Event-related evoked potential versus clinical tests in assessment of subclinical cognitive impairment in chronic hepatitis C virus

Impairment of cognitive functions increases with the increase in grade of hepatic fibrosis in HCV patients. P300 can detect minimal and subclinical impairment of cognitive function at early stages of chronic hepatitis.

Hepatitis C virus (HCV) infection is a serious global health problem that affects 180 million people worldwide. Hepatitis C virus causes acute and chronic hepatitis which can eventually lead to permanent liver damage and hepatocellular carcinoma [1]. HCV infection is considered a systemic disease. Symptoms of brain dysfunction such as fatigue and depression are frequent in patients with chronic hepatitis C than in chronic hepatitis B, and these symptoms improved after clearing the virus with treatment [2]. HCV is neurovirulent. The exact mechanism by which HCV enters the central nervous system is unknown; HCV may cross the blood–brain barrier via infected monocytes using a Trojan horse mechanism [3]. Neuroimaging studies suggest that HCV-positive individuals show altered structure and function of several neuronal systems, including the frontal neocortex, basal ganglia, and connecting white matter tracts [3]. Neurocognitive disorders have been reported in up to 50% of chronic HCV infected patients [4]. HCV patients had significant deficits in attention, learning, psychomotor speed, and mental flexibility; greater impairment was associated with greater fibrosis stage [5]. Forton et al. [6] compared cognitive function in individuals with HCV viremia and those with only anti-HCV antibodies. He found that HCV-infected patients were impaired on more cognitive tasks than the HCV-cleared group and viremic individuals showed specific impairment in power of concentration and speed of working memory [6]. Cognitive deficits may be found in HCV (hepatitis c virus) patients even prior to the development of cirrhosis and liver dysfunction [2]. P300-evoked response is an objective and independent measure of cerebral information processing to avoid the potential bias of fatigue, latent depression, or impaired self-rating in psychometric assessment [7].

This study aimed at early detection of neurocognitive impairment in chronic hepatitis C patients and investigating the cognitive function in HCV patient by p300 and clinical test.

Cognitive dysfunction in patients with chronic hepatitis C virus (HCV) infection is a distinct form of minimal hepatic encephalopathy (MHE). In fact, the majority of HCV-positive patients, irrespective of the grading of liver fibrosis, display alterations of verbal learning, attention, executive function, and memory when they are evaluated by suitable neuropsychological tests. Similarities between the cognitive dysfunction of HCV patients and MHE of patients with different etiologies are unclear [2, 13, 14]. HCV is neurovirulent that may cross the blood–brain barrier via infected monocytes using a Trojan horse mechanism [3]. Microglial cells and, to a lesser extent, astrocytes harbored HCV-RNA sequences and HCV-specific proteins [15]. HCV replicates in the brain and plays a role in the pathogenesis of neuroinflammation [16] with the increase in the proinflammatory cytokines in the brain. There is also an increase in the choline/creatine and myo-inositol/creatine ratios in the basal ganglia. N-Acetyl aspartate (NNA) and NNA-glutamate are raised in the basal ganglia and prefrontal cortex. These metabolites are raised as a compensatory mechanism to HCV inflammation. When these compensatory mechanisms fail, fatigue and possibly other signs of neurocognitive impairment take place [17–20]. Neuroimaging studies suggest that HCV-positive individuals show altered structure and function of several neuronal systems, including the frontal neocortex, basal ganglia, and connecting white matter tracts [3].

In the present study, the F0-F1 group had no cognitive impairment (MMSE score 25–30). Fourteen patients had mild cognitive impairment (MMSE total score 20–24), eight of them in the F2 group and six in the F3 group; 19 patients had moderate cognitive impairment (MMSE total score 11–19), seven of them in the F2 group and 12 in the F3 group, and none had severe cognitive impairment. There was also a significant difference in impairment in digit span, attention, concentration, and memory between patients and control which increased with increasing the grade of fibrosis evidenced by MoCA and MMSE. In agreement with these results, Hamdy et al. [21] found that most of his accidentally discovered HCV patients showed mild cognitive impairment, which was higher in dominant hemisphere functions: attention, naming, memory, fluency, abstraction, and orientation. However, their patients were accidentally discovered blood donors and recently diagnosed that explain the mild impairment. Hilsabeck et al., [5] who studied 80 patients, also found that HCV patients had a significant deficits in attention, learning, psychomotor speed, and mental flexibility and reported that greater impairment was associated with greater fibrosis stage. Similarly, Forton et al. [22] who evaluated the cognitive performances of 43 HCV patients found that HCV patients had worse concentration and psychomotor speed. Huckans et al. [23] also found that HCV patients have a lower score in memory, recognition, and attention tests than those without the infection. In a different study which was evaluating the impact of HCV infection on cognitive functions in children with normal liver function tests, Abu Faddan et al. [24] found that HCV-infected patients were impaired in more cognitive tasks than healthy volunteers. The most significant differences found on measures of concentration and information processing speed. In contrast, Cordoba et al. [25] and Soogoor et al. [26] both reported no correlation between HCV and cognition (very young subjects); however, for Cordoba, patients were accidentally discovered. Similarly, Abrantes et al. [27] found no evidence of an association between HCV infection and cognitive impairment. However, the small number of subjects examined in the last study may have affected result interpretation.

In our study, we also detected the cognitive function by p300 method. We found that the frequency of delayed P300 peak latency was increased in the three groups of chronic hepatitis than controls (P = 0.029) and that the delay of P300 peak latency and reduction of P300 amplitude were significantly evident in F2 and F3 groups than control group while F0-F1 showed delay in latency of P300 and reduction in amplitude of P300 than control but they were statistically not significant. The prolonged latency and amplitude reduction of P300-evoked responses were significantly increased with increasing the stage of fibrosis. These results were agreed with that of Kramer [2] who studied 100 patients (25 cirrhotic); he found that HCV individuals had P300 delayed latencies and reduced amplitudes. He also reported that abnormal P300 characteristics were not related to the degree of histological or biochemical activity of hepatitis. In another study [28] involving patients with cirrhotic as well as non-cirrhotic liver disease, P300 latencies have been reported to be similar in non-encephalopathic patients as well as the control, thereby suggesting that P300 latencies were not sensitive in detection of subacute hepatic encephalopathy. Moreover, some investigators, Amido et al. [29] and Senzolo et al. [30], reported that P300 was not useful in detecting cerebral function alterations in cirrhotic patients with no apparent encephalopathy. In this study, the percentage of abnormal p300 peak latency in studied patients, which was significantly greater than those of cognitive impairment (measured by MMSE).In our study, we detected the sensitivity, specificity, PPV, NPV, and accuracy of p300. We found that the p300 is a sensitive and accurate method in detecting early changes in the brain function of patients with chronic hepatitis (sensitivity 100%, specificity 59.26%, positive predictive value 75%, negative predictive value 100% and accuracy 81.67%). Ciećko-Michalska [31] suggested that ERPs are a more sensitive method than psychometric tests in detecting early changes in the brain function of patients with cirrhosis. In partial agreement, Jones et al. [32] had also found in the visual ERP study that the prolongation of P300 latency in cirrhotic patients without overt hepatic encephalopathy (HE) may occur in the absence of abnormalities of a standard psychometric test.

Patients with CHC infection has significant impairment of digit span, attention, concentration and memory and this cognitive impairment increases with severity of hepatic fibrosis. Patients without fibrosis show no cognitive impairment by psychometric tests while showing impairment by event-related potential. P300 can detect minimal and subclinical impairment of cognitive function at early stages of chronic hepatitis (F0) with a sensitivity 100% and accuracy 81.67% even with normal standard psychometric tests. A future study is needed with larger F0 chronic hepatitis patients to confirm this suggestion.