While there is a body of literature supporting the hypothesis that neuroinvasion by HCV occurs (post-mortem data derived by Vargas et al, 2002; Radowski et al., 2002; Wilkinson et al., 2009 etc.), these studies are limited by factors including some patients being co-infected with HIV, small numbers and severe liver damage. Nevertheless, the findings are very interesting and provide a strong basis for a HCV neuroinvasive model of reported cognitive dysfunction in CHC.

It should be noted, however, that studies employing rigorous methodological controls report very little to no evidence of any clinical neurocognitive impairment in CHC samples. These studies include McAndrews et al, 2005, Pattullo et al, 2011 and a study I conducted on a relatively unique state-infected hepatitis C sample, Lowry et al, 2009. Having just completed my doctorate on this topic, I can report that further investigation of this Irish, female, non-cirrhotic HCV sample, exposed to HCV over 30 years ago (including approximately half of whom who spontaneously cleared) has yielded little evidence of any clinically relevant dysfunction across multiple cognitive domains. These cognitive test performances are not only healthy in relation to an age-, gender-, education- and IQ-matched sample of healthy controls, but also in relation to standardised normative parameters.

What's of greater interest is the fact that many of these individuals report significant HRQoL impairment (including those who spontaneously cleared immediately following initial HCV exposure). So, while their self-reports are markedly reduced, their objective cognitive performance is. for all intents and purposes, healthy. Notably, depressed mood and fatigue reports appear to predict this HRQoL impairment. What makes that interesting is that if one looks at the H-MRS data for depression and fatigue, one finds similar reports of cerebral metabolite disturbance to that reported in CHC.

To my mind, it is worth considering whether these spectrocopy studies on CHC samples are actually reflecting the effects of HCV neuroinvasion, as is being claimed, or accompanying symptomatic reports, most notably mood and fatigue disturbances, which are probably the most common symptoms associated with hepatitis C.

Lowry's answer is good. Perhaps it is incomplete. Possibly VASCULITIS is a major contributor, in turn is relates to Cryoglobulinemia. VALT=vascular associated lymphoid tissue is another co-factor. It comes and goes, as any other lymphoid accumulation during acute and chronic infections (otitis, acne, Hpylori....)

Neuroferritin, ferrite, magnetite accumulation should never be forgotten. Chronic infections, HCV being only one of MANY of them, cause iron storage in cells. In brain it relates to neurodegeneration, slowly (see Kirschwink, and many others). A concept was put forward by stroke scholars: TOTAL INFECTIOUS BURDEN should be taken into account. It includes Chlamidiae spp (in the North), UTI in the South (Israel e.g.) and many others; teeth and gum diseases perhaps a major issue. In the Mediterranean haemolytic anemias are highly prevalent, thereby iron accumulation.

Copper accumulation. One in 90 born is reported the genetic risk for Cu accumulation in europe, 1in 30 in sardinia.

Manganese Accumulation was reported in cerebellum of a majority of cirrhotic patients in italy, Causes are fully obscure. Acute Mn intoxication causes "parkinsonism".

CFTR mutation are possible cofactor. One in 24 Europeans carry mutations, one in 13 Askehanzy Jews..

L'vov reported HCV infection in neonate mice CNS cells.

We demonstrated platelets to be a carrier of HCV. Its entry in cells depends on Occludin opening, which many viruses use to enter, e.g influenza, EBV, CMV (HIV also). Hence HCV could possible exploit these openings.,

I refrain from discussing the enormous importance of Gut biota, coeliac disease, that many are reporting as extremely important.

Vasculitis might be a potential etiological factor, albeit only in a minority of patients. McAndrews et al 2005 found subtle cognitive impairment, but the studied HCV population didn't have cryoglobulinemia, and the Forton-studies didn't find any evidence of vasculitis in their sample. In our unpublished study of 45 HCV patients, we didn't find any evidence of vasculitis.

Good discussion. I agree that comorbidities play an important role, as does severity of fibrosis/cirrhosis and probably the aging process. Perhaps there is a threshold for when the brain can no longer compensate and cognitive dysfunction occurs.

As Simon Wessely pointed out in his 2002 review, we're in a sort of "missing link" situation at the moment.

We know that HCV patients are commonly suffer from cognitive impairment. We also know from post mortem and in vitro studies that HCV can infect the central nervous system (either endothelial cells and/or macroglia) and PET studies have shown microglia activation in the brains of HCV patients. But we urgently need studies tying clinical data (eg. fatigue, cognition) with these supposed biological mechanism. And this all has to take place in a patient group often marred by confounding comorbidities such as the long term effects of substance abuse and liver pathology on the brain. It's quite a challenge...

Or indeed, cleared-HCV patients with similar profiles of symptomatology.

When looking at the litterature, some imaging studies (like the PET study of Heeren et al out of the Weissenborn group) combine HCV RNA pos with HCV RNA neg patients (both groups HCV Ab+) into one "HCV group". Is that justifiable? Some might say that given the fact that former HCV patients also seem to be impaired it's ok, and in the light of potential "occult HCV" in the CNS, but what's your take on this? Is it ok?