Hepatitis C Neuropsychiatric symptoms-“brain fog”
2013
Mar 1
SVR = Cognitive Improvement
Alan Franciscus, Editor-in-Chief
The staff at the HCV Advocate have written multiple articles on the relationship between the hepatitis C virus and difficulties with cognitive abilities in ourselves, those we love and the general HCV community at-large. Two excellent articles come to mind—Lucinda Porter’s May 2010 HealthWise: “Hepatitis C and Brain Fog” and Dr. Chaim-David Mazoff’s January 2013 article “Brain Fog: It Really Is All in Your Head.”
Both articles discuss serious problems that many people with hepatitis C experience. We call it ‘Brain Fog’ which is a cute name, but from
my own experience and others I talk with about it, it is anything but a cute or funny condition. As one of my friends exclaimed: “This is really scary stuff.” I have to agree—nothing would be more frightening to me than losing the ability to think clearly, retain information and/or have difficulty with trying to work on multiple tasks (to name a few) that affect your everyday life........
Continue reading...
Feb 12
Neuropsychiatric and Psychosocial Issues of Patients With Hepatitis C Infection: A Selective Literature Review
We briefly reviewed the evidence on the association of hepatitis C (HCV) infection with several aspects of mental and psychosocial health..
Fatigue and Psychosomatic Symptoms
Fatigue is probably the most common extra hepatic manifestation of HCV infection with a prevalence of around 50% (21). Most studies have shown higher fatigue levels in the patients with HCV compared with patients with HBV infection and healthy controls
Jan 2013
Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C
2012
HCV-Related Nervous System Disorders
More than half of patients with chronic HCV infection complain of brain fog-(fatigue, impaired concentration, and poor memory) and have a reduced quality of life, regardless of the severity of liver involvement or virus replication rate.
Fatigue, cognitive dysfunction, and mood alterations display a profound effect on social and physical functioning, thus further impacting health-related quality of life (HRQL). In earlier studies, fatigue was shown to have a major functional role in patients with chronic HCV infection
HCV Treatment and the Brain
Alan Franciscus, Editor-in-Chief
From The July 2012
Newsletter @ HCV Advocate
HCV Treatment and the Brain
—Alan Franciscus, Editor-in-Chief
People living with hepatitis C suffer from a variety of complaints including fatigue, muscle/joint pain and cognitive issues commonly referred to as “brain fog” (poor memory, lack of concentration, etc.). These symptoms are generally
found in people with hepatitis C regardless of severity of liver disease.
For many people with hepatitis C, the cognitive issues are one of the most worrisome symptoms because they can affect almost every area of their lives.
The reason for the “brain fog” in people with hepatitis C is not fully understood. Some experts believe that it could be caused by the immune response that is sending out immune system cells to attack and kill the virus.
Other experts theorize that it could be caused by the constant state of fatigue that many people with hepatitis C experience. Still other experts believe that it may be a result of the hepatitis C virus crossing the blood brain barrier and causing
inflammation and damage. The last theory has picked up steam in the last couple of years and a new study is adding to a body of knowledge about the relationship between HCV and the brain. But the big question is what can be done about it? If “brain fog” is caused by the virus or the fatigue associated with HCV then treatment should help to alleviate or at least reduce some of the symptoms of “brain fog.”
With respect to the point that hepatitis C replicates in the brain—to date there have not been any rigorous scientific studies that clearly establish this fact.
For a review of some of the data on HCV and the brain read “Brain Fog: It Really Is All in Your Head,” by C.D. Mazoff, in the January 2012 HCV Advocate.
But a recent study, however, at least leads some credence to the notion that treatment may help to improve some of the symptoms of “brain fog.”
V. Byrnes and colleagues studied 15 non-cirrhotic hepatitis C-infected patients with a variety of tests. Seven HCV-infected
patients were used as a control group. All 15 patients were given brain imaging tests of three different regions of the brain before, during and after treatment as well as tests to evaluate verbal learning, memory, attention, language, executive functioning (overall cognitive processes) and motor skills (muscle and nerve coordination). The control group also had the tests except that the tests were conducted 12-weeks apart. Both groups had mild chronic hepatitis C disease progression.
The authors found that there were markers that showed “improvements in verbal learning, memory, and visuo-spatial emory,” and concluded that “HCV eradication has a beneficial effect on cerebral metabolism and selective aspects of neurocognitive function and is an important factor when contemplating anti-viral therapy in HCV, especially in those with mild disease.”
But not so fast, commented D.M Forton in an editorial titled “Hepatitis C treatment—Clearing the mind” that appeared in the same journal. Dr. Forton remarked that while the study was important and interesting, it did not settle the important question of whether HCV infects and replicates in the brain and that HCV treatment could restore cognitive function.
He went on to remark that “the pilot study from Byrnes and colleagues is small but it serves to re-energise the debate as to whether there is a virological effect of HCV on brain function.” He went on to comment that, “Further large studies are now indicated to determine whether successful antiviral treatment is definitively associated with improvements in rain biochemistry and function.”
Personally, the thought of HCV infecting and replicating in the brain is frightening. This is one theory that I hope is thoroughly debunked.
References:
From The July 2012 Newsletter @ HCV Advocate
Download printable version
In This Issue:
HCV Treatment and the Brain
Alan Franciscus, Editor-in-Chief
HCV Snapshots: DDW 2012
Lucinda K. Porter, RN
Disability & Benefits: SSD – Financial Eligibility
Jacques Chambers, CLU
HealthWise: Hepatitis C: One World, Many Faces
Lucinda K. Porter, RN
HCV Advocate Eblast
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June
Depression Induced by Interferon Therapy
Determining the role of genetic vulnerability to harmful side effects is becoming a crucial issue in order to progress toward
individualized drug therapy with successful outcome. A major obstacle of IFN therapy for chronic hepatitis C is that about a quarter of these patients will develop depressive side effects that can even lead to suicide in some cases.....
May
Interferon - Hepatitis C Drug Can Cause Depression
Hepatitis C Drug can Cause Depression
Released:5/1/2012
Source: Loyola University Health System
Newswise — MAYWOOD, Ill. -- There's a high rate of depression among patients with hepatitis C, but a standard treatment for the disease includes a drug, interferon, that can cause depression.
In a review article, researchers tackle the complexities of diagnosing and managing depression before and after initiating treatment with interferon.
Dr. Murali S. Rao of Loyola University Medical Center is a co-author of the study, published in the International
Journal of Interferon, Cytokine and Mediator Research.
"Depression is a relatively frequent and potentially serious complication of interferon therapy for hepatitis C virus infection," the
researchers write. "However, other etiologies [causes] of depression may coexist and have to be carefully excluded."
Hepatitis C is the most common chronic blood-borne infection in the United States. At least 4 million people have been exposed and 3.2 million are chronic carriers.
The drugs ribavirin and pegylated interferon are mainstay treatments. Pegylated interferon can help relieve muscle and joint pain and reduce the disabling fatigue. But a well-established side effect of interferon is depression of variable severity -- including suicidal thoughts. The prevalence of depression among hepatitis C patients receiving interferon has been reported to be between 10 percent and 40 percent, depending on the screening method used.
One of the main concerns in treating hepatitis C patients is the risk of suicide, especially since many patients already are depressed before beginning therapy. Patients who have a personal or family history of a serious mood disorder, depression, suicidal thoughts or suicide attempts "should be carefully interviewed and referred to a specialist for assessment of suicide
risk and treatment of the underlying disorder before treatment with interferon can be considered," the authors write.
The SSRI class of antidepressants, such as citalopram (brand name, Celexa), have been shown to be effective in treating depression in hepatitis patients treated with interferon. The related SNRI class of antidepressants, such as milnacipran (Savella), also can reduce depressive symptoms in patients taking interferon. But there have been conflicting results
in studies on whether giving antidepressants before starting interferon can prevent depression, the authors write.
Interferon can affect the level of serotonin, a compound that is responsible in part for regulating mood and other brain functions. This may be the reason why antidepressants don't always work in patients who take interferon, the authors write.
Rao, an expert on depression, is chair of the Department of Psychiatry and Behavioral Neurosciences of Loyola University
Chicago Stritch School of Medicine. Other authors are Dr. Haris Papafragkakis (first author) and Dr. Paul Martin of the University of Miami, Dr. Martin Moehlen of Tulane University and Dr. Sonu Dhillon of St. Francis Medical Center in Peoria, Ill.
Source
January
Hep C Can Enter the Human Brain
January 25, 2012
The hepatitis C virus (HCV) not only affects liver cells, it may also establish infection in other cells, notably those associated with the central nervous system (CNS), according to a University of Birmingham, England,study reported by HealthCanal.com.
Though it is unclear if these new findings help explain the increased risk of CNS problems in people living with chronic HCV infection, they do suggest that the CNS is a reservoir for the virus that is not easily reached by HCV treatments; the findings may also explain why therapy does not always cure the infection.
The blood-brain barrier—a network of microvascular endothelial cells—is responsible for keeping microscopic objects, such as
hostile microorganisms, out of the brain. "If this barrier is compromised," said lead author Nicola Fletcher, BSc, PhD, postdoctoral researcher at University of Birmingham, "all kinds of substances can gain access to the brain, which may
explain the fatigue and other symptoms reported by HCV-infected patients."
For the study, researchers examined brain tissue from 10 posthumous donors who had hepatitis C. The researchers found HCV in the brain cells of four of the donors.
Examination of endothelial brain cells verified that they have all the receptors needed for HCV to attach and enter those cells. Indeed, when cultured in the laboratory, these cells released infectious copies of the virus.
"This is the first report that cells of the central nervous system support HCV replication," said corresponding author Jane
McKeating, BSc, PhD, professor of molecular virology at the University of Birmingham. "These observations could have clinical implications providing a reservoir for the virus to persist during anti-viral treatment."
In addition to barring the passage of microorganisms, the blood-brain barrier keeps out a wide range of larger molecules—including, Fletcher believes, many antiviral drugs currently under development. "HCV-infected brain microvascular endothelial cells may provide a reservoir for the virus to persist during anti-viral treatment," Fletcher said.
http://www.hepmag.com/articles/HCV_Brain_Endothelium_2501_21818.shtml
Hepatitis C Virus and the Brain
HCV Infection is Associated With Immune Responses in the Brain
Recent studies have suggested that HCV infection is associated with inflammatory responses in the brain. The brain metabolites choline, creatine and inositol were significantly increased in HCV-infected patients compared with healthy controls..
Liver-induced inflammation hurts the brain
The immune system is activated following injury or infection. The local response can be accompanied by a systemic response, which includes the synthesis and release of different mediators by innate immune cells. The liver is not an exception and when exposed to an acute or chronic insult generates an inflammatory response that may affect other organs. Liver-induced inflammation is able to cause disturbances in the central nervous system (CNS) including metabolic (hyperthermia, somnolence, loss of body weight) and behavioural manifestations (lethargy, anhedonia, decreased social interaction).
These manifestations are collectively termed “sickness behaviour” [1], and are attributed to dysfunction of the CNS.....
The brain on fire-inflammation and depression
Interferons, a form of cytokines which activate the immune system and act as antiviral agents, is a common treatment for hepatitis C infection. Research and clinical studies have shown that interferon therapy can actually lead to depression in patients who have hepatitis C. It's been reported that between 20% and 30% of patients who have hepatitis C and who receive interferon treatment are at risk for depression.........
Journal of Hepatology
Hepatitis C treatment – Clearing the mind
Received 11 November 2011; accepted 14 November 2011. published online 23 November 2011.
Uncorrected Proof
The issue of whether the hepatitis C virus (HCV) affects brain function continues to arouse interest, investigation, and debate. Symptoms such as fatigue, poor memory, and concentration (“brain fog”) are commonplace and an effect of this infection on mental health related quality of life, which is independent of liver fibrosis, is well established [1]. However, despite convergent lines of evidence pointing to a biological effect of HCV within the CNS and some hypothesised mechanisms, there remains, as yet, a lack of incontrovertible evidence to definitively prove the fact. Parallels with HIV infection are commonly drawn, where AIDS related dementia is now rare with highly active anti-retroviral therapy (HAART) but milder neurocognitive impairments can persist despite immune reconstitution and viral suppression [2]. A degenerative brain process is not seen in HCV monoinfection and there remains doubt in the hepatology community as to whether HCV is a virus that can trigger neurological dysfunction. Furthermore, there does not appear to be a clinical consensus as to whether the relatively mild neurocognitive symptoms in HCV infection represent a significant or important element of the disease.
The possibility of a cerebral effect of HCV was raised ten years ago with the publication of proton magnetic resonance spectroscopy (MRS) and neuropsychological data, which showed evidence of altered cerebral metabolism and cognitive impairment in patients without advanced liver disease [3], [4], [5]. A number of further imaging studies, using MRS [6], [7], positron emission tomography (PET) and single-photon emission computed tomography (SPECT) [8] in patients without cirrhosis have demonstrated metabolic and neurochemical brain abnormalities, which differ to those described in hepatic encephalopathy. Rather, the findings suggest an inflammatory state within the brain with altered serotonergic and dopaminergic neurotransmission. In particular, elevated basal ganglia and white matter choline (Cho) and myo-inositol (mI), measured with proton MRS and often reported relative to creatine (Cr), are consistent with glial cell activation and proliferation and parallel changes observed in cerebral HIV infection [9], [10]. Reduced N-acetylaspartate (NAA) has also been reported in HIV and HCV monoinfections [6], [7].
A greater number of reports have documented mild but measureable cognitive deficits in patients with HCV infection, which are not readily accounted for by the severity of liver disease, associated recreational drug use or other potential confounding factors [11]. Although the studies have varied with respect to the degree to which confounders were excluded or controlled for and in terms of their cognitive assessment methodology, there is a reported pattern of deficits in attention, working memory, and learning ability with increased reaction times and relatively preserved accuracy. The prevalence of depression and anxiety was high in these reports but there do not appear to be clear associations between affective symptoms and cognitive function. However, fatigue, perhaps the commonest symptom in HCV infection, was reported to be associated with worse cognitive performance [6].
Despite the increasing body of descriptive literature, there are very few longitudinal reports of the effect of treatment and, in particular, of the effect of successful viral clearance on brain metabolism [12]. It is in this context that the small pilot study from Byrnes and colleagues, published in the current issue, is welcome [13]. Large treatment studies have demonstrated an improvement in HRQL and fatigue after a sustained virological response (SVR) to pegylated interferon and ribavirin but these studies have not generally blinded their subjects to treatment outcome and the knowledge of a “cure” is highly likely to skew results [14]. If the hypothesis to be tested were that a cerebral abnormality is due to HCV itself, objective demonstration of an improvement of that abnormality after SVR would be highly supportive of the hypothesis. Byrnes and colleagues report their findings in a small patient cohort who was studied with proton MRS and cognitive assessment before, during and after standard antiviral treatment with pegylated interferon and ribavirin. A second group of untreated patients was also studied at two time points. Overall, there were no significant changes in cerebral MRS during and after antiviral treatment. However, a sub-group analysis of viral responders and non-responders showed significant metabolic changes over time in the responder group only, consistent with normalisation of the metabolites, previously reported as elevated in HCV infection [9], [10]. Significant reductions were observed in basal ganglia Cho/Cr and mI/Cr ratios in SVRs (n=8) but not in non-responders or relapsers (n=6). The authors interpret this as an improvement in cerebral immune activation in those who cleared the virus. Patients in the treated and untreated groups tended to show an improvement in cognitive function over time, which was ascribed to a practice effect on the cognitive battery. However, when responders and non-responders were compared again, SVRs demonstrated significant improvements in verbal learning, memory and visuospatial memory, which were not seen in the non-responders.
This study is important because it is the first to demonstrate that successful clearance of HCV infection can result in changes in cerebral metabolism that may underlie improvements in neurocognitive performance. The obvious weakness in this paper, which limits the conclusions that can be drawn at this time, is the small sample size. The significant findings are only seen in a sub-group analysis, with very small groups. It is possible that a treatment effect was not seen in the non-responders because of a type II error. Furthermore, the absence of a healthy control group prevents conclusions about the importance of the observed changes. In a study published this year, Pattullo and colleagues also used MRS to assess the effect of SVR on brain metabolism [12]. In a larger study of 40 patients (31 SVRs and 9 non-responders) significant increases in globus pallidus Cho/Cr and NAA/Cr were seen in SVRs after treatment compared to baseline. These changes were not associated with cognitive measures, which did not improve with viral eradication. The opposite effect of viral eradication on Cho/Cr in the report from Byrne and colleagues is not readily explained but may be related to different patient characteristics, voxel position and acquisition parameters. Pattullo does however report reductions in globus pallidus NAA/Cr at baseline compared to controls, which increased significantly in the SVRs. Despite this, the authors concluded that when all other causes for cerebral dysfunction are excluded, viral clearance does not contribute to significant changes in brain function or biochemistry.
There are a number of strands of evidence, in addition to clinical data, that support a biological effect of HCV on the brain. Positive and negative strand HCV genetic sequences have been amplified from RNA extracted from human post-mortem brain samples and quasispecies analyses suggest replication within the CNS, albeit at a low level [15], [16]. Immunohistochemical staining for HCV non-structural protein 3 (NS3) in brain tissue suggests that astrocytes and microglia might be the host cell for HCV infection [17]. Gene expression analysis in laser dissected microglia, which stained with antibodies against HCV NS3, revealed up-regulation of proinflammatory genes such as TNF alpha and IL-1b that was not seen in NS3−ve microglia or in cells from HCV−ve individuals [18]. There are emerging in vitro data to support neuroimmune activation by HCV [19] and a recent report demonstrated that a human neuroepithelioma cell line expressed HCV entry receptors and allowed productive infection by the JFH-1 HCV strain, being the first non-hepatocyte line to do so [20].
These studies lead to the hypothesis that certain HCV variants or strains may gain entry to the CNS in susceptible individuals, to replicate at low but sufficient levels to cause immune activation of resident microglia, triggering established pathways that result in neuronal dysfunction [21]. In this hypothesis, successful viral eradication might reverse or attenuate the process, as suggested by the preliminary data from Byrnes and colleagues. If this is the case, it will be of interest to discover whether the evolving interferon-free regimes of direct acting anti-virals have the same effect or whether neurocognitive impairments could persist as in the case of HAART for HIV infection. Alternatively, one might consider that eradication of HCV from the liver results in normalisation of a chronic low-level inflammatory state, with concomitant improvements in brain function and metabolism secondary to a reduction of abnormal signalling, possibly by cytokines, from the periphery across the blood brain barrier.
The pilot study from Byrnes and colleagues is small but it serves to re-energise the debate as to whether there is a virological effect of HCV on brain function. A better knowledge of this is important for our understanding of the natural history of this infection and the symptoms it causes and for our ability to design appropriate therapeutic regimes. Further large studies are now indicated to determine whether successful antiviral treatment is definitively associated with improvements in brain biochemistry and function.
References
Effect of anti-viral therapy and HCV clearance on cerebral metabolism and cognition
Jnl of Hepatology Jan 2012
Download the PDF here
Valerie Byrnes1, Anne Miller2, Damien Lowry4, Erin Hill2, Cheryl Weinstein2, David Alsop3,Robert Lenkinski3, Nezam H. Afdhal1, 1Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States; 2Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States; 3Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States; 4Liver Centre, Mater Misericordiae University Hospital, Dublin 7, Ireland
Background & Aims
Chronic hepatitis C virus (HCV) infection is associated with altered cerebral metabolism and cognitive dysfunction. We aimed to evaluate the effect of pegylated interferon/ribavirin (PIFN/R) and HCV clearance on cerebral metabolism, and neuropsychological performance.
Methods
Fifteen non-cirrhotic HCV positive subjects underwent 1H MR spectroscopy (MRS) before, during, and after treatment with PIFN/R. The metabolites of interest namely, N-acetylaspartate (NAA), choline (Cho), myo-inositol (MI), and the control metabolite creatine (Cr), were acquired from 3 different brain regions; left basal ganglia, left frontal cortex, and left dorso-lateral pre-frontal cortex. Coinciding with this, subjects also underwent a battery of neuropsychological tests to evaluate the domains of verbal learning, memory, attention, language, executive functioning, and motor skills. Seven HCV positive controls (not receiving anti-viral therapy) underwent MRS and neuropsychological testing at two time points, 12weeks apart, to examine for variation in cerebral metabolites over time and the practice effect of repeat neuropsychological testing.
Results
Significant reductions in basal ganglia Cho/Cr (p=0.03) and basal ganglia MI/Cr (p=0.03) were observed in sustained virological responders (SVRs, n=8), but not non-responders/relapsers (NR/R, n=6), indicative of reduced cerebral
infection and/or immune activation in those who cleared virus. SVRs demonstrated significant improvements in verbal learning, memory, and visuo-spatial memory. A small but significant improvement in neurocognitive function secondary to the practice effect was seen in both HCV controls and HCV subjects during treatment.
Conclusions
HCV eradication has a beneficial effect on cerebral metabolism and selective aspects of neurocognitive function and is an important factor when contemplating anti-viral therapy in HCV, especially in those with mild disease.
Discussion Only
Download the PDF here
This study sought to investigate the cerebral effects of anti viral therapy
in patients with mild chronic HCV. Our findings failed to demonstrate adverse
effects of PIFN on cerebral metabolism or cognition. What we found instead were
improvements in the spectroscopic markers of cerebral inflammation (reductions
in Cho and MI) in addition to improvements in selective cognitive domains, in
patients who cleared virus following treatment with PIFN/R, an effect that was
not observed in those who failed to respond to therapy. This appears to be the
first demonstration of improved cerebral inflammation and healthier
neurocognitive function in SVRs and is directly attributable to the successful
eradication of the virus.
Cho and MI are putative markers for glial cell inflammation and activation.
Elevated levels of Cho in HCV positive subjects is believed to reflect cellular
proliferation due to infection or inflammation [2], [9]. MI is found only in
glial cells and is also a constituent of membrane lipids [18]. Increased levels
are believed to reflect glial cell activation and increased cell membrane
turnover [11], [19], [20]. While the exact pathogenesis of glial activation in
HCV is unclear, HCV RNA has been found in brain tissue and within the CSF of
HCV infected individuals supporting direct infection of the central nervous
system [21], [22], [23], [24], [25]. One hypothesis is that HCV may be
introduced to the CNS via infected monocytes ('Trojan Horse' mechanism) and can
infect brain microglial cells, which are essentially tissue resident
macrophages of blood monocytic origin [26]. Alternatively, glial activation and
inflammation in HCV may occur indirectly due to the mediation of peripherally
derived pro-inflammatory cytokines such as 1L-6, IL8, IL12, and TNF-α [27],
[28], [29], [30]. Our finding of statistically significant reductions in Cho/Cr
and MI/Cr in the basal ganglia following HCV eradication is suggestive of
reduced glial cell inflammation ('gliosis') and adds support to the biologic
link between HCV and cerebral metabolism as suggested by numerous other studies
[1], [8], [10], [30]. Trends towards significance exist in relation to the
decline in basal ganglia Cho/Cr following 12weeks of PIFN/R in both SVRs and
the HCV patient group as a whole. The latter observation is likely due to the
high proportion of patients who were serum HCV RNA negative at this time point.
Interestingly, significant reductions in basal ganglia MI and non-significant
reductions in basal ganglia Cho have also been reported in HIV positive
subjects following initiation of aggressive anti-retroviral therapy [20]. We
did not observe increased cerebral NAA following HCV eradication. Two studies
have shown reduced NAA in HCV positive subjects when compared to HCV-negative
controls, suggestive of reduced neuronal viability [8], [9]. No observed
'restoration' of NAA in the current study may be due to voxel positioning,
which did not include the occipital grey matter, a site of reduced NAA in prior
studies. Moreover, in spite of the etiology of neuronal loss, neuronal
regeneration, as indicated by increased levels of NAA, is an unlikely expected
occurrence over the time frame of this study if it at all [20].
Coinciding with a reduction in the markers of cerebral inflammation, we found
statistically significant improvements in neurocognitive performance among SVRs
at the time of last follow up when compared to baseline, a trend not observed
among NR/R. Areas of improvement fall particularly within verbal memory domains
but also visuo-spatial abilities. It is likely that these improvements are
attributable to the successful eradication of virus as NR/R exposed to the same
testing procedures did not exhibit such improvements, although it is conceded
that larger group sizes would strengthen such conclusions.
It must be noted that significant improvements in test performances were
observed across a number of cognitive domains among both HCV controls and
treatment recipients at Time 2 compared to baseline. While HCV treatment
recipients reported significant deterioration in mood and HRQoL functioning, it
was not associated with any deleterious effect on cognition, contrary to our
working hypothesis at the outset. In fact, the opposite proved true with a
number of significantly improved performances following 12weeks of PIFN/R
treatment. It would appear improvements at this juncture were likely to result
from a practice effect as demonstrated by concomitant improvements in the HCV
control group. These findings signal caution around interpreting data from
repeat neuropsychological testing of patients using short interim periods.
Validity of neurocognitive test outcomes can be optimized when test sittings
occur after a minimum of 6months.
This study is not without its limitations. Firstly, its small sample size may
have precluded the finding of a treatment effect in the NR arm. Secondly, we
also employed the use of multiple comparisons, increasing the likelihood of
type I errors. We felt that the use of a Bonferroni correction for such a pilot
study would have been too conservative increasing the risk of incorrectly
failing to find a treatment effect. In spite of these limitations and the
preliminary nature of this study, the improvements in the variables examined
were consistent across the SVR group and absent from the NR/R group, but larger
studies are required to validate this.
In conclusion, this study provides a substantial link between HCV and
cerebral dysfunction by demonstrating a reduction in spectroscopic markers of
cerebral inflammation and an improvement in cognition, following HCV
eradication. While further larger-scale studies are required to confirm these
findings, the cerebral benefit of HCV clearance should be recognized and
considered an integral part of any anti-viral therapy dialog.
2011
Hepatitis C Neuropsychiatric symptoms-“brain fog”
World J Gastroenterol. 2011 August 7; 17(29): 3369-3374.
Published online 2011 August 7. doi: 10.3748/wjg.v17.i29.3369.
Copyright©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
Neuropsychological alterations in hepatitis C infection: The role of inflammation
Marco Senzolo, Sami Schiff, Cristina Maria D’Aloiso, Chiara Crivellin, Evangelos Cholongitas, Patrizia Burra and Sara Montagnese. Marco Senzolo, Cristina Maria D’Aloiso ,Chiara Crivellin, Patrizia Burra, Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University Hospital of Padua, 35128 Padua, Italy Sami Schiff, Sara Montagnese, Department of Clinical and Experimental Medicine, University Hospital of Padua, 35128 Padua, Italy Evangelos Cholongitas, The Royal Free Sheila Sherlock Liver Centre and Department of Surgery, UCL and Royal Free Hospital, Pond Street, London NW3 2QG, United Kindom
Author contributions: Senzolo M and Montagnese S designed of the study and wrote the manuscript; Schiff S, Cholongitas E and Crivellin C reviewed the literature; D’Aloiso CM and Burra P performed the study on cytokines in hepatitis C virus.
Correspondence to: Dr. Marco Senzolo, Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University Hospital of Padua, Via Giustiniani 2, 35136, Padua, Italy. marcosenzolo@hotmail.com
Telephone: +39-49-8218726 Fax: +39-49-8760820
Abstract
About 50% of patients with hepatitis C virus (HCV) infection complain of neuropsychiatric symptoms, “brain fog”, weakness, fatigue, and exhibit some degree of quality of life impairment, irrespective of the severity of liver disease. Since the first observation of HCV-related cognitive deficits, 10 studies have been published that have evaluated neuropsychiatric performance in patients with HCV infection and different degrees of hepatic impairment. Unfortunately, these have often included patients with cirrhosis, patients who had acquired the infection through previous intravenous drug misuse, who had a history of relatively recent treatment with interferon, or were on psychoactive medication. In addition, different neuropsychological batteries and tests that explored different cognitive domains were used, which makes the results of the studies difficult to compare. Finally, limited information is available on the pathogenesis of HCV-related cognitive impairment. Cerebral and/or systemic inflammation may be important players but their potential role has not been substantiated by experimental data. The present review outlines the available evidence of the presence of cognitive impairment in patients with HCV infection, with a focus on the potential relationship with cerebral and/or systemic inflammation.
Keywords: Cognitive alterations, Hepatitis C virus, Inflammation
INTRODUCTION
Hepatitis C virus (HCV) infection affects up to 2% of the world population and almost 4 million people in America. Although evolution to chronic HCV infection is extremely common, only 30% of chronically infected patients go on to develop end-stage liver disease and hepatocellular carcinoma.
The occurrence of hepatic encephalopathy is well documented in patients with viral cirrhosis, as in patients with cirrhosis of other etiologies[1]. However, in recent years, there has been growing evidence that alterations in cerebral function in patients with chronic HCV infection may appear long before the development of severe liver fibrosis/cirrhosis. These alterations cannot be ascribed to hepatic encephalopathy. About 50% of patients with HCV infection complain of neuropsychiatric symptoms, “brain fog”, weakness, fatigue, and exhibit some degree of quality of life impairment, irrespective of the severity of liver disease[2]. These alterations do not seem to relate to HCV genotype or replication[3]. Their etiology is unclear but it has been hypothesized that it is related to: (1) a direct effect of HCV on the brain; or (2) the neurotoxic effect of HCV-related systemic inflammation.
In the present review, we outline the available evidence of cognitive impairment in patients with HCV infection, and the possible role of cerebral and systemic inflammation
COGNITIVE ALTERATIONS IN PATIENTS WITH HCV LIVER DISEASE
Early in the course of infection, patients with HCV infection report symptoms like fatigue, malaise, weakness and problems in maintaining attention and recalling information. These alterations can interfere with their ability to perform their activities, thus leading to impairment in health-related quality of life, which is well documented[4-12]. In addition, although treatment of chronic HCV infection can temporarily worsen health-related quality of life, the relationship between sustained viral response and improvement in quality of life is also well accepted[13].
The first significant evidence for a specific role of HCV in causing cerebral function abnormalities was produced in 2001 by Forton and colleagues, who detected cerebral metabolic abnormalities (elevated choline/creatine ratio) in the frontal white matter and basal ganglia of HCV-infected patients, using proton magnetic resonance spectroscopy (1H MRS); these alterations were not present in either controls or patients with HBV infection[14]. In the following year, the same group showed significant impairment in concentration and working memory in 27 HCV-infected patients with active viral replication, compared to 20 controls and 16 anti-HCV-positive but HCV-RNA-negative patients[15].
Since these original observations, 10 studies have been published that have evaluated neuropsychiatric performance in patients with HCV infection and different degrees of hepatic impairment. Unfortunately, these have often included patients with cirrhosis (potentially, also those with minimal hepatic encephalopathy); patients who had acquired the infection by previous intravenous drug misuse; patients who had a history of relatively recent treatment with interferon; patients on psychoactive medication; or those who complained of significant fatigue; all of which could impinge on cognitive performance, in terms of motivation and psychomotor speed. In addition, different neuropsychological batteries and tests that explore different cognitive domains have been utilized, which makes it difficult to compare the results of the studies.
Hilsabeck and colleagues have documented a prevalence of cognitive dysfunction which ranged from 0% on a design copy task to 49% on a measure of sustained attention in a group of 66 HCV-infected patients; 44 (66%) of whom had cirrhosis[16]. The HCV-infected patients were compared to a cohort of 14 patients with liver disease of other etiology, who had normal cognitive performance. However, within the study group, there were factors that could have contributed to cognitive impairment, such as previous alcohol intake and HIV co-infection; the control group also included patients with previous alcohol misuse and those with cirrhosis, and possibly minimal hepatic encephalopathy. The authors were able to correlate the degree of fibrosis with that of cognitive impairment, and suggested that the latter might parallel progressive liver injury in HCV-infected patients. However, the inclusion of even a small number of patients with cirrhosis and hepatic encephalopathy might well be responsible for the correlations observed. In addition, sustained attention, which was found to be abnormal in almost half of the study group, is known to be impaired in patients with hepatic encephalopathy[17,18].
When the same authors administered a similar test battery to an independent group of HCV-infected patients, 33% of whom had cirrhosis, there was no correlation between perceived cognitive impairment, fatigue or depression and neuropsychological performance, which suggests that the latter might not be clinically relevant[19]. Similarly to the previous study, a correlation was observed between neuropsychological performance and the degree of fibrosis, which led the authors to suggest that progressive liver injury might result in worsening neuropsychiatric function in HCV-infected patients. Within this setting, it would be difficult to explain how a significant proportion of patients with HCV-related cirrhosis, just like those with cirrhosis of other etiology, would show completely normal neuropsychiatric function on extensive screening for hepatic encephalopathy.
The issue of the relationship between cognitive impairment and perceived fatigue in HCV-infected patients was subsequently addressed by Weissenborn and colleagues, who compared neuropsychological performance in 30 PCR-positive HCV-infected patients with normal liver function, 15 of whom reported moderate to severe fatigue[20]; patients with previous drug misuse, interferon treatment, psychiatric disease and patients on psychoactive drugs were excluded. The authors found a significant deficit in attention and higher executive function in patients compared to controls, in parallel with an increase in depression and anxiety. Patients with self-reported fatigue performed worse on the neuropsychological battery, whereas there was no correlation between anxiety/depression and cognitive performance. In the same study, patients with HCV infection showed a significant decrease of the N-acetyl-aspartate/creatine ratio in the cerebral cortex on 1H MRS, while the electroencephalogram was slowed in 25%[20]. In contrast, in a published abstract, Montagnese and colleagues have reported on an unexpectedly high prevalence of fast (β-dominated) electroencephalograms in a similarly well-selected population of HCV-infected patients. Similar features had been previously reported in HIV-infected individuals[21] and could be related to some degree of desynchronization of the cerebral electrical activity.
McAndrews and co-workers have confirmed the presence of minor attention deficits and impairment in verbal learning ability in their study of 37 well-selected HCV patients without disease-associated risk factors, such as substance misuse, cirrhosis or depression[22]. When compared with 46 age-matched controls, 13% of patients with HCV infection showed impairment in verbal learning ability; however, the chosen threshold for a pathological performance was 1.5 SDs below the norm, which is stricter than the usual 2 SDs. The authors themselves qualify the detected abnormalities as having limited clinical relevance. As in previous studies, McAndrews and colleagues also detected an increase in choline and a reduction in N-acetyl aspartate by MRS in the central white matter of patients compared to controls.
In contrast, Fontana and co-workers have found that 33% of 177 patients with HCV infection and advanced fibrosis who were enrolled in the HALT-C trial could be considered to have cognitive impairment (before interferon and ribavirin treatment), based on a composite score of 10 neuropsychological tests[23]. The most affected domains were verbal recall and working memory. However, 38% of patients had cirrhosis, and working memory is known to be impaired in patients with cirrhosis and hepatic encephalopathy[24], which was probably a significant confounder in this study. In addition, 50% of patients had been alcohol misusers and 46% had a history of intravenous drug abuse. In contrast with the findings by Hilsabeck and colleagues, Fontana and co-workers observed no relationship between cognitive alterations and the degree of fibrosis or mood disturbances[23].
More recently, Lowry and colleagues studied neuropsychiatric function in a well-selected, homogeneous cohort of 20 female, iatrogenically-infected patients; of whom, 11 were positive for HCV RNA and nine had spontaneously cleared the virus[25]. The authors showed that PCR-positive women had significantly poorer scores in the areas of memory, auditory recognition and sustained attention compared to a small group of nine healthy controls; these abnormalities were not present in the PCR-negative women.
To date, two studies that explored cognitive function in chronically HCV-infected patients were completely negative. The first was published by Cordoba and colleagues[26], who showed normal neuropsychiatric performance in 40 HCV patients with normal hepatic function; however, these individuals still exhibited some degree of quality of life impairment. In the same study, significant alterations in attention, executive function and motor performance were detected in a control group of patients with HCV-related cirrhosis. In contrast to most previous studies, Cordoba and co-workers selected their HCV-positive patients amongst healthy individuals screened for blood donation[26]; this is a fairly different population compared to patients with known chronic HCV infection.
The second negative study included 103 HCV-PCR-positive young patients (aged 6-19 years) who were studied with the Adaptive Behavioural and WAIS scales. In this group, the time lag between infection and cognitive assessment might have been significantly lower compared to the other, adult cohorts, thus possibly explaining, at least to some extent, the negative results[27].
One study that compared cognitive performance in 32 patients with chronic hepatitis C against 29 chronic hepatitis B showed than HCV patients had worse performance in verbal learning and memory compared to controls, but they did not differ from patients with hepatitis B virus liver disease[28]. However, about 20% of patients had liver cirrhosis in both groups. Moreover, only 50% of the study group had histological assessment and no clinical exclusion of cirrhosis was described by the authors.
INFLAMMATION AND HCV
The etiology of cognitive dysfunction in patients with chronic HCV infection remains unclear but two hypotheses have been put forward: (1) the virus infects the brain and has a direct neurotoxic effect; and (2) the virus is indirectly neurotoxic via cerebral and/or systemic inflammation.
A direct neurotoxic role for HCV is supported by reports of HCV replication within the central nervous system[29-31]. It has been suggested that the virus enters the brain by infecting peripheral blood mononuclear cells, which are precursors of the microglia and could act as a “Trojan horse”[32]. However, data on the association between the virus in the brain and impaired cognitive function are still lacking. Indeed, replication of quasispecies is very low within the brain; HCV RNA is almost undetectable in the cerebrospinal fluid[33,34] and there is no correlation between viral load and cognitive impairment in patients with HCV infection[20]. However, this is sometimes also the case for other HCV-related complications, such as cryoglobulinemia or vasculitis[35].
It is well known that the cytolytic effect of HCV within the liver relates to the activation of the immune system. Thus, chronic activation of the immune system could account, at least in part, for the observed cerebral alterations, due to increased systemic and/or local inflammation. A growing body of evidence supports immune system-to-brain communication, with peripheral immune activation being associated with behavioral, affective and cognitive disturbances. Peripheral proinflammatory cytokines such as interleukin (IL)-1, and IL-6 are likely mediators of these effects, and penetrate the blood-brain barrier directly through active transport mechanisms, activation of the vagus nerve, stimulation of neurotransmitter systems, and therefore, modulation of brain activity. Most of the evidence that directly links peripheral proinflammatory cytokines with neurocognitive function is derived from animal models, in which increased peripheral IL-1 and IL-6 are associated with increased levels of these cytokines in the prefrontal cortex and hippocampus[36].
Increased levels of IL-6 have been associated with impairment in spatial learning and memory, which are prevented by the administration of specific antagonists. This suggests a primary role for inflammatory cytokines in mediating cognitive decline and deficits in chronic inflammation[37,38]. Likewise, peripheral markers of inflammation have been associated with cognitive decline in elderly patients. In a recent study that evaluated the correlation between IL-6 and cognitive performance in middle-aged volunteers, an inverse relationship was observed between circulating levels of IL-6 and auditory recognition memory, attention, working memory and executive function[39].
Once a patient has chronic HCV infection, proinflammatory cytokines such as IL-6, IL-4 and tumor necrosis factor (TNF)-α are produced and may be elevated for several decades. During this period, proinflammatory cytokines can cross the blood-brain barrier and therefore contribute to cognitive impairment.
Moreover, another possible contribution of inflammation to cognitive degeneration in HCV patients is local cerebral inflammation[34,40,41]. It has been shown that small amounts of HCV within the brain evoke a local inflammatory response, because macrophages infected with HCV in vitro can induce TNF-α and IL-8[32]. In addition, a recent study has shown activation of brain macrophages/microglia in autopsy brain tissue from HCV-positive patients[42]. Peripheral markers of the activation of cellular immunity have recently been assessed by Gess and colleagues in a group of 53 HCV-infected patients with mild liver disease. No association was observed between activated cellular immunity and subjectively perceived or objectively measured cognitive impairment[43].
FUTURE PERSPECTIVES
The studies that have explored cognitive function in patients with chronic HCV were extremely heterogeneous in terms of patient characteristics, confounding factors (e.g. intravenous drug misuse and previous alcohol intake), control groups, methodology and tests used to assess cognitive performance. An additional issue might be the fact that the study subjects ranged from patients who had cleared HCV to those with HCV-related cirrhosis, even within the same study group. Furthermore, the role of systemic inflammation in the pathogenesis of cognitive alterations in patients with HCV infection has never been directly explored.
It is possible that patients with chronic HCV infection and persistently normal transaminases for 6 mo (PNALT) could represent an extremely useful study group to provide additional information, particularly in relation to the role of HCV per se in causing neurocognitive dysfunction. When we evaluated systemic inflammation in this group of patients, no activation of systemic inflammation was observed[44]. This finding suggests that patients with normal transaminases have a different immunological response profile, compared to those whose transaminases remain elevated. In line with this hypothesis, previous studies have demonstrated an increase in HCV-specific CD4+CD25+ regulatory T cells and a decrease in CD4+ response in patients with normal transaminases compared to patients with high transaminases[45].
Whether the absence of an activated systemic inflammatory response in PNALT patients also reflects better cognitive performance needs to be explored. In a preliminary study, we found that PNALT patients with normal serum levels of proinflammatory cytokines performed similarly to controls as far as memory, attention and cognitive evoked potential N400, which relates to semantic memory and verbal working memory. Patients with chronic hepatitis due to HCV had impairment in memory in 60% of cases, with concomitant increased amplitude of N400, which indicated the need for increased neuronal recruitment to perform the task[44].
In the two studies that did not demonstrate cognitive alterations in patients with HCV, HCV-positive individuals were selected from healthy volunteers screened for blood donation and young patients with hemophilia, respectively. These subjects were classified as HCV-positive individuals with normal transaminases but were not further characterized, and some might well have qualified as PNALT.
Future, prospective cohort studies should probably include patients with chronic HCV infection with minimal or no fibrosis, PNALT, hepatitis B surface antigen-positive patients with/without transaminitis and a control group with chronic systemic inflammation (i.e. inflammatory bowel disease). In addition, the neuropsychological evaluation should probably be conducted in a structured, comprehensive way, by cognitive domain, and test results scored against adequate, large and local normative databases, rather than simply compared to small internal control groups. Mood, fatigue and quality of life should also be assessed. This approach might provide more solid information on whether HCV-related cognitive impairment exists and, if so, on its clinical relevance.
Footnotes
Peer reviewers: Yukihiro Shimizu, MD, PhD, Kyoto Katsura Hospital, 17 Yamada-Hirao, Nishikyo, Kyoto 615-8256, Japan; Alexandra A Alexopoulou, MD, 2nd Department of Internal Medicine, University of Athens, Medical School, Hippokration General Hosp, 40 Konstantinoupoleos St, 16342 Hilioupolois Athens, Greece
S- Editor Tian L L- Editor Kerr C E- Editor Zheng XM
References
The reason for the “brain fog” in people with hepatitis C is not fully understood. Some experts believe that it could be caused by the immune response that is sending out immune system cells to attack and kill the virus.
Other experts theorize that it could be caused by the constant state of fatigue that many people with hepatitis C experience. Still other experts believe that it may be a result of the hepatitis C virus crossing the blood brain barrier and causing
inflammation and damage. The last theory has picked up steam in the last couple of years and a new study is adding to a body of knowledge about the relationship between HCV and the brain. But the big question is what can be done about it? If “brain fog” is caused by the virus or the fatigue associated with HCV then treatment should help to alleviate or at least reduce some of the symptoms of “brain fog.”
With respect to the point that hepatitis C replicates in the brain—to date there have not been any rigorous scientific studies that clearly establish this fact.
For a review of some of the data on HCV and the brain read “Brain Fog: It Really Is All in Your Head,” by C.D. Mazoff, in the January 2012 HCV Advocate.
But a recent study, however, at least leads some credence to the notion that treatment may help to improve some of the symptoms of “brain fog.”
V. Byrnes and colleagues studied 15 non-cirrhotic hepatitis C-infected patients with a variety of tests. Seven HCV-infected
patients were used as a control group. All 15 patients were given brain imaging tests of three different regions of the brain before, during and after treatment as well as tests to evaluate verbal learning, memory, attention, language, executive functioning (overall cognitive processes) and motor skills (muscle and nerve coordination). The control group also had the tests except that the tests were conducted 12-weeks apart. Both groups had mild chronic hepatitis C disease progression.
The authors found that there were markers that showed “improvements in verbal learning, memory, and visuo-spatial emory,” and concluded that “HCV eradication has a beneficial effect on cerebral metabolism and selective aspects of neurocognitive function and is an important factor when contemplating anti-viral therapy in HCV, especially in those with mild disease.”
But not so fast, commented D.M Forton in an editorial titled “Hepatitis C treatment—Clearing the mind” that appeared in the same journal. Dr. Forton remarked that while the study was important and interesting, it did not settle the important question of whether HCV infects and replicates in the brain and that HCV treatment could restore cognitive function.
He went on to remark that “the pilot study from Byrnes and colleagues is small but it serves to re-energise the debate as to whether there is a virological effect of HCV on brain function.” He went on to comment that, “Further large studies are now indicated to determine whether successful antiviral treatment is definitively associated with improvements in rain biochemistry and function.”
Personally, the thought of HCV infecting and replicating in the brain is frightening. This is one theory that I hope is thoroughly debunked.
References:
- Effects of anti-viral therapy and HCV clearance on cerebral metabolism
and cognition. Valerie Byrnes, Anne Miller, Damien Lowry, Erin Hill, et al.
Journal of Hepatology, Vol 56, Issue 3, Pages 549-556, March 2012.
- Hepatitis C treatment—clearing the mind. Forton DM. Journal of
Hepatology, Vol 56, Issue 3, Pages 513-514, March 2012.
From The July 2012 Newsletter @ HCV Advocate
Download printable version
In This Issue:
HCV Treatment and the Brain
Alan Franciscus, Editor-in-Chief
HCV Snapshots: DDW 2012
Lucinda K. Porter, RN
Disability & Benefits: SSD – Financial Eligibility
Jacques Chambers, CLU
HealthWise: Hepatitis C: One World, Many Faces
Lucinda K. Porter, RN
HCV Advocate Eblast
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June
Depression Induced by Interferon Therapy
Determining the role of genetic vulnerability to harmful side effects is becoming a crucial issue in order to progress toward
individualized drug therapy with successful outcome. A major obstacle of IFN therapy for chronic hepatitis C is that about a quarter of these patients will develop depressive side effects that can even lead to suicide in some cases.....
May
Interferon - Hepatitis C Drug Can Cause Depression
Hepatitis C Drug can Cause Depression
Released:5/1/2012
Source: Loyola University Health System
Newswise — MAYWOOD, Ill. -- There's a high rate of depression among patients with hepatitis C, but a standard treatment for the disease includes a drug, interferon, that can cause depression.
In a review article, researchers tackle the complexities of diagnosing and managing depression before and after initiating treatment with interferon.
Dr. Murali S. Rao of Loyola University Medical Center is a co-author of the study, published in the International
Journal of Interferon, Cytokine and Mediator Research.
"Depression is a relatively frequent and potentially serious complication of interferon therapy for hepatitis C virus infection," the
researchers write. "However, other etiologies [causes] of depression may coexist and have to be carefully excluded."
Hepatitis C is the most common chronic blood-borne infection in the United States. At least 4 million people have been exposed and 3.2 million are chronic carriers.
The drugs ribavirin and pegylated interferon are mainstay treatments. Pegylated interferon can help relieve muscle and joint pain and reduce the disabling fatigue. But a well-established side effect of interferon is depression of variable severity -- including suicidal thoughts. The prevalence of depression among hepatitis C patients receiving interferon has been reported to be between 10 percent and 40 percent, depending on the screening method used.
One of the main concerns in treating hepatitis C patients is the risk of suicide, especially since many patients already are depressed before beginning therapy. Patients who have a personal or family history of a serious mood disorder, depression, suicidal thoughts or suicide attempts "should be carefully interviewed and referred to a specialist for assessment of suicide
risk and treatment of the underlying disorder before treatment with interferon can be considered," the authors write.
The SSRI class of antidepressants, such as citalopram (brand name, Celexa), have been shown to be effective in treating depression in hepatitis patients treated with interferon. The related SNRI class of antidepressants, such as milnacipran (Savella), also can reduce depressive symptoms in patients taking interferon. But there have been conflicting results
in studies on whether giving antidepressants before starting interferon can prevent depression, the authors write.
Interferon can affect the level of serotonin, a compound that is responsible in part for regulating mood and other brain functions. This may be the reason why antidepressants don't always work in patients who take interferon, the authors write.
Rao, an expert on depression, is chair of the Department of Psychiatry and Behavioral Neurosciences of Loyola University
Chicago Stritch School of Medicine. Other authors are Dr. Haris Papafragkakis (first author) and Dr. Paul Martin of the University of Miami, Dr. Martin Moehlen of Tulane University and Dr. Sonu Dhillon of St. Francis Medical Center in Peoria, Ill.
Source
January
Hep C Can Enter the Human Brain
January 25, 2012
The hepatitis C virus (HCV) not only affects liver cells, it may also establish infection in other cells, notably those associated with the central nervous system (CNS), according to a University of Birmingham, England,study reported by HealthCanal.com.
Though it is unclear if these new findings help explain the increased risk of CNS problems in people living with chronic HCV infection, they do suggest that the CNS is a reservoir for the virus that is not easily reached by HCV treatments; the findings may also explain why therapy does not always cure the infection.
The blood-brain barrier—a network of microvascular endothelial cells—is responsible for keeping microscopic objects, such as
hostile microorganisms, out of the brain. "If this barrier is compromised," said lead author Nicola Fletcher, BSc, PhD, postdoctoral researcher at University of Birmingham, "all kinds of substances can gain access to the brain, which may
explain the fatigue and other symptoms reported by HCV-infected patients."
For the study, researchers examined brain tissue from 10 posthumous donors who had hepatitis C. The researchers found HCV in the brain cells of four of the donors.
Examination of endothelial brain cells verified that they have all the receptors needed for HCV to attach and enter those cells. Indeed, when cultured in the laboratory, these cells released infectious copies of the virus.
"This is the first report that cells of the central nervous system support HCV replication," said corresponding author Jane
McKeating, BSc, PhD, professor of molecular virology at the University of Birmingham. "These observations could have clinical implications providing a reservoir for the virus to persist during anti-viral treatment."
In addition to barring the passage of microorganisms, the blood-brain barrier keeps out a wide range of larger molecules—including, Fletcher believes, many antiviral drugs currently under development. "HCV-infected brain microvascular endothelial cells may provide a reservoir for the virus to persist during anti-viral treatment," Fletcher said.
http://www.hepmag.com/articles/HCV_Brain_Endothelium_2501_21818.shtml
Hepatitis C Virus and the Brain
HCV Infection is Associated With Immune Responses in the Brain
Recent studies have suggested that HCV infection is associated with inflammatory responses in the brain. The brain metabolites choline, creatine and inositol were significantly increased in HCV-infected patients compared with healthy controls..
Liver-induced inflammation hurts the brain
The immune system is activated following injury or infection. The local response can be accompanied by a systemic response, which includes the synthesis and release of different mediators by innate immune cells. The liver is not an exception and when exposed to an acute or chronic insult generates an inflammatory response that may affect other organs. Liver-induced inflammation is able to cause disturbances in the central nervous system (CNS) including metabolic (hyperthermia, somnolence, loss of body weight) and behavioural manifestations (lethargy, anhedonia, decreased social interaction).
These manifestations are collectively termed “sickness behaviour” [1], and are attributed to dysfunction of the CNS.....
The brain on fire-inflammation and depression
Interferons, a form of cytokines which activate the immune system and act as antiviral agents, is a common treatment for hepatitis C infection. Research and clinical studies have shown that interferon therapy can actually lead to depression in patients who have hepatitis C. It's been reported that between 20% and 30% of patients who have hepatitis C and who receive interferon treatment are at risk for depression.........
Journal of Hepatology
Hepatitis C treatment – Clearing the mind
Received 11 November 2011; accepted 14 November 2011. published online 23 November 2011.
Uncorrected Proof
The issue of whether the hepatitis C virus (HCV) affects brain function continues to arouse interest, investigation, and debate. Symptoms such as fatigue, poor memory, and concentration (“brain fog”) are commonplace and an effect of this infection on mental health related quality of life, which is independent of liver fibrosis, is well established [1]. However, despite convergent lines of evidence pointing to a biological effect of HCV within the CNS and some hypothesised mechanisms, there remains, as yet, a lack of incontrovertible evidence to definitively prove the fact. Parallels with HIV infection are commonly drawn, where AIDS related dementia is now rare with highly active anti-retroviral therapy (HAART) but milder neurocognitive impairments can persist despite immune reconstitution and viral suppression [2]. A degenerative brain process is not seen in HCV monoinfection and there remains doubt in the hepatology community as to whether HCV is a virus that can trigger neurological dysfunction. Furthermore, there does not appear to be a clinical consensus as to whether the relatively mild neurocognitive symptoms in HCV infection represent a significant or important element of the disease.
The possibility of a cerebral effect of HCV was raised ten years ago with the publication of proton magnetic resonance spectroscopy (MRS) and neuropsychological data, which showed evidence of altered cerebral metabolism and cognitive impairment in patients without advanced liver disease [3], [4], [5]. A number of further imaging studies, using MRS [6], [7], positron emission tomography (PET) and single-photon emission computed tomography (SPECT) [8] in patients without cirrhosis have demonstrated metabolic and neurochemical brain abnormalities, which differ to those described in hepatic encephalopathy. Rather, the findings suggest an inflammatory state within the brain with altered serotonergic and dopaminergic neurotransmission. In particular, elevated basal ganglia and white matter choline (Cho) and myo-inositol (mI), measured with proton MRS and often reported relative to creatine (Cr), are consistent with glial cell activation and proliferation and parallel changes observed in cerebral HIV infection [9], [10]. Reduced N-acetylaspartate (NAA) has also been reported in HIV and HCV monoinfections [6], [7].
A greater number of reports have documented mild but measureable cognitive deficits in patients with HCV infection, which are not readily accounted for by the severity of liver disease, associated recreational drug use or other potential confounding factors [11]. Although the studies have varied with respect to the degree to which confounders were excluded or controlled for and in terms of their cognitive assessment methodology, there is a reported pattern of deficits in attention, working memory, and learning ability with increased reaction times and relatively preserved accuracy. The prevalence of depression and anxiety was high in these reports but there do not appear to be clear associations between affective symptoms and cognitive function. However, fatigue, perhaps the commonest symptom in HCV infection, was reported to be associated with worse cognitive performance [6].
Despite the increasing body of descriptive literature, there are very few longitudinal reports of the effect of treatment and, in particular, of the effect of successful viral clearance on brain metabolism [12]. It is in this context that the small pilot study from Byrnes and colleagues, published in the current issue, is welcome [13]. Large treatment studies have demonstrated an improvement in HRQL and fatigue after a sustained virological response (SVR) to pegylated interferon and ribavirin but these studies have not generally blinded their subjects to treatment outcome and the knowledge of a “cure” is highly likely to skew results [14]. If the hypothesis to be tested were that a cerebral abnormality is due to HCV itself, objective demonstration of an improvement of that abnormality after SVR would be highly supportive of the hypothesis. Byrnes and colleagues report their findings in a small patient cohort who was studied with proton MRS and cognitive assessment before, during and after standard antiviral treatment with pegylated interferon and ribavirin. A second group of untreated patients was also studied at two time points. Overall, there were no significant changes in cerebral MRS during and after antiviral treatment. However, a sub-group analysis of viral responders and non-responders showed significant metabolic changes over time in the responder group only, consistent with normalisation of the metabolites, previously reported as elevated in HCV infection [9], [10]. Significant reductions were observed in basal ganglia Cho/Cr and mI/Cr ratios in SVRs (n=8) but not in non-responders or relapsers (n=6). The authors interpret this as an improvement in cerebral immune activation in those who cleared the virus. Patients in the treated and untreated groups tended to show an improvement in cognitive function over time, which was ascribed to a practice effect on the cognitive battery. However, when responders and non-responders were compared again, SVRs demonstrated significant improvements in verbal learning, memory and visuospatial memory, which were not seen in the non-responders.
This study is important because it is the first to demonstrate that successful clearance of HCV infection can result in changes in cerebral metabolism that may underlie improvements in neurocognitive performance. The obvious weakness in this paper, which limits the conclusions that can be drawn at this time, is the small sample size. The significant findings are only seen in a sub-group analysis, with very small groups. It is possible that a treatment effect was not seen in the non-responders because of a type II error. Furthermore, the absence of a healthy control group prevents conclusions about the importance of the observed changes. In a study published this year, Pattullo and colleagues also used MRS to assess the effect of SVR on brain metabolism [12]. In a larger study of 40 patients (31 SVRs and 9 non-responders) significant increases in globus pallidus Cho/Cr and NAA/Cr were seen in SVRs after treatment compared to baseline. These changes were not associated with cognitive measures, which did not improve with viral eradication. The opposite effect of viral eradication on Cho/Cr in the report from Byrne and colleagues is not readily explained but may be related to different patient characteristics, voxel position and acquisition parameters. Pattullo does however report reductions in globus pallidus NAA/Cr at baseline compared to controls, which increased significantly in the SVRs. Despite this, the authors concluded that when all other causes for cerebral dysfunction are excluded, viral clearance does not contribute to significant changes in brain function or biochemistry.
There are a number of strands of evidence, in addition to clinical data, that support a biological effect of HCV on the brain. Positive and negative strand HCV genetic sequences have been amplified from RNA extracted from human post-mortem brain samples and quasispecies analyses suggest replication within the CNS, albeit at a low level [15], [16]. Immunohistochemical staining for HCV non-structural protein 3 (NS3) in brain tissue suggests that astrocytes and microglia might be the host cell for HCV infection [17]. Gene expression analysis in laser dissected microglia, which stained with antibodies against HCV NS3, revealed up-regulation of proinflammatory genes such as TNF alpha and IL-1b that was not seen in NS3−ve microglia or in cells from HCV−ve individuals [18]. There are emerging in vitro data to support neuroimmune activation by HCV [19] and a recent report demonstrated that a human neuroepithelioma cell line expressed HCV entry receptors and allowed productive infection by the JFH-1 HCV strain, being the first non-hepatocyte line to do so [20].
These studies lead to the hypothesis that certain HCV variants or strains may gain entry to the CNS in susceptible individuals, to replicate at low but sufficient levels to cause immune activation of resident microglia, triggering established pathways that result in neuronal dysfunction [21]. In this hypothesis, successful viral eradication might reverse or attenuate the process, as suggested by the preliminary data from Byrnes and colleagues. If this is the case, it will be of interest to discover whether the evolving interferon-free regimes of direct acting anti-virals have the same effect or whether neurocognitive impairments could persist as in the case of HAART for HIV infection. Alternatively, one might consider that eradication of HCV from the liver results in normalisation of a chronic low-level inflammatory state, with concomitant improvements in brain function and metabolism secondary to a reduction of abnormal signalling, possibly by cytokines, from the periphery across the blood brain barrier.
The pilot study from Byrnes and colleagues is small but it serves to re-energise the debate as to whether there is a virological effect of HCV on brain function. A better knowledge of this is important for our understanding of the natural history of this infection and the symptoms it causes and for our ability to design appropriate therapeutic regimes. Further large studies are now indicated to determine whether successful antiviral treatment is definitively associated with improvements in brain biochemistry and function.
References
Effect of anti-viral therapy and HCV clearance on cerebral metabolism and cognition
Jnl of Hepatology Jan 2012
Download the PDF here
Valerie Byrnes1, Anne Miller2, Damien Lowry4, Erin Hill2, Cheryl Weinstein2, David Alsop3,Robert Lenkinski3, Nezam H. Afdhal1, 1Department of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States; 2Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States; 3Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States; 4Liver Centre, Mater Misericordiae University Hospital, Dublin 7, Ireland
Background & Aims
Chronic hepatitis C virus (HCV) infection is associated with altered cerebral metabolism and cognitive dysfunction. We aimed to evaluate the effect of pegylated interferon/ribavirin (PIFN/R) and HCV clearance on cerebral metabolism, and neuropsychological performance.
Methods
Fifteen non-cirrhotic HCV positive subjects underwent 1H MR spectroscopy (MRS) before, during, and after treatment with PIFN/R. The metabolites of interest namely, N-acetylaspartate (NAA), choline (Cho), myo-inositol (MI), and the control metabolite creatine (Cr), were acquired from 3 different brain regions; left basal ganglia, left frontal cortex, and left dorso-lateral pre-frontal cortex. Coinciding with this, subjects also underwent a battery of neuropsychological tests to evaluate the domains of verbal learning, memory, attention, language, executive functioning, and motor skills. Seven HCV positive controls (not receiving anti-viral therapy) underwent MRS and neuropsychological testing at two time points, 12weeks apart, to examine for variation in cerebral metabolites over time and the practice effect of repeat neuropsychological testing.
Results
Significant reductions in basal ganglia Cho/Cr (p=0.03) and basal ganglia MI/Cr (p=0.03) were observed in sustained virological responders (SVRs, n=8), but not non-responders/relapsers (NR/R, n=6), indicative of reduced cerebral
infection and/or immune activation in those who cleared virus. SVRs demonstrated significant improvements in verbal learning, memory, and visuo-spatial memory. A small but significant improvement in neurocognitive function secondary to the practice effect was seen in both HCV controls and HCV subjects during treatment.
Conclusions
HCV eradication has a beneficial effect on cerebral metabolism and selective aspects of neurocognitive function and is an important factor when contemplating anti-viral therapy in HCV, especially in those with mild disease.
Discussion Only
Download the PDF here
This study sought to investigate the cerebral effects of anti viral therapy
in patients with mild chronic HCV. Our findings failed to demonstrate adverse
effects of PIFN on cerebral metabolism or cognition. What we found instead were
improvements in the spectroscopic markers of cerebral inflammation (reductions
in Cho and MI) in addition to improvements in selective cognitive domains, in
patients who cleared virus following treatment with PIFN/R, an effect that was
not observed in those who failed to respond to therapy. This appears to be the
first demonstration of improved cerebral inflammation and healthier
neurocognitive function in SVRs and is directly attributable to the successful
eradication of the virus.
Cho and MI are putative markers for glial cell inflammation and activation.
Elevated levels of Cho in HCV positive subjects is believed to reflect cellular
proliferation due to infection or inflammation [2], [9]. MI is found only in
glial cells and is also a constituent of membrane lipids [18]. Increased levels
are believed to reflect glial cell activation and increased cell membrane
turnover [11], [19], [20]. While the exact pathogenesis of glial activation in
HCV is unclear, HCV RNA has been found in brain tissue and within the CSF of
HCV infected individuals supporting direct infection of the central nervous
system [21], [22], [23], [24], [25]. One hypothesis is that HCV may be
introduced to the CNS via infected monocytes ('Trojan Horse' mechanism) and can
infect brain microglial cells, which are essentially tissue resident
macrophages of blood monocytic origin [26]. Alternatively, glial activation and
inflammation in HCV may occur indirectly due to the mediation of peripherally
derived pro-inflammatory cytokines such as 1L-6, IL8, IL12, and TNF-α [27],
[28], [29], [30]. Our finding of statistically significant reductions in Cho/Cr
and MI/Cr in the basal ganglia following HCV eradication is suggestive of
reduced glial cell inflammation ('gliosis') and adds support to the biologic
link between HCV and cerebral metabolism as suggested by numerous other studies
[1], [8], [10], [30]. Trends towards significance exist in relation to the
decline in basal ganglia Cho/Cr following 12weeks of PIFN/R in both SVRs and
the HCV patient group as a whole. The latter observation is likely due to the
high proportion of patients who were serum HCV RNA negative at this time point.
Interestingly, significant reductions in basal ganglia MI and non-significant
reductions in basal ganglia Cho have also been reported in HIV positive
subjects following initiation of aggressive anti-retroviral therapy [20]. We
did not observe increased cerebral NAA following HCV eradication. Two studies
have shown reduced NAA in HCV positive subjects when compared to HCV-negative
controls, suggestive of reduced neuronal viability [8], [9]. No observed
'restoration' of NAA in the current study may be due to voxel positioning,
which did not include the occipital grey matter, a site of reduced NAA in prior
studies. Moreover, in spite of the etiology of neuronal loss, neuronal
regeneration, as indicated by increased levels of NAA, is an unlikely expected
occurrence over the time frame of this study if it at all [20].
Coinciding with a reduction in the markers of cerebral inflammation, we found
statistically significant improvements in neurocognitive performance among SVRs
at the time of last follow up when compared to baseline, a trend not observed
among NR/R. Areas of improvement fall particularly within verbal memory domains
but also visuo-spatial abilities. It is likely that these improvements are
attributable to the successful eradication of virus as NR/R exposed to the same
testing procedures did not exhibit such improvements, although it is conceded
that larger group sizes would strengthen such conclusions.
It must be noted that significant improvements in test performances were
observed across a number of cognitive domains among both HCV controls and
treatment recipients at Time 2 compared to baseline. While HCV treatment
recipients reported significant deterioration in mood and HRQoL functioning, it
was not associated with any deleterious effect on cognition, contrary to our
working hypothesis at the outset. In fact, the opposite proved true with a
number of significantly improved performances following 12weeks of PIFN/R
treatment. It would appear improvements at this juncture were likely to result
from a practice effect as demonstrated by concomitant improvements in the HCV
control group. These findings signal caution around interpreting data from
repeat neuropsychological testing of patients using short interim periods.
Validity of neurocognitive test outcomes can be optimized when test sittings
occur after a minimum of 6months.
This study is not without its limitations. Firstly, its small sample size may
have precluded the finding of a treatment effect in the NR arm. Secondly, we
also employed the use of multiple comparisons, increasing the likelihood of
type I errors. We felt that the use of a Bonferroni correction for such a pilot
study would have been too conservative increasing the risk of incorrectly
failing to find a treatment effect. In spite of these limitations and the
preliminary nature of this study, the improvements in the variables examined
were consistent across the SVR group and absent from the NR/R group, but larger
studies are required to validate this.
In conclusion, this study provides a substantial link between HCV and
cerebral dysfunction by demonstrating a reduction in spectroscopic markers of
cerebral inflammation and an improvement in cognition, following HCV
eradication. While further larger-scale studies are required to confirm these
findings, the cerebral benefit of HCV clearance should be recognized and
considered an integral part of any anti-viral therapy dialog.
2011
Hepatitis C Neuropsychiatric symptoms-“brain fog”
World J Gastroenterol. 2011 August 7; 17(29): 3369-3374.
Published online 2011 August 7. doi: 10.3748/wjg.v17.i29.3369.
Copyright©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
Neuropsychological alterations in hepatitis C infection: The role of inflammation
Marco Senzolo, Sami Schiff, Cristina Maria D’Aloiso, Chiara Crivellin, Evangelos Cholongitas, Patrizia Burra and Sara Montagnese. Marco Senzolo, Cristina Maria D’Aloiso ,Chiara Crivellin, Patrizia Burra, Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University Hospital of Padua, 35128 Padua, Italy Sami Schiff, Sara Montagnese, Department of Clinical and Experimental Medicine, University Hospital of Padua, 35128 Padua, Italy Evangelos Cholongitas, The Royal Free Sheila Sherlock Liver Centre and Department of Surgery, UCL and Royal Free Hospital, Pond Street, London NW3 2QG, United Kindom
Author contributions: Senzolo M and Montagnese S designed of the study and wrote the manuscript; Schiff S, Cholongitas E and Crivellin C reviewed the literature; D’Aloiso CM and Burra P performed the study on cytokines in hepatitis C virus.
Correspondence to: Dr. Marco Senzolo, Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University Hospital of Padua, Via Giustiniani 2, 35136, Padua, Italy. marcosenzolo@hotmail.com
Telephone: +39-49-8218726 Fax: +39-49-8760820
Abstract
About 50% of patients with hepatitis C virus (HCV) infection complain of neuropsychiatric symptoms, “brain fog”, weakness, fatigue, and exhibit some degree of quality of life impairment, irrespective of the severity of liver disease. Since the first observation of HCV-related cognitive deficits, 10 studies have been published that have evaluated neuropsychiatric performance in patients with HCV infection and different degrees of hepatic impairment. Unfortunately, these have often included patients with cirrhosis, patients who had acquired the infection through previous intravenous drug misuse, who had a history of relatively recent treatment with interferon, or were on psychoactive medication. In addition, different neuropsychological batteries and tests that explored different cognitive domains were used, which makes the results of the studies difficult to compare. Finally, limited information is available on the pathogenesis of HCV-related cognitive impairment. Cerebral and/or systemic inflammation may be important players but their potential role has not been substantiated by experimental data. The present review outlines the available evidence of the presence of cognitive impairment in patients with HCV infection, with a focus on the potential relationship with cerebral and/or systemic inflammation.
Keywords: Cognitive alterations, Hepatitis C virus, Inflammation
INTRODUCTION
Hepatitis C virus (HCV) infection affects up to 2% of the world population and almost 4 million people in America. Although evolution to chronic HCV infection is extremely common, only 30% of chronically infected patients go on to develop end-stage liver disease and hepatocellular carcinoma.
The occurrence of hepatic encephalopathy is well documented in patients with viral cirrhosis, as in patients with cirrhosis of other etiologies[1]. However, in recent years, there has been growing evidence that alterations in cerebral function in patients with chronic HCV infection may appear long before the development of severe liver fibrosis/cirrhosis. These alterations cannot be ascribed to hepatic encephalopathy. About 50% of patients with HCV infection complain of neuropsychiatric symptoms, “brain fog”, weakness, fatigue, and exhibit some degree of quality of life impairment, irrespective of the severity of liver disease[2]. These alterations do not seem to relate to HCV genotype or replication[3]. Their etiology is unclear but it has been hypothesized that it is related to: (1) a direct effect of HCV on the brain; or (2) the neurotoxic effect of HCV-related systemic inflammation.
In the present review, we outline the available evidence of cognitive impairment in patients with HCV infection, and the possible role of cerebral and systemic inflammation
COGNITIVE ALTERATIONS IN PATIENTS WITH HCV LIVER DISEASE
Early in the course of infection, patients with HCV infection report symptoms like fatigue, malaise, weakness and problems in maintaining attention and recalling information. These alterations can interfere with their ability to perform their activities, thus leading to impairment in health-related quality of life, which is well documented[4-12]. In addition, although treatment of chronic HCV infection can temporarily worsen health-related quality of life, the relationship between sustained viral response and improvement in quality of life is also well accepted[13].
The first significant evidence for a specific role of HCV in causing cerebral function abnormalities was produced in 2001 by Forton and colleagues, who detected cerebral metabolic abnormalities (elevated choline/creatine ratio) in the frontal white matter and basal ganglia of HCV-infected patients, using proton magnetic resonance spectroscopy (1H MRS); these alterations were not present in either controls or patients with HBV infection[14]. In the following year, the same group showed significant impairment in concentration and working memory in 27 HCV-infected patients with active viral replication, compared to 20 controls and 16 anti-HCV-positive but HCV-RNA-negative patients[15].
Since these original observations, 10 studies have been published that have evaluated neuropsychiatric performance in patients with HCV infection and different degrees of hepatic impairment. Unfortunately, these have often included patients with cirrhosis (potentially, also those with minimal hepatic encephalopathy); patients who had acquired the infection by previous intravenous drug misuse; patients who had a history of relatively recent treatment with interferon; patients on psychoactive medication; or those who complained of significant fatigue; all of which could impinge on cognitive performance, in terms of motivation and psychomotor speed. In addition, different neuropsychological batteries and tests that explore different cognitive domains have been utilized, which makes it difficult to compare the results of the studies.
Hilsabeck and colleagues have documented a prevalence of cognitive dysfunction which ranged from 0% on a design copy task to 49% on a measure of sustained attention in a group of 66 HCV-infected patients; 44 (66%) of whom had cirrhosis[16]. The HCV-infected patients were compared to a cohort of 14 patients with liver disease of other etiology, who had normal cognitive performance. However, within the study group, there were factors that could have contributed to cognitive impairment, such as previous alcohol intake and HIV co-infection; the control group also included patients with previous alcohol misuse and those with cirrhosis, and possibly minimal hepatic encephalopathy. The authors were able to correlate the degree of fibrosis with that of cognitive impairment, and suggested that the latter might parallel progressive liver injury in HCV-infected patients. However, the inclusion of even a small number of patients with cirrhosis and hepatic encephalopathy might well be responsible for the correlations observed. In addition, sustained attention, which was found to be abnormal in almost half of the study group, is known to be impaired in patients with hepatic encephalopathy[17,18].
When the same authors administered a similar test battery to an independent group of HCV-infected patients, 33% of whom had cirrhosis, there was no correlation between perceived cognitive impairment, fatigue or depression and neuropsychological performance, which suggests that the latter might not be clinically relevant[19]. Similarly to the previous study, a correlation was observed between neuropsychological performance and the degree of fibrosis, which led the authors to suggest that progressive liver injury might result in worsening neuropsychiatric function in HCV-infected patients. Within this setting, it would be difficult to explain how a significant proportion of patients with HCV-related cirrhosis, just like those with cirrhosis of other etiology, would show completely normal neuropsychiatric function on extensive screening for hepatic encephalopathy.
The issue of the relationship between cognitive impairment and perceived fatigue in HCV-infected patients was subsequently addressed by Weissenborn and colleagues, who compared neuropsychological performance in 30 PCR-positive HCV-infected patients with normal liver function, 15 of whom reported moderate to severe fatigue[20]; patients with previous drug misuse, interferon treatment, psychiatric disease and patients on psychoactive drugs were excluded. The authors found a significant deficit in attention and higher executive function in patients compared to controls, in parallel with an increase in depression and anxiety. Patients with self-reported fatigue performed worse on the neuropsychological battery, whereas there was no correlation between anxiety/depression and cognitive performance. In the same study, patients with HCV infection showed a significant decrease of the N-acetyl-aspartate/creatine ratio in the cerebral cortex on 1H MRS, while the electroencephalogram was slowed in 25%[20]. In contrast, in a published abstract, Montagnese and colleagues have reported on an unexpectedly high prevalence of fast (β-dominated) electroencephalograms in a similarly well-selected population of HCV-infected patients. Similar features had been previously reported in HIV-infected individuals[21] and could be related to some degree of desynchronization of the cerebral electrical activity.
McAndrews and co-workers have confirmed the presence of minor attention deficits and impairment in verbal learning ability in their study of 37 well-selected HCV patients without disease-associated risk factors, such as substance misuse, cirrhosis or depression[22]. When compared with 46 age-matched controls, 13% of patients with HCV infection showed impairment in verbal learning ability; however, the chosen threshold for a pathological performance was 1.5 SDs below the norm, which is stricter than the usual 2 SDs. The authors themselves qualify the detected abnormalities as having limited clinical relevance. As in previous studies, McAndrews and colleagues also detected an increase in choline and a reduction in N-acetyl aspartate by MRS in the central white matter of patients compared to controls.
In contrast, Fontana and co-workers have found that 33% of 177 patients with HCV infection and advanced fibrosis who were enrolled in the HALT-C trial could be considered to have cognitive impairment (before interferon and ribavirin treatment), based on a composite score of 10 neuropsychological tests[23]. The most affected domains were verbal recall and working memory. However, 38% of patients had cirrhosis, and working memory is known to be impaired in patients with cirrhosis and hepatic encephalopathy[24], which was probably a significant confounder in this study. In addition, 50% of patients had been alcohol misusers and 46% had a history of intravenous drug abuse. In contrast with the findings by Hilsabeck and colleagues, Fontana and co-workers observed no relationship between cognitive alterations and the degree of fibrosis or mood disturbances[23].
More recently, Lowry and colleagues studied neuropsychiatric function in a well-selected, homogeneous cohort of 20 female, iatrogenically-infected patients; of whom, 11 were positive for HCV RNA and nine had spontaneously cleared the virus[25]. The authors showed that PCR-positive women had significantly poorer scores in the areas of memory, auditory recognition and sustained attention compared to a small group of nine healthy controls; these abnormalities were not present in the PCR-negative women.
To date, two studies that explored cognitive function in chronically HCV-infected patients were completely negative. The first was published by Cordoba and colleagues[26], who showed normal neuropsychiatric performance in 40 HCV patients with normal hepatic function; however, these individuals still exhibited some degree of quality of life impairment. In the same study, significant alterations in attention, executive function and motor performance were detected in a control group of patients with HCV-related cirrhosis. In contrast to most previous studies, Cordoba and co-workers selected their HCV-positive patients amongst healthy individuals screened for blood donation[26]; this is a fairly different population compared to patients with known chronic HCV infection.
The second negative study included 103 HCV-PCR-positive young patients (aged 6-19 years) who were studied with the Adaptive Behavioural and WAIS scales. In this group, the time lag between infection and cognitive assessment might have been significantly lower compared to the other, adult cohorts, thus possibly explaining, at least to some extent, the negative results[27].
One study that compared cognitive performance in 32 patients with chronic hepatitis C against 29 chronic hepatitis B showed than HCV patients had worse performance in verbal learning and memory compared to controls, but they did not differ from patients with hepatitis B virus liver disease[28]. However, about 20% of patients had liver cirrhosis in both groups. Moreover, only 50% of the study group had histological assessment and no clinical exclusion of cirrhosis was described by the authors.
INFLAMMATION AND HCV
The etiology of cognitive dysfunction in patients with chronic HCV infection remains unclear but two hypotheses have been put forward: (1) the virus infects the brain and has a direct neurotoxic effect; and (2) the virus is indirectly neurotoxic via cerebral and/or systemic inflammation.
A direct neurotoxic role for HCV is supported by reports of HCV replication within the central nervous system[29-31]. It has been suggested that the virus enters the brain by infecting peripheral blood mononuclear cells, which are precursors of the microglia and could act as a “Trojan horse”[32]. However, data on the association between the virus in the brain and impaired cognitive function are still lacking. Indeed, replication of quasispecies is very low within the brain; HCV RNA is almost undetectable in the cerebrospinal fluid[33,34] and there is no correlation between viral load and cognitive impairment in patients with HCV infection[20]. However, this is sometimes also the case for other HCV-related complications, such as cryoglobulinemia or vasculitis[35].
It is well known that the cytolytic effect of HCV within the liver relates to the activation of the immune system. Thus, chronic activation of the immune system could account, at least in part, for the observed cerebral alterations, due to increased systemic and/or local inflammation. A growing body of evidence supports immune system-to-brain communication, with peripheral immune activation being associated with behavioral, affective and cognitive disturbances. Peripheral proinflammatory cytokines such as interleukin (IL)-1, and IL-6 are likely mediators of these effects, and penetrate the blood-brain barrier directly through active transport mechanisms, activation of the vagus nerve, stimulation of neurotransmitter systems, and therefore, modulation of brain activity. Most of the evidence that directly links peripheral proinflammatory cytokines with neurocognitive function is derived from animal models, in which increased peripheral IL-1 and IL-6 are associated with increased levels of these cytokines in the prefrontal cortex and hippocampus[36].
Increased levels of IL-6 have been associated with impairment in spatial learning and memory, which are prevented by the administration of specific antagonists. This suggests a primary role for inflammatory cytokines in mediating cognitive decline and deficits in chronic inflammation[37,38]. Likewise, peripheral markers of inflammation have been associated with cognitive decline in elderly patients. In a recent study that evaluated the correlation between IL-6 and cognitive performance in middle-aged volunteers, an inverse relationship was observed between circulating levels of IL-6 and auditory recognition memory, attention, working memory and executive function[39].
Once a patient has chronic HCV infection, proinflammatory cytokines such as IL-6, IL-4 and tumor necrosis factor (TNF)-α are produced and may be elevated for several decades. During this period, proinflammatory cytokines can cross the blood-brain barrier and therefore contribute to cognitive impairment.
Moreover, another possible contribution of inflammation to cognitive degeneration in HCV patients is local cerebral inflammation[34,40,41]. It has been shown that small amounts of HCV within the brain evoke a local inflammatory response, because macrophages infected with HCV in vitro can induce TNF-α and IL-8[32]. In addition, a recent study has shown activation of brain macrophages/microglia in autopsy brain tissue from HCV-positive patients[42]. Peripheral markers of the activation of cellular immunity have recently been assessed by Gess and colleagues in a group of 53 HCV-infected patients with mild liver disease. No association was observed between activated cellular immunity and subjectively perceived or objectively measured cognitive impairment[43].
FUTURE PERSPECTIVES
The studies that have explored cognitive function in patients with chronic HCV were extremely heterogeneous in terms of patient characteristics, confounding factors (e.g. intravenous drug misuse and previous alcohol intake), control groups, methodology and tests used to assess cognitive performance. An additional issue might be the fact that the study subjects ranged from patients who had cleared HCV to those with HCV-related cirrhosis, even within the same study group. Furthermore, the role of systemic inflammation in the pathogenesis of cognitive alterations in patients with HCV infection has never been directly explored.
It is possible that patients with chronic HCV infection and persistently normal transaminases for 6 mo (PNALT) could represent an extremely useful study group to provide additional information, particularly in relation to the role of HCV per se in causing neurocognitive dysfunction. When we evaluated systemic inflammation in this group of patients, no activation of systemic inflammation was observed[44]. This finding suggests that patients with normal transaminases have a different immunological response profile, compared to those whose transaminases remain elevated. In line with this hypothesis, previous studies have demonstrated an increase in HCV-specific CD4+CD25+ regulatory T cells and a decrease in CD4+ response in patients with normal transaminases compared to patients with high transaminases[45].
Whether the absence of an activated systemic inflammatory response in PNALT patients also reflects better cognitive performance needs to be explored. In a preliminary study, we found that PNALT patients with normal serum levels of proinflammatory cytokines performed similarly to controls as far as memory, attention and cognitive evoked potential N400, which relates to semantic memory and verbal working memory. Patients with chronic hepatitis due to HCV had impairment in memory in 60% of cases, with concomitant increased amplitude of N400, which indicated the need for increased neuronal recruitment to perform the task[44].
In the two studies that did not demonstrate cognitive alterations in patients with HCV, HCV-positive individuals were selected from healthy volunteers screened for blood donation and young patients with hemophilia, respectively. These subjects were classified as HCV-positive individuals with normal transaminases but were not further characterized, and some might well have qualified as PNALT.
Future, prospective cohort studies should probably include patients with chronic HCV infection with minimal or no fibrosis, PNALT, hepatitis B surface antigen-positive patients with/without transaminitis and a control group with chronic systemic inflammation (i.e. inflammatory bowel disease). In addition, the neuropsychological evaluation should probably be conducted in a structured, comprehensive way, by cognitive domain, and test results scored against adequate, large and local normative databases, rather than simply compared to small internal control groups. Mood, fatigue and quality of life should also be assessed. This approach might provide more solid information on whether HCV-related cognitive impairment exists and, if so, on its clinical relevance.
Footnotes
Peer reviewers: Yukihiro Shimizu, MD, PhD, Kyoto Katsura Hospital, 17 Yamada-Hirao, Nishikyo, Kyoto 615-8256, Japan; Alexandra A Alexopoulou, MD, 2nd Department of Internal Medicine, University of Athens, Medical School, Hippokration General Hosp, 40 Konstantinoupoleos St, 16342 Hilioupolois Athens, Greece
S- Editor Tian L L- Editor Kerr C E- Editor Zheng XM
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