCV. Co infection of HCV and HBV was not associated with an increased risk for PD. The increased risk for PD in the group of patients with NASH, raises the possibility that liver disease per se is a risk factor for PD rather than viral infection. In addition, it cannot be ruled out that the association is, at least in part, the result of the occurrence of cirrhosis induced parkinsonism that was misclassified as PD.
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Affiliation(s)
- Lilach Goldstein
- Department of Neurology, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Haya Fogel-Grinvald
- School of occupational Therapy, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Israel Steiner
- Department of Neurology, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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24
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Cerebral patterns of neuropsychological disturbances in hepatitis C patients. J Neurovirol 2019; 25:229-238. [PMID: 30610739 DOI: 10.1007/s13365-018-0709-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 09/01/2018] [Accepted: 11/20/2018] [Indexed: 12/20/2022]
Abstract
Neuropsychiatric symptoms and cognitive impairment have been consistently reported in patients with hepatitis C virus (HCV) infection. Since the mechanisms behind remain to be established, the present study attempted to assess whether neuropsychological impairments in HCV-infected patients are accompanied by structural alterations in the brain. Therefore, 19 anti-HCV-antibody-positive women with mild liver disease and 16 healthy controls underwent extensive neuropsychological testing and cranial magnetic resonance imaging (MRI) examination. Nine of the patients and five controls were followed up after 6-7 years. Voxel-based morphometry and magnetization transfer imaging were utilized to study HCV-associated structural gray and white matter changes. The HCV-infected patients had significantly worse fatigue and depression scores and significantly poorer performance on attention and memory tests than controls. The patients displayed gray matter (GM) atrophy in the bilateral insula and thalamus and a profound GM volume increases in the cerebellum. Microstructural GM changes in the insula were also evident by a reduced magnetization transfer ratio. Structural white matter changes were observed along several descending and crossing fiber tracts. Follow-up at 7 years revealed increased GM atrophy in the left amygdala and left parahippocampal regions over time. We conclude that our data provide evidence for structural alterations in the brains of patients with chronic HCV infection. Disturbances of cerebellothalamocortical regions and circuits, linking cerebellar projections to the prefrontal cortex through the thalamus, underpin the emotional and cognitive dysfunction characteristically observed in these patients.
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25
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Abo Hagar A, Ashour Y, Negm M, Abdelfatah M, Gad KA, Hashish E. Brain magnetic resonance spectroscopy and cognitive impairment in chronic hepatitis C patients. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2018; 54:43. [PMID: 30613130 PMCID: PMC6302099 DOI: 10.1186/s41983-018-0046-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 12/04/2018] [Indexed: 01/18/2023] Open
Abstract
Background Cognitive dysfunction in patients with chronic hepatitis C virus (HCV) infection may appear long before the development of severe liver cirrhosis. These alterations are not ascribed to hepatic encephalopathy; however, early detection is always difficult. Objective The aim of this study was to assess the changes of magnetic resonance spectroscopy (MRS) metabolites among chronic hepatitis C virus patients with and without cognitive impairment. Patients and methods A cross-sectional study was conducted in Suez Canal University Hospital. Forty-six HCV patients was included and divided into two groups: patients with and without cognitive impairment. Assessment of cognitive function was done using mini-mental state examination and Wechsler Memory Scale - Revised. Both groups were subjected to single-voxel MRS to evaluate metabolites in three brain regions: the basal ganglia, hippocampus, and posterior cingulate gyrus. Results The CHO/Cr was significantly higher, and NAA/Cr was significantly lower in group with cognitive impairment in the basal ganglia and posterior cingulate gyrus. Mini-mental state score had negative significant correlation with PCR of HCV. Mini-mental state score had significant negative and positive correlation with CHO/Cr and NAA/Cr, respectively, in the basal ganglia. All values of the Wechsler Memory Scale were statistically higher in the group without cognitive impairment except verbal memory score. Conclusion There were changes at brain metabolites associated with cognitive impairment in chronic hepatitis C patients regarding a decrease of NAA/Cr ratio and an increase of CHO/Cr ratio at the basal ganglia.
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Affiliation(s)
| | - Youssri Ashour
- Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Mohamed Negm
- Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | | | - Khaled A Gad
- Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Ehab Hashish
- Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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26
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McCready H, Kohno M, Kolessar M, Dennis L, Kriz D, Luber H, Anderson R, Chang M, Sasaki A, Flora K, Vandenbark A, Mitchell SH, Loftis JM, Hoffman WF, Huckans M. Functional MRI and delay discounting in patients infected with hepatitis C. J Neurovirol 2018; 24:738-751. [PMID: 30298201 PMCID: PMC6279508 DOI: 10.1007/s13365-018-0670-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 04/23/2018] [Accepted: 08/15/2018] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus-infected (HCV+) adults evidence increased rates of psychiatric and cognitive difficulties. This is the first study to use functional magnetic resonance imaging (fMRI) to examine brain activation in untreated HCV+ adults. To determine whether, relative to non-infected controls (CTLs), HCV+ adults exhibit differences in brain activation during a delay discounting task (DDT), a measure of one's tendency to choose smaller immediate rewards over larger delayed rewards-one aspect of impulsivity. Twenty adults with HCV and 26 CTLs completed an fMRI protocol during the DDT. Mixed effects regression analyses of hard versus easy trials of the DDT showed that, compared with CTLs, the HCV+ group exhibited less activation in the left lateral occipital gyrus, precuneus, and superior frontal gyrus. There were also significant interactive effects for hard-easy contrasts in the bilateral medial frontal gyrus, left insula, left precuneus, left inferior parietal lobule, and right temporal occipital gyrus; the CTL group evidenced a positive relationship between impulsivity and activation, while the HCV+ group exhibited a negative relationship. Within the HCV+ group, those with high viral load chose immediate rewards more often than those with low viral load, regardless of choice difficulty; those with low viral load chose immediate rewards more often on hard choices relative to easy choices. Results show that HCV+ patients exhibit greater impulsive behavior when presented with difficult choices, and impulsivity is negatively related to activation in regions important for cognitive control. Thus, interventions that decrease impulsive choice may be warranted with some HCV+ patients.
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Affiliation(s)
- Holly McCready
- Research and Development, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA
- Department of Behavioral Neuroscience, School of Medicine, Oregon Health and Science University, Portland, OR, USA
- Department of Psychiatry, School of Medicine, Oregon Health and Science University, Portland, OR, USA
| | - Milky Kohno
- Research and Development, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA
- Department of Behavioral Neuroscience, School of Medicine, Oregon Health and Science University, Portland, OR, USA
- Department of Psychiatry, School of Medicine, Oregon Health and Science University, Portland, OR, USA
| | - Michael Kolessar
- Research and Development, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA
- Department of PM&R and Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Laura Dennis
- Research and Development, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA
- Department of Behavioral Neuroscience, School of Medicine, Oregon Health and Science University, Portland, OR, USA
- Department of Psychiatry, School of Medicine, Oregon Health and Science University, Portland, OR, USA
| | - Daniel Kriz
- Research and Development, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA
| | - Hannah Luber
- Research and Development, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA
| | - Renee Anderson
- Research and Development, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA
| | - Michael Chang
- Research and Development, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA
- The Northwest Hepatitis C Resource Center, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA
| | - Anna Sasaki
- Research and Development, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA
- The Northwest Hepatitis C Resource Center, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA
| | - Kenneth Flora
- Department of Gastroenterology, The Oregon Clinic, Portland, OR, USA
| | - Arthur Vandenbark
- Research and Development, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA
- Department of Neurology, School of Medicine, Oregon Health and Science University, Portland, OR, USA
- Department of Molecular Microbiology and Immunology, School of Medicine, Oregon Health and Science University, Portland, OR, USA
| | - Suzanne H Mitchell
- Department of Behavioral Neuroscience, School of Medicine, Oregon Health and Science University, Portland, OR, USA
- Department of Psychiatry, School of Medicine, Oregon Health and Science University, Portland, OR, USA
- Oregon Institute of Occupational Health Sciences, School of Medicine, Oregon Health and Science University, Portland, OR, USA
| | - Jennifer M Loftis
- Research and Development, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA
- Department of Psychiatry, School of Medicine, Oregon Health and Science University, Portland, OR, USA
- The Northwest Hepatitis C Resource Center, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA
| | - William F Hoffman
- Research and Development, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA
- Department of Behavioral Neuroscience, School of Medicine, Oregon Health and Science University, Portland, OR, USA
- Department of Psychiatry, School of Medicine, Oregon Health and Science University, Portland, OR, USA
- Behavioral Health & Clinical Neurosciences Division, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA
| | - Marilyn Huckans
- Research and Development, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA.
- Department of Psychiatry, School of Medicine, Oregon Health and Science University, Portland, OR, USA.
- The Northwest Hepatitis C Resource Center, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA.
- Behavioral Health & Clinical Neurosciences Division, VA Portland Health Care System, 3710 SW US Veteran's Hospital Road, Portland, OR, 97239, USA.
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García-Guerrero MA, Sánchez Gómez P, Peña Lasa J, Portu Zapirain J, Elizagárate Zabala E, Gorria Bernal V, Ojeda Del Pozo N. Effect of psychiatric symptoms and quality of life on cognitive performance in HCV patients. REVISTA DE PSIQUIATRIA Y SALUD MENTAL 2018; 13:22-30. [PMID: 30082230 DOI: 10.1016/j.rpsm.2018.06.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 03/17/2018] [Accepted: 06/16/2018] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Reduced performance in several cognitive domains has been repeatedly related to hepatitis C virus (HCV). Nevertheless, there is no consensus about the severity or cognitive profile. Moreover, other possible influential variables are scarcely controlled. The aim of this study is to define the specific cognitive profile in HCV after controlling for confounding variables. METHODS Forty-two HCV patients were distributed in 2groups according to the presence of co-infection with human immunodeficiency virus; a third group with 22 healthy controls was also included. The neuropsychological assessment included tests that assess processing speed, executive functioning, verbal memory, visual memory and working memory. Measures of depression (BDI), anxiety (HAM-A), fatigue (MAF), anhedonia (PAS), insomnia (ISI), quality of life (SF-36) and history of drug abuse (DAST-20) were taken in order to explore differences among groups and to control for their possible influence on cognitive performance. RESULTS HCV patients (including human immunodeficiency virus-coinfection) performed significantly worse in all cognitive measures. However, when the effect of BDI, HAM-A, MAF, ISI, SF-36 & DAST-20 was controlled, only verbal memory of HCV patients differed among groups. Coinfected patients performed worse in verbal memory. CONCLUSIONS According to previous studies verbal memory is the unique cognitive domain related to the effect of HCV. The present study does not support that the neurovirulence effect of HCV is decreasing cognitive performance in HCV patients. Nevertheless, the present study cannot relate the fronto-striatal disruption with the cognitive performance in HCV patients.
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Affiliation(s)
- M Acebo García-Guerrero
- Departamento de Métodos y Psicología Experimental, Facultad de Psicología y Educación, Universidad de Deusto, Bilbao, España.
| | - Pedro Sánchez Gómez
- Unidad de Psicosis Refractaria, Hospital Psiquiátrico de Álava, Vitoria, España; Departamento de Neurociencia, Sección de Psiquiatría, Escuela de Medicina y Odontología, Universidad del País Vasco, Vizcaya, España
| | - Javier Peña Lasa
- Departamento de Métodos y Psicología Experimental, Facultad de Psicología y Educación, Universidad de Deusto, Bilbao, España
| | - Joseba Portu Zapirain
- Servicio de Enfermedades Infecciosas, Hospital Universitario de Álava-Hospital Txagorritxu, Vitoria, España
| | - Edorta Elizagárate Zabala
- Unidad de Psicosis Refractaria, Hospital Psiquiátrico de Álava, Vitoria, España; Departamento de Neurociencia, Sección de Psiquiatría, Escuela de Medicina y Odontología, Universidad del País Vasco, Vizcaya, España; CIBERSAM, Centro de Investigación Biomédica en Red de Salud Mental, Madrid, España
| | - Victoria Gorria Bernal
- Departamento de Métodos y Psicología Experimental, Facultad de Psicología y Educación, Universidad de Deusto, Bilbao, España
| | - Natalia Ojeda Del Pozo
- Departamento de Métodos y Psicología Experimental, Facultad de Psicología y Educación, Universidad de Deusto, Bilbao, España
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28
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Yeoh SW, Holmes ACN, Saling MM, Everall IP, Nicoll AJ. Depression, fatigue and neurocognitive deficits in chronic hepatitis C. Hepatol Int 2018; 12:294-304. [PMID: 29931590 DOI: 10.1007/s12072-018-9879-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Accepted: 06/05/2018] [Indexed: 12/11/2022]
Abstract
Patients with chronic hepatitis C virus (HCV) infection experience a range of symptoms including depression, fatigue and neurocognitive deficits, impairing quality of life. Depression, in particular, may be reactive to increased psychosocial stress, and the physical symptoms of advanced HCV or associated comorbidities. However, even patients at an early stage of HCV infection, with minimal hepatic inflammation or comorbidities, report more depressive symptoms and fatigue than the general population. Similarly, specific neurocognitive deficits occur in early stage HCV infection and are independent of the presence of depression or encephalopathy. Therefore, intracerebral neurobiological changes associated with HCV may potentially explain these symptoms. These changes may arise from infiltration of the brain by peripherally induced cytokines, as well as direct neuropathic effects of HCV viral particles penetrating the blood-brain barrier. These phenomena parallel those reported in human immunodeficiency virus (HIV) infection. HCV-associated intracerebral changes include upregulated inflammatory responses, altered neurotransmitter levels, hormonal dysregulation, and release of neurotoxic substances. These may subsequently lead to abnormal neuronal conduction and function in areas of the brain governing affective responses, emotional processing, motivation, attention and concentration. Although direct-acting antiviral medications lead to high rates of HCV clearance, intracerebral changes may not be subsequently reversed and symptoms of depression, fatigue and neurocognitive deficits may persist. There is an ongoing role for multidisciplinary care and pharmacotherapy to manage these symptoms in HCV patients. Furthermore, there may be opportunities for future therapies to specifically target and ameliorate HCV-associated intracerebral changes.
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Affiliation(s)
- Sern Wei Yeoh
- Department of Gastroenterology, Eastern Health, 3 West, Building B, 8 Arnold St, Box Hill, VIC, 3128, Australia.
| | - Alex C N Holmes
- Department of Psychiatry, University of Melbourne, Level 1 North, Main Block, Royal Melbourne Hospital, 300 Grattan St, Parkville, VIC, 3050, Australia
| | - Michael M Saling
- Melbourne School of Psychological Sciences, 12th Floor, Redmond Barry Building, Parkville Campus, University of Melbourne, Parkville, VIC, Australia, 3010.,Department of Clinical Neuropsychology, Austin Health, Heidelberg Repatriation Hospital, 300 Waterdale Rd, Ivanhoe, VIC, 3079, Australia.,Florey Institute for Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia
| | - Ian P Everall
- Department of Psychiatry, University of Melbourne, Level 1 North, Main Block, Royal Melbourne Hospital, 300 Grattan St, Parkville, VIC, 3050, Australia.,Institute of Psychiatry, Psychology and Neuroscience, Kings College London, 16 De Crespigny Park, London, SE5 8AF, UK.,South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Monks Orchard Road, Beckenham, BR3 3BX, UK
| | - Amanda J Nicoll
- Department of Gastroenterology, Eastern Health, 3 West, Building B, 8 Arnold St, Box Hill, VIC, 3128, Australia.,Department of Gastroenterology and Hepatology, Royal Melbourne Hospital, 300 Grattan St, Parkville, VIC, 3050, Australia
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29
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Psychiatric and functional neuroimaging abnormalities in chronic hepatitis C virus patients: Is vasculitis a contributing factor? Arab J Gastroenterol 2018; 19:71-75. [PMID: 29935864 DOI: 10.1016/j.ajg.2018.06.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 03/21/2018] [Accepted: 06/05/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND STUDY AIMS Central nervous system (CNS) involvement in hepatitis C virus (HCV) infection has different facets such as anxiety, depression, cognitive impairment and vasculitis. We were interested in detecting subclinical CNS involvement in chronic HCV infected subjects with and without systemic vasculitis. PATIENTS AND METHODS Nineteen patients (15 females and 4 males) with chronic HCV infection (mean age 46.5 ± 7 and mean duration since diagnosis of HCV infection 4.7 ± 4 years, including 6 (32%) Child-Pugh class A cirrhotic patients) and 30 age, sex and education matched healthy control subjects were studied. Thirteen patients had associated vasculitis. Patients and control subjects were assessed using the block design and comprehension subtests of Wechsler Bellevue Adult Intelligence Scale, Wechsler Memory scale (WMS), Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI). Brain HMPAO Single Photon Emission Computed Tomography (SPECT) was performed for HCV patients. RESULTS Patients with HCV had lower scores on the block design test compared to control subjects (8.37 ± 1.89 versus 10.37 ± 1.47, p < 0.001), lower total WMS scores (43.15 ± 10.49 versus 60.27 ± 8.08, p < 0.001) and higher anxiety and depression scores (16.94 ± 10.46 and 37.17 ± 10.38 versus 10.3 ± 4.67 and 28.9 ± 5.99, p = 0.004 and 0.001, respectively). Total WMS were lower in HCV patients with vasculitis compared to those without vasculitis (39.14 ± 9.3 versus 51.17 ± 8.3, p = 0.019) while the block design and comprehension tests, BAI and BDI were not significantly different between both groups. The block design and comprehension tests, WMS, BAI and BDI were not significantly different between cirrhotic and non-cirrhotic patients. Seven patients had different patterns of cerebral hypoperfusion on SPECT, and all of them had associated vasculitis. Abnormal SPECT was associated with lower total WMS scores (35.87 ± 10.8 versus 46.79 ± 8.6 in those with normal SPECT, p = 0.049). CONCLUSIONS Vasculitis may contribute to the development of neuropsychiatric involvement in HCV patients.
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30
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Oriolo G, Egmond E, Mariño Z, Cavero M, Navines R, Zamarrenho L, Solà R, Pujol J, Bargallo N, Forns X, Martin-Santos R. Systematic review with meta-analysis: neuroimaging in hepatitis C chronic infection. Aliment Pharmacol Ther 2018. [PMID: 29536563 DOI: 10.1111/apt.14594] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Chronic hepatitis C is considered a systemic disease because of extra-hepatic manifestations. Neuroimaging has been employed in hepatitis C virus-infected patients to find in vivo evidence of central nervous system alterations. AIMS Systematic review and meta-analysis of neuroimaging research in chronic hepatitis C treatment naive patients, or patients previously treated without sustained viral response, to study structural and functional brain impact of hepatitis C. METHODS Using PRISMA guidelines a database search was conducted from inception up until 1 May 2017 for peer-reviewed studies on structural or functional neuroimaging assessment of chronic hepatitis C patients without cirrhosis or encephalopathy, with control group. Meta-analyses were performed when possible. RESULTS The final sample comprised 25 studies (magnetic resonance spectroscopy [N = 12], perfusion weighted imaging [N = 1], positron emission tomography [N = 3], single-photon emission computed tomography [N = 4], functional connectivity in resting state [N = 1], diffusion tensor imaging [N = 2] and structural magnetic resonance imaging [N = 2]). The whole sample was of 509 chronic hepatitis C patients, with an average age of 41.5 years old and mild liver disease. A meta-analysis of magnetic resonance spectroscopy studies showed increased levels of choline/creatine ratio (mean difference [MD] 0.12, 95% confidence interval [CI] 0.06-0.18), creatine (MD 0.85, 95% CI 0.42-1.27) and glutamate plus glutamine (MD 1.67, 95% CI 0.39-2.96) in basal ganglia and increased levels of choline/creatine ratio in centrum semiovale white matter (MD 0.13, 95% CI 0.07-0.19) in chronic hepatitis C patients compared with healthy controls. Photon emission tomography studies meta-analyses did not find significant differences in PK11195 binding potential in cortical and subcortical regions of chronic hepatitis C patients compared with controls. Correlations were observed between various neuroimaging alterations and neurocognitive impairment, fatigue and depressive symptoms in some studies. CONCLUSIONS Patients with chronic hepatitis C exhibit cerebral metabolite alterations and structural or functional neuroimaging abnormalities, which sustain the hypothesis of hepatitis C virus involvement in brain disturbances.
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Affiliation(s)
- G Oriolo
- Department of Psychiatry and Psychology, Hospital Clinic, Institut d'Investigació Biomèdica Arthur Pi I Sunyer (IDIBAPS), Centro Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of Barcelona, Barcelona, Spain.,Department of Medicine, Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | - E Egmond
- Department of Psychiatry and Psychology, Hospital Clinic, Institut d'Investigació Biomèdica Arthur Pi I Sunyer (IDIBAPS), Centro Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of Barcelona, Barcelona, Spain.,Department of Medicine, Institute of Neuroscience, University of Barcelona, Barcelona, Spain.,Department of Health and Clinical Psychology, Faculty of Psychology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Z Mariño
- Liver Unit, Hospital Clinic, IDIBAPS, Centro Investigación Biomédica en Red de Enfermedades hepáticas y digestivas, (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - M Cavero
- Department of Psychiatry and Psychology, Hospital Clinic, Institut d'Investigació Biomèdica Arthur Pi I Sunyer (IDIBAPS), Centro Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of Barcelona, Barcelona, Spain.,Department of Medicine, Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | - R Navines
- Department of Psychiatry and Psychology, Hospital Clinic, Institut d'Investigació Biomèdica Arthur Pi I Sunyer (IDIBAPS), Centro Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of Barcelona, Barcelona, Spain.,Department of Medicine, Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | - L Zamarrenho
- Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto - Universidade de São Paulo (USP), Ribeirão Preto (SP), Brazil
| | - R Solà
- Liver Unit, Parc de Salut Mar, Universitat Autonoma de Barcelona, Barcelona, Spain
| | - J Pujol
- MRI Research Unit, Department of Radiology, Hospital del Mar, CIBERSAM, Barcelona, Spain
| | - N Bargallo
- Center of Diagnostic Image (CDIC), Hospital Clinic, Magnetic Resonance Image Core Facility, IDIBAPS, Barcelona, Spain
| | - X Forns
- Liver Unit, Hospital Clinic, IDIBAPS, Centro Investigación Biomédica en Red de Enfermedades hepáticas y digestivas, (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - R Martin-Santos
- Department of Psychiatry and Psychology, Hospital Clinic, Institut d'Investigació Biomèdica Arthur Pi I Sunyer (IDIBAPS), Centro Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of Barcelona, Barcelona, Spain.,Department of Medicine, Institute of Neuroscience, University of Barcelona, Barcelona, Spain.,Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto - Universidade de São Paulo (USP), Ribeirão Preto (SP), Brazil
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31
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Zahr NM. The Aging Brain With HIV Infection: Effects of Alcoholism or Hepatitis C Comorbidity. Front Aging Neurosci 2018; 10:56. [PMID: 29623036 PMCID: PMC5874324 DOI: 10.3389/fnagi.2018.00056] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 02/20/2018] [Indexed: 12/11/2022] Open
Abstract
As successfully treated individuals with Human Immunodeficiency Virus (HIV)-infected age, cognitive and health challenges of normal aging ensue, burdened by HIV, treatment side effects, and high prevalence comorbidities, notably, Alcohol Use Disorders (AUD) and Hepatitis C virus (HCV) infection. In 2013, people over 55 years old accounted for 26% of the estimated number of people living with HIV (~1.2 million). The aging brain is increasingly vulnerable to endogenous and exogenous insult which, coupled with HIV infection and comorbid risk factors, can lead to additive or synergistic effects on cognitive and motor function. This paper reviews the literature on neuropsychological and in vivo Magnetic Resonance Imaging (MRI) evaluation of the aging HIV brain, while also considering the effects of comorbidity for AUD and HCV.
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Affiliation(s)
- Natalie M Zahr
- Neuroscience Program, SRI International, Menlo Park, CA, United States.,Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA, United States
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32
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de Almeida SM, de Pereira AP, Pedroso MLA, Ribeiro CE, Rotta I, Tang B, Umlauf A, Franklin D, Saloner RG, Batista MGR, Letendre S, Heaton RK, Ellis RJ, Cherner M. Neurocognitive impairment with hepatitis C and HIV co-infection in Southern Brazil. J Neurovirol 2018. [PMID: 29516346 PMCID: PMC5993600 DOI: 10.1007/s13365-018-0617-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Although cognitive impairment has been well documented in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) mono-infections, research on neurocognitive effects is limited in the context of HIV/HCV co-infection. The aims of this study were to explore the interplay between HIV and HCV infections in the expression of neurocognitive impairment (NCI), and to examine the differences in test performance between HIV/HCV co-infected and HIV or HCV mono-infected patients. A total of 128 participants from Southern Brazil underwent a comprehensive neuropsychological (NP) battery comprising 18 tests. Participants were grouped according to their serological status: HCV mono-infected (n = 20), HIV mono-infected (n = 48), HIV/HCV co-infected (n = 12), and HIV-/HCV-uninfected controls (n = 48). The frequencies of HIV subtypes B and C between the HIV mono-infected and HIV/HCV co-infected groups were comparable. There was greater prevalence of neuropsychological impairment among all three infection groups compared with the uninfected control group, but no statistically significant differences among mono- and co-infected groups were found. HCV infection was associated with cognitive deficits, independently of liver dysfunction. HCV infection did not show an additive effect on neurocognitive function among HIV+. NCI was independent of HCV RNA on peripheral blood, CSF, and hepatic injury. While we did not find additive global effect, in the present study, there was some evidence of additive HIV/HCV co-infection effects in speed of information processing, executive function, and verbal fluency domains when comparing the co-infected group with the other three groups. NP impairment was not dependent on HCV subtypes.
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Affiliation(s)
- Sérgio Monteiro de Almeida
- Hospital de Clínicas-UFPR, Universidade Federal do Paraná, Seção de Virologia, Setor Análises Clínicas, Rua Padre Camargo, 280, Curitiba, PR, 80060-240, Brazil.
- Faculdades Pequeno Príncipe, Curitiba, Paraná, Brazil.
- Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Paraná, Brazil.
| | - Ana Paula de Pereira
- Hospital de Clínicas-UFPR, Universidade Federal do Paraná, Seção de Virologia, Setor Análises Clínicas, Rua Padre Camargo, 280, Curitiba, PR, 80060-240, Brazil
| | - Maria Lucia Alves Pedroso
- Hospital de Clínicas-UFPR, Universidade Federal do Paraná, Seção de Virologia, Setor Análises Clínicas, Rua Padre Camargo, 280, Curitiba, PR, 80060-240, Brazil
| | - Clea E Ribeiro
- Hospital de Clínicas-UFPR, Universidade Federal do Paraná, Seção de Virologia, Setor Análises Clínicas, Rua Padre Camargo, 280, Curitiba, PR, 80060-240, Brazil
| | - Indianara Rotta
- Hospital de Clínicas-UFPR, Universidade Federal do Paraná, Seção de Virologia, Setor Análises Clínicas, Rua Padre Camargo, 280, Curitiba, PR, 80060-240, Brazil
- Faculdades Pequeno Príncipe, Curitiba, Paraná, Brazil
- Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Paraná, Brazil
| | - Bin Tang
- University of California San Diego, San Diego, CA, USA
| | - Anya Umlauf
- University of California San Diego, San Diego, CA, USA
| | | | | | - Maria Geny Ribas Batista
- Hospital de Clínicas-UFPR, Universidade Federal do Paraná, Seção de Virologia, Setor Análises Clínicas, Rua Padre Camargo, 280, Curitiba, PR, 80060-240, Brazil
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Mapoure NY, Budzi MN, Eloumou SAFB, Malongue A, Okalla C, Luma HN. Neurological manifestations in chronic hepatitis C patients receiving care in a reference hospital in sub-Saharan Africa: A cross-sectional study. PLoS One 2018; 13:e0192406. [PMID: 29513678 PMCID: PMC5841655 DOI: 10.1371/journal.pone.0192406] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 01/22/2018] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Chronic hepatitis C infection is a major public health concern, with a high burden in Sub-Saharan Africa. There is growing evidence that chronic hepatitis C virus (HCV) infection causes neurological complications. This study aimed at assessing the prevalence and factors associated with neurological manifestations in chronic hepatitis C patients. METHODS Through a cross-sectional design, a semi-structured questionnaire was used to collect data from consecutive chronic HCV infected patients attending the outpatient gastroenterology unit of the Douala General Hospital (DGH). Data collection was by interview, patient record review (including HCV RNA quantification, HCV genotyping and the assessment of liver fibrosis and necroinflammatory activity), clinical examination complemented by 3 tools; Neuropathic pain diagnostic questionnaire, Brief peripheral neuropathy screen and mini mental state examination score. Data were analysed using Statistical package for social sciences version 20 for windows. RESULTS Of the 121 chronic hepatitis C patients (51.2% males) recruited, 54.5% (95% Confidence interval: 46.3%, 62.8%) had at least one neurological manifestation, with peripheral nervous system manifestations being more common (50.4%). Age ≥ 55 years (Adjusted Odds Ratio: 4.82, 95%CI: 1.02-18.81, p = 0.02), longer duration of illness (AOR: 1.012, 95%CI: 1.00-1.02, p = 0.01) and high viral load (AOR: 3.40, 95% CI: 1.20-9.64, p = 0.02) were significantly associated with neurological manifestations. Peripheral neuropathy was the most common neurological manifestation (49.6%), presenting mainly as sensory neuropathy (47.9%). Age ≥ 55 years (AOR: 6.25, 95%CI: 1.33-29.08, p = 0.02) and longer duration of illness (AOR: 1.01, 1.00-1.02, p = 0.01) were significantly associated with peripheral neuropathy. CONCLUSION Over half of the patients with chronic hepatitis C attending the DGH have a neurological manifestation, mainly presenting as sensory peripheral neuropathy. Routine screening of chronic hepatitis C patients for peripheral neuropathy is therefore necessary, with prime focus on those with older age and longer duration of illness.
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Affiliation(s)
- N. Y. Mapoure
- Department of Clinical Sciences, Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Douala, Cameroon
- Department of Internal Medicine, Douala General Hospital, Douala, Cameroon
| | - M. N. Budzi
- Faculty of Health Sciences, University of Buea, Buea, Cameroon
| | - S. A. F. B. Eloumou
- Department of Clinical Sciences, Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Douala, Cameroon
- Department of Internal Medicine, Douala General Hospital, Douala, Cameroon
| | - A. Malongue
- Department of Internal Medicine, Douala General Hospital, Douala, Cameroon
| | - C. Okalla
- Department of Internal Medicine, Douala General Hospital, Douala, Cameroon
- Department of Biological Sciences, Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Douala, Cameroon
| | - H. N. Luma
- Department of Internal Medicine, Douala General Hospital, Douala, Cameroon
- Department of Internal Medicine, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaounde, Cameroon
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Forton D, Weissenborn K, Bondin M, Cacoub P. Expert opinion on managing chronic HCV in patients with neuropsychiatric manifestations. Antivir Ther 2018; 23:47-55. [PMID: 30451150 DOI: 10.3851/imp3245] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2018] [Indexed: 10/27/2022]
Abstract
Neurological manifestations of HCV infection appear to be under-recognized in clinical practice despite the majority of HCV-infected patients experiencing symptoms such as fatigue, depression and cognitive dysfunction. There is also growing evidence for a link between HCV infection and an increased risk of Parkinson's disease. The mechanism underpinning the association between HCV and these neuropsychiatric syndromes still requires further investigation. Here we review the pre-clinical and clinical evidence for a link between HCV and effects on the central nervous system leading to neuropsychiatric syndromes. Lastly, we describe how improvements in neuropsychiatric manifestations of HCV following treatment have been observed, which is subsequently reflected in an overall improvement in health-related quality of life.
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Affiliation(s)
- Daniel Forton
- Department of Gastroenterology and Hepatology, St George's Hospital London, London, UK
- St George's University of London, London, UK
| | | | | | - Patrice Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France
- INSERM, UMR_S 959, Paris, France
- CNRS, FRE3632, F-75005, Paris, France
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France
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35
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Triantos CK, Tsintoni A, Karaivazoglou K, Grigoropoulou X, Tsolias C, Diamantopoulou G, Iconomou G, Thomopoulos K, Labropoulou-Karatza C, Assimakopoulos K. Male hepatitis C patients' sexual functioning and its determinants. Eur J Gastroenterol Hepatol 2017; 29:1241-1246. [PMID: 28914698 DOI: 10.1097/meg.0000000000000971] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVE The aim of the study was to detect sexual impairment in male hepatitis C virus patients and determine its associations. PATIENTS AND METHODS A total of 61 male hepatitis C virus patients were enrolled in this cross-sectional study. Sexual functioning was assessed using the International Index of Erectile Function. Health-related quality of life (HRQOL) was evaluated using the Greek version of the Short Form 36 Health Survey, and the presence and severity of anxiety and depression were assessed using the Greek version of the Hospital Anxiety and Depression Scale. RESULTS Noncirrhotic patients showed clinically significant dysfunction, mainly in intercourse (59.6%) and overall satisfaction (57.4%). Erectile functioning and desire were correlated with depression (r=-0.520, P=0.000 and r=-0.473, P=0.000), anxiety (r=-0.443, P=0.000 and r=-0.428, P=0.001), physical (r=0.427, P=0.001 and r=0.329, P=0.012), and mental (r=0.379, P=0.003 and r=0.432, P=0.001) HRQOL, platelet count (r=-0.357, P=0.012 and r=0.366, P=0.010), and international normalized ratio (INR) levels (r=-0.373, P=0.013 and r=-0.440, P=0.003). Erection was also correlated with albumin levels (r=0.310, P=0.032). Orgasmic functioning was associated significantly with platelet count (r=0.322, P=0.024) and INR levels (r=-0.425, P=0.004). Intercourse satisfaction was significantly related to depression (r=-0.435, P=0.001) and anxiety (r=-0.335, P=0.008) levels, physical (r=0.374, P=0.004) and mental (r=0.300, P=0.022) HRQOL, platelet count (r=0.333, P=0.020), and INR levels (r=-0.373, P=0.013), and overall satisfaction was significantly correlated with depressive (r=-0.435, P=0.001) and anxiety (r=-0.278, P=0.033) symptoms, mental HRQOL (r=0.340, P=0.010), platelet count (r=0.316, P=0.029), and INR levels (r=-0.332, P=0.030). CONCLUSION Hepatitis C is accompanied by poor sexual functioning even in the absence of cirrhosis and different correlations emerge for distinct subdomains of male sexuality.
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Affiliation(s)
- Christos K Triantos
- Departments of aGastroenterology bInternal Medicine cDepartment of Psychiatry, School of Medicine, University of Patras, Patras, Greece
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Kumar A, Deep A, Gupta RK, Atam V, Mohindra S. Brain Microstructural Correlates of Cognitive Dysfunction in Clinically and Biochemically Normal Hepatitis C Virus Infection. J Clin Exp Hepatol 2017; 7:198-204. [PMID: 28970706 PMCID: PMC5620352 DOI: 10.1016/j.jceh.2017.03.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Accepted: 03/14/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIMS This study examined correlates of the brain's neurocognitive performance among clinically and biochemically normal adult patient with hepatitis C virus (HCV). We hypothesized that anti-HCV positive individuals would demonstrate structural brain abnormalities and neurocognitive dysfunction as well as the changes in cell component and extracellular space in the white matter regions of brain in asymptomatic HCV infection by using diffusion tensor tractrography (DTT) metrics. METHODS Anti-HCV positive patient (n = 40), and healthy controls (n = 31), fulfilling inclusion criteria (incidentally detected anti-HCV positive) and able to provide informed consent were screened and recruited for the study. All these subjects and controls underwent subjective assessment of their quality of life related symptoms, neuropsychometric tests (NPT) and magnetic resonance imaging. RESULTS The patients were subjected to neuroimaging as well as psychological testing. There was no significant difference in basic laboratory parameters in these two groups. Independent t-test reveals significantly lower neuropsychological functioning as compared to healthy control. A significantly decreased FA values and myoinsitol were observed in HCV subjects on sensory, inferior longitudinal fascicules, and STR fiber bundles as compared to healthy control. Bivariate correlation analysis reveals that neuropsychological scores are significantly positive. CONCLUSION Our result show that HCV positive individuals would demonstrate structural brain abnormalities and neurocognitive dysfunction as well as the changes in cell component and extracellular space in the white matter regions of brain in asymptomatic HCV infection by using DTT metrics.
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Key Words
- BD, block design
- CC, central cortex
- Cho, choline
- DS, digit symbol
- DTT, diffusion tensor tractrography
- FA, fractional anisotrophy
- FCA, figure connection test A
- FCB, figure connection test B
- Gln, glutamine
- Glx, glutamate
- ILF, inferior longitudinal fascicules
- Ins, inositol
- MD, mean diffusivity
- MRI
- NAA, N-acetylaspartate
- OA, object assembly
- PA, picture arrangement
- PC, picture completion
- QOL, quality of life
- SLF, superior longitudinal fascicules
- STR fiber bundles
- STR, superior thalamic radiations
- hepatitis C virus
- myoinsitol
- neuropsychometric tests
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Affiliation(s)
- Ajay Kumar
- Department of Medical Gastroenterology, King George's Medical University, Lucknow 226003, India,Address for correspondence: Ajay Kumar, Assistant Prof, Department of Medical Gastroenterology, K.G. Medical University, Lucknow, UP 226003, India. Tel.: +91 9455519306.Department of Medical Gastroenterology, K.G. Medical UniversityLucknowUP226003India
| | - Amar Deep
- Department of Medical Gastroenterology, King George's Medical University, Lucknow 226003, India,Experimental and Public Health Lab, Department of Zoology, University of Lucknow, 226003, India
| | - Rakesh K. Gupta
- Department of Radiodiagnosis, SGPGIMS, Lucknow 226003, India
| | - Virendra Atam
- Department of Medicine, King George's Medical University, India
| | - Samir Mohindra
- Department of Gastroenterology, SGPGIMS, Lucknow, UP, India
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37
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Hadjihambi A, Arias N, Sheikh M, Jalan R. Hepatic encephalopathy: a critical current review. Hepatol Int 2017; 12:135-147. [PMID: 28770516 PMCID: PMC5830466 DOI: 10.1007/s12072-017-9812-3] [Citation(s) in RCA: 123] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Accepted: 07/06/2017] [Indexed: 12/12/2022]
Abstract
Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of cirrhosis and/or porto-systemic shunting. The clinical symptoms are widely variable, extending from subtle impairment in mental state to coma. The utility of categorizing the severity of HE accurately and efficiently serves not only to provide practical functional information about the current clinical status of the patient but also gives valuable prognostic information. In the past 20–30 years, there has been rapid progress in understanding the pathophysiological basis of HE; however, the lack of direct correlation between pathogenic factors and the severity of HE make it difficult to select appropriate therapy for HE patients. In this review, we will discuss the classification system and its limitations, the neuropsychometric assessments and their challenges, as well as the present knowledge on the pathophysiological mechanisms. Despite the many prevalent hypotheses around the pathogenesis of the disease, most treatments focus on targeting and lowering the accumulation of ammonia as well as inflammation. However, treatment of minimal HE remains a huge unmet need and a big concerted effort is needed to better define this condition to allow the development of new therapies. We review the currently available therapies and future approaches to treat HE as well as the scientific and clinical data that support their effectiveness.
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Affiliation(s)
- Anna Hadjihambi
- Division of Medicine, UCL Medical School, Royal Free Hospital, UCL Institute for Liver and Digestive Health, Rowland Hill Street, London, NW3 2PF, UK.,Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, UK
| | - Natalia Arias
- Division of Medicine, UCL Medical School, Royal Free Hospital, UCL Institute for Liver and Digestive Health, Rowland Hill Street, London, NW3 2PF, UK.,INEUROPA (Instituto de Neurociencias del Principado de Asturias), Oviedo, Spain
| | - Mohammed Sheikh
- Division of Medicine, UCL Medical School, Royal Free Hospital, UCL Institute for Liver and Digestive Health, Rowland Hill Street, London, NW3 2PF, UK
| | - Rajiv Jalan
- Division of Medicine, UCL Medical School, Royal Free Hospital, UCL Institute for Liver and Digestive Health, Rowland Hill Street, London, NW3 2PF, UK.
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Adinolfi LE, Nevola R, Rinaldi L, Romano C, Giordano M. Chronic Hepatitis C Virus Infection and Depression. Clin Liver Dis 2017; 21:517-534. [PMID: 28689590 DOI: 10.1016/j.cld.2017.03.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) infection is a systemic disease with hepatic and extrahepatic manifestations, including neuropsychiatric conditions. Depression is a frequent disorder, which has been reported in one-third of patients with HCV infection and has an estimated prevalence of 1.5 to 4.0 times higher than that observed in patients with chronic hepatitis B virus infection or the general population. HCV seems to play a direct and indirect role in the development of depression. Impaired quality of life and increasing health care costs have been reported for patients with HCV infection with depression. Treatment-induced HCV clearance has been associated with improvement of depression and quality of life.
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Affiliation(s)
- Luigi Elio Adinolfi
- Department of Medicine, Surgery, Neurology, Metabolism, and Aging Sciences, University of Study of Campania "Luigi Vanvitelli", Piazza Miraglia, Naples 80100, Italy.
| | - Riccardo Nevola
- Department of Medicine, Surgery, Neurology, Metabolism, and Aging Sciences, University of Study of Campania "Luigi Vanvitelli", Piazza Miraglia, Naples 80100, Italy
| | - Luca Rinaldi
- Department of Medicine, Surgery, Neurology, Metabolism, and Aging Sciences, University of Study of Campania "Luigi Vanvitelli", Piazza Miraglia, Naples 80100, Italy
| | - Ciro Romano
- Department of Medicine, Surgery, Neurology, Metabolism, and Aging Sciences, University of Study of Campania "Luigi Vanvitelli", Piazza Miraglia, Naples 80100, Italy
| | - Mauro Giordano
- Department of Medicine, Surgery, Neurology, Metabolism, and Aging Sciences, University of Study of Campania "Luigi Vanvitelli", Piazza Miraglia, Naples 80100, Italy
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Golabi P, Sayiner M, Bush H, Gerber LH, Younossi ZM. Patient-Reported Outcomes and Fatigue in Patients with Chronic Hepatitis C Infection. Clin Liver Dis 2017; 21:565-578. [PMID: 28689594 DOI: 10.1016/j.cld.2017.03.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Fatigue is a common symptom. Diagnosis is difficult. Fatigue is often a complex symptom. In the recent years, fatigue has gained considerable amount of attention. It has 2 major types, central and peripheral, which may occur together or alone. Although fatigue has many strong relations with depression and sleep disorders, it is a separate entity. For the diagnosis of fatigue, self-reports and patient-reported outcomes are highly valuable tools because these methods can reflect patients' perceptions. Treating the underlying disease with newly developed direct-acting antivirals often improves the perceived fatigue. Healthy lifestyle changes are the cornerstone of the treatment.
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Affiliation(s)
- Pegah Golabi
- Betty and Guy Beatty Center for Integrated Research, Inova Health system, Claude Moore Health Education and Research Building, 3rd floor, 300 Gallows Road, Falls Church, VA 22042, USA
| | - Mehmet Sayiner
- Betty and Guy Beatty Center for Integrated Research, Inova Health system, Claude Moore Health Education and Research Building, 3rd floor, 300 Gallows Road, Falls Church, VA 22042, USA; Center for Liver Disease, Department of Medicine, Inova Fairfax Hospital, Claude Moore Health Education and Research Building, 3rd floor, 3300 Gallows Road, Falls Church, VA 22042, USA
| | - Haley Bush
- Betty and Guy Beatty Center for Integrated Research, Inova Health system, Claude Moore Health Education and Research Building, 3rd floor, 300 Gallows Road, Falls Church, VA 22042, USA
| | - Lynn H Gerber
- Betty and Guy Beatty Center for Integrated Research, Inova Health system, Claude Moore Health Education and Research Building, 3rd floor, 300 Gallows Road, Falls Church, VA 22042, USA; Center for Liver Disease, Department of Medicine, Inova Fairfax Hospital, Claude Moore Health Education and Research Building, 3rd floor, 3300 Gallows Road, Falls Church, VA 22042, USA
| | - Zobair M Younossi
- Betty and Guy Beatty Center for Integrated Research, Inova Health system, Claude Moore Health Education and Research Building, 3rd floor, 300 Gallows Road, Falls Church, VA 22042, USA; Center for Liver Disease, Department of Medicine, Inova Fairfax Hospital, Claude Moore Health Education and Research Building, 3rd floor, 3300 Gallows Road, Falls Church, VA 22042, USA.
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40
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Improvements in brain and behavior following eradication of hepatitis C. J Neurovirol 2017; 23:593-602. [PMID: 28560632 DOI: 10.1007/s13365-017-0533-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 04/19/2017] [Accepted: 05/02/2017] [Indexed: 01/18/2023]
Abstract
Despite recent advances in treatment, hepatitis C remains a significant public health problem. The hepatitis C virus (HCV) is known to infiltrate the brain, yet findings from studies on associated neurocognitive and neuropathological changes are mixed. Furthermore, it remains unclear if HCV eradication improves HCV-associated neurological compromise. This study examined the longitudinal relationship between neurocognitive and neurophysiologic markers among healthy HCV- controls and HCV+ adults following successful HCV eradication. We hypothesized that neurocognitive outcomes following treatment would be related to both improved cognition and white matter integrity. Participants included 57 HCV+ participants who successfully cleared the virus at the end of treatment (sustained virologic responders [SVRs]) and 22 HCV- controls. Participants underwent neuropsychological testing and, for a nested subset of participants, neuroimaging (diffusion tensor imaging) at baseline and 12 weeks following completion of HCV therapy. Contrary to expectation, group-level longitudinal analyses did not reveal significant improvement in neurocognitive performance in the SVRs compared to the control group. However, a subgroup of SVRs demonstrated a significant improvement in cognition relative to controls, which was related to improved white matter integrity. Indeed, neuroimaging data revealed beneficial effects associated with clearing the virus, particularly in the posterior corona radiata and the superior longitudinal fasciculus. Findings suggest that a subgroup of HCV+ patients experienced improvements in cognitive functioning following eradication of HCV, which appears related to positive changes in white matter integrity. Future research should examine whether any additional improvements in neurocognition and white matter integrity among SVRs occur with longer follow-up periods.
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41
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Miller TR, Weiss JJ, Bräu N, Dieterich DT, Stivala A, Rivera-Mindt M. Greater decline in memory and global neurocognitive function in HIV/hepatitis C co-infected than in hepatitis C mono-infected patients treated with pegylated interferon and ribavirin. J Neurovirol 2017; 23:260-272. [PMID: 27896573 PMCID: PMC5334364 DOI: 10.1007/s13365-016-0494-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 09/21/2016] [Accepted: 10/20/2016] [Indexed: 12/18/2022]
Abstract
The human immunodeficiency virus (HIV), hepatitis C virus (HCV), and the treatment of HCV with pegylated interferon and ribavirin (IFN/RBV) have been associated with neurocognitive and psychiatric abnormalities. The goal of this research was to prospectively evaluate neurocognitive functioning among a group of HCV mono-infected and HIV/HCV co-infected patients during the first 24 weeks of IFN/RBV treatment while accounting for practice effects, normal variations in change over time, and variations in IFN/RBV treatment exposure. Forty-four HCV mono-infected and 30 HIV/HCV co-infected patients were enrolled in a prospective study of patients beginning on IFN/RBV for chronic HCV infection. Patients were administered a depression inventory, a measure of fatigue, a structured psychiatric interview, and a neurocognitive battery at baseline and 24 weeks after initiation of treatment. Analyses were conducted to explore possible associations between neurocognitive functioning and the following: HIV/HCV co-infection vs. HCV mono-infection, IFN and RBV treatment exposure, psychiatric status, liver disease stage, and other medical characteristics. At baseline, there were no significant differences between the two groups' neuropsychiatric or neurocognitive function other than the mono-infected group had significantly higher reports of fatigue (p = 0.033). Over the course of 24 weeks of treatment after controlling for practice effects, the HIV/HCV co-infected patients experienced significantly greater declines in memory (t(56) = 2.14, p = 0.037) and global neurocognitive functioning (t(53) = 2.28, p = 0.027). In a well-characterized sample of mono-infected and co-infected patients, it appears that persons with HIV/HCV co-infection are potentially more vulnerable to neurocognitive sequalae during HCV treatment.
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Affiliation(s)
- Theodore R Miller
- Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, PO Box 1087, New York, NY, 10029, USA
- Yale School of Nursing, 400 West Campus Drive, Orange, CT, 06477, USA
| | - Jeffrey J Weiss
- Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, PO Box 1087, New York, NY, 10029, USA.
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
| | - Norbert Bräu
- Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, PO Box 1087, New York, NY, 10029, USA
- Infectious Disease Section, Bronx Veterans Affairs Medical Center, 130 W. Kingsbridge Road, Bronx, New York, NY, 10468, USA
| | - Douglas T Dieterich
- Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, PO Box 1087, New York, NY, 10029, USA
| | - Alicia Stivala
- Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, PO Box 1087, New York, NY, 10029, USA
| | - Monica Rivera-Mindt
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- Psychology Department, Fordham University, DE 340, 441 E. Fordham Road, Bronx, NY, 10458, USA
- Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
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Pakpoor J, Noyce A, Goldacre R, Selkihova M, Mullin S, Schrag A, Lees A, Goldacre M. Viral hepatitis and Parkinson disease. Neurology 2017; 88:1630-1633. [DOI: 10.1212/wnl.0000000000003848] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 01/25/2017] [Indexed: 11/15/2022] Open
Abstract
Objective:To study associations between viral hepatitis and Parkinson disease (PD).Methods:A retrospective cohort study was done by analyzing linked English National Hospital Episode Statistics and mortality data (1999–2011). Cohorts of individuals with hepatitis B, hepatitis C, autoimmune hepatitis, chronic active hepatitis, and HIV were constructed, and compared to a reference cohort for subsequent rates of PD.Results:The standardized rate ratio (RR) of PD following hepatitis B was 1.76 (95% confidence interval [CI] 1.28–2.37) (p < 0.001), based on 44 observed compared with 25 expected cases. The RR of PD following hepatitis C was 1.51 (95% CI, 1.18–1.9) (p < 0.001), based on 48.5 expected and 73 observed cases. There was no significant association between autoimmune hepatitis, chronic active hepatitis or HIV, and subsequent PD. When including only those episodes of care for PD that occurred first at least 1 year following each exposure condition, the RR for hepatitis B and hepatitis C were 1.82 (1.29–2.5) and 1.43 (1.09–1.84), respectively.Conclusions:We report strong evidence in favor of an elevation of rates of subsequent PD in patients with hepatitis B and hepatitis C. These findings may be explained by factors peculiar to viral hepatitis, but whether it reflects consequences of infection, shared disease mechanisms, or the result of antiviral treatment remains to be elucidated. Further work is needed to confirm this association and to investigate pathophysiologic pathways, potentially advancing etiologic understanding of PD more broadly.
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Zignego AL, Ramos-Casals M, Ferri C, Saadoun D, Arcaini L, Roccatello D, Antonelli A, Desbois AC, Comarmond C, Gragnani L, Casato M, Lamprecht P, Mangia A, Tzioufas AG, Younossi ZM, Cacoub P. International therapeutic guidelines for patients with HCV-related extrahepatic disorders. A multidisciplinary expert statement. Autoimmun Rev 2017; 16:523-541. [PMID: 28286108 DOI: 10.1016/j.autrev.2017.03.004] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Accepted: 02/26/2017] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) is both hepatotrophic and lymphotropic virus that causes liver as well extrahepatic manifestations including cryoglobulinemic vasculitis, the most frequent and studied condition, lymphoma, and neurologic, cardiovascular, endocrine-metabolic or renal diseases. HCV-extrahepatic manifestations (HCV-EHMs) may severely affect the overall prognosis, while viral eradication significantly reduces non-liver related deaths. Different clinical manifestations may coexist in the same patient. Due to the variety of HCV clinical manifestations, a multidisciplinary approach along with appropriate therapeutic strategies are required. In the era of interferon-free anti-HCV treatments, international recommendations for the therapeutic management of HCV-EHMs are needed. This implies the need to define the best criteria to use antivirals and/or other therapeutic approaches. The present recommendations, based on qualified expert experience and specific literature, will focus on etiological (antiviral) therapies and/or traditional pathogenetic treatments that still maintain their therapeutic utility.
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Affiliation(s)
- Anna Linda Zignego
- Interdepartmental Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
| | - Manuel Ramos-Casals
- Department of Autoimmune Diseases, ICMiD Josep Font Autoimmune Lab, CELLEX-IDIBAPS, Hospital Clinic, Barcelona, Spain
| | - Clodoveo Ferri
- Chair and Rheumatology Unit, Medical School, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria, Policlinico di Modena, 41124 Modena, Italy
| | - David Saadoun
- Sorbonne University, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France; INSERM, UMR S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France
| | - Luca Arcaini
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Dario Roccatello
- Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Center of Research of Immunopathology and Rare Diseases, and Nephrology and Dialysis Unit, San G. Bosco Hospital and University of Turin, Italy
| | - Alessandro Antonelli
- Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, Pisa 56126, Italy
| | - Anne Claire Desbois
- Sorbonne University, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France; INSERM, UMR S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France
| | - Cloe Comarmond
- Sorbonne University, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France; INSERM, UMR S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France
| | - Laura Gragnani
- Interdepartmental Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Milvia Casato
- Department of Clinical Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185 Rome, Italy.
| | - Peter Lamprecht
- Klinik für Rheumatologie Oberarzt, Ratzeburger Allee 160 (Haus 40), 23538 Lübeck, Germany.
| | - Alessandra Mangia
- Liver Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
| | - Athanasios G Tzioufas
- Department of Pathophysiology, School of Medicine, University of Athens, 75 M. Asias st, Building 16, Room, 32 11527 Athens, Greece.
| | - Zobair M Younossi
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA; Beatty Liver and Obesity Program, Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA
| | - Patrice Cacoub
- Sorbonne University, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France; INSERM, UMR S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France
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Kharabian Masouleh S, Herzig S, Klose L, Roggenhofer E, Tenckhoff H, Kaiser T, Thöne-Otto A, Wiese M, Berg T, Schroeter ML, Margulies DS, Villringer A. Functional connectivity alterations in patients with chronic hepatitis C virus infection: A multimodal MRI study. J Viral Hepat 2017; 24:216-225. [PMID: 27813284 DOI: 10.1111/jvh.12634] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 10/05/2016] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis C virus (HCV) infection is associated with fatigue and depression. Cognitive impairments are also reported in a smaller number of HCV-positive patients. Recent studies linked HCV to low-grade inflammation in brain. Here, we test the hypothesis that chronic HCV is associated with 3T-neuroimaging-derived grey matter volume (GMV) and functional connectivity alterations in a sample of chronic HCV (1b), without severe liver disease. Regional GMV and resting-state fMRI-derived eigenvector centrality (EC) were compared between 19 HCV-positive patients and 23 healthy controls (all females, 50-69 and 52-64 years, respectively), controlling for white matter hyperintensities and age. Standard tests were used to assess fatigue, depression and cognitive performance. Also, liver fibrosis stage and viral load were quantified among patients. In comparison with controls, HCV-positive patients had higher scores in fatigue and depression, and worse alertness scores. The groups performed similarly in other cognitive domains. We report higher EC in a cluster in the right anterior superior parietal lobule in patients, while no differences are found in GMV. Post hoc functional connectivity analysis showed increased connectivity of this cluster with primary and secondary somatosensory cortex, and temporal and occipital lobes in patients. Higher mean EC in the superior parietal cluster, adjusted for mean framewise displacement, was associated with better memory and attention performance, but not with fatigue, depression, viral load or level of liver fibrosis, among patients. These results suggest a compensatory mechanism in chronic hepatitis C and explain equivocal results in the literature about cognitive deficits in infected persons. Further studies should define the relation of these connectivity changes to the brain's inflammatory activity.
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Affiliation(s)
- S Kharabian Masouleh
- Department of Neurology, Max Planck Institute for Cognitive and Brain Sciences, Leipzig, Germany
| | - S Herzig
- Clinic for Cognitive Neurology, University of Leipzig, Leipzig, Germany
| | - L Klose
- Clinic for Cognitive Neurology, University of Leipzig, Leipzig, Germany
| | - E Roggenhofer
- Department of Neurology, Max Planck Institute for Cognitive and Brain Sciences, Leipzig, Germany.,LREN, Department for Clinical Neurosciences, CHUV, University of Lausanne, Lausanne, Switzerland
| | - H Tenckhoff
- Section of Hepatology, Department of Gastroenterology and Rheumatology, University Hospital, Leipzig, Germany
| | - T Kaiser
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany
| | - A Thöne-Otto
- Clinic for Cognitive Neurology, University of Leipzig, Leipzig, Germany
| | - M Wiese
- Section of Hepatology, Department of Gastroenterology and Rheumatology, University Hospital, Leipzig, Germany
| | - T Berg
- Section of Hepatology, Department of Gastroenterology and Rheumatology, University Hospital, Leipzig, Germany
| | - M L Schroeter
- Department of Neurology, Max Planck Institute for Cognitive and Brain Sciences, Leipzig, Germany.,Clinic for Cognitive Neurology, University of Leipzig, Leipzig, Germany
| | - D S Margulies
- Max Planck Research Group for Neuroanatomy and Connectivity, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
| | - A Villringer
- Department of Neurology, Max Planck Institute for Cognitive and Brain Sciences, Leipzig, Germany.,Clinic for Cognitive Neurology, University of Leipzig, Leipzig, Germany
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45
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Yarlott L, Heald E, Forton D. Hepatitis C virus infection, and neurological and psychiatric disorders - A review. J Adv Res 2016; 8:139-148. [PMID: 28149649 PMCID: PMC5272938 DOI: 10.1016/j.jare.2016.09.005] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 09/09/2016] [Accepted: 09/09/2016] [Indexed: 02/06/2023] Open
Abstract
An association between hepatitis C virus infection and neuropsychiatric symptoms has been proposed for some years. A variety of studies have been undertaken to assess the nature and severity of these symptoms, which range from fatigue and depression to defects in attention and verbal reasoning. There is evidence of mild neurocognitive impairment in some patients with HCV infection, which is not fully attributable to liver dysfunction or psychosocial factors. Further evidence of a biological cerebral effect has arisen from studies using magnetic resonance spectroscopy; metabolic abnormalities correlate with cognitive dysfunction and resemble the patterns of neuroinflammation that have been described in HIV infection. Recent research has suggested that, in common with HIV infection, HCV may cross the blood brain barrier leading to neuroinflammation. Brain microvascular endothelial cells, astrocytes and microglia may be minor replication sites for HCV. Importantly, patient reported outcomes improve following successful antiviral therapy. Further research is required to elucidate the molecular basis for HCV entry and replication in the brain, and to clarify implications and recommendations for treatment.
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Affiliation(s)
- Lydia Yarlott
- Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, Blackshaw Rd, London SW17 0QT, United Kingdom
| | - Eleanor Heald
- Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, Blackshaw Rd, London SW17 0QT, United Kingdom
| | - Daniel Forton
- Department of Gastroenterology and Hepatology, St George's University Hospitals NHS Foundation Trust, Blackshaw Rd, London SW17 0QT, United Kingdom; St George's, University of London, Cranmer Terrace, London SW17 0RE, United Kingdom
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46
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Weissenborn K, Tillmann HL. HCV encephalopathy - an artefact due to medical care? J Viral Hepat 2016; 23:580-3. [PMID: 27225063 DOI: 10.1111/jvh.12547] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 04/26/2016] [Indexed: 12/14/2022]
Abstract
Anti-HCV positive individuals frequently complain about chronic disabling fatigue, mood alterations and deficits in concentration and memory. Several data provide evidence that such alterations are unrelated to hepatitis C virus (HCV) viremia. Thus, merely being exposed to HCV in the past may be sufficient to trigger, but the HCV exposure itself. This commentary reviews the available data upon this topic with special reference to the paper by Lowry and colleagues published in this issue of the Journal of Viral hepatitis. We will carefully discuss scientific reasons, why HCV may be directly involved in the development of neuropsychiatric symptoms independent from ongoing detectable viremia, as suggested by epidemiological data.
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Affiliation(s)
- K Weissenborn
- Clinic for Neurology, Hannover Medical School, Hannover, Germany
| | - H L Tillmann
- Division of Gastroenterology Hepatology & Nutrition, East Carolina University, Greenville, NC, USA
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47
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Lowry D, Burke T, Galvin Z, Ryan JD, Russell J, Murphy A, Hegarty J, Stewart S, Crowe J. Is psychosocial and cognitive dysfunction misattributed to the virus in hepatitis C infection? Select psychosocial contributors identified. J Viral Hepat 2016; 23:584-95. [PMID: 27167497 DOI: 10.1111/jvh.12544] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 03/29/2016] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C is associated with health-related quality of life and cognitive impairments, even in mild disease. Recent evidence demonstrating hepatitis C virus (HCV) neurotropism has strengthened a neuropathophysiological hypothesis. However, sample heterogeneity confounds study outcomes. A uniquely homogeneous cohort of Irish women, following an iatrogenic HCV outbreak, offers a rare opportunity to control for HCV chronicity and the virus' purported impact on quality of life and cognition. A multi site, three-group, cross-sectional design was employed. Noncirrhotic, iatrogenically infected women, developing either acute or chronic infection, were recruited from prospective tertiary-care liver clinics and the community. Well-matched healthy controls were also recruited. All participants completed a psychosocial survey and were invited to undergo a comprehensive neuropsychological test battery. Significantly distressed psychosocial symptom profiles were observed in those with an iatrogenic HCV exposure history, which was independent of viral chronicity. Chronic and cleared HCV cohorts were not differentiated from each other. Two distinct subgroups, demarcated along 'impaired' vs 'nonimpaired' quality-of-life reports, were clearly identified and logistic regression analysis identified depressed mood and cognitive fatigue, rather than viral status, as statistically significant predictors of group membership. Compared with matched controls, significant cognitive impairments were not observed in either HCV cohort. Our findings provide strong evidence of nonviral factors accounting for quality of life impairment in chronic HCV and they also appear to question existing reports of cognitive dysfunction in mild disease. Depressed mood and cognitive fatigue appear to be critical psychosocial mediators of reduced quality-of-life and we hypothesize that metabolite abnormalities reported in HCV samples may also be confounded by these factors, given the associated literature.
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Affiliation(s)
- D Lowry
- Liver Centre, Mater Misericordiae University Hospital, Dublin 7, Ireland.,Cognitive and Behavioural Neuroscience Research Group, School of Psychology, University College Dublin, Belfield, Dublin 4, Ireland
| | - T Burke
- Cognitive and Behavioural Neuroscience Research Group, School of Psychology, University College Dublin, Belfield, Dublin 4, Ireland.,School of Nursing and Human Sciences, Dublin City University, Dublin 9, Ireland
| | - Z Galvin
- Liver Centre, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - J D Ryan
- Liver Centre, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - J Russell
- Liver Centre, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - A Murphy
- Liver Unit, St. Vincent's University Hospital, Dublin 4, Ireland
| | - J Hegarty
- Liver Unit, St. Vincent's University Hospital, Dublin 4, Ireland
| | - S Stewart
- Liver Centre, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - J Crowe
- Liver Centre, Mater Misericordiae University Hospital, Dublin 7, Ireland
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48
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Ibrahim I, Salah H, El Sayed H, Mansour H, Eissa A, Wood J, Fathi W, Tobar S, Gur RC, Gur RE, Dickerson F, Yolken RH, El Bahaey W, Nimgaonkar V. Hepatitis C virus antibody titers associated with cognitive dysfunction in an asymptomatic community-based sample. J Clin Exp Neuropsychol 2016; 38:861-8. [PMID: 27269819 DOI: 10.1080/13803395.2016.1168780] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is associated with cognitive dysfunction in clinic-based studies. The risk could be attributed to factors such as antiviral medications, substance abuse, or coincidental infection. AIM The aim was to evaluate cognitive function in relation to HCV antibody titers in a community-based sample of asymptomatic individuals at low risk for substance abuse. METHOD Adults were ascertained from a community in Mansoura, Egypt, where HCV is endemic (n = 258). Cognitive performance was evaluated using the Arabic version of the Penn Computerized Neurocognitive Battery. Substance abuse and psychopathology were also assessed. Antibodies to HCV and Toxoplasma gondii (TOX), a common protozoan that can affect cognition, were estimated using serological IgG assays. RESULTS The prevalence of HCV and TOX infection was 17.6% and 52.9%, respectively. HCV antibody titers were significantly associated with worse function in four cognitive tests for accuracy and three tests for speed, after adjusting for covariates (p < .05, beta coefficients, 2.1-3.2). TOX antibody titers were associated with impaired accuracy in one test. CONCLUSIONS The association between HCV antibody titers and cognitive impairment is not mediated by antiviral treatment or substance abuse in this sample. Whether HCV has a causal role in the cognitive dysfunction should be investigated.
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Affiliation(s)
- Ibtihal Ibrahim
- b Department of Psychiatry , Mansoura University School of Medicine , Mansoura , Egypt
| | - Hala Salah
- b Department of Psychiatry , Mansoura University School of Medicine , Mansoura , Egypt
| | - Hanan El Sayed
- b Department of Psychiatry , Mansoura University School of Medicine , Mansoura , Egypt
| | - Hader Mansour
- a Department of Psychiatry , University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic , Pittsburgh , PA , USA.,b Department of Psychiatry , Mansoura University School of Medicine , Mansoura , Egypt
| | - Ahmed Eissa
- b Department of Psychiatry , Mansoura University School of Medicine , Mansoura , Egypt
| | - Joel Wood
- a Department of Psychiatry , University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic , Pittsburgh , PA , USA
| | - Warda Fathi
- b Department of Psychiatry , Mansoura University School of Medicine , Mansoura , Egypt
| | - Salwa Tobar
- b Department of Psychiatry , Mansoura University School of Medicine , Mansoura , Egypt
| | - Ruben C Gur
- d Neuropsychiatry Section, Department of Psychiatry , University of Pennsylvania Perelman School of Medicine , Philadelphia , PA , USA
| | - Raquel E Gur
- d Neuropsychiatry Section, Department of Psychiatry , University of Pennsylvania Perelman School of Medicine , Philadelphia , PA , USA
| | - Faith Dickerson
- e Department of Pediatrics , Johns Hopkins School of Medicine , Baltimore , MD , USA
| | - Robert H Yolken
- f Department of Pediatrics , Stanley Division of Developmental Neurovirology , Baltimore , MD , USA
| | - Wafaa El Bahaey
- b Department of Psychiatry , Mansoura University School of Medicine , Mansoura , Egypt
| | - Vishwajit Nimgaonkar
- a Department of Psychiatry , University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic , Pittsburgh , PA , USA.,c Department of Human Genetics , Graduate School of Public Health, University of Pittsburgh , Pittsburgh , PA , USA
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Mathew S, Faheem M, Ibrahim SM, Iqbal W, Rauff B, Fatima K, Qadri I. Hepatitis C virus and neurological damage. World J Hepatol 2016; 8:545-556. [PMID: 27134702 PMCID: PMC4840160 DOI: 10.4254/wjh.v8.i12.545] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 03/19/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection exhibits a wide range of extrahepatic complications, affecting various organs in the human body. Numerous HCV patients suffer neurological manifestations, ranging from cognitive impairment to peripheral neuropathy. Overexpression of the host immune response leads to the production of immune complexes, cryoglobulins, as well as autoantibodies, which is a major pathogenic mechanism responsible for nervous system dysfunction. Alternatively circulating inflammatory cytokines and chemokines and HCV replication in neurons is another factor that severely affects the nervous system. Furthermore, HCV infection causes both sensory and motor peripheral neuropathy in the mixed cryoglobulinemia as well as known as an important risk aspect for stroke. These extrahepatic manifestations are the reason behind underlying hepatic encephalopathy and chronic liver disease. The brain is an apt location for HCV replication, where the HCV virus may directly wield neurotoxicity. Other mechanisms that takes place by chronic HCV infection due the pathogenesis of neuropsychiatric disorders includes derangement of metabolic pathways of infected cells, autoimmune disorders, systemic or cerebral inflammation and alterations in neurotransmitter circuits. HCV and its pathogenic role is suggested by enhancement of psychiatric and neurological symptoms in patients attaining a sustained virologic response followed by treatment with interferon; however, further studies are required to fully assess the impact of HCV infection and its specific antiviral targets associated with neuropsychiatric disorders.
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Affiliation(s)
- Shilu Mathew
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Muhammed Faheem
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Sara M Ibrahim
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Waqas Iqbal
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Bisma Rauff
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Kaneez Fatima
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ishtiaq Qadri
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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50
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Hjerrild S, Renvillard SG, Leutscher P, Sørensen LH, Østergaard L, Eskildsen SF, Videbech P. Reduced cerebral cortical thickness in Non-cirrhotic patients with hepatitis C. Metab Brain Dis 2016; 31:311-9. [PMID: 26530221 DOI: 10.1007/s11011-015-9752-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 10/21/2015] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection is associated with fatigue, depression, and cognitive impairment even in the absence of severe liver fibrosis or cirrhosis. HCV has been hypothesised to cause neurodegenerative changes through low-grade neuroinflammation. Our aim was to examine whether cortical thickness (CTh) differs between chronic HCV patients and healthy controls, suggestive of cortical atrophy. In this case-control study 43 HCV patients without severe liver fibrosis, substance abuse, or comorbid HIV or hepatitis B virus infection, and 43 age and sex matched controls underwent MRI. Cortical thickness was measured using a surface based approach. Participants underwent semi-structured psychiatric interview and fatigue was assessed using the fatigue severity scale. HCV was associated with higher fatigue scores, and 58 % of HCV patients suffered from significant fatigue (p < 0.0001). Depression was observed in 16 % of patients. Areas of significantly reduced CTh were found in both left and right occipital cortex and in the left frontal lobe after correction for multiple comparisons (p < 0.05). No association between fatigue, former substance abuse, or psychotropic medication and CTh was found. No overall difference in cerebral white and grey matter volume was found. The findings support the hypothesis that HCV is associated with neurodegenerative changes.
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Affiliation(s)
- Simon Hjerrild
- Department for Affective Disorders, Aarhus University Hospital, Skovagervej 2, 8240, Risskov, Denmark.
- Center of Functionally Integrative Neuroscience (CFIN), Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark.
| | - Signe Groth Renvillard
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
- Department for Affective Disorders, Aarhus University Hospital, Skovagervej 2, 8240, Risskov, Denmark
| | - Peter Leutscher
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
| | | | - Leif Østergaard
- Center of Functionally Integrative Neuroscience (CFIN), Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Simon Fristed Eskildsen
- Center of Functionally Integrative Neuroscience (CFIN), Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Poul Videbech
- Department for Affective Disorders, Aarhus University Hospital, Skovagervej 2, 8240, Risskov, Denmark
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