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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 40  |  Issue : 2  |  Page : 114-122

Auditory P300 and neuropsychological cognitive functioning assessment of patients with chronic hepatitis B and C infection


1 Department of Neuropsychiatry, Faculty of Medicine, South Valley University, Qena, Egypt
2 Department of Neuropsychiatry, Faculty of Medicine, Sohag University, Sohag, Egypt

Date of Submission04-Feb-2019
Date of Acceptance17-Feb-2019
Date of Web Publication11-Jul-2019

Correspondence Address:
Tarek Desoky
Department of Neuropsychiatry, Faculty of Medicine, South Valley University, Qena, 83511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejpsy.ejpsy_6_19

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  Abstract 


Background A growing body of interest was addressed to the concept of minimal rather than overt hepatic encephalopathy as a subclinical manifestation in chronic hepatitis B- and C-infected patients with normal liver function. This study aims to neuropsychologically and neurophysiologically assess those patients for minimal cognitive impairment and its correlates.
Patients and methods Thorough neuropsychological evaluation including Wechsler Memory Scale-Revised, Wisconsin Card Sorting Test, Trail Making Test, Montreal Cognitive Assessment Test, and Beck Depression Inventory (BDI), and neurophysiological (P300-evoked potential) assessment were conducted on untreated blood donors with hepatitis C virus (n=24) and hepatitis B virus (n=16) infection and 40 healthy controls.
Results All tools of assessment showed a significant difference between cases and controls that suggests higher incidence of depression and cognitive dysfunction among hepatitis patients with no difference between B and C types of infection apart from BDI, which showed higher scores (more depressive features) among hepatitis C rather than B. Among variables such as patient age, BMI, BDI, and viral load titer, only BDI showed a significant positive correlation with such impairments.
Conclusion Neuropsychological- and neurophysiological-based evidence of cognitive impairment was proved to be significantly present among cases with chronic hepatitis B and C infection. The value of such evaluation in the management plan of such group of patients needs further future studies.

Keywords: cognitive impairment, depression, hepatitis B virus, hepatitis C virus


How to cite this article:
Desoky T, Baddary H, Moneim MA, Ali A. Auditory P300 and neuropsychological cognitive functioning assessment of patients with chronic hepatitis B and C infection. Egypt J Psychiatr 2019;40:114-22

How to cite this URL:
Desoky T, Baddary H, Moneim MA, Ali A. Auditory P300 and neuropsychological cognitive functioning assessment of patients with chronic hepatitis B and C infection. Egypt J Psychiatr [serial online] 2019 [cited 2019 Nov 19];40:114-22. Available from: http://new.ejpsy.eg.net/text.asp?2019/40/2/114/262553




  Introduction Top


Chronic hepatitis represents a major health problem and a main cause of liver disease in Egypt and the whole world. Egypt has the highest prevalence of hepatitis C infection in the world (Blach et al., 2017) with a prevalence of 10% among adults aged from 15 to 59 years in the Egyptian Ministry of Health Survey in 2015 (Ministry of Health and Population Egypt, El-Zanaty and Associates Egypt & and ICF International, 2015), while hepatitis B showed a lower prevalence at 1.7% in Egypt (Owiti et al., 2015).

Cognitive dysfunction in cases of decompensated liver cirrhosis complicating chronic hepatitis is understandable by the effect of liver impairment on the brain functioning as being demonstrated in chronic hepatic encephalopathy (Córdoba et al., 2003).

However, cases of chronic hepatitis with normal liver functioning showed some element of subtle cognitive impairment which might affect one-third of chronic hepatitis C virus (HCV) infection cases without decompensated liver cirrhosis (Monaco et al., 2012).

The concept of minimal rather than overt hepatic encephalopathy as a complication of chronic liver disease had been highlighted in many researches in the last years. Minimal hepatic encephalopathy (MHE) has its impact on the quality of life and fate of illness of such patients and hence, it had been focused and received much concern in research. MHE was defined as the test-dependent mental dysfunction while no clinical evidence of overt hepatic encephalopathy is being existent (Vilstrup et al., 2014).


  Aim of the work Top


This study aimed to investigate a group of HCV and hepatitis B virus (HBV) infected patients who did not undergo any current or previous specific antiviral treatment for cognitive dysfunction and depression, to compare chronic hepatitis C and hepatitis B and to define the possible correlates of cognitive functioning in such group of patients.


  Patients and methods Top


Study population

The study involved a total of 40 consecutive patients recruited from the blood donors at the blood bank of Sohag University Hospital (de novo nontreated cases). The participants were grouped into three categories: group a included 24 patients having the diagnosis of chronic hepatitis C infection, group b included 16 patients having the diagnosis of chronic hepatitis B infection, and group c included age-matched and sex-matched 40 healthy controls for correlation. The study was conducted during a 1-year period from March 2015 to March 2016. An informed written consent was obtained from all participants for participation in the study and the rules of the ethics committee of Sohag University had been respected.

The inclusion criteria included de novo (no current or previous treatment with interferon), uncomplicated (Child–Pugh score class A) HCV and HBV patients, aged (20–50) years and the exclusion criteria included complicated cases (Child–Pugh score class B/C), concomitant HIV infection, current or previous interferon therapy, neurological or psychiatric, illicit or psychotropic drug use, and relevant concomitant medial illnesses (renal failure, cardiac failure, chronic obstructive pulmonary disease, hypothyroidism, or uncontrolled diabetes).

Methods

The following tools were performed on all participants under the study: (a) thorough general and neurological examination for exclusion of medical and neurological disorders that might represent a cause of cognitive impairment; (b) blood tests included complete blood count, random blood glucose (RBG), renal function tests, liver function tests, HBV surface antigens, anti-HCV antibodies, PCR viral titer, HIV serology, and thyroid-stimulating hormone; (c) pelvi-abdominal ultrasonography was performed for assessment of the liver and exclusion of cirrhosis or marked fibrosis; (d) Beck Depression Inventory (BDI): a self-reported 21-item questionnaire widely used to assess severity of depressive symptoms, 0–3 choices for each item, with a score of more than or equal to 10 considered abnormal; 10–20 mild, 20–30 moderate, and more than 30 severe depression (Beck et al., 1996); (e) neuropsychological cognitive battery which comprised (i) Wechsler Memory Scale-Revised, short form (WMS-R): a widely used psychometric tool for assessment of the various aspects of memory in adults. It includes a group of subtests that evaluates the different areas of memory and learning. These subtests are figural memory, logical memory, visual paired associate I, visual reproduction I, and visual memory span. It has five summary scores which are: general memory, verbal memory, visual memory, attention/concentration, and delayed recall (Butters et al., 1988). (ii) Wisconsin Card Sorting Test (WCST) is a widely used psychometric tool for the assessment of executive functioning which was first developed by Grant and Berg (1948). The participants are asked to sort and switch a group of cards that are typed according to their color, shape, and number. Perseverative error is considered when the previous rule is employed incorrectly (Heaton et al., 1993). Executive functions tested by the WCST include: sequencing, planning, decision-making, ability to form abstract concepts, and working memory (Lezak et al., 2012). We used the computerized form of the test which is available online (PEBL WCST). (iii) Trail Making Test (TMT-A and TMT-B): is a wide-spectrum cognitive tool that addresses visual attention, speed of processing, mental flexibility, and executive functioning, which is formed of two parts, TMT-A of 25 circles of consecutive numbers from 1 to 25 and TMT-B of 24 circles of A–L letters and 1–12 numbers. The test taker is asked to match numbers in TMT-A and number to letter in TMT-B and timing the task in each. Average score for parts A and B are 29 and 78 s, respectively, and considered deficient if more than 75 and 273 s, respectively (Reitan, 1958). (iv) Montreal Cognitive Assessment (MOCA) test: is a screening test for dementia and sensitive for mild cognitive impairment and considered more sensitive than the more popular Mini-Mental State Examination. It measures attention, memory, orientation, language, executive function, naming, visuospatial orientation, and abstraction. The total score is 30 points divided into separate subscores and less than 26 points is considered abnormal (Nasreddine et al., 2003, 2005). (f) Auditory P300-evoked brain potential: an event-related potential of cognitive neurophysiological significance. It represents the brain response to certain sensory/cognitive stimuli by paying attention to the different stimulus among the stereotypical ones (the auditory oddball paradigm). It measures mainly the decision-making process (Polich and Kok, 1995).

Statistical analysis

Statistical analysis of data was done using the IBM SPSS software, version 24. Data were displayed as frequency with the percentage for categorical data and mean with SD for numerical data. Independent Student’s t test was used to compare the means of two groups. For testing the relationship between variables we used Pearson’s correlation coefficient. The P value was considered significant if less than 0.05 with 95% confidence interval.


  Results Top


Demographic and clinical data

Twenty-four patients with HCV infection and 16 patients with HBV infection, collected from the blood donors attending the Blood Bank Unit at Sohag University Hospital and 40 age-matched and sex-matched healthy controls participated this study. Demographic and clinical data of cases and controls are shown in [Table 1].
Table 1 Demographic and clinical data of the study groups

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Beck depression inventory

Twelve (50%) patients with HCV and six (37.5%) patients with HBV had a BDI score of more than or equal to 10 (significant depression). There was a significant difference suggesting higher depression scores in cases than in controls and in HCV than in HBV ([Table 2]).
Table 2 Diagnosis of depression among cases and controls

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Neuropsychological assessment

All subtests of the WMS-R, WCST, TMT-A and TMT-B, and MOCA test showed significant lower scores in cases compared with controls suggesting cognitive impairment among chronic hepatitis patients with no significant difference between hepatitis C and B groups ([Table 3],[Table 4],[Table 5],[Table 6],[Table 7],[Table 8],[Table 9]).
Table 3 Wechsler Memory Scale in patients and controls

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Table 4 Wechsler Memory Scale in hepatitis B virus and hepatitis C virus patients

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Table 5 Wisconsin Card Sorting Test in patients and controls

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Table 6 Wisconsin Card Sorting Test in between hepatitis B virus and hepatitis C virus patients

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Table 7 Trail Making Test and Montreal Cognitive Assessment Test between patients and controls

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Table 8 Auditory P 300-evoked potential in patients and controls

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Table 9 Auditory P 300-evoked potential in hepatitis B virus and hepatitis C virus patients

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Auditory P300-evoked potential

It showed a significantly reduced P300 amplitude (P=0.011) and prolonged latencies (P=0.035) in patients with chronic hepatitis C and B compared with healthy controls with no significant difference between both groups of patients ([Table 8] and [Table 9]).

Correlates of cognitive impairment among cases with chronic hepatitis

Patients’ age, BMI, and viral load titer all showed no correlation with any of the cognitive tools used for the assessment of cognitive function among cases which are WMS, WCST, TMT, MOCA tests, and P300-evoked potential. However, BDI only showed a significant positive correlation with all mentioned cognitive battery tools; more depressive features were positively correlated with more cognitive impairment ([Table 10],[Table 11],[Table 12],[Table 13]).
Table 10 Correlation between patient age, BMI, Beck Depression Inventory, and virus load titer on one hand and Trail Making Test and Montreal Cognitive Assessment Test on the other hand

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Table 11 Correlation between patient age, BMI, Beck Depression Inventory, and virus load titer on one hand and Wechsler Memory Scale on the other hand

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Table 12 Correlation between patient age, BMI, Beck Depression Inventory, and virus load titer on one hand and Wisconsin Card Sorting Test on the other hand

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Table 13 Correlation between patient age, BMI, Beck Depression Inventory, and virus load titer on one hand and auditory P300-evoked potential on the other hand

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  Discussion Top


Forton et al. (2003) and Kramer et al. (2005) had reported that subclinical cognitive dysfunction proved by neuropsychological tests had been encountered in the vast majority of chronic hepatitis C-infected patients without evident sequelae on hepatic functions.

However, cognitive dysfunction in patients with chronic hepatitis precedes the process of cirrhosis and was not related to the degree of liver affection, the viral load titer, or the genotype (Forton et al., 2001, 2002).

Despite that the larger amount of studies in that theme reported the presence of cognitive impairment among the patients with chronic hepatitis; Cordoba and Soogoor reports denied any correlation of HCV and cognition. However, Córdoba et al. (2003) collected his sample from blood donation patients, while Soogoor et al. (2006) had a very young aged sample which means the two cases are in the early phase of illness.

Although the treatment with interferon, the concomitant substance abuse, the longer duration of illness (Foster, 2009) or higher hepatitis C viral load or HIV coinfection (Sun et al., 2013) were assumed to be responsible for chronic hepatitis-related cognitive impairment, the direct involvement of the brain was considered as well (Forton et al., 2001).

Recently, the hypothesis of HCV neuroinflammation without evident central nervous system (CNS) infection had received much emphasis and is considered as a probable explanation for what was termed MHE. Detection of sequences of the virus in CSF of a significant number of patients had been reported in some reports (Laskus et al., 2002). These virus strains were identical to that visualized in the peripheral mononuclear blood cells, which have the ability to cross the blood–brain barrier, hence, the possibility of brain infection by such strains through an immune-mediated mechanism starting with HCV-infected peripheral mononuclear blood cells, generation of microglial cells, and macrophages in the CNS and the production of excess brain levels of cytokines such as interleukin 8 and tumor necrosis factor α that represents the end of a cascade where cognitive impairment may be an outcome (Senzolo et al., 2011; Abrantes et al., 2013; Liu et al., 2014). Reduced production of brain-derived neurotrophic factor by the effect of HCV was assumed in some studies (Modabbernia et al., 2011).

More interesting was the recent fact that the microvascular endothelial cells of the brain expressed HCV receptors. This suggests the hypothesis that a low rate of replication of distinct strains of HCV occurs in the brain which may explain the disorder of MHE (Fletcher et al., 2012).

Furthermore, an additional MRI spectroscopy evidence of neuroinflammation was suggested (Chang et al., 2013; Zahr et al., 2014). Many suggestions were made for such findings: abnormal calcium homeostasis (Schwer et al., 2004), disturbance of monoamine neurotransmission (Forton et al., 2006), abnormal gene expression (Senzolo et al., 2011), cytokine immune response (Abrantes et al., 2013), or concomitant CNS infection (Abrantes et al., 2013).

Structural and functional neuroimaging-based evidence of structural and functional brain (frontal, basal ganglionic, and white matter) changes had been suggested in patients with chronic hepatitis C infection without liver decompensation (Posada et al., 2009).

The study of minimal cognitive impairment and its attribution to chronic hepatitis free of any other influencing factors may represent a matter of difficulty. This is because the extrahepatic manifestations of chronic hepatitis particularly the neuropsychiatric ones such as depression and fatigue are common among those patients. In some reports, depression was estimated to affect about one-third of chronic hepatitis C patients compared with the general population (Adinolfi et al., 2017). Although some authors went to report that depressive features were more common in chronic hepatitis C than in chronic hepatitis B (Qureshi et al., 2012; Mohamed et al., 2013), this study revealed no significant difference in the severity of depression between both groups. This concomitant depression might be intimately associated with at least minimal cognitive deficits (Lam et al., 2014) which might be attributed to depression rather than chronic hepatitis itself.

Depression occurs in all stages of illness even in the early stages and may be a reaction to the psychosocial stress of the illness (Yeoh et al., 2018). Incidence of depression and anxiety was reported to be higher in patients with chronic HCV and HBV infection in a large amount of old and recent studies either in de novo (Kasraian et al., 2016) or in interferon-treated patients (Huckans et al., 2015). In some researches, chronic hepatitis-related depression was restricted and positively correlated to the severity of cirrhosis (Zhu et al., 2016).

Psychosocial impact of chronic hepatitis infection including depression has many sources of origin among such patients; patients with chronic hepatitis have persistent fear about their fate of illness, its progress and its complications, feel stigmatized, and feel guilty about the possibility to infect their spouses or their kids (Tu and Shao, 2009). Moreover, the suspected completely curable nature of chronic hepatitis B makes the patients feel depressed and desperate (Fan et al., 2004).

In the last few years, the progress of antiviral treatments for hepatitis had achieved a better spread and success in lowering the prevalence of the disease all over the world. Interferon therapy had reached a large sector of diseased populations and was provided free to a large the disease-affected area all over the world. This makes the study on de novo cases a matter of difficulty and this makes testing of cognitive impairment either related to the disease or to the treatment a matter of great challenge. This is because interferon therapy itself was associated in many studies with cognitive impairment (Lieb et al., 2006; Tanaka and Sasaki, 2017) rather than other psychiatric side effects including depression, fatigue, anxiety, and pain (Huckans et al., 2015). Because of this, we targeted de novo cases for neuropsychological assessment to avoid such causative overlap.

Some researchers went to attribute such subtle impairment of cognitive function to the treatment with interferon alpha where the pretreatment cognitive and psychiatric assessment were unremarkable (Lieb et al., 2006), while others reported that the effect of interferon was restricted to the development of psychiatric symptoms such as depression, fatigue, and pain rather than the development of cognitive impairment (Amodioa et al., 2005; Huckans et al., 2015).

Most of the literature about the predilection of chronic hepatitis to impair cognition in asymptomatic patients had addressed the functional rather than the structural assessment. Recently, the combined approach had been addressed in the current rather than the backdated research. Novel functional MRI techniques had been used for achieving that purpose. Diffusion tensor imaging is an example of such novel techniques which has a specific value in detecting the microstructural changes in the brain through the measurement of metabolic and diffusion changes in different brain areas. Recently, Ajay Kumar had used a combined psychometric and anatomical approach in detecting microstructural changes in patients with chronic hepatitis using the diffusion tensor imaging MRI technique and, to our knowledge, it was the first study to address such combined approach. They reported decreased values of fractional anisotropy and myoinositol on inferior longitudinal bundles, and superior thalamic radiations in comparison to controls and this had a positive correlation with the lower performance on the cognitive psychometric tests (Kumar et al., 2017).

Due to its wider prevalence, HCV infection had received much more growing interest for research. However, Mohamed et al. (2013) compared the pattern of cognitive dysfunction related to HCV to that related to HBV infection which was shown to be similar in both groups.

Being considered as an index of severity, viral load titer was studied as a possible correlate of chronic hepatitis-related cognitive dysfunction. The viral load was considered as a correlate to chronic hepatitis-related cognitive impairment in some reports (Sun et al., 2013), while in this study and similarly in other previous reports (McAndrews et al., 2005; Mohamed et al., 2013), it did not reveal to be a relevant correlate. This controversy may be added to the amount of support of the hypothesis that the direct involvement of the brain by the virus may contribute to the pathogenesis of chronic hepatitis-related cognitive impairment which is not viral load dependent (Kramer et al., 2002, Perry et al., 2008).

Furthermore, the relationship between obesity and depression (Stunkard et al., 2003) and the relationship between chronic hepatitis and depression are common findings in the literature, so, the study of obesity as a separate correlate was logic and relevant. Although BMI showed a negative correlation with the cognitive functions of healthy people in some studies (Cournot et al., 2006), BMI showed no relationship with the cognitive impairment detected in patients with chronic hepatitis in this study. Hashemi et al. (2015), who reported that obesity was not a correlate of cognitive impairment in patients with chronic hepatitis, had explained that by the fact that the body weight was paradoxically correlated to the progress of illness, obese patients are mostly in the early phases of the disease where cognitive functions are still preserved.

Limitations of the study

The small size of the sample, the absence of liver biopsy as an important tool of evaluation of liver state, and the absence of advanced neuroimaging as a brain structure assessment tool are a group of study limitations that should be considered in the future work about that issue.


  Conclusion Top


Neuropsychological- and neurophysiological-based cognitive assessment in patients with chronic hepatitis C and B had been a target of many previous studies. A strong evidence of cognitive impairment among those patients was considered. This study was added to the body of support of such evidence. Further studies should be encouraged in such field for better quality of life and treatment outcome of such group of high-incidence patients.[53]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12], [Table 13]



 

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Abstract
Introduction
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