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HCV and Neuropathy

Hepatitis C Virus Can Damage the Central Nerve System

It is generally believed that the hepatitis C virus can damage only liver and blood. However, studies from Russian scientists have showed that this is not the case. Researchers from the Evanovsky Institute of Virology, Russian Science Academy, found that not only did hepatitis C virus damage the liver and blood, but that it could also infect neurons and destroy the central nerve system.

Hepatitis C virus can be in a latent stage for 15 to 20 years without causing jaundice symptoms. The patients experience only fatigue, weakness, and loss of appetite. Doctors misdiagnose this condition quite often and when they eventually make the right diagnosis, patients have already progressed to chronic hepatitis or even developed liver cirrhosis.

Studying the physiology of hepatitis C virus, scientists from the Evanovsky Institute found that viruses similar to the hepatitis C virus could survive and replicate in the neuron cell. They therefore, they started to focus their study on the neuron cells.

In order to thoroughly detect the damage to the central nervous system caused by hepatitis C, scientists used mice as study subjects and injected serum containing the hepatitis C virus into the brain medulla. Five to ten days later, the central nerve system was severely hampered. A total of 30% of the mice died. The brain medullae from the dead mice were suspended in solution and injected into healthy mice. Between 2 and 4 days later, all the mice died. Examination of the brain medullae of the dead mice showed that the mice had died of hepatitis C infection. This experiment proved the hypothesis that hepatitis C virus could invade and replicate very fast and damage the neuron cells. This could quickly result in the death of the infected neuron cells.

This finding tells us that once hepatitis C virus invades the nervous system, it can quickly and irreversibly destroy the nervous system and result in death. The Russian scientists pointed out that this finding was not inspiring and made it very difficult to conquer hepatitis C. However, the new knowledge gained could help the study of the hepatitis C virus from going astray.

The Russian scientists also pointed out that the public should know that though the transmission of hepatitis C is mainly via blood transfusion, drug use and prostitution can transmit hepatitis C virus, as well as AIDS.

A Painful Connection:  HCV and Neuropathy  

By Roger Smith

People with Hepatitis C who suffer numbness or tingling in their extremities know from experience there is an association between HCV and neuropathy. Increasingly, their claims are finding support: according to medical researchers and clinical physicians, there is a "very strong   association" between hepatitis C virus and a blood condition called essential mixed cryoglobulinemia (EMC). Among other symptoms, EMC can cause nervous system abnormalities. Researchers have not yet explained the  precise connection between HCV, EMC, and neuropathy,  nor have they  found significantly effective treatments, but knowledge is sure to increase  as more people are diagnosed with HCV and its symptoms increasingly studied.

                  Neuropathy refers to any disease of the nervous system resulting from   localized inflammation of the nerves. If symptoms appear in the body's extremities, the condition is called "peripheral neuropathy," and most  HCV-related neuropathies are of this sort. Patients complain of numbness, tingling, and muscle weakness. A physical examination may also reveal   decreased deep tendon reflexes. Occasionally, arm and back pain occurs. 

                  One patient has even blamed the nerve inflammation for lost teeth. If symptoms derive from brain malfunction, the condition is an  encephalopathy, or central nervous system disease, and the symptoms are  more sinister than those of peripheral neuropathy. A team led by George   W. Petty reported two cases of encephalopathy in HCV- infected patients   in the July 1996 issue of the Mayo Clinic Proceedings. In both cases small    vessels in the brain became inflamed, impairing blood flow. One patient had  numbness in the right lip, hand, and leg, weakness in the right hand and  arm, and word-finding difficulty. The other patient had headaches and seizures, although the latter may have come in part from medication for the  headaches.

                  In both peripheral neuropathy and encephalopathy the key physiologic  change is the inflammation of blood vessels (vasculitis). The hepatitis C virus probably does not inflame the blood vessels directly. Instead, the   vessels are responding to immune system products floating through the  blood stream.

 emc

                  When the body senses an invasion by foreign organisms, such as HCV,  chemical responses are triggered. Among those responses are various  kinds of immunoglobulin, proteins that help kill the foreigners or regulate the immune response. For some reason -- biologists are not sure why -- these  immunoglobulins can "glob" together and lodge on the walls of medium and small blood vessels.

                  The immunoglobulins that are involved are called cryoglobulins because  they turn into a gel at cool temperatures (cryo comes from the Greek word for cold). Since cold temperature readily affects the small and middle-sized vessels in the body's extremities, the cryoglobulins are most likely to form  in them. It appears that this glob-and-lodge action causes the inflammation   of blood vessels. Cryoglobulinemia is the condition of having cryoglobulins  in the blood.

                  Cryoglobulinemia and HCV became linked when researchers found bits of HCV and HCV-specific antibodies trapped in globs of cryoglobulin. They   speculated that the cryoglobulinemia was HCV-incited, occurring when cryoglobulins specifically attacked the hepatitis virus. Other organisms can  cause cryoglobulinemia -- cancerous lymph cells, for instance -- but the HCV-related version always involves a particular mixture of two types of   immunoglobulins. Hence, the "essential mixed" of EMC.

                  However, the link between HCV and EMC is not entirely straightforward. The chemical tests used to identify specific immunoglobulins and the blood  assays used to spot HCV products are complex. Doctors do not order   them routinely. As for neuropathies, unless there is an obvious reason to suppose they result from HCV infection, doctors are likely to assume that  another, more common system-disturbing disease is responsible. Diabetes  mellitus may cause very similar symptoms, for instance.

                  Medical journals have described only a few cases of the  HCV-EMC-neuropathy connection. Reviews of the published literature  found that 36 to 54 percent of HCV-infected subjects also had    cryoglobulins. According to one study, 21 percent of those with the   cryoglobulins showed symptoms, but the authors did not specifically   mention neuropathy.

                  The article by Petty's research team cited a handful of other reported cases of HCV-associated cerebral ischemia similar to their two but added  that no detailed description of the condition is available. All the articles  warn that their findings are exploratory, not definitive.

                  The experience of clinical gastroenterologists agrees with the research  estimates. Mark Schiele, M.D., a gastroenterologist for Health First, Inc., in Portland, Oregon, estimates that fewer than one percent of HCV  patients develop neuropathy. "In general," he said, "it's thought to be quitean uncommon manifestation of HCV infection." Sandra Wilborn, M.D.,  also a Health First gastroenterologist, concurs. "It's not something that has  been clinically important to my practice," she said.In fact, Dr. Wilborn has seen only four cases of cryoglobulinemia altogether, and she encountered them before research uncovered the HCV-EMC link. She typically cares   for 25 new HCV-infected patients a year.

                  Dr. Wilborn emphasizes that the long-term effects of HCV infection are only slowly becoming clear because HCV is so recent a discovery. First  identified in 1989 as a distinct viral type, HCV usually takes years to  become symptomatic. Most patients are diagnosed with chronic HCV ten  to 13 years following infection. Typically, about 20 years pass before the   most common serious result, liver cirrhosis, appears. But, Dr. Wilborn points out, the virus causes a "cascade effect" from the immune system, and the symptoms that might come from the cascade,  including neuropathy,  are just beginning to surface in sufficient numbers to study.

                  It is a good thing that EMC-related neuropathy is uncommon, according to   Dr. Schiele, because "it can be a very disabling consequence of viral infection."

                  The standard treatment for HCV with EMC-caused neuropathy is   interferon alfa, which is also the standard treatment for uncomplicated  chronic HCV. Unfortunately, interferon alfa treatment eases EMC symptoms in only about one half to two-thirds of patients, and the side effects include headaches, cognitive changes, irritability, and depression.  Still, current research supports long-term treatment with interferon alfa.

                  There are several possible new treatments in the pipeline, either used alone or in combination with interferon alfa. Ribavirin combined with interferon  alfa apparently can trick the hepatitis C virus into becoming harmless by   mimicking part of its RNA structure, although on its own ribavirin    treatment has proven only partially effective. The antiviral agent amantadine has shown promise in clinical trials, and researchers are   developing several HCV-specific protease inhibitors similar to those used  to quell HIV retrovirus.

Source

 Mark Schiele, M.D., gastroenterologist, Health First

Medical Group, Portland, OR.

 Sandra L. Wilborn, M.D., gastroenterologist, Health

First Medical Group,  Portland, OR.  "Immunologic and Extrahepatic Manifestations of HCV Infection,"

Linda Scully, Update on Liver Disease and Hepatitis

Conference, Florida, June  4-8, 1997 (Webmaster@hepnet.com).

"Cerebral Ischemia in Patients with Hepatitis C Virus

Infection and Mixed Cryoglobulinemia," George W. Petty, et al., Mayo Clinic Proceedings, Vo. 71 (July 1966), pp. 671-678.

 "Hepatitis C: A Multifaceted Disease," by Subhash C.

Gumbar and Sanjiv  Chopra, Annals of Internal Medicine, Vol. 123, No. 8 (October 15, 1995), pp. 615-620.

"Serum Cryoglobulin and Chronic Hepatitis C Virus

Disease Among Japanese Patients," by Kazuma Tanaka, et al., The

American Journal of  Gastroenterology, Vol. 90, No. 10 (1995), pp. 1847-52. "Summary of the NIH Consensus Development Conference Statement on the Management of Hepatitis C," Clinical Courier, Vol. 16, No. 4 (June1997), pp. 1-8.

"Hepatitis C Virus Genotype Analysis In Patients with

Type II Mixed Cryoglobulinemia," Anna Linda Zignego, et al., Annals of Internal  Medicine, Vol. 124, No. 1 (January 1, 1996), pp.

31-34.

 "HCV Infection May Cause Mixed Cryoglobulinemia,"

Salynn Boyles, Cancer Weekly Plus, July 22, 1996, pp. 20-22.

"Mixed Cryoglobulinemia and Hepatitis C Virus,"

Vincent Agnello, Hospital Practice, Vol. 30, No. 3, pp. 35-43.

 Exclusive to SHN.

Copyright © 1998 by Sapient Health Network. All rights

reserved. 

  Peripheral neuropathies and chronic hepatitis C: a frequent association?

Ripault MP, Borderie C, Dumas P, Vallat JM, Goujon JM, Brecheteau P, Beauchant M, Silvain C
Gastroenterol Clin Biol 1998 Nov 22:11 891-6

Vernaclular Title
Neuropathies périphériques et hépatite chronique virale C: une association fréquente?

Abstract
OBJECTIVE: The aim of this prospective study was to evaluate the prevalence of the peripheral neuropathies associated with chronic hepatitis C and their clinical, electrophysiological and histological characteristics. PATIENTS AND METHODS: Thirty six patients admitted from December 1994 to January 1996 for chronic hepatitis C were prospectively investigated. Laboratory data included liver blood tests, serum cryoprecipitate immunoelectrophoresis, assays for anti-nuclear antibody, rheumatoid factor, circulating immune complexes, anti-SSA and anti-SSB antibodies. For each patient, a clinical neurological evaluation as well as an electrophysiological evaluation were performed by the same operator. In presence of peripheral neuropathy, a neuromuscular biopsy was performed. RESULTS: In seven patients (19%), a peripheral neuropathy was diagnosed related to hepatitis C virus in 3 patients. In these 3 patients presenting with leg paresthesia, an axonal sensitive neuropathy was evidenced by electromyography. A neuromuscular biopsy performed in two of these patients showed a severe diminution of the myelinated fibers associated with vasculitis lesions in one patient. A skin biopsy was performed in the third patient with leg purpura revealing a leukocytoclasic vasculitis. A positive cryoglobulinemia was found in two of these patients. CONCLUSION: In chronic hepatitis C, the prevalence of peripheral neuropathy is 8% and usually associated with cryoglobulinemia. It is an axonal neuropathy with diminution of the myelinated fibers and vasculitis lesions in the absence of cryoglobulinemia.

Hepatitis C virus infection of peripheral nerves in type II cryoglobulinaemia.

AUTHOR: Bonetti B, Scardoni M, Monaco S, Rizzuto N, Scarpa A Dipartimento di Scienze Neurologiche e della Visione, Universita di Verona, Italy.
SOURCE: Virchows Arch 1999 Jun;434(6):533-5

Peripheral neuropathy is a frequent complication in patients suffering from type II mixed cryoglobulinaemia (mCGII), a sort of vasculitis that is strongly associated with hepatitis C virus (HCV) infection and characterised by high concentrations of anti-HCV antibodies and HCV RNA in the cryoprecipitates. We report the finding of HCV RNA in homogenates of nerve biopsies from five such patients, by reverse transcription-polymerase chain reaction (RT-PCR) amplification of different regions of the viral genome. HCV RNA was localized in epineurial cells by in situ RT-PCR. Our data suggest that HCV infection of nerves plays a major role in mCGII-associated neuropathy.

HIV and HCV co-infection: Neurological Manifestations and Implications

The number of people estimated to be infected with Hepatitis C virus (HCV) worldwide is a staggering 200 million.1,2 An estimated 40 million people are infected with HIV. Both these viruses have been shown to infect lymphocytes and to cause serious damage to the peripheral and central nervous systems (PNS and CNS). The neurological manifestations 
of HIV have been well delineated, because researchers have had 20 years to study HIV neuropathogenesis. However, the neurological manifestations of HCV have been less well characterized and reported, in part because the virus has been identified only for one decade. In time, the neurological manifestations of HCV are certain to be considered as very important extrahepatic complications of this virus, just as the neurological manifestations of HIV are seen to be of critical importance among HIV's complications. Moreover, because the routes of transmission of HIV and HCV are similar, it is estimated that between 9% and 40% of HIV-infected individuals are co-infected with HCV, with an average estimate of between 25% and 30%. The highest percentages of co-infection 
have been found in injection drug users (IDUs) and hemophiliacs (52% to 90% and 60% to 85%, respectively).1,2 Many of our patients have multiple risk factors for transmission of both these viruses, mandating that we test for HCV regularly in HIV-infected patients. While both HIV and HCV clearly have been shown to cause neurological complications, the exact nature of how these viruses may interact to promote or amplify neurological disease is not well understood. This paper reviews the less well reported neurological complications of HCV and discusses the neurological implications of HIV and HCV co-infection.

It is agreed that HIV penetrates the CNS early in the course of infection. The same may be true for HCV. Fujita et al reported a case of acute viral encephalitis with subsequent discovery of acute HCV infection.3 Two teams have reported the presence of HCV by quantitative polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF) of HCV-infected patients.4,5 Because, in most of the cases, the HCV genotype was the same in the individual patient's plasma and CSF, it was postulated that the virus was of plasma origin. The mechanism of transport of HCV from the systemic circulation into the CNS is likely to be similar to that of HIV because both viruses have been shown to infect 
monocytes6 and these cells can cross the blood­brain barrier.

Direct productive infection with HCV. often associated with mixed cryoglobulinemia, has been shown to cause numerous CNS diseases, even in the absence of hepatic failure. The presumed mechanism is a vasculitis associated with cryoglobulinemia and multiple ischemic infarcts. Encephalopathy ranging from minor confusion to severe cognitive-motor dysfunction has been described.7­9 In 1998, Origgi and colleagues 
described three patients with chronic HCV infection and cryoglobulinemia who complained of mild CNS problems, including confusion and disequilibrium. Magnetic Resonance Imaging (MRI) of these patients showed small hyperintensities consistent with ischemic lesions.8 

In Heckmann et al's 1999 review of a small series of HCV- infected patients showing neurological manifestations, a patient with systemic vasculitis associated with cryoglobulinemia is described who progressed from apathy to severe drowsiness with myoclonic jerks and multiple pyramidal tract signs. MRI showed increased prolonged spin echo signal diffusely throughout the deep white matter that by description resembles that of HIV-associated leukoencephalopathy seen in HIV-associated  dementia.10 Cerebrovascular accidents (CVAs, commonly known as strokes), including hemorrhagic events, also have been described in HCV-infected persons.11,12 In addition, some cases of HCV CNS disease appear to be unrelated to vasculitis. Bolay et al reported a case in 1996 of severe progressive encephalomyelitis associated with HCV where postmortem analysis of brain and spinal cord showed perivascular lymphocytic cuffing and diffuse infiltration and neuronal loss. HCV was detected by PCR in all of these specimens.13 

Pure myelopathies (spinal cord dysfunction) have also been associated with HCV. In 1994, Hino et al reported on 13 patients with a progressive spastic paraparesis. These patients were seronegative for HIV, HTLV-I, or HTLV-II. They all had evidence for chronic Hepatitis B virus infection, and five also had detectable HCV. These patients were studied 
at a time when HCV PCR was imprecise, and it is not clear whether it was the HBV or HCV that caused the myelopathies.14 This year, Spencer and Forno described a case of severe HCV where the myelopathy on postmortem was correlated with dramatic vacuolation of the spinal cord. Once again, this finding is analogous to that seen with HIV-associated vacuolar myelopathy.15

Similarities between some of the reported cellular metabolic abnormalities seen in HIV and HCV also are striking. Levels of toxic cytokines, such as TNF-alpha and IFN-gamma, are elevated in both these viral infections. These pro-inflammatory cytokines have been implicated in the multifactorial etiology of HIV encephalopathy.16,17 Additionally, 
Quinolinic acid (Quin) is a neurotoxic metabolite of the amino acid tryptophan that is found in elevated concentrations in HIV-infected patients and is also implicated in HIV encephalopathy. Quin is both a direct neurotoxin and an NMDA receptor agonist that precipitates neuronal apoptosis and cell death. Levels of Quin are elevated in patients with HCV infection.18

We were not able to find any references that reported mutual up-regulation of HIV and HCV, a process that has been reported in co-infection with HIV and other viruses, most notably Cytomegalovirus (CMV), Epstein­Barr virus (EBV), Human Herpes virus-8 (HHV-8), and JC virus. However, if both HIV and HCV independently cause neurological disease via similar mechanisms, their effect on the nervous system must not be underestimated. 

HCV has also been associated with neuropsychiatric abnormalities such as depression and mood disorders.19 However, it has been difficult in some cases to differentiate the contribution of HCV versus the neuropsychiatric complications caused by the most common treatment for HCV infection, IFN-alpha.20 Thomas et alevaluated chronic fatigue 
associated with HCV infection in 1999. They performed formal neuropsychological testing in 19 patients with mild HCV infection and performed MR Spectroscopy (MRS) on three groups: (1) an additional 27 similar patients; (2) matched controls who had only chronic hepatitis B; and (3) a set of healthy controls. Only the HCV- infected group showed  neuropsychological abnormalities. Additionally, the MRS in the HCV group showed an increase in the levels of choline to creatine, whereas the hepatitis B and healthy control groups had normal MRS scans. These MRS changes are similar to those reported in HIV-associated dementia.21 

Most of the literature reporting on the neurological manifestation of HCV pertains to the peripheral nervous system and describes painful neuropathies. However, rare cases of HCV- associated myopathy have also been reported,22 and one recent report described an association with fibromyalgia.23 The most common type of peripheral neuropathy associated with HCV is that associated with essential mixed cryoglobulinemia (EMC.) 
Ripault et al reported in 1999 on a series of 36 patients with HCV and found that seven (19%) had a peripheral neuropathy associated with HCV; 8% had EMC-associated peripheral neuropathy. While these patients did not have HIV, it was not clear whether ethanol abuse contributed to the characteristic findings of axonopathy with some minimal demyelination and vasculitic lesion seen on electromyography with nerve conduction 
velocity testing (EMG/NCV) and sural nerve biopsies.24 In a similar series, Zaltron et al reported in 1998 on 89 patients with HCV who underwent EMG/NCV testing. They found that 37% of patients showed electrical evidence of peripheral neuropathy. However one-third of these patients did not have evidence of cryoglobulinemia.25 Bonetti et al 
reported in 1999on five HCV patients with EMC-associated peripheral neuropathy. In all five, HCV was detected in nerve biopsy by PCR and was localized to the epineurial cells by reverse transcription PCR.26 In 1997, Caudal and associates published a case report of a patient with chronic HCV and painful sensory neuropathy where no other etiology was evident. This patient also had detectable HCV by PCR in his CSF indicating both CNS and PNS productive HCV infection.27 Two independent studies reported that HCV subtype 1b correlated more significantly with peripheral neuropathy.28,29 Both plasma exchange and corticosteroids have been used with some success to treat these patients when they have evidence of either vasculitis or demyelination.30,31

There have been rare reported cases of cryoglobulin associated peripheral neuropathy in HIV infection without HCV.32 However, most cases of HIV-related peripheral neuropathy are due to HIV alone, "D" nucleoside analogue toxicity, or a combination of these factors. Because painful sensory neuropathy is so common in HIV infection (it occurs in 30% to 35% of cases), intuitively it seems that the combined effects of HIV and HCV on peripheral nerves would be worse than the effect of either viral infection alone. However, no study to date has examined the effects of co-infection with HIV and HCV on the PNS and CNS, and due to the multiplicity of confounding factors that could cause neuropathy in this subject sample, such a study would be inherently complex. All other types of peripheral neuropathies including Guillain­Barre, chronic inflammatory demyelinating polyneuropathy and mononeritis have also been reported, infrequently, in association with HCV infection.33­36 

Longitudinal studies that include careful neurological examination of patients who are HCV-infected and who are co-infected with HCV and HIV are needed if we are to understand the effects of co-infection on the nervous system. We must heed the lessons learned from studying HIV and commence these studies now so that we do not waste another decade in our quest for answers. By doing so, we will determine whether the effects of each virus are additive or whether they augment one another in their attacks on the nervous system, and we can adopt treatment strategies as newer drugs emerge. We face many dilemmas in studying these patients, including the fact that the most common treatment (IFN-alpha) can itself cause encephalopathy and peripheral neuropathy (though usually self- limited to the course of treatment).19,37 Many co-infected patients have 
CNS and PNS damage from the effects of chronic use of ethanol and injection drugs. Additionally, so many of the medications used to treat HIV are potentially hepatotoxic, and end-stage liver disease with hyperbilirubinemia and hyperammonemia often make neurological and neuropsychological assessment difficult. In spite of these obstacles, we 
must begin to study these co-infected patients, paying particular attention to potentially devastating and life-impacting neurological complications.

The authors wish to acknowledge Ms. Teresa Hanbey, Director of the Hepatitis C Outreach Project, for her assistance in the preparation of this manuscript. 

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20. Maunder RG, Hunter JJ, Feinman SV. Interferon treatment of hepatitis 
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rheumatoid arthritis, seronegative rheumatoid arthritis, systemic lupus 
erythematosus, and psoriatic arthritis) http://www.med.upenn.edu/rheum/schumacher.html Professor of Medicine
HUP Clinic: 8 Penn Tower
34th & Civic Center Boulevard
Philadelphia, PA 19104

Professor of Medicine
HUP Clinic: 8 Penn Tower
34th & Civic Center Boulevard
Philadelphia, PA 19104

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