Hepatitis C virus (HCV) is an RNA virus belonging to the Flaviviridae family. More than 170 million people worldwide are chronically infected with HCV, an estimated 2.7 million of whom are in the United States and 5 million are in western Europe . HCV is transmitted primarily by exposure to blood in the form of unscreened transfusions, intravenous drug use, inadequately sterilised medical equipment and other types of blood exposure. More than 80% of patients with HCV infection progress into chronicity; 20–30% of patients with chronic hepatitis C infection will develop cirrhosis after 10–20 years of follow-up, and some will develop hepatocellular carcinoma . Chronic liver disease caused by HCV infection is commonly associated with extrahepatic manifestations, mainly mixed cryoglobulinaemia . HCV infection is the most common cause of what has been named ‘essential mixed cryoglobulinaemia’. Between 50 and 80% of patients with essential mixed cryoglobulinaemia are infected with HCV and up to 50% of patients with hepatitis C infection have mixed cryoglobulinaemia . In HCV/mixed cryoglobulinaemia patients, clinical involvement is mainly characterised by purpura, arthralgias, kidney disease, and peripheral neuropathy (Table 1) . HCV infection is involved in various neurological syndromes, particularly peripheral neuropathy. Central nervous system (CNS) involvement is more rarely reported. In this review, peripheral and CNS involvement associated with chronic HCV infection are described. The underlying mechanisms and treatment possibilities are discussed.
Peripheral nerve manifestations associated with hepatitis C virus infection
Neurological complications in HCV-infected patients occur predominantly in the peripheral nervous system. The prevalence of peripheral nervous system involvement varies in the literature, and can be as high as 50% of cases. The exact frequency of peripheral neuropathy in HCV patients is difficult to assess, as it varies depending on the definition criteria, the method of ascertainment (i.e. clinical examination versus electromyography) and the population studied. In a prospective study of 321 patients with chronic HCV infection, 50% of whom were cryoglobulin positive, clinically symptomatic sensory or motor peripheral neuropathy was found in 9% . In a study of 26 HCV/mixed cryoglobulinaemia patients, Ferri et al.  found 77% with peripheral neuropathy, as defined only by the presence of paresthesias.
Peripheral neuropathy in HCV infection is primarily associated with mixed cryoglobulinaemia, generally type II IgM kappa . Neurological manifestations range from pure sensory axonopathy to mononeuritis multiplex. The most frequently described form is a distal sensory or sensory-motor peripheral neuropathy. Polyneuropathy usually presents with painful, asymmetric paresthesias that later become symmetric . The pain is positively associated with the presence of vasculitis . Motor deficit is inconsistent and mainly affects the lower limbs, appearing a few months to a few years after sensory symptoms. Other extrahepatic manifestations related to mixed cryoglobulinaemia, i.e. purpura, membranoproliferative glomerulonephritis or arthralgia, are often seen. The tempo of the vasculitic neuropathy may be subacute, chronic, or acute on chronic . The exacerbation of neuropathy occurs simultaneously with the failure of other organs, as a result of the increased activity of the underlying vasculitis. Hypocomplementaemia is an important finding in mixed cryoglobulinaemia (Table 1) and helps to distinguish this vasculitis from antipolymorphonuclear cytoplasmic antibody-associated vasculitides. Hypocomplementaemia, found in 90% of patients, includes low serum C4 and CH50 levels, whereas C3 is normal . In patients with distal polyneuropathy, nerve conduction studies are in keeping with a predominantly axonal process, mainly affecting the sensory nerves. Neuropathological data show axonal degeneration, differential fascicular loss of axons, signs of demyelinization and small-vessel vasculitis, with mononuclear cell infiltrates in the perivascular area (Fig. 1a) .
We recently reported on the features of patients with HCV peripheral neuropathy related to polyarteritis nodosa vasculitis . Patients with this disorder present with different features than those with mixed cryoglobulinaemia vasculitis, i.e. life-threatening systemic vasculitis, severe multifocal sensorimotor neuropathies, cerebral angiitis, ischaemic abdominal pain, kidney and liver microaneurysms, increased erythrocyte sedimentation rate and C-reactive protein level, and renal insufficiency. Neuromuscular biopsies (Fig. 1b) typically show necrotizing vasculitis lesions involving medium-size arteries with mononuclear and polymorphonuclear neutrophil cell infiltrates.
Other types of neuropathies reported in HCV-infected patients include inflammatory demyelinating polyneuropathy [7,12], optic neuropathy  and small-fibre sensory neuropathy associated with the restless leg syndrome . Demyelinating neuropathy was reported in two out of 30 patients (7%) in a recent study of patients with HCV peripheral neuropathy . Mixed cryoglobulinaemia was detected in one, and nerve biopsy showed perivascular infiltrates and lymphocytic vasculitis . In a series of 51 HCV-infected patients, Nemni et al.  reported eight cases of cranial neuropathy, three of whom had mixed cryoglobulinaemia. Tembl et al.  described one patient with visual loss related to anterior optic neuropathy who responded to corticosteroids.
Peripheral nervous system involvement has also been reported in HCV-infected patients who had been persistently negative for mixed cryoglobulinaemia [3,7,13,14]. Indirect signs of mixed cryoglobulinaemia, i.e. purpura, positive rheumatoid factor and low serum C4 levels were absent. HCV-infected mixed cryoglobulinaemia-negative patients may develop mononeuropathy or multiple neuropathy [7,14]. Morphological findings disclose either lymphoid infiltrates or axonal damage . Some of these patients had non-inflammatory peripheral neuropathy, which could not be attributed with certainty to HCV infection . A significant improvement has been reported after anti-HCV treatment in such patients, suggesting a role for HCV itself in the pathogenesis of such peripheral neuropathy .
A new onset or worsening of neuropathy after treatment with IFN-α in HCV-infected patients has been infrequently reported [15,16]. Seventeen patients were reported with de novo or worsening peripheral neuropathy within the first 2–28 weeks after starting IFN-α . The development of peripheral neuropathy did not appear to be dose-dependent. Severe sensorimotor peripheral neuropathy was the most frequent presentation. Others have reported mononeuropathy multiplex, chronic inflammatory demyelinating polyneuropathy, and cranial neuropathy [7,8]. Nerve biopsy revealed either necrotizing vasculitis or axonal involvement. An improvement of neuropathy was usually noted after the discontinuation of IFN-α . In other cases, treatment with immunosuppressive agents successfully controlled the neuropathy .
The pathophysiology of HCV neuropathies remains largely speculative. Genomic HCV RNA has been detected in both skin and nerve biopsy samples showing vasculitis [17,18] and in a muscle sample showing polymyositis . The vascular deposition of HCV-RNA-containing mixed cryoglobulinaemia , and the direct infection of endothelial cells through low-density lipoprotein receptors  or perivascular mononuclear inflammatory cells  have been considered the origin of HCV-associated inflammatory vascular lesions. In a recent study , 26 out of 30 HCV-infected patients (87%) presenting with peripheral neuropathy showed inflammatory vascular lesions. Positive-strand genomic HCV RNA was detected in 10 out of 30 patients (muscle, nine; nerve, three). However, negative-strand replicative HCV RNA was never detected. Therefore, the usual detection of mixed cryoglobulinaemia and the lack of local HCV replication indicate that HCV neuropathy results from virus-triggered immune-mediated mechanisms rather than direct nerve infection and in-situ replication.
The treatment of HCV-associated peripheral neuropathy is based on anti-HCV drugs. Initially, the treatment of HCV-related cryoglobulinaemia with IFN alone was associated with a relatively poor response and a high relapse rate, especially in severe cases [21,22]. IFN monotherapy was effective in 50–100% of patients with purpuric skin lesions, but did not clearly show efficacy on nerve or renal involvement. Combination therapy with IFN plus ribavirin is much more efficacious, with a sustained virological response in 45–80% of patients with chronic hepatitis C, depending on their pretreatment characteristics [23–25]. In three recent uncontrolled studies [26–28], combination therapy with IFN and ribavirin demonstrated enhanced efficacy on the main HCV-related vasculitic manifestations (cutaneous, 100%; renal, 50%; and neural, 25–75%). In the largest published study, we analysed the clinical and virological features of 27 patients with chronic hepatitis C complicated by systemic vasculitis who had received antiviral therapy with IFN plus ribavirin for 24 months . For 12 out of 19 patients with peripheral neuropathy, serial electrophysiological studies before and after antiviral treatment were analysed. Seven patients had a dramatic improvement and three were stable; however, two patients had an increase in nerve damage (worsening of both clinical and electrophysiological parameters). After a mean delay of 36 ± 16 months (12–48) between the initial and last electrophysiological examinations, an increase in the mean distal compound motor and mean sensory potential amplitudes were observed in HCV patients with peripheral neuropathy after antiviral therapy. Our results suggest that treatment with IFN plus ribavirin can achieve a complete clinical response in most patients (75%) with HCV-related peripheral neuropathy. A complete clinical response usually correlates with the virological response.
In comparison with IFN plus ribavirin, other treatment strategies have not shown superior efficacy [21,29]. Corticosteroids, used alone or in addition to IFN, did not improve the response of HCV-related vasculitic manifestations in two controlled studies [21,29]. However, the use of high-dose intravenous corticosteroids may be useful initially for the control of life-threatening organ involvement while awaiting the generally slow response to antiviral treatments. Low-dose corticosteroids may help to control minor intermittent inflammatory signs such as arthralgia, but do not succeed in cases of major organ involvement (i.e. neurological, renal), or in the long-term control of vasculitis. Plasmatic exchange may allow life-threatening symptoms of vasculitis to be rapidly controlled without the use of high-dose intravenous corticosteroids or immunosuppressive treatments .
More recently, two small uncontrolled studies reported on the efficacy of anti-CD20 monoclonal antibody (rituximab) in patients with HCV/mixed cryoglobulinaemia vasculitis resistant to IFN-α monotherapy [30,31]. A complete clinical response was observed in 80% of patients, including those with peripheral neuropathy, and most responders also had a disappearance/deletion of peripheral B-cell clones. Rituximab was well tolerated without severe side-effects; however, it had a deep impact on hepatitis C viraemia. HCV RNA increased approximately two times from baseline levels in the responders, whereas it remained much the same in the non-responders. It is possible that the impact of rituximab on immunoglobulin levels (notably IgG anti-HCV antibodies) is an effective mechanism capable of modulating and interfering with HCV replication. A decline of anti-HCV titres allows HCV to avoid immune pressure and favours its replication. This suggests the presence of immunoglobulin with neutralizing properties in the immune response of chronic HCV carriers . After a follow-up of 6–12 months, most responders (75–87%) remained in remission. However, the lack of efficacy on HCV viral clearance and the increase in HCV viral load may lead patients to develop more severe HCV-induced liver lesions or cryoglobulinaemic relapses in the future.
The clinical relapse of HCV-related vasculitis is usually associated with HCV viraemia relapse. The higher efficacy of IFN plus ribavirin therapy seems to be associated with a prolonged duration of 18–24 months of treatment, particularly in cases with peripheral nerve involvement, in order to avoid such relapses [26,28]. The recurrence of vasculitis-related symptoms after the withdrawal of antiviral therapies with virological relapse (HCV RNA becoming positive again) can be successfully treated with another course of combination antiviral therapy [27,28].
Central nervous system manifestations associated with hepatitis C virus infection
Specific CNS involvement is more rarely reported in HCV-infected patients. CNS involvement, however, may present different facets, such as fatigue, depression, cognitive impairment and vasculitis.
Numerous surveys have reported a high prevalence of fatigue (20–80%) in HCV-infected patients, and have found no association between the severity of fatigue and the severity of liver disease [33–35]. Depression is a common finding in HCV-infected patients, even before any treatment with IFN . The greatest reservoir of HCV infection is in intravenous drug users who frequently present with pre-existing depression . Conversely, depression may exist as a secondary phenomenon to HCV infection. In addition, a biological effect of HCV infection itself may underlie the depression.
Cognitive impairment has also been reported in HCV-infected patients. There is evidence of mild but significant neurocognitive impairment in HCV infection, which cannot be attributed to substance abuse, depression or hepatic encephalopathy . In a study by Hilsabeck et al. , impairment of various neuropsychological tasks was found in up to 49% of HCV-infected patients without cirrhosis. In vivo magnetic resonance spectroscopy and neuropsychological studies have suggested that a biological mechanism may underlie these cognitive findings . In a recent prospective study , we performed neuropsychological tests and cerebral magnetic resonance imaging (MRI) in HCV/mixed cryoglobulinaemia vasculitis patients. Thirty-two of the 34 HCV/mixed cryoglobulinaemia patients (94%) had a deficiency in one or more of the 10 cognitive domains examined. The number of impaired cognitive functions was significantly higher in mixed cryoglobulinaemia vasculitis patients (2.18 ± 1.84, P < 0.05) compared with HCV controls (0.87 ± 3.1). MRI analysis showed that HCV/mixed cryoglobulinaemia patients, when compared with HCV controls and healthy volunteers, respectively, had a higher mean number of total (7.03 ± 9.9 versus 0.90 ± 1.81 and 2.03 ± 3.1, P < 0.05) and periventricular white matter high intensity signals (2.4 ± 3.0 versus 0.38 ± 0.5 and 0.8 ± 1.4, P < 0.05). The cryoglobulin level was positively correlated with the number of impaired cognitive functions. Specific major clinical manifestations of cryoglobulinaemia did not correlate with the extent of brain lesions on MRI or on cognitive tests. Notably, peripheral neuropathy was not associated with either MRI findings or cognitive abnormalities.
The mechanism by which lesions are produced in the CNS of HCV-infected patients is still unclear, as are the respective roles of cryoglobulin and HCV. The recent detection of HCV replicative intermediaries and HCV genetic sequences in postmortem brain tissue raises the possibility that neuropsychological symptoms and cognitive impairment may be related to HCV infection of the CNS . Along this line, alterations of serotoninergic neurotransmission and tryptophan metabolism have recently been shown in HCV-infected patients with psychopathological disorders [41,42]. The improvement of fatigue after anti-HCV therapy also suggests an effect of the virus itself on CNS involvement [35,43,44]. We prospectively studied the impact of anti-HCV treatment on fatigue in a cohort of 431 HCV-infected patients . Fatigue improved in 34% of virological responders versus 22% of patients with persistent HCV RNA (P = 0.01). The impact of virological response on fatigue persisted after adjusting for age, sex, fibrosis stage and depression. In HCV/mixed cryoglobulinaemia vasculitis patients who have a higher frequency of impaired cognitive function and MRI brain abnormalities than HCV controls without mixed cryoglobulinaemia, a specific inflammatory involvement of small cerebral vessels by the cerebral vasculitis is also possible . The white matter is much more vulnerable to hypoxaemia–ischaemia than the grey matter of the cortex because of rather widely spaced linear arterioles, few anastomoses, and sparse collateralization .
Reports on well-documented CNS involvement in patients with HCV-associated vasculitis are rare [47–49], although it may be the initial extra hepatic manifestation of HCV infection . Clinically, stroke episodes, transient ischaemic attacks, progressive reversible ischaemic neurological deficits, lacunar infarctions, or encephalopathic syndrome may occur [8,48,51]. Stroke episodes and encephalopathic syndromes have been attributed to ischaemia or rarely to hemorrhage [48,50,52]. Patients with cryoglobulinaemia and CNS manifestations have normal or abnormal cerebrospinal fluid, including increased protein concentrations and pleiocytosis . MRI findings of the brain have been consistent with ischaemia, showing either small lesions of the periventricular white matter and the cerebral trunk or extensive supra and infratentorial white matter lesions, suggesting cerebral vasculitis [8,10,49]. Cerebral angiography in patients with HCV/mixed cryoglobulinaemia and CNS involvement has occasionally suggested vasculitis or vasculopathy, demonstrating focal narrowing, multiple irregularities, or occlusion of the affected arteries [48,53]. There have been few instances of histopathological documentation of the mechanisms of cerebral ischaemia in patients with HCV/mixed cryoglobulinaemia and stroke [5,53–55]. The presence of CNS vasculitis involving small and medium-sized vessels has been documented in two patients [5,55]. In other patients, no vasculitis has been confirmed [53,54].
Favourable outcomes have been observed under corticosteroids or IFN-α therapy in the treatment of CNS involvement in HCV/mixed cryoglobulinaemia patients [8,50,55]. We have described three HCV/mixed cryoglobulinaemia patients with cerebral involvement (ischaemia, three out of three; or haemorrhage, two out of three) who recovered in 3–6 months with prednisone and IFN-α . Dawson et al.  reported two cases of stroke associated with HCV infection secondary to CNS vasculitis, one case being confirmed by biopsy. The first patient recovered from the stroke symptoms with cyclophosphamide and prednisone. The second patient was able to return to work 18 months after treatment with cyclophosphamide, prednisone, IFN-α and warfarin. However, such reports cannot prove a definite cause-and-effect of HCV infection and stroke, as clinical improvement is the natural history of stroke in most cases. Tembl et al.  reported two patients with an encephalopathic picture occurring at the same time as peripheral neuropathy, purpura, and mixed cryoglobulinaemia, suggesting a common vasculitic pathogenesis. They were treated with corticosteroids alone or in association with cyclophosphamide, and experienced a rapid recovery.
Hepatitis C virus and HIV co-infection
Although HIV/HCV co-infection is frequent (ranging from 20 to 50%) [3,56,57], few studies have attempted to evaluate the differences between HCV-infected patients who are HIV-positive or HIV-negative [58,59]. The neuropsychiatric impact of HCV infection on HIV-infected patients was recently demonstrated in a cohort of 116 HIV-positive patients, including 67 who were HCV co-infected . Co-infected (HIV-positive/HCV-positive) individuals had significantly greater rates of past substance-induced major depression. A total of 42% of the co-infected patients met the criteria for current major depression. There was a trend for co-infected patients to have worse neurocognitive function. HCV/HIV-co-infected individuals exhibited a greater rate of impairment on tests of executive functioning. Differences in cognitive functioning were associated with HCV infection, but did not correlate with indices of liver disease severity. In comparison with HIV-positive/HCV-negative patients, those who were co-infected were also more likely to be diagnosed with HIV-associated dementia. A recent cross-sectional study  investigated the clinical and biological signs of autoimmunity in 97 HIV-infected patients, 62 of whom were HCV co-infected. In patients with HIV infection only, cryoglobulinaemia was detected in 17%, a positive rheumatoid factor in 19%, antinuclear antibodies in 21%, anticardiolipin antibodies in 51%, and antipolymorphonuclear cytoplasmic antibody in 17%. There was a trend towards a higher level of cryoglobulinaemia and anticardiolipin antibodies in patients with HIV infection only, having CD4 lymphocyte counts greater than 350 cells/mm3. Patients co-infected with HCV had a higher prevalence of cryoglobulinaemia than those who were HCV negative (42 versus 17%). In another prospective study of HCV-infected patients , multivariate analysis showed significant differences between the 242 HIV-negative and 74 HIV-positive cases. HIV co-infection was associated with the presence of anticardiolipin antibodies [P = 0.003, odds ratio (OR) 4.18], thrombocytopaenia (P = 0.01, OR 3.56), and the presence of arthralgia/myalgia (P = 0.017, OR 0.23). The hepatic effects of HCV infection were more severe in HIV-positive patients, with higher Knodell (P = 0.0004) and Metavir scores (P = 0.0003) . Several studies have confirmed that HIV/HCV co-infection accelerates the natural course of chronic hepatitis C, increasing the risks of liver cirrhosis, decompensated liver disease and hepatocellular carcinoma [62–64]. Conversely, other studies have shown an increased risk of progression to AIDS and AIDS-related death among HIV/HCV-positive individuals, suggesting that HCV co-infection may accelerate the course of HIV disease [65,66]. Chronic infection by HCV may also affect the management of HIV infection, increasing the incidence of liver toxicity associated with antiretroviral regimens [67,68].
In summary, the neurological complications of HCV-infected patients are predominantly in the peripheral nervous system and are mainly associated with mixed cryoglobulinaemia. The most frequently described form is a distal sensory or sensory-motor peripheral neuropathy. Treatment with IFN plus ribavirin can achieve a complete clinical response in most patients with HCV-related peripheral neuropathy. A complete clinical response usually correlates with the eradication of HCV. CNS involvement is more rarely reported in HCV infection. CNS involvement, however, may present different facets, such as fatigue, depression, cognitive impairment and vasculitis. Co-infected (HIV-positive/HCV-positive) individuals might have higher rates of depression and a trend towards higher neurocognitive function impairment. Cryoglobulinaemia is more likely to occur in HIV patients with CD4 lymphocyte counts greater than 300 cells/mm3. However, data regarding peripheral nerve involvement in co-infected patients are lacking.
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