Patients evaluated in this study complained of a decline in cognitive function. In addition, they felt abnormally fatigued, and some also reported mood alterations with increased anxiety and depression. They were referred to our clinic to clarify the cause of their neuropsychiatric symptoms. There was no indication in any of the patients of the presence of liver cirrhosis and/or hepatic encephalopathy. Other causes of cerebral dysfunction were also excluded via a comprehensive diagnostic workup.
Patients scored significantly worse than healthy controls in the FIS, HADS, and SF‐36. As these measures rely on self report, the abnormal findings could result from anxiety due to knowledge of the HCV infection rather than somatic alterations. However, a study analysing HCV positive patients unaware of their diagnosis also found them to be impaired compared with HCV negative controls.14
Previous studies have indicated that approximately half of HCV positive patients with only mild liver disease complain of abnormal fatigue, depression, and cognitive dysfunction, irrespective of their PCR status.2,5,6,10
Evaluation of cognitive function in HCV positive patients with normal or only mildly impaired liver function has shown that they suffer from deficits in attention, learning ability, and memory predominantly.17,18
Magnetic resonance spectroscopic studies revealed significant alterations in the choline/creatine and/or N‐acetyl‐aspartate/creatine ratio as an indication of cerebral metabolic alterations whereas MRI was normal.16,17,18,19
In agreement with this, Kramer and colleagues20
were able to show a significant increase in P300 latency, a measure of stimulus evaluation processing, in non‐cirrhotic hepatitis C patients compared with healthy controls. Thus there is increasing evidence that hepatitis C virus infection is accompanied by cerebral dysfunction in some patients.
Our present findings emphasise this assumption. We have recently shown that cognitive decline in patients with hepatitis C is especially due to deficits in attention, higher executive functions, learning ability, and memory.18
This was confirmed in the present study. All but two of the 16 evaluated patients showed pathological results in the divided attention test, and approximately two thirds had pathological results in the simple and warned reaction time test, intermodal comparison test, incompatibility test, and attention shift test. In particular, we observed an above normal reaction time in most patients. Furthermore, especially in the divided attention test and the attention shift test, the number of errors and missings were increased compared with controls. Therefore, increased reaction times could not be attributed to motor slowing but to attention deficits. This assumption is supported by the fact that none of the patients gained pathological results in the “serial dotting” subtest of the PSE syndrome test, a test of pure motor speed.
The observations of Jones21
and Piche and colleagues22
that disabling fatigue can be significantly improved in patients with chronic hepatitis C by treatment with the 5‐hydroxytryptamine‐3 receptor antagonist ondansetron suggests a role for the serotonergic system in the pathophysiology of chronic fatigue and cognitive decline in HCV infected patients. Serotonergic neurotransmission can be studied in vivo by SPECT. I‐123‐Beta‐CIT is normally used for evaluation of striatal dopamine transporter binding. This tracer however also binds to serotonin transporters. Due to the fact that high densities of SERT and DAT are present in different anatomical locations and because of the different binding kinetics of I‐123‐beta‐CIT to DAT or SERT, early scans—performed approximately four hours after injection of the tracer—can be used to study SERT binding in the hypothalamus/midbrain region while later scans—approximately 24 hours after injection—represent DAT binding in the striatum.33,34
Using I‐123‐beta‐CIT‐SPECT we were able to show decreased binding capacity of the midbrain serotonin transporters and/or the striatal dopamine transporters in 14 of the 20 patients examined. Interestingly, those patients with altered monoamine transporter binding performed significantly worse than healthy controls in most of the psychometric tests. Based on these data we conclude that psychometric alterations in HCV infected patients are related to alterations in neurotransmission. FIS scores did not significantly differ between the patient groups. Thus fatigue seems to be caused by additional factors apart from monoaminergic dysfunction. This assumption is also supported by the fact that ondansetron treatment is effective in only about a third of patients.22
Decreased β‐CIT binding, as shown in our patients, may be due to structural and/or functional alteration of the serotonin and dopamine transporter or a decrease in the number of serotonergic or dopaminergic neurones within the region of interest. As we cannot differentiate between these different pathologies and also we do not know about the presence and function of the respective receptors, the mechanisms of monoaminergic dysfunction in HCV exposed patients cannot be described in detail.
Dopamine has been shown to be a “key regulator to adapt action, emotion, motivation, and cognition”.35
With regard to cognition, alteration of striatal dopaminergic neurotransmission is considered to result in deficits in mental flexibility, working memory, learning ability, sustained attention, attention shift, and higher executive functions.36,37,38
In common with dopamine, serotonin is also involved in the modulation of perception, attention, emotion, and cognition.39
The vast majority of serotonergic neurones are located in the brainstem. The rostral group, which includes the dorsal and median raphe nuclei, is reciprocally connected to several cortical areas, especially the medial prefrontal cortex.40,41
This region is associated with a large number of cognitive functions and is involved in the planning and execution of complex tasks. Dorsal raphe neurones are also involved in the modulation of the sleep‐waking cycle, major depression, suicidal behaviour, and aggressive and anxiety behaviour.40
According to Severson and colleagues,42
serotonergic neurones located in the midbrain maintain pH homeostasis by inducing arousal, anxiety, and changes in cerebrovascular tone. Structural or functional alterations of these neurones are considered to be the cause of otherwise unrelated diseases such as sudden infant death syndrome, panic disorder, and migraine.
It must be emphasised that four of the 20 patients examined were PCR negative. These four patients did not differ from the PCR positive patients with regard to their clinical presentation, neuropsychological findings, or SPECT results. Thus it could be questioned whether the neuropsychiatric symptoms and alterations in neurotransmission found in our patients are a consequence of their HCV infection. However, it is well known from previous studies that chronic fatigue, cognitive dysfunction, and a decrease in quality of life are independent of the grade of liver disease or the virus replication rate.10,12,13,14,15
Also, there is increasing evidence that the virus may enter the brain via lympho‐ or monocytic blood cells.43
In common with HIV infection, the “Trojan horse” hypothesis must be considered in HCV infection. The virus enters the brain in blood derived macrophagic cells, is hosted by microglial cells, and alters the function of these microglial cells thereby inducing neuronal dysfunction.44
Radkowski and colleagues45
and Forton and colleagues46
provided evidence that the CNS is a site of HCV replication and that within the CNS virus replication occurs at a lower level than in the liver. In addition, they showed that different HCV quasispecies may be present within brain tissue and serum. Thereby the responsiveness of brain and liver hosted virus to any antiviral therapy may be different, and while there is no evidence of viral replication in serum, the virus may persist in the brain and alter neuronal function.
In conclusion, some HCV infected patients with normal liver function show alterations in both the midbrain serotonergic and striatal dopaminergic systems, irrespective of their PCR status. In addition, these patients show alterations of mood and cognition consistent with impaired dopaminergic and serotonergic function (that is, depression, anxiety, and marked attention deficits). Thus the present findings implicate a role for altered monoaminergic neurotransmission in the pathophysiology of cerebral dysfunction concomitant with HCV infection. Even the less frequently reported symptoms nausea, migraine‐like headaches, increased or decreased food intake, or aggressive behaviour, which are part of the “encephalopathy” associated with HCV infection, may be explained by these findings. Further studies should be performed aiming for both detection of the causes of these alterations at the cellular level and development of adequate treatment strategies.