Infection
DOI 10.1007/s15010-013-0448-5
CASE REPORT
GuillainBarre syndrome associated with autochthonous infection
by hepatitis E virus subgenotype 3c
N. Scharn T. Ganzenmueller J. J. Wenzel
R. Dengler A. Heim F. Wegner
Received: 1 March 2013 / Accepted: 11 March 2013
Springer-Verlag Berlin Heidelberg 2013
Abstract In this report, we present a case of a 50-year-
old immunocompetent man with GuillainBarre syndrome
(GBS) associated with an autochthonous hepatitis E virus
(HEV) infection. The patient presented with tetraparesis
and elevated liver enzymes. HEV infection was confirmed
serologically and by polymerase chain reaction (PCR) from
blood and stool. Phylogenetic analysis revealed a novel
HEV genotype 3 isolate closely related to other subgeno-
type 3c isolates from pig livers purchased in Germany. This
indicates an autochthonous, potentially food-related hepa-
titis E and is, to our knowledge, the first report about a
neurological syndrome associated with an HEV subgeno-
type 3c infection.
Keywords GuillainBarre syndrome
Hepatitis E virus

Subgenotype 3c
Abbreviations
CSF Cerebrospinal fluid
GBS GuillainBarre syndrome
HEV Hepatitis E virus
N. Scharn and T. Ganzenmueller contributed equally to this work.
N. Scharn
R. Dengler
F. Wegner
Department of Neurology, Hannover Medical School,
Carl-Neuberg-Strae 1, 30625 Hannover, Germany
T. Ganzenmueller (&)
A. Heim
Institute of Virology, Hannover Medical School,
Carl-Neuberg-Strae 1, 30625 Hannover, Germany
e-mail: Ganzenmueller.Tina@mh-hannover.de
J. J. Wenzel
Institute of Clinical Microbiology and Hygiene,
University of Regensburg, Franz-Josef-Strauss-Allee 11,
93053 Regensburg, Germany
Introduction
The GuillainBarre syndrome (GBS) causes neuromuscu-
lar paralysis with an annual incidence of 1.11.8/100,000
[13]. In Western countries, acute inflammatory demye-
linating polyradiculoneuropathy is the predominant sub-
type, occurring in about 90 % of all GBS cases [4]. About
two-thirds of GBS patients present with symptoms of
infection within 6 weeks prior to the neurological onset,
e.g. flu-like episodes or gastroenteritis. Besides Campylo-
bacter jejuni, the most frequently identified pathogen
associated with GBS, other infectious agents such as
cytomegalovirus, varicella zoster virus, EpsteinBarr virus,
or Mycoplasma pneumoniae are also related to GBS
(reviewed in [5]). Recently, an increasing number of GBS
cases linked to hepatitis E virus (HEV) infections have
been reported [611]. However, a particular HEV subge-
notype (3f) could only be identified in one case [7]. HEV
genotype 3 is responsible for sporadic hepatitis E in
industrialized countries [12], where the infection with an
incubation period of 29 weeks [13] is suspected to be
caused zoonotically by the consumption of pork or close
contact to pigs [14, 15]. During the last several years, these
autochthonous cases of hepatitis E in developed countries
have been recognized to occur more often than previously
assumed [13].
Case report
Here, we report, for the first time, a case of GBS associated
with an infection by HEV subgenotype 3c. A 50-year-old
non-immunocompromised man developed burning pain in
his calves, followed by an increasing weakness of his legs
on the second day of a vacation in Egypt. There were no
123
 N. Scharn et al.

Table 1 Results of serologic and molecular hepatitis E virus (HEV) testing

Specimen Days after admission HEV-RNA (copies/ml) HEV-IgM Mikrogen HEV-IgG Mikrogen HEV-IgG MP Biomedicals

Serum 0 ? (2.5 9 103 copies/ml) ? ? Not detected

CSF 0 Not detected
Serum 3 Not detected ? ?
EDTA plasma 8 Not detected
Stool 8 ? (2.9 9 104 copies/ml)
Serum 180 ?
Findings of the performed HEV serology and polymerase chain reaction (PCR) assays in different specimens during the period following
admission are summarized

preceding infections except a 1-day episode of watery

diarrhea in Germany 1 week before onset of the neuro-
logical symptoms. No relevant medical history was
reported, except a mild residual peroneal lesion due to a
knee surgery 34 years ago. The patient had not traveled
abroad during the last year, nor did he report any contact
with pigs. Clinical investigation at the Hannover Medical
School 3 days after onset of the neurological symptoms
showed a tetraparesis pronounced at the distal legs and
absent Achilles tendon reflexes. The patient was unable to
stand or walk unsupportedly.
Nerve conduction studies demonstrated decreased
velocities, reduced amplitudes, and delayed or absent
F-waves, consistent with an acute demyelinating and axo-
nal polyneuropathy of the lower limbs. Examination of the
cerebrospinal fluid (CSF) showed an elevated protein
concentration (0.81 g/l) and \1 leukocytes/ll. Polymerase
chain reaction (PCR) from CSF showed negative results for
herpes simplex virus, varicella zoster virus, cytomegalo-
virus, and EpsteinBarr virus. Blood investigations dem-
onstrated a negative borreliosis and lues serology, the
absence of ganglioside antibodies (GM1, GM2), and ele-
vated liver enzyme levels [aspartate aminotransferase Fig. 1 Rooted maximum likelihood phylogenetic consensus tree for
(AST) 131 U/l, alanine aminotransferase (ALT) 334 U/l, open reading frame (ORF)1 nucleotide sequences of selected hepatitis
E virus (HEV) isolates. The sequence of the presented case
gamma-glutamyltranspeptidase (c-GT 297) U/l]. Two (V1114818, in bold) clusters in subgenotype 3c. The selected
months prior to consultation, the patients liver enzymes sequences represent the nearest homologs in GenBank and typical
had been normal. Therefore, we tested for viral hepatitis, members of genotype 1, 2, and 4. An avian HEV sequence was used
which resulted in positive hepatitis A-IgG and anti-HBs- as an outgroup. Numbers at the nodes indicate bootstrap values of
greater than 50 %. Sequences are denoted by GenBank ID, Interna-
IgG, consistent with prior vaccination against hepatitis A tional Organization for Standardization (ISO) country code, source,
and B. Unexpectedly, HEV-IgM and -IgG were positive and year of isolation (or publication). ch chicken isolate, CN China,
(recomLine HEV-IgG/IgM, Mikrogen, Neuried, Germany) DE Germany, hu human, gt genotype, JP Japan, MM Myanmar, MX
and a second HEV-IgG enzyme-linked immunosorbent Mexico, NL The Netherlands, sw swine, TD Chad, US United States,
wb wild boar. Sequence data from this paper have been deposited with
assay (ELISA) (MP Biomedicals, Eschwege, Germany) the European Nucleotide Archive under Accession Nos. HF912156-
showed seroconversion 3 days after admission. HEV real- HF912157
time reverse transcription PCR (RT-PCR) [15] was positive
in a serum sample on the day of admission (viral load isolates from humans and pigs, indicating an autochtho-
2.5 9 103 copies/ml) and from stool (1 week after admis- nous infection (Fig. 1).
sion; 2.9 9 104 copies/ml), while HEV-RNA was not The patient was treated with intravenous immunoglob-
detectable in the CSF (Table 1). Sequence determination ulins (0.4 g per kg of body weight per day) for 5 days and
and phylogenetic analysis revealed a novel HEV genotype his symptoms gradually improved. However, upon dis-
3 isolate clustering with other European subgenotype 3c charge 10 days after admission, he could only walk with

123
GuillainBarre syndrome associated with autochthonous hepatitis E virus infection
support and was transferred to a neurological rehabilitation
center, where he was treated for 5 months. Thereafter, a
follow-up examination showed nearly reconstituted
strength of the lower extremities, whereas electrophysiol-
ogy only detected slight improvements. His laboratory
findings indicated normal liver enzyme levels and, as
expected, positive HEV-IgG from serum.
Discussion
Previous reports on autochthonous hepatitis E infections in
European countries identified subgenotype 3a, c, e, f, and g
strains [13]. Colson et al. [16] reported two patients
infected with HEV subgenotype 3c who had presented
initially with arthromyalgia, leading to the diagnosis of
hepatitis E. An HEV subgenotype 3c strain closely related
to the isolate detected in our GBS patient has been found in
pig livers purchased in Germany (Fig. 1, isolate swR269,
GenBank FR846455) [15, 17]. The patients alimentary
habits also comprised the consumption of pork and liver
sausage, thus, a food-related zoonotic infection cannot be
excluded. This first report of a neurological disorder
associated with HEV subgenotype 3c infection suggests
that, in GBS patients showing an unexplained elevation of
liver enzyme levels, infectious hepatitis including autoch-
thonous HEV infection should be considered.
Conflict of interest The authors declare that they have no conflict
of interest.
References
1. McGrogan A, Madle GC, Seaman HE, de Vries CS. The epide-
miology of GuillainBarre syndrome worldwide. A systematic
literature review. Neuroepidemiology. 2009;32:15063.
2. van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogen-
esis, and treatment of GuillainBarre syndrome. Lancet Neurol.
2008;7:93950.
3. Pritchard J. Whats new in GuillainBarre syndrome? Postgrad
Med J. 2008;84:5328.
4. Cosi V, Versino M. GuillainBarre syndrome. Neurol Sci.
2006;27:S4751.
5. Yuki N, Hartung HP. GuillainBarre syndrome. N Engl J Med.
2012;366:2294304.
6. Cronin S, McNicholas R, Kavanagh E, Reid V, ORourke K.
Anti-glycolipid GM2-positive GuillainBarre syndrome due to
hepatitis E infection. Ir J Med Sci. 2011;180:2557.
7. Kamar N, Bendall RP, Peron JM, Cintas P, Prudhomme L,
Mansuy JM, et al. Hepatitis E virus and neurologic disorders.
Emerg Infect Dis. 2011;17:1739.
8. Loly JP, Rikir E, Seivert M, Legros E, Defrance P, Belaiche J,
et al. GuillainBarre syndrome following hepatitis E. World J
Gastroenterol. 2009;15:16457.
9. Maurissen I, Jeurissen A, Strauven T, Sprengers D, De Schepper B.
First case of anti-ganglioside GM1-positive GuillainBarre syn-
drome due to hepatitis E virus infection. Infection. 2012;40:3236.
10. Sood A, Midha V, Sood N. GuillainBarre syndrome with acute
hepatitis E. Am J Gastroenterol. 2000;95:36678.
11. Tse AC, Cheung RT, Ho SL, Chan KH. GuillainBarre syndrome
associated with acute hepatitis E infection. J Clin Neurosci.
2012;19:6078.
12. Purdy MA, Khudyakov YE. The molecular epidemiology of
hepatitis E virus infection. Virus Res. 2011;161:319.
13. Dalton HR, Bendall R, Ijaz S, Banks M. Hepatitis E: an emerging
infection in developed countries. Lancet Infect Dis. 2008;8:
698709.
14. Aggarwal R, Naik S. Epidemiology of hepatitis E: current status.
J Gastroenterol Hepatol. 2009;24:148493.
15. Wenzel JJ, Preiss J, Schemmerer M, Huber B, Plentz A, Jilg W.
Detection of hepatitis E virus (HEV) from porcine livers in
Southeastern Germany and high sequence homology to human
HEV isolates. J Clin Virol. 2011;52:504.
16. Colson P, Borentain P, Motte A, Lagrange X, Kaba M, Henry M,
et al. First human cases of hepatitis E infection with genotype 3c
strains. J Clin Virol. 2007;40:31820.
17. Rose N, Lunazzi A, Dorenlor V, Merbah T, Eono F, Eloit M,
et al. High prevalence of Hepatitis E virus in French domestic
pigs. Comp Immunol Microbiol Infect Dis. 2011;34:41927.
123