Section II: Neurocognitive and neuropsychological studies
A review of cognitive impairment and cerebral metabolite abnormalities in patients with hepatitis C infection
Forton, Daniel Ma,b; Allsop, Joanna Mb; Cox, I Janeb; Hamilton, Gavinb; Wesnes, Keithc; Thomas, Howard Ca; Taylor-Robinson, Simon Da,b
From the aLiver Unit, Division of Medicine, Faculty of Medicine, Imperial College London, St Mary's Hospital Campus, London, UK
bRobert Steiner MR Unit, Imaging Sciences Department, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK
cCognitive Drug Research Ltd., Goring-on-Thames, UK.
Correspondence to Daniel M. Forton, Hepatology Section, Faculty of Medicine, Imperial College London, 10th Floor QEQM Building, St Mary's Hospital, South Wharf Road, London W2 1NY, UK. Tel: +44 207 886 1247; fax: +44 207 724 9369; e-mail: firstname.lastname@example.org
Numerous studies have reported associations between chronic hepatitis C virus (HCV) infection and fatigue, depression and impairments in health-related quality of life, which are independent of the severity of liver disease. Although there are a large number of potential explanations for these symptoms, including a history of substance abuse and associated personality types, or the effect of the diagnosis of HCV infection itself, there has been recent interest in the possibility of a biological effect of HCV infection on cerebral function. There is emerging evidence of mild, but significant neurocognitive impairment in HCV infection, which cannot be wholly attributed to substance abuse, co-existent depression or hepatic encephalopathy. Impairments are predominantly in the domains of attention, concentration and information processing speed. Furthermore, in-vivo cerebral magnetic resonance spectroscopy studies in patients with hepatitis C and normal liver function have reported elevations in cerebral choline-containing compounds and reductions in N-acetyl aspartate, suggesting that a biological mechanism may underlie the cognitive findings. The recent detection of HCV genetic sequences in post-mortem brain tissue raises the intriguing possibility that HCV infection of the central nervous system may be related to the reported neuropsychological symptoms and cognitive impairment.
Most textbooks state that chronic hepatitis C virus (HCV) infection is an asymptomatic disease. However, both general physical complaints such as fatigue, musculoskeletal and right upper abdominal discomfort and also neuropsychological complaints, including depression, mental clouding (‘brain fog’) and a perceived inability to function effectively, are common and have led to a number of published reports documenting the prevalence of such symptoms and their impact on quality of life scales in cohorts of patients with HCV infection [1–9].
The presence of these symptoms in the context of HCV infection does not necessarily imply causality, because there are many associated factors that may independently affect patients' perceptions of well-being, such as anxiety regarding the diagnosis, prognosis and treatment, previous or ongoing substance abuse, and associated emotional problems or personality traits . There has been recent interest in a possible link between HCV infection and cerebral function, occurring at an early stage of chronic infection, before the development of cirrhosis. We will first briefly review the epidemiological evidence for a causal relationship between HCV infection and neuropsychological symptoms in HIV-negative patients. This is followed by a review of studies, from our group and others, which have employed neuropsychological testing, cerebral magnetic resonance spectroscopy (MRS) and neurophysiological measurements to determine whether there is evidence of neurocognitive dysfunction in patients with chronic HCV infection.
Health-related quality of life
Health-related quality of life (HRQL) questionnaires have been used extensively to study both the effect of HCV infection on patients' well-being and the effect of antiviral therapy. The SF-36 questionnaire, a generic health instrument, has been used most widely in this context and generates a health profile, divided into eight separate categories, reflecting physical and emotional performance . The results from several large studies challenge the perception that HCV infection is an ‘asymptomatic’ disease, with general agreement that physical and mental HRQL is significantly reduced in HCV-infected patients, compared with published normative data [1,6,7,12]. This reduction in HRQL appears to be independent of the severity of the liver disease and is seen in all domains of HRQL. In one study , which contained a healthy control group, SF-36 scores were lower in patients with HCV infection compared with both healthy controls and patients with chronic hepatitis B virus (HBV) infection. Furthermore, HRQL impairments were not explained by the mode of HCV acquisition (the presence of previous intravenous drug usage). These findings, together with large studies that have shown significant improvements in HRQL in combined cohorts of many thousands of patients after successful antiviral therapy, suggest that the viral infection itself is an important determinant of reduced HRQL [6,7,13]. However, whether a biological mechanism underlies this remains controversial. Other relevant determinants of HRQL, which have been described in the literature, include medical comorbidity, the effect of the diagnosis, depression and labelling [14–16]. Importantly, many studies did not blind their subjects to the HCV polymerase chain reaction status. The impact of the diagnosis and subsequent anxiety is likely to impair HRQL [14,17]. It is also possible that some of the improvement in HRQL, seen after successful antiviral therapy, is a result of the patients’ knowledge of their response.
Although HRQL studies have been useful in quantifying the impact of chronic HCV infection on patient well-being and in monitoring a response to treatment, they shed little light on the question of cerebral involvement in HCV infection. Importantly, the SF-36 does not include a cognitive function scale and this aspect of HRQL has not been systematically studied in chronic HCV infection.
Fatigue is often said to be the commonest symptom in patients with chronic HCV infection. Numerous uncontrolled surveys have reported the prevalence of fatigue to be between 20 and 80% in HCV-infected patients [2,4,8,9,18–20], and have found no association between the severity of fatigue and the degree of hepatitis [3,9,15] or the presence of autoimmune disorders . Although improvements in fatigue have been reported after treatment [19,20], it appears to persist in some individuals despite a virological response. Many of the studies in the field can be criticized for not adequately controlling for relevant confounding factors. Fatigue in chronic HCV infection is a multidimensional symptom and is influenced by multiple interrelating social, behavioural, psychological and personality factors [15,21–23]. It has been argued that, because most studies have been methodologically flawed in some way and fail to take account of all confounding factors, there is no evidence of a causal association between HCV infection per se and fatigue . One controlled, but retrospective study showed no excess of fatigue in HCV-infected patients compared with non-infected blood donors . However, the prevalence of fatigue in the apparently healthy blood donors was surprisingly high at 70%, suggesting that the fatigue rating tool was oversensitive. The absence of a relationship between fatigue and markers of liver inflammation [3,9,15] has been used to argue against a causal relationship between HCV infection and this symptom . However, this position ignores the possibility that the pathogenesis of fatigue in HCV-infected individuals may be unrelated to the severity of liver disease. In summary, it is likely that the fatigue reported by HCV-infected patients is the result of multiple, co-existent causes and the relative contribution of a biological mechanism remains unclear.
Depression is a common finding in HCV-infected patients [2,15,16,26,27]. Antiviral therapy with α-interferon may precipitate or exacerbate depression , and this symptom may thus limit the tolerability of treatment and reduce compliance . The relationship between HCV and depression is undoubtedly complex. There is currently little evidence that a biological effect of HCV infection itself underlies depression. In one blinded study of intravenous drug users , HCV-positive individuals had significantly lower positive affect scores than HCV-negative drug users. In another study  there was no difference in psychological morbidity between HCV-positive and HCV-negative drug users, although in both of the studies, the effect of HCV may have been masked by the high background prevalence of depression in active drug users. It is more likely that patients with depression may have a higher incidence of HCV infection. The greatest reservoir of HCV infection is in intravenous drug users, many of whom have clinical depression . Conversely, depression may exist as a secondary phenomenon to HCV infection. This may take the form of a reactive depression, related to the diagnosis and concerns over long-term health, or may be secondary to symptoms such as fatigue and cognitive impairment .
In summary, there is a large burden of neuropsychological and neuropsychiatric symptomatology associated with chronic HCV infection, but whether this is a direct consequence of the viral infection or whether it is related to associated factors remains unclear. It is therefore apparent that objective measures of cerebral function are required to determine the nature and degree of cerebral dysfunction in chronic HCV infection.
Cognitive function in chronic liver disease
Before considering the possible effects of HCV on the brain, it is necessary to set the scene in the context of potential confounding factors that arise in patients with chronic liver disease of any etiology. Chronic hepatic encephalopathy describes the neuropsychiatric syndrome most commonly associated with hepatic failure and portal–systemic shunting in cirrhosis of the liver, but which may also exist in patients with surgical portal–systemic shunts . In 1954, Sherlock and colleagues  performed the first systematic study of overt hepatic encephalopathy, describing the clinical presentation of 18 patients with advanced liver disease, whose signs and symptoms consisted of an altered level of consciousness, asterixis, ataxia, confusion, spatial disorientation and visual hallucinations.
Since the 1970s, several groups have reported impairments using neuropsychological testing in patients with cirrhosis and no appreciable clinical signs of hepatic encephalopathy [34–38]. Those studies, together with many others, have demonstrated selective impairments of psychomotor speed, visual perception and attention with preserved verbal ability. This constellation of findings has variously been termed latent, subclinical and minimal hepatic encephalopathy (MHE), with a recent consensus emerging to support the latter . The possibility that cognitive impairment might result from minor impairments in liver function, in the absence of cirrhosis, had not been examined before the recent studies described below. Furthermore, the possibility that cognitive dysfunction might occur as a result of chronic HCV infection per se in patients with non-cirrhotic liver disease is also novel.
Cognitive impairment in hepatitis C infection
It has previously been hypothesized that chronic HCV infection may result in cognitive impairment before the development of cirrhosis, that cognitive impairment in chronic hepatitis C may be unrelated to a history of illicit drug usage or mood disorder in some patients, and that cognitive impairment in chronic hepatitis C directly affects the health-related quality of life . Five studies have been published that have examined whether HCV infection has an impact on cognitive function in HIV-negative individuals [40–44]. A further three published studies have evaluated the effect of HCV infection on cognitive function in HIV-positive individuals [45–47].
As cognitive impairment in the form of MHE is frequently detectable in patients with cirrhosis, any study that tests for a direct effect of HCV infection on cognitive function should either exclude patients with advanced liver disease or study sufficiently large numbers to allow subgroup analyses. The published studies have considered and controlled for the presence of advanced liver disease and other relevant factors, such as medical comorbidity and drug abuse, to varying degrees. Furthermore, there have been inconsistencies in the use of control groups and definitions of impairment, which have led to different conclusions regarding the prevalence and severity of cognitive impairment attributable to chronic HCV infection.
Using a computer-based cognitive battery, Forton and colleagues  reported data from 27 antiviral treatment-naive patients with histologically confirmed minimal HCV hepatitis and 16 patients who had been exposed to HCV but were negative for HCV RNA on repeated testing. The second group served as a control group and were well matched for education and a history of recreational drug usage. None of the subjects were taking central nervous system (CNS)-altering medication or recreational drugs. Individuals were asked whether they had ever used any of five substances (heroin, methadone, LSD, cocaine, ecstasy) after reassurance that no clinical record would be kept of their answers. The clinical notes were then cross-checked, and individuals were only classified as non-users if a history of major drug usage was unequivocally absent. The test data were also compared with previously acquired age and sex-matched normative data from healthy volunteers. In addition to cognitive assessment, the subjects completed depression, fatigue and quality of life questionnaires.
The HCV-infected subjects were impaired on more tasks (performance more than one standard deviation below the normative mean) than the HCV-cleared subjects. There were selective impairments of attention, concentration and working memory in the subjects compared with healthy controls. There were no statistical differences between individuals with and without a history of recreational drug usage. Although the HCV-infected patients had higher levels of depression and reported impairments in quality of life, these variables did not correlate with the cognitive test scores. The study concluded that mild neurocognitive impairment was evident in a proportion of patients with histologically mild chronic HCV infection, and that it was not accounted for by depression, fatigue or a history of drug abuse.
The proportion of patients with neurocognitive impairment clearly depends on the criteria used to define it. In an expanded cohort of HCV-infected patients with histologically mild liver disease (n = 40), the same investigators recorded impairments of greater than one standard deviation below normative means, on two or more tasks out of a maximum of six in 38% of HCV-infected patients (unpublished data). This level of impairment was seen in 11% of the HCV-cleared individuals (P = 0.04). When compared directly with the HCV-cleared individuals, 17.5 and 25% of the performances of the HCV-infected patients were below the fifth centile of the results of the HCV-cleared patients, on composite scores measuring concentration and speed of memory processing, respectively. Physical fatigue was the only predictor of performance (on the speed of memory processes score in the HCV-infected patients).
A similar prevalence of cognitive dysfunction was reported by Hilsabeck and colleagues , who administered a battery measuring visuoconstructional skills, learning, forgetting, sustained visual attention and concentration, psychomotor speed, visual scanning and tracking and mental flexibility to 66 HCV-infected individuals (44 without cirrhosis). The authors found that the proportion of impaired performance ranged from 0% on a design copy task to 49% on a measure of sustained attention. Impairment was again defined as performance one standard deviation below the normative mean. The HCV-infected patients were a heterogeneous group, with 27% taking psychiatric medication and 23% undergoing interferon therapy at the time of testing. The HCV-infected patients were compared with a cohort of 14 patients with liver disease of other causes, and no excess of cognitive impairment was seen in the HCV group. However, the comparison group included patients with alcoholic liver disease and was small, with only six patients without cirrhosis. Perhaps unsurprisingly, patients with HCV and a second chronic medical condition, such as alcoholic hepatitis or HIV, showed greater levels of cognitive dysfunction. Furthermore, patients with more hepatic fibrosis were more likely to show greater cognitive impairment. Whether this was a direct consequence of increased fibrosis or whether it was somehow related to the duration of infection was not addressed in the study. The authors concluded that progressive liver injury may result in cognitive problems in patients with hepatitis C, even before the development of cirrhosis. The same researchers administered a similar test battery to an independent sample of 21 patients infected with HCV , and examined more thoroughly the relationship of neuropsychiatric symptoms, including complaints of cognitive dysfunction, with objective neuropsychological test performance. The cohort was similarly mixed as that in their previous study; 33% had cirrhosis, 19% had alcoholic hepatitis on liver biopsy, 9% were HIV co-infected, 24% were undergoing antiviral therapy, and 55% were taking psychiatric medication at the time of testing. Similar rates of impairment in complex attention, concentration and working memory were reported. There were no significant differences on any of the cognitive measures between individuals reporting higher and lower levels of fatigue, depression or perceived cognitive dysfunction, similar to the findings of Forton and colleagues . Although the authors presented data to support their conclusion that a significant proportion of patients with chronic HCV infection may experience cognitive difficulties, it is not clear that the impairments described were directly attributable to HCV infection. Furthermore, the lack of an association between cognitive measures and fatigue, depression or cognitive symptoms in the above studies leads one to question the clinical significance of the impairments.
This issue was addressed in a recent study by Weissenborn and colleagues . They studied 30 patients with HCV infection without cirrhosis or advanced liver disease. Medical and psychiatric comorbidity, active drug abuse and treatment with any CNS-altering medication were exclusion criteria for recruitment to the study. The aim of the study was to determine whether patients’ subjective impression of fatigue was accompanied by objective evidence of cerebral dysfunction. They employed a well-validated battery of traditional neuropsychological tests together with the fatigue impact scale, the functional activities questionnaire, and the hospital anxiety and depression scale. Fifteen healthy control subjects were also studied. The HCV-infected patients were divided into mild and moderate fatigued groups on the basis of the fatigue impact scale results. In agreement with the earlier studies, HCV-infected patients displayed attention deficits, slight memory disturbances, functional impairments in activities of daily living and depression. These deficits were associated with fatigue, being present in the mildly fatigued patients but more pronounced in the moderately fatigued group. The cognitive deficits reflected attentional processes and higher executive functions, whereas visuoconstructive abilities and motor performance, which are often impaired in MHE, were preserved. As these abnormalities were selective rather than global, it was argued that, rather than being a consequence of mood disturbance, they provided objective evidence of CNS involvement in HCV infection. In parallel with most of the studies in this field, the study subjects were recruited from a tertiary referral centre. No conclusions can therefore be drawn regarding the prevalence of CNS involvement in the broader population of HCV-infected individuals.
Cordoba and colleagues  attempted to address this question by studying patients with chronic hepatitis, who were found to be HCV infected when applying to donate blood. The study was designed to evaluate cognitive function and quality of life at three different stages of HCV infection: first chronic hepatitis, second cirrhosis without previous decompensation, and finally, cirrhosis with previous decompensation, but no overt encephalopathy at the time of testing. A total of 120 patients were studied and compared with an age, sex and educationally matched control group. Quality of life was assessed using SF-36, and cognitive testing was performed using a comprehensive battery of standardized tests, assessing memory, attention, executive function, visual perception and psychomotor function. In contrast to earlier studies, the authors found no evidence of cognitive impairment in HCV-infected patients without cirrhosis and in those with compensated cirrhosis. Impairments were only detected in patients with previous hepatic decompensation, which were almost certainly caused by MHE. There was a non-significant trend towards impaired executive function in the pre-cirrhotic group. A number of factors may explain this finding. The majority of patients in the non-cirrhotic and compensated cirrhotic groups were enrolled after HCV infection was diagnosed at blood donation. Therefore, these groups were positively selected for good health, because symptomatic individuals are unlikely to volunteer to give blood. This is reflected in the SF-36 quality of life scores of the chronic hepatitis C group, who only differed significantly to the control group in one out of the eight scores (role physical). In addition, patients with overt cognitive dysfunction as assessed by the mini-mental test were excluded from the study. The battery employed in this study was broad, covering five neuropsychological domains, which may not all be relevant to chronic hepatitis C. The other studies suggested that attention may be the most relevant domain, and this was tested using three tests in this study; Trail A, Symbol Digit Oral and Stroop. The former two tests were of low sensitivity in pre-cirrhotic individuals in one previous study (20–23% impairment)  and were insensitive in another . Furthermore, the study used stringent criteria for cognitive impairment, by performing statistical analyses on raw scores compared with a healthy control group, rather than defining impairment by comparison with population norms. These factors, together with differences in the sensitivity of paper-based tests compared with the computer-based recording of reaction times, may explain the discrepant findings in the study. The study was consistent with earlier studies, in that no association was found between cognitive function and physical and mental quality of life, as measured by SF-36.
Although there are important differences between these studies in terms of patient characteristics, the use of control groups, methodology and statistical analysis, there has been broad agreement that, in a proportion of patients with chronic HCV infection, there is evidence of mild neurocognitive impairment. The data are consistent with the common complaint of ‘brain fog’ . Similar findings of slowed processing speed and impaired working memory are the most prominent features of cognitive dysfunction in patients with the chronic fatigue syndrome . Such findings have also been reported in the medically asymptomatic stages of HIV infection , and are consistent with the involvement of subcortical or frontostriatal brain systems . Questions remain, however, regarding the prevalence, clinical significance and, above all, the etiology of these findings in chronic HCV infection.
A number of potential explanations may be postulated to account for, or contribute to, the cognitive dysfunction observed in HCV patients. These include the presence of MHE, the effect of personality or HCV acquisition-associated factors, such as a history of major recreational drug usage, the presence of affective disorders, and of subjectively experienced symptoms, such as fatigue. Furthermore, there may also be a biological effect of HCV infection on the CNS. It should be noted that these explanations are not necessarily mutually exclusive and might interact. Although there is ample evidence for a deleterious effect of active drug use on cognitive function, particularly in cases of polydrug usage , few studies have addressed the effect of prolonged abstention from recreational drug use. Studies have shown neuropsychological impairment in the first few weeks of abstinence, particularly from opiates and sedatives , which may persist for up to 3 months. There is also evidence that cognitive function improves during abstinence . The lack of an association between previous drug use and cognitive impairment in the published studies is probably explained by the long periods of abstinence before enrolment.
No consistent association between cognitive impairment and depression in HCV-infected patients has been demonstrated, although most studies included patients with mild depression. It is possible that the reported mild mood disturbance is a component of a neuropsychological syndrome associated with HCV infection, and may itself be secondary to physical or cognitive symptoms, or the impact of diagnosis and illness perception [22,27]. Cognitive studies in patients without any depressive features are awaited to resolve this issue.
The studies have also not demonstrated a consistent association between fatigue and cognitive impairment, although Weissenborn and colleagues  reported greater cognitive dysfunction in more fatigued patients. It is interesting to speculate whether slowed thinking and psychomotor speed, in combination with reduced attention, might result in routine tasks taking longer to complete. This reduced accomplishment for a given effort may be interpreted by the individual as fatigue. Alternatively, fatigue and cognitive impairment may both be caused by a third, as yet unidentified factor.
Although health-related quality of life is consistently reduced in HCV-infected patients, impaired well-being on general health measures has not been associated with cognitive dysfunction in the studies to date. The SF-36 scores reflect impairments in physical and mental function, and are insensitive to cognitive symptoms such as forgetfulness, mental fatigue and difficulty maintaining concentration and attention, which are the symptoms that patients frequently report. Hilsabeck and colleagues  employed a cognitive HRQL scale, but found no relationship between patient reports of cognitive impairment and objective evidence of neuropsychological dysfunction. The impact of mild neurocognitive impairment therefore remains of uncertain significance in this patient group.
To date, there are no published longitudinal studies examining the effect of successful antiviral therapy on cognitive function in chronic HCV infection. Assuming that the treatment itself has no long-term effect on cognitive function, such studies could theoretically control for many potential confounding factors, and provide an answer as to whether HCV infection itself is truly the cause of the observed impairments in HCV-mono-infected patients.
Cognitive impairment in hepatitis C and HIV co-infection
Both HIV and HCV are blood-borne viruses that can result in chronic infection. HIV/HCV co-infection is not uncommon, with a reported HCV prevalence rate of 16% in an HIV seropositive study cohort . HCV is emerging as the most important cause of liver disease in patients infected with HIV. In addition, there has been recent interest in the possibility that HCV may contribute to CNS dysfunction in HIV-infected individuals. Three studies have been published that have addressed this issue in cohorts of HIV-seropositive individuals at different stages of disease [45–47].
Ryan and colleagues  studied 116 patients with advanced HIV infection, divided into two groups according to HCV antibody status; 67 patients were co-infected and 49 were HCV seronegative. There were no significant differences between the two groups in respect of demography and CD4 cell counts. Subjects were administered a broad range of neuropsychological tests, and the prevalence of HIV-1-associated dementia complex and HIV-associated minor cognitive/motor disorder (MCMD) was assessed using a modified American Academy of Neurology algorithm. Co-infected patients were more likely to have had past cocaine, opiate or stimulant dependence, although HIV-mono-infected patients had more frequent positive urine toxicology screens at the time of testing. There was a high prevalence of major depression (42%), which was equivalent in both groups. There was a high background level of neuropsychological impairment in both groups in all domains (29–72%). On tests of executive functioning, co-infected patients exhibited a greater rate of impairment. Co-infected patients were also more likely to be diagnosed with AIDS dementia complex than HCV-negative patients. The authors concluded that, despite the advanced nature of their HIV cohort, there was a detectable neurocognitive impact of HCV co-infection. However, with such a high background burden of neuropsychological impairment in that study, the clinical significance of the additional effect caused by HCV was unclear. Although the differences in cognitive functioning were not associated with indices of liver disease, only a minority of subjects had histopathological liver assessment, and it is conceivable that a proportion of HIV/HCV-co-infected patients had cirrhosis and associated MHE.
Von Giesen and colleagues  studied a cohort of HIV and HCV infected patients at an earlier stage of disease, in which HIV-associated dementia and clinical/radiological evidence of cirrhosis were exclusion criteria. They studied 43 HIV/HCV-co-infected patients, 43 HIV-seropositive, HCV-seronegative patients and 44 HIV-seronegative, HCV-sepositive patients. All patients underwent brief neuropsychological testing and electrophysiological assessment of basal ganglia-mediated motor function. There were no significant differences between the patient groups on cognitive tasks, with only minor disturbances in function. However, there were significant impairments in electrophysiological measurements of psychomotor speed in all three study groups compared with HIV-negative/HCV-negative controls. Each group showed significant pathological slowing of most rapid alternating movements and prolonged hand contraction times, similar to previous reports in HIV subjects . The authors concluded that infection with either virus can cause subclinical psychomotor slowing, which does not deteriorate in HIV/HCV co-infection, at least at a relatively early stage of disease. There was a history of intravenous drug use in 48% of the subjects, but this was not found to affect psychomotor speed in any of the three groups. The HIV-negative/HCV-positive patients were found to have more affective disturbance and depression than either HIV-seropositive group, although the interaction between this and psychomotor speed was not analysed. However, a previous report from the same group  suggested that basal ganglia-mediated psychomotor speed in HIV infection is not influenced by concomitant depressive symptoms.
In contrast to the above study, Martin and colleagues  identified an additive effect of HIV/HCV co-infection on cognitive function over mono-infection with either virus. The authors tested 159 drug users with known HIV and HCV serostatus using a voice-activated reaction time version of the Stroop task, sensitive to HIV-associated cognitive dysfunction. A total of 39 HIV-positive/HCV-negative, 28 HIV-positive/HCV-positive, 69 HIV-negative/HCV-negative and 20 HIV-negative/HCV-positive subjects were tested. Although all the subjects had at least one Diagnostic and Statistical Manual of Mental Disorders, version IV, substance-dependent disorder, there was an excess of previous intravenous drug usage in HCV-infected patients. All toxicology screens were negative at the time of testing. The HCV-infected subjects responded more slowly than the HCV-negative patients, regardless of HIV status, although the Stroop effect fell just short of significance. There was a significant Stroop effect in the HIV-infected subjects, with worse performance in the incongruent condition, compared with the neutral and congruent conditions. The authors concluded that HIV infection may result in impaired executive function, whereas HCV infection may cause overall slowed information processing. When an overall measure of Stroop performance was calculated, there was a significant monotonic trend for poorer performance among subject groups ordered hierarchically according to infection status (seronegative, mono-infected, dually infected), although no distinction was made between HCV and HIV mono-infection. The authors acknowledged that studies such as this are beset by problems, as a result of multiple potential confounders, e.g. the HCV-seropositive subjects had used drugs for a longer period, including more injection drug use. In addition, no account was taken of liver function and the possibility of MHE. As in the study by Ryan and colleagues , it is unclear whether the additional effect of HCV infection on cognitive dysfunction in HIV-seropositive subjects is mediated by a direct CNS effect of HCV or through cirrhosis and MHE.
Cerebral proton magnetic resonance spectroscopy in chronic hepatitis C infection
In vivo cerebral MRS provides a non-invasive tool for the measurement of metabolite concentrations and allows an assessment of the metabolic state of tissue, both in health and disease and a search for any association with either cognitive impairment or fatigue and depression seen in patients with HCV. Three published studies have used MRS to study this group of patients [40,44,58].
A typical brain spectrum contains resonances that can be assigned to choline, the methyl moieties of creatine and phosphocreatine, myo-inositol and N-acetyl aspartate (NAA). The exact physiological role of NAA is not known, but it is generally accepted that it is of neuronal origin [59,60]. The choline resonance contains contributions from different choline-containing compounds such as glycerophosphocholine and phosphocholine. These compounds participate in phospholipid metabolism and osmotic regulation in glial cells. Increases in the choline resonance are seen in a variety of inflammatory CNS conditions [61,62], and probably represent increased cellularity, gliosis and macrophage infiltration as well as membrane degradation associated with myelin destruction [60,63]. Decreases in choline are associated with osmolar changes . Creatine and phosphocreatine play a role in energy metabolism and have been thought to exist at similar levels in neuronal and non-neuronal cells, in health and disease, thus serving as an internal reference in some studies. Myo-inositol is involved in the synthesis of phosphoinositides, and plays a role in osmotic regulation within the brain . Microglial activation and astrogliosis are associated with increased myo-inositol .
Forton and colleagues [40,58] examined whether there were any abnormalities in cerebral metabolites, as measured by in vivo cerebral 1H MRS, in treatment-naive patients with chronic hepatitis C infection and histologically mild liver disease, and whether there were any associations between cerebral metabolites and neuropsychological symptoms, cognitive dysfunction and other demographic factors, such as a history of illicit drug use. A total of 49 randomly selected patients with histologically defined mild chronic hepatitis caused by HCV infection, 12 patients with chronic hepatitis B and viraemia (e antigen positive) as a control group and 29 healthy controls, recruited from available hospital staff were studied, using an automated PRESS sequence (TR 1500 ms, TE 135 ms). In the basal ganglia, choline/creatine and phosphocreatine was significantly elevated compared with both the HBV group and healthy volunteers. There were no differences in NAA/creatine and phosphocreatine. These results suggest that choline-containing compounds were increased in the basal ganglia in the HCV patients. Similarly, in the frontal cerebral white matter, choline/creatine and phosphocreatine was significantly increased and NAA/choline was significantly reduced, compared with both other groups. There were no statistically significant differences between the HBV group and the healthy volunteers. No statistically significant differences were seen between study groups in the occipital grey matter metabolite ratios. There were no statistical differences in the ratios between the HCV patients with a history of injection drug use and those without. A subgroup of patients underwent neuropsychological testing . There were no statistical associations between any of the cognitive scores and the cerebral 1H MRS metabolites, although there was a trend for patients with cognitive impairment on the battery as a whole to have elevated basal ganglia choline/creatine and phosphocreatine. There were no associations between the MRS metabolite ratios and fatigue, depression or HRQL scores.
Weissenborn and colleagues  recently reported results from an MRS study of 29 patients with hepatitis C and normal liver function. Using a short echo STEAM sequence (TR 1500 ms, TE 18 ms), they reported reduced NAA/creatine and phosphocreatine ratios in the occipital grey matter compared with healthy controls. There were no abnormalities in any other regions (parieto-occipital white matter, basal ganglia or pons) or any perturbations of choline/creatine and phosphocreatine or myo-inositol/creatine and phosphocreatine. There were also no associations between the MRS data and abnormal neuropsychological and fatigues scores, as reported by Forton and colleagues [40,58].
Elevations in basal ganglia choline/creatine and phosphocreatine in the HCV patients may possibly be explained by elevations in choline and reductions in creatine and phosphocreatine, as seen in HIV [66–68]. This interpretation remains hypothetical and will only be proved by further larger studies, employing the absolute quantitation of cerebral metabolites. Similarly, the reduced cortical NAA/creatine and phosphocreatine reported by Weissenborn and colleagues  may reflect true reductions in NAA, although this finding is normally associated with the more severe end of the clinical spectrum in HIV infection . The situation is further complicated by different acquisition and analysis parameters in the different studies. However, the results do suggest that a cerebral metabolic abnormality does exist in a proportion of patients with HCV infection and normal liver function.
An important finding in these studies was the absence of an association between cognitive dysfunction, depression or quality of life measures and cerebral metabolite ratios, despite the presence of impairments in these neuropsychological domains. Although, at first sight, this finding appears to run counter to the possibility of a causative relationship between abnormal cerebral biochemistry and neuropsychological impairments in these patients, it is important to note that MRS metabolites and neuropsychological test scores do not represent the same phenomenon. MRS metabolites are a direct, biological measure reflecting ‘brain pathology’ when abnormal. Although neuropsychological tests may be sensitive for detecting brain dysfunction, they do not directly reflect brain injury and may be affected by education, socioeconomic and cultural influences, fatigue, depression and motivation, all of which may be relevant confounding variables in this patient group.
In addition, the analysis of metabolite ratios, rather than quantitative metabolite concentrations, the use of the particular MRS sequences and the use of single voxel techniques only allow the generation of limited data sets, which may not be appropriate for testing associations with neuropsychological function. For example, MRS sequences that employ shorter echo times allow the quantitation of cerebral myo-inositol, which has the strongest association with neuropsychological dysfunction in HIV infection , and that may be a better biochemical marker in HCV-infected patients. Preliminary data from our group indicate an association between elevations in white matter myo-inositol and impairments in working memory in HCV-infected patients with normal liver function .
At present, there are no other published MRS studies, directly examining patients with chronic HCV infection. Taylor and colleagues  used MRS to determine whether HCV infection may exacerbate methamphetamine-associated neuronal injury. In a small study, reductions in frontal white matter NAA were detected in abstinent HCV-positive methamphetamine users compared with HCV-negative users. No abnormalities were seen in choline or myo-inositol. The authors concluded that HCV may exacerbate drug-induced brain injury, but in the absence of an HCV-positive, methamphetamine-negative group, they were unable to examine the effect of HCV infection in isolation.
Possible pathogenic mechanisms underlying magnetic resonance spectroscopy observations
Similar 1H MRS metabolite abnormalities to those reviewed here have been extensively documented in early cerebral HIV infection, both in neurosymptomatic and neuroasymptomatic individuals [67,69,72,73]. In the case of HIV, infection of cerebral microglia , brought about possibly via infected monocytes entering the brain, and subsequent microglial activation is thought to underlie the MRS changes in choline, creatine and phosphocreatine and myo-inositol. This occurs before the advent of dementia when there is neuronal cell and NAA loss . This raises the prospect that the metabolite abnormalities reported in HCV-infected patients are caused by direct infection of the brain by HCV. The concept of extrahepatic replication of HCV is not novel, with several lines of evidence to suggest that peripheral blood mononuclear cells are infected, particularly in the context of HIV co-infection [75–78]. Microglia comprise up to 20% of all glial cells, and are developmentally derived from bone marrow precursors of monocytic lineage . It is believed that resident microglia turn over slowly and are replaced by circulating monocytes . It is therefore possible that HCV may be introduced to the CNS via infected monocytes, through a ‘trojan horse’ mechanism. The recent detection of HCV variants in autopsy brain samples is consistent with this hypothesis [81,82].
The immune response to HCV viral proteins within the CNS may underlie cerebral dysfunction, as is the case in early HIV infection. Activated microglia are thought to liberate neurosteroids such as pregnenalone , which may have an upregulatory role on neuroinhibitory pathways in the brain. Activated microglia also release excitatory amino acids, which can induce neuronal apoptosis through a process known as excitotoxicity , and are potent producers of neurotoxins such as nitric oxide. These processes may be amplified by the release of cytokines and chemokines [85,86] as well as recruiting further virally infected peripheral blood mononuclear cells across the blood–brain barrier. It is tempting to speculate that cerebral immune activation in HIV infection may somehow be compounded in HCV co-infection, resulting in greater CNS dysfunction.
An alternative or indeed parallel explanation for the CNS effects of chronic HCV infection is the possibility that systemic factors, involved in the chronic inflammatory processes affecting the liver, may in some way alter cerebral function. For example, it could be postulated that peripherally derived cytokines might exert an effect in the CNS . The absence of cerebral MRS abnormalities in the patients with HBV infection suggests that this might not be the case, although it is accepted that there may be different serum cytokine profiles in chronic HCV and HBV infections [88,89].
The findings in such studies will require verification in larger studies of patients with HCV infection. Measurement of cerebral metabolite concentrations, employing absolute quantitation MRS techniques, and the use of shorter echo time sequences to measure metabolites such as myo-inositol may allow the demonstration of an association of symptoms or cognitive dysfunction with MRS results. Finally, longitudinal studies to measure the effect of successful antiviral therapy, with α-interferon-based regimes, will be important to determine whether the CNS effects of HCV infection are reversible.
Sponsorship: The British Medical Research Council supported some of the studies outlined in this article (grant no. G9900178). D.M.F. was also supported by a fellowship from the European Association for the Study of the Liver and by St Mary's Hospital Trustees.
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