HEV Related Neuro-chr Hep 2010-Fr

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American Journal of Transplantation 2010; 10: 1321–1324Wiley Periodicals Inc.

C 2010 The Authors Journal compilation C 2010 The American Society of

Transplantation and the American Society of Transplant Surgeons

doi: 10.1111/j.1600-6143.2010.03068.xCase Report

Hepatitis E Virus-Induced NeurologicalSymptoms in a Kidney-Transplant Patient

with Chronic Hepatitis

N. Kamara,b,*, J. Izopetc,d, P. Cintase,C. Garroustea,d, E. Uro-Costef, O. Cointaulta,L. Rostainga,d

aDepartment of Nephrology, Dialysis and OrganTransplantation, bINSERM U858, IFR-BMT, cDepartment of Virology, dINSERM U563, IFR-BMT, eDepartment of Neurology and fDepartment of Pathology, CHU Rangueil,Toulouse, France *Corresponding author: Nassim Kamar,

[email protected]

It has been shown that hepatitis E virus (HEV) may beresponsible for chronic hepatitis in solid-organ trans-plant patients. It has also been suggested that HEVmay be responsible for atypical neurological symp-toms during the acute phase. However, the relation-ship between the neurological symptoms and HEV in-fection was based on the detection of anti-HEV IgMin the sera. Herein, we report a case where neurolog-ical symptoms, that is peripheral nerve involvementwith proximal muscular weakness that affected thefour limbs joints with central nervous-system involve-ment and bilateral pyramidal syndrome, occurred ina kidney-transplant patient who was chronically in-

fected by HEV. For the first time, HEV RNA was de-tected in the serum and cerebrospinal fluid. In addition,clonal HEV sequences were analyzed in both compart-ments, that is serum and cerebrospinal fluid. The dis-covery of quasispecies compartmentalization and itstemporal association suggests that neurological symp-toms could be linked to the emergence of neurotropicvariants.

Key words: Cerebrospinal fluid, chronic hepatitis, hep-atitis E virus, neurological symptoms, organ-transplantpatients, quasispecies

Received 19 November 2009, revised 07 January 2010and accepted for publication 21 January 2010

Introduction

Hepatitis E virus (HEV) is a well-known cause of acute

hepatitis (1). Recently, it has been shown that it is also re-

sponsible for chronic hepatitis that can evolve to cirrhosis

(2). It has also been suggested that HEV may be responsi-

ble for an extra-hepatic manifestations, that is neurological

symptoms. Indeed, neurological manifestations, such as

Guillain–Barre syndrome, neuralgic amyotrophy or acute

transverse myelitis, have been previously reported to be

associated with acute HEV-infection (3–7). Herein, we re-

port on a case where neurological symptoms occurred in a

kidney-transplant patient who was chronically infected by

HEV, and in whom, for the first time, HEV RNA was de-

tected and characterized in the serum and cerebrospinal

fluid (CSF).

Case Report

A 44-year-old kidney-transplant patient presented at 50

months posttransplant with an acute autochthonous HEV

infection that evolved to chronicity. At HEV infection di-

agnosis, hepatitis C virus (HCV), hepatitis B virus (HBV)

human-immunodeficiency virus (HIV) and hepatitis E virus

(HEV) serologies, hepatitis A virus (HAV) IgM, as well as

HCV RNA, HBV DNA and HIV RNA, which were all negative

at transplantation, were still negative. There was no evi-

dence of cytomegalovirus (CMV), Epstein Barr virus (EBV)

and herpes simplex virus (HSV) infections. Antinuclear au-toantibodies (ANA), anti-liver-kidney microsomal (LKM) an-

tibodies, anti-smooth-muscle cell (SMC) antibodies and an-

timitochondrial antibodies were not detected. EBV DNA

concentration in the blood was unchanged as compared to

4 months before the acute hepatitis episod, for example

4.3 log10 copies/mL. Biliary-tract complications were ruled

out by abdominal ultrasonography. Toxin- and drug-related

causes of abnormal liver-function tests were ruled out by

anamnesis. In contrast, HEV RNA was found to be posi-

tive in the serum and the stools. Phylogenetic analysis of

HEV RNA revealed that the strain belonged to genotype

3f (Genbank number FJ665423). By 6 months later, liver

enzymes were still elevated HEV RNA was still detected

in the serum and the stools, and anti-HEV IgG was posi-

tive. By 33 months after the acute phase, he was admitted

for progressive bilateral muscular weakness, difficulties in

walking and palmar and plantar dysesthesia without evi-

dence of systemic infection. The patient had no signs of

meningeal infection, no fever and no biological markers

of inflammation (white blood cell counts were 5700/mm3

with 82% polymorphonuclear cells, C-reactive protein was

<2 mg/L). He was receiving tacrolimus (trough level of

1321



Kamar et al.

Figure 1: HEV compartmentalization between cerebrospinal fluid and serum. Phylogenetic tree of hepatitis E virus sequences

obtained by clonal analyses of PCR products (nt 1780 to 2829 in ORF1 according to HEV 1b-L08816) from serum obtained after

12 months of infection (empty squares), and from serum (full squares) and cerebrospinal fluid (full circles) obtained after 33 months of

infection. Consensus HEV sequence at the first time point is shown using an empty circle.

8 ng/mL), mycophenolate mofetil (1 g/d) and low-dose

steroids (2.5 mg/d).

An examination revealed peripheral nerve involvement

with proximal muscular weakness that affected the four

limbs joints with central nervous-system involvement and

bilateral pyramidal syndrome. Electrophysiological stud-

ies revealed signs of peripheral demyelinating polyradicu-loneuropathy. Cerebral magnetic-resonance imaging (MRI)

was considered to be normal. In the cerebrospinal fluid

(CSF), protein and glucose levels, and red- and white-blood

counts were, respectively, 0.76 g/L, 3.9 mmol/L, 0.4/mm3

and 7/mm3.

Anti-HEV IgG and IgM, determined by an EIAgen HEV

IgG kit, Adaltis (Ingen, France), were both positive in the

serum but negative in the CSF. HEV RNA was detected

in both the serum and CSF, and was quantified using a

real-time PCR protocol (8) and a plasmidic standard (the

limit of quantification was 500 copies/mL). HEV RNA con-

centrations were 260 000 and 1113 copies/mL, respec-

tively, in the serum and CSF. Clonal HEV sequences (ORF1)

were analyzed in both compartments and compared to

clonal sequences from serum taken 21 months earlier(Figure 1). ORF1 is the most variable region of HEV

genome, and consequently the most interesting to study

quasispecies.

The viral sequences found in the serum at two time points

appeared to be intermixed whereas the sequences in the

CSF were clearly distinct from all sequences found in

the serum. No cytomegalovirus DNA, Epstein–Barr virus

1322 American Journal of Transplantation 2010; 10: 1321–1324



HEV-Induced Neurological Symptoms

DNA, Herpes simplex 1 and 2 DNA, Varicella Zoster virus

DNA, JC virus DNA, cryptococcal antigen, Toxoplasma

gondii DNA or Candida was detected in the CSF. Stan-

dard cultures of CSF remained negative. Serum HCV, HBV

and HIV serologies, as well as HCV RNA, HBV DNA,

HIV RNA and CMV DNA were still negative. EBV DNA

concentration in the blood was unchanged at 4.4 log10

copies/mL. Alanine aminotransferase level was 105 IU/L.

A liver biopsy showed the presence of cirrhosis with aMetavir score of A2F4. Serum CD4-positive cell count was

167/mm3. Antigangliosides 1A (titer 125) and anticytoplas-

mic nuclear (titer 100) antibodies were found to be pos-

itive in the serum. The CSF to serum–albumin ratio was

12.26. The CSF (IgG:albumin) to serum (IgG:albumin) ratio

was 0.54.

Three months later, because of severe ataxia, and loss of

bladder and bowel sensations, he underwent a neuromus-

cular biopsy. This showed nonspecific signs of neurogenic

muscular atrophy without signs of vasculitis on both mus-

cular and nerve specimens. Consequently, tacrolimus dose

was significantly reduced to target a trough level of 2.5

ng/mL and intravenous immunoglobulins were adminis-

trated (0.4 g/kg/d for 5 days, total dose 2 g/kg). However, no

significant improvement was observed. One month later,

he presented with decompensated cirrhosis and deceased

from hemorrhagic shock.

Discussion

HEV infection is an emerging disease in industrialized coun-

tries. Initially, it was thought to only be responsible for

acute hepatitis. However, HEV has been recently shown

to lead to chronic hepatitis in solid-organ transplants (SOT)

(2,9), and in HIV (10) and hematological patients (11).Scarce case reports suggest that HEV may be responsi-

ble for atypical neurological symptoms.

To date, three cases of Guillain–Barre syndrome associated

with an acute HEV episode have been reported (3,5,4).

Mandal and Chopra reported a case of acute transverse

myelitis following HEV infection (7). More recently, Fong

and Illahi reported a case of neuralgic amyotrophy, also

called Parsonage–Turner syndrome, associated with HEV

(6). In all these cases, the relationship between the neu-

rological symptoms and HEV infection was based on the

detection of anti-HEV IgM in the sera. However, HEV RNA

was not looked for in either the sera or CSF.

Herein, we report for the first time that HEV RNA can be

detected in the CSF of a patient with chronic HEV infection,

and can be responsible for atypical neurological symptoms.

In addition, for the first time, clonal HEV sequences were

analyzed in both compartments, that is serum and CSF.

The discovery of quasispecies compartmentalization and

its temporal association suggests that neurological symp-

toms could be linked to the emergence of neurotropic vari-

ants. However, we can exclude that small amount of HEV

RNA entered the CSF due to a problem in the brain–blood

barrier and that the evolution of HEVquasispecies occurred

later on.

Infections may lead to neurological manifestations through

an autoimmune-mediated process. Autoimmune dysfunc-

tion can occur in chronic active hepatitis, such as hepatitis

C virus or hepatitis B virus infection. Interestingly, antigan-gliosides 1A and anticytoplasmic nuclear antibodies were

found to be positive in the serum of our patient, suggest-

ing that chronic HEV infection may also induce an autoim-

mune dysfunction. In the case of Guillain–Barre syndrome

associated with HEV infection, as reported by Lolly et al.

(5), serum antiganglioside antibodies can also be positive.

However, the mechanism by which antiganglioside anti-

bodies may induce neurological symptoms in the setting

of HEV infection remains unknown. Thus, further studies

are required to document the relationship between HEV-

induced neurological symptoms and the detection of anti-

ganglioside antibodies.

Unfortunately, in the present case, the use of intravenous

immunoglobulin associated with immunosuppressant-

dose reduction did not result in improved neurological

symptoms. However, in liver-transplant patients chroni-

cally infected by HEV, we have recently shown that 3

months of pegylated-interferon therapy may effectively

clear this virus (12). Thus, the use of interferon-a in the set-

ting of HEV-induced neurological symptoms needs to be

evaluated.

Conclusion

In patients with elevated liver enzymes or with a knownHEV infection, and who present with neurological symp-toms, HEV RNA should be looked for in the serum andCSF.

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1324 American Journal of Transplantation 2010; 10: 1321–1324

HEV Related Neuro-chr Hep 2010-Fr

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