With the availability of highly active antiretroviral therapy (HAART), HIV-related morbidity and mortality have decreased and other comorbidities have assumed greater importance . Liver disease, particularly of viral etiology and associated with hepatitis C virus (HCV), has become a prominent problem in the management of patients with HIV. This dual infection is a pernicious problem: the progression of hepatic fibrosis is more rapid in HIV/HCV patients than in those with HCV alone [2–4]. In addition, the hepatotoxicity of antiretroviral compounds is more prevalent in patients with chronic viral hepatitis [5–7]. In a Spanish study of HIV-related hospital admissions , the proportion of deaths caused by liver disease rose from 9.3% in 1996 to 45% in 2000. Similarly, in an American report , 50% of deaths in HIV-infected individuals between 1998 and 1999 were caused by liver disease, in contrast to 13.9% in 1996 and 11.5% in 1991. In our previous autopsy analysis , cirrhosis was seen in increasing proportions of patients dying with HIV: 9.1% between the years 1979 and 1986, 15% between 1987 and 1995, and 22% between 1996 and 2000. Over these same years, the percentages dying with HCV were 0, 3.9 and 24% . It is thus clear that liver disease has become an important cause of morbidity and mortality in the HAART era, and this is reflected in the population under study at the Manhattan HIV Brain Bank (MHBB).
Although the systemic impacts of HCV and liver disease are amply documented in HAART-era HIV-infected cohorts, less is known about their nervous system sequelae. The MHBB is a longitudinal neurological, neuropsychological, and psychiatric study of advanced-stage HAART-era patients with HIV infection. Therefore, it is a population ideally suited to examining the nervous system consequences of both HCV and liver disease in patients with advanced HIV. Accordingly, we present here an observational analyses of the baseline characteristics of this cohort, and ask whether HCV and liver disease have made a discernable impact on its nervous system functioning. Portions of this analysis pertinent to neuropsychological and psychiatric dysfunction have been reported in greater detail elsewhere, and are summarized in the discussion .
The eligibility criteria for the MHBB have been reported elsewhere . Upon recruitment, patients undergo a battery of neurological, neuropsychological, and psychiatric examinations. General medical information, plasma viral load, CD4 cell count, and antiretroviral history are obtained through patient interview and medical record review. The neurological evaluation is performed by a neurologist specializing in the evaluation of HIV-infected individuals, and includes a comprehensive evaluation of motor and sensory systems. Psychiatric and substance use histories are obtained through the Psychiatric Research Interview for Substance and Mental Disorders (PRISM) . This instrument is designed to elucidate both past and present disorders, with past disorders defined as having occurred before the past 12 months, and current disorders within the past 12 months. In addition, urine toxicologies are obtained when medically and logistically feasible, to screen for active substance use. Participants are administered a battery of neuropsychological tests that assess a broad range of cognitive abilities, including psychomotor speed, attention, memory, verbal fluency, executive function, and premorbid cognitive functioning . The individual tests are grouped according to the following domains: motor – grooved pegboard test – dominant and non-dominant hands; psychomotor speed – trailmaking test (TMT) part A, digit symbol, symbol search; working memory – letter number sequencing, paced auditory serial addition task; learning – Hopkins verbal learning test (HVLT) total recall, brief visual memory test (BVMT)-revised total recall; memory – HVLT delayed recall, BVMT-revised delayed recall; verbal fluency – controlled oral word association test; executive functioning – Wisconsin card sorting test (WCST) 64-card version perseverative responses and TMT part B. The reading sub-test of the Wide Range Achievement Test 3 was utilized as an indicator of premorbid function. Cognitive diagnoses are rendered according to the 1996 Dana consortium operationalization of the American Academy of Neurology algorithm. For a diagnosis of HIV-associated dementia, a participant must: (i) score 1 SD below age and education-adjusted norms on two out of 10 neuropsychological tests (TMT-A, TMT-B, HVLT, BVMT, WCST 64-card version, controlled oral word association test, digit symbol, symbol search, letter number sequencing, paced auditory serial addition task) or 2 SD below the norms on one of 10 tests; and (ii) have difficulty in at least one activity of daily life. They must also have: (i) impairment in lower extremity strength, coordination, leg agility, or performance on grooved pegboard (dominant hand) 2 SD below mean; or (ii) depression that interferes with function, loss of interest in usual activities, or emotional lability.
Indices of liver disease
Serum chemistry and hepatitis serology were obtained by chart review. The subpopulation of the MHBB population for whom these values were obtained was determined solely by chart availability. The model for end-stage liver disease (MELD) score, utilized by the United Network for Organ Sharing as a scoring system for liver allocation, was employed as a continuous scale variable to assess liver function . MELD scores, computed from serum bilirubin, creatinine, and international normalized ratio, are accurate predictors of mortality risk and suitable for use as a disease severity index in patients with cirrhosis. In addition, serum albumin was utilized in some correlative analyses of neuropsychological dysfunction.
Statistical analyses were performed on an iMac computer utilizing Statview version 5.0.1 software. Characteristics were compared between different diagnostic and liver disease groups by either t-tests, chi square tests, analysis of variance, or regression analyses.
At the time of analysis, 25% of the baseline MHBB cohort was female, 43% black, 33% hispanic, 23% white, 1% other, and the major risk factors for HIV were intravenous drug use in 45%, homosexual activity in 27%, and heterosexual activity in 49%. Two-thirds of patients presenting to the study were on HAART, and over 90% of those not on HAART at baseline were extensively antiretroviral agent experienced. The mean CD4 cell count was 165 cells/mm3, and the log plasma HIV viral load was 3.7 copies/ml. A subpopulation of 137 out of 219 patients had charted HCV serologies, and MELD scores could be calculated in a subset of 105. The mean MELD score of the population was 8.1 ± 0.3 (SD), with a range of 6–22, and the majority of patients had scores under 12, indicative of compensated liver function (see Fig. 1). Subpopulations of patients for the neurological, neuropsychological, and psychiatric analyses were determined by pertinent examination availability (for example, for neurological analysis a comprehensive neurological examination must have been performed, for psychiatric analysis the PRISM must have been administered, and for neurocognitive analysis the neuropsychological test battery must have been administered). For previously published analyses of neurocognitive and psychiatric disorders, the total number of subjects analysed were 116 (67 HCV seropositive, 49 seronegative) and 107 (62 HCV seropositive, 45 seronegative), respectively. As the results of neurocognitive and psychiatric analyses have been published previously, they are summarized in the discussion. For neurological assessment, 105 subjects were examined (63 HCV seropositive, 42 seronegative).
Correlation of neurological findings with indices of liver disease
The severity of liver disease, as indicated by the MELD score, did not significantly correlate with any major HIV-related neurological diagnosis (see the following list), with the sole exception of four patients who at baseline had cryptococcal leptomeningitis. The mean MELD score of this group was 12.3 ± 3.4, in contrast to a mean MELD score of 7.9 ± 0.2 in patients without cryptococcal leptomeningitis (P = 0.0005, analysis of variance). No differences in MELD scores were seen in patients with progressive multifocal leukoencephalopathy, central nervous system (CNS) lymphoma, toxoplasmosis, cytomegalovirus encephalitis, aseptic, bacterial or mycobacterial leptomeningitis, myelopathy, neuropathy, and myopathy when compared with individuals without these neurological disorders. There were no associations between HCV serology and any neurological diagnostic category.
We next looked at non-syndromal abnormalities (that is, neurological deficits not accounted for by the diagnostic categories described above) in tests of motor coordination (finger tapping, finger to nose, supination/pronation, bicycling, heel to shin), gait (rapid walking with turns, tandem walking, toe and heel walking), and the Hillel clinical disability scale. MELD scores correlated with deficits in all three components of the motor examination (Table 1). There were significantly higher mean MELD scores in patients demonstrating abnormalities in motor coordination and gait when contrasted with individuals with normal findings. MELD scores did not correlate with other aspects of the neurological examination, including the sensory examination (pinprick, vibration, joint position sense). Neurological abnormalities did not correlate with HCV serology.
The severity of motor and gait impairments was evaluated semiquantitatively by study neurologists on a scale of 1 to 4, with 1 being the mildest and 4 being the most severe abnormalities. The Hillel is an integer scale ranging from 1 to 10, with 10 representing normal ambulation, and 1 total paralysis. Results of correlational analyses between MELD scores and the severity of motor or gait impairment are displayed in Table 2. There was a mild but significant correlation between the severity of gait disturbance and MELD scores, but no relationship was discerned for the restricted range of motor impairments (Table 2).
A subset of 42 patients was followed through to brain donations, in whom motor coordination was examined in the last neurological evaluation occuring before death. Twelve of these patients demonstrated Alzheimer type 2 gliosis on brain histology, a classic indicator of hepatic dysfunction. The mean ‘score’ (severity of deficit) recorded on the motor examination was 1.3 ± 0.3 for patients with Alzheimer type 2 gliosis, whereas for patients without hepatic changes, the mean ‘score’ was 0.8 ± 0.2. These values approached but did not achieve significance (P = 0.0860, t-test).
Numerous neurological, neuropsychological, and psychiatric abnormalities occur in patients with liver dysfunction, both of viral and non-viral etiology. Patients may display euphoria or depression, and have inappropriate behavior . In the neurological evaluation, autonomic dysfunction, asterixis, myelopathy, neuropathy, encephalopathy, and extrapyramidal signs including Parkinsonism may be seen [16–19]. Minimal (or subclinical) hepatic encephalopathy and persistent mild hepatic encephalopathy are characterized by fatigue, sleep disorders, and cognitive deficits . These cognitive syndromes are primarily subcortical, and are characterized by decreases in psychomotor speed, attention, visual construction, and visuospatial orientation [16,20–27]. This profile overlaps that classically described in subcortical, HIV-associated neuropsychological dysfunction .
The role of HCV in the generation of CNS and peripheral nervous system disorders is unclear. Malaise, fatigue and depressive symptoms are frequently reported . Individual patients with HCV-associated acute disseminated or progressive encephalomyelitis and myelopathy have been reported [30–32]. HCV infection may be associated with several forms of peripheral neuropathy, including mononeuropathy multiplex, distal polyneuropathy, and Guillain–Barré syndrome [33–35]. In the context of HCV/HIV co-infection, acute meningoradiculitis/polyradiculitis has been described, with HCV detected in the cerebrospinal fluid . A fuller discussion of peripheral nerve syndromes associated with HCV and HIV infection are presented elsewhere in this issue. The extent to which HCV contributes to neuropsychological impairment is controversial. Some authors have reported HCV-related deficits in psychomotor speed and attention, and others have found that effects are secondary to liver disease per se, and not specifically HCV [29,37,38]. In the context of HIV, only one abstract has been published, describing worse overall neuropsychological test performance in patients with HIV/HCV co-infection, when contrasted with those with either HIV alone, HCV alone, or no viral infection .
Although an expanding literature has documented the increasing morbidity and mortality of liver disease in HIV-infected individuals, little to date has focused on nervous system sequelae. The MHBB cohort is ideally suited to the analysis of CNS and peripheral nervous system impact of liver disorders and HCV infection in HIV-infected individuals. There is a high rate of HCV seropositivity in this population, and at death, a high percentage of individuals demonstrate significant hepatic pathology and CNS sequelae .
We have previously published correlative analyses of psychiatric and neuropsychological findings with indices of liver disease in our cohort . For psychiatric analyses, a subset of 107 participants, 62 of whom were HCV positive, was evaluated. Past histories of cocaine dependence, opiate dependence, and stimulant dependence were significantly more frequent in HCV-infected patients when contrasted with those without evidence of HCV. There was also a statistically significant difference in the number of past substance-induced depressions between the two groups, which were found only in HCV-positive participants. There were no differences in the frequency of primary mental disorders (primary depression, dysthymia, mania, post traumatic stress disorder, conduct disorders, panic disorders, generalized anxiety disorders, bipolar) between the two serological groups. A subset of 116 participants was available for neuropsychological analyses, with 67 seropositive for HCV. There was no correlation of any cognitive test or domain with either the MELD score or serum albumin, or substance use disorders. Therefore, in contrast to neurological dysfunction, indices of liver function had no bearing on neuropsychological performance. Both HCV-positive and negative groups had high and equivalent levels of impairment in motor, learning, and memory domains. However, patients with HCV infection had greater rates of impairment in executive functioning, with 43% of HCV-positive and 29% of HCV-negative individuals showing deficits of greater than 1.5 standard deviations in the domain T score, a numerical mean of performance on the TMT-B and WCST perseverative responses. When patients were assigned neurocognitive diagnoses by a modification of the American Academy of Neurology algorithm , those who were HCV positive were significantly more likely to meet criteria for HIV-associated dementia than those who were HCV negative. This phenomenon was related to the severity of neuropsychological impairment, and not to increased deficits in the activities of daily life. Conversely, individuals seronegative for HCV were more likely to be diagnosed with minor cognitive motor dysfunction.
From the present examination, it appears that liver function and HCV infection may have differential importance in the pathogenesis of HIV-related nervous system disorders. Whereas the index of hepatic function utilized in this analysis, the MELD score, showed correlations with neurological dysfunction, this was not the case for psychiatric and neuropsychological abnormalities, which showed associations with HCV. This differential effect might suggest that these aspects of liver disease act on different neuroanatomical pathways and in variable cellular compartments. It seems reasonable to speculate that HCV, a macrophage-tropic flavivirus, might manifest in the nervous system through monocyte/macrophage-associated pathways, whereas hepatic dysfunction, whose pathology is traditionally associated with metabolic glial perturbation, might more preferentially impact astrocytes (the histopathological correlate being the Alzheimer type 2 astrocyte).
MELD scores showed an association with movement and gait abnormalities in this cohort, despite a restricted scoring range for documenting these abnormalities, and without targeting the examination to be sensitive to extrapyramidal disease. An important caveat in this analysis is the recognition that some HIV dementia-related motor manifestations are reminiscent of the dysfunction seen in extrapyramidal disorders . However, some literature has related these motor phenomena to liver dysfunction, and chronic Parkinsonism occurs with high frequency (over 20%) in individuals with cirrhosis . In our cohort, there was no linkage of increased MELD scores to HIV-related cognitive deficits, making the MELD-associated movement abnormalities less likely to be manifestations of HIV dementia. Therefore, although dissecting out the CNS effects of HIV and liver dysfunction may not be straightforward by virtue of potential clinical overlap, in the future we plan to delineate their relationship further with an expanded panel of hepatic chemistries and inclusion of the unified Parkinson's disease rating scale as part of our neurological evaluations . This will allow us to characterize the level of extrapyramidal dysfunction more finely, and to expand the scale available for analysis (increase the statistical variance).
Although cognitive abnormalities may be related to both severe and subclinical liver disease in HIV-negative cohorts, there is no literature in HIV-positive patients examining similar phenomena [22–26]. This analysis presents methodological challenges, because both liver disease and HIV overlap in their neuropsychiatric manifestations, with prominent motor slowing. It is possible that in our cohort, HIV-induced damage masked liver-induced dysfunction, as there may be an overlap in the neuroanatomical substrate of both disorders. It is also possible that with the low mean entry MELD score for our cohort, this is a population less suitable to detect a profound hepatic effect on cognition. This type of effect may emerge as we analyse longitudinal data and determine whether, with increasing MELD scores, a liver-related neurocognitive deficit becomes apparent. Alternatively, our battery (based on early experience with HIV) may not be optimal for detecting hepatic effects, and it is possible that a subtle interaction might be missed. In future years, we will utilize more sensitive tests to minimal hepatic encephalopathy .
Although an effect on cognitive function could be seen for patients with HIV/HCV co-infection in our cohort, this analysis was limited by a lack of quantitative HCV virological data. We could only obtain serological analyses on our patients, and did not have HCV viral loads available to determine whether their HCV infections were productive of viremia at the time of analysis. This will be an important aspect of future investigations; it is postulated that the effects of HCV go beyond hepatic metabolic perturbation, and evolve from direct viral effects on the CNS. Various authors have published preliminary evidence of HCV in the cerebrospinal fluid and brain tissue of HIV-positive and negative patients; it is unknown whether these findings will be correlated with discrete syndromes of cognitive impairment [43–46].
In summary, this preliminary analysis of the MHBB cohort revealed divergent aspects of liver disease having variable associations with nervous system function. Although much work is needed to clarify the nature and mechanisms of these associations with the increasing hepatic morbidity in HAART-era patients, this will be an important emerging consideration in the assessment of HIV-related nervous system abnormalities.
The authors would like to thank the patients, investigators, and staff of the Manhattan HIV Brain Bank. Investigators and staff of the Manhattan HIV Brain Bank include: Laurie Abromowitz, CSW, Sherly Altidor, PA, Laura Banks, MD, Desiree Byrd, PhD, Yvonne Brown, RN, Jacqueline Crittendon, BS, David Dorfman PhD, Colleen Dowling, RN, Victoria Ernst, RN, Yan Ling Gao, MD, Anthony Geraci, MD, Tauseef Haider, MD, Deborah Hesketh, RN, Talha Idrees, MD, Keren Isaacs, MS, Geraldine Joseph, PA, Shafat Khan, MD, Victoria Kozlowski, RN, Damien Laudier, BS, Rashid Mahboob, MD, Lalitha Mantha, RN, Aleks Maryanchik, MS, Natalie Massenberg, BS, Letty Mintz, NP, Christine Mondragon, RN, Jennifer Monzones, BA, Jacinta Murray, BS, Mubasher Naseer, MA, Daniel Polowetsky, RN, Phyllis Ristau, RN, Monica Rivera Mindt, PhD, Amy Scarano, BS, Ruijin Shi, MD PhD, JoAnne Sweeney, RN, Michele Tagliati, MD, Milana Veytsman, BS, Enrique Wulff, MD, Tatiana Yakoushina, MD, and Mohammad Zaidi, MD.
Sponsorship: Supported by grants R24MH59724 (the Manhattan HIV Brain Bank) and M01 RR00071 (the Mount Sinai General Clinical Research Center) from the National Institutes of Health.
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