Prevalence and characteristics of peripheral
neuropathy in hepatitis C virus population
L Santoro, F Manganelli, C Briani, F Giannini, L Benedetti, E Vitelli, A Mazzeo, E Beghi,
HCV Peripheral Nerve Study Group*
............................................................... ............................................................... .
See end of article for
Professor L Santoro,
Dipartimento di Scienze
Neurologiche, Universita `
degli Studi di Napoli
‘‘Federico II’’, Via Sergio
Pansini 5, 80131 Napoli,
Received 3 October 2005
In revised form
13 January 2006
Accepted 17 January2006
Published Online First
7 February 2006
J Neurol Neurosurg Psychiatry 2006;77:626–629. doi: 10.1136/jnnp.2005.081570
Objective: To assess the prevalence of peripheral neuropathy (PN) and its correlation with
cryoglobulinemia (CG) in an unselected, untreated referral hepatitis C virus (HCV) population.
Patients and Methods: Two hundred and thirty four patients (120 women and 114 men) with untreated
HCV infection were consecutively enrolled by seven Italian centres. Clinical neuropathy was diagnosed
when symptoms and signs of peripheral sensory or motor involvement were present. Median, ulnar,
peroneal, and sural nerves were explored in all patients and distal symmetric polyneuropathy was
diagnosed when all explored nerves or both lower limb nerves were affected. Mononeuropathy and
mononeuropathy multiplex were diagnosed when one nerve or two non-contiguous nerves with
asymmetrical distribution were affected. Screening for CG was done in 191 unselected patients.
Results: Clinical signs of PN were observed in 25 of the 234 patients (10.6%). Electrophysiological PN was
found in 36 (15.3%). CG was present in 56/191 patients (29.3%). The prevalence of CG increased
significantly with age (p,0.001) and disease duration (p,0.05). PN was present in 12/56 (21%) patients
with CG and 18/135 (13%) without CG (p=NS). PN increased significantly with age (p,0.001) and
logistic regression analysis confirmed age as the only independent predictor of PN (OR 1.10 for each
year; 95% CI 1.04 to 1.15; p,0.001).
Conclusions: Electrophysiological examination detected subclinical neuropathy in 11 patients (4.7%).
Statistical analysis showed that CG was not a risk factor for PN whereas PN prevalence increased
significantly with age.
wide1and is the major cause of chronic hepatitis, cirrhosis,
and hepatocellular carcinoma. The infection may be asso-
ciated with mixed cryoglobulinaemia (CG), lymphoprolifera-
tion, and a variety of extrahepatic manifestations including
membranoproliferative glomerulonephritis, sicca syndrome,
porphyria cutanea tarda, thyroiditis, and peripheral neuro-
pathy (PN).2A subacute, distal sensory-motor polyneuro-
pathy frequently associated with CG is the commonest
neurological complication, but mono and multiple mono-
neuritis have also been reported.3–5
The pathophysiology of HCV related PN remains largely
speculative; vascular deposition of HCV RNA containing CG,6
direct viral infection7or perivascular mononuclear inflam-
matory cells8 9may be at the origin of HCV associated
inflammatory vascular lesions. However, it is likely that HCV
neuropathy results from virus triggered immune mediated
mechanisms rather than from direct nerve infection and in
situ replication.10The clinical and electrophysiological spec-
trum of HCV associated PN has been mainly explored in HCV
patients with CG, and only a few papers have investigated the
prevalence of the PN in an unselected HCV population.11 12
The present study is a multicentre prospective study and it
was designed to assess clinically and electrophysiologically
the prevalence and the characteristics of PN in an unselected,
untreated referral HCV population, and the correlation
between PN and CG.
epatitis C virus (HCV) is a parenterally transmitted,
hepatotropic, and lymphotropic RNA virus. HCV infec-
tion affects approximately 170 million people world-
PATIENTS AND METHODS
Patients with HCV infection were consecutively enrolled by
seven Italian centres (Genoa, Lodi, Messina, Monza, Naples,
Padua, and Siena) from January 2001 to December 2003.
These were all secondary or tertiary centres with a sound
electrophysiological background and easy access to a gastro-
enterology/hepatology service. In each centre, a neurologist
participating in the study contacted the local gastroenterol-
ogists/hepathologists to identify potentially eligible patients.
Care was taken to enroll only patients with untreated HCV
infection. The inclusion criteria were: (1) HCV infection
assessed by ELISA and recombinant immunoblot, and (2) no
specific immunomodulating or antiviral therapy. Exclusion
criteria were any other causes of PN (diabetes, alcohol abuse,
renal failure, vitamin deficiency, thyroid disorders, neoplasm,
toxic agents), which were ruled out through history and ad
hoc laboratory investigations.13The duration of HCV positiv-
ity was assessed from the first laboratory detection of HCV
Eligible patients were evaluated by an expert neurologist. A
diagnosis of clinical neuropathy was made when symptoms
(weakness, sensory disturbances) and signs (weakness and
atrophy and/or sensation abnormalities and/or reduced/
absent tendon reflexes) of peripheral sensory and/or motor
involvement were present. Asymmetrical or symmetrical
distribution of neurological
Patients with symptoms such as pain, burning paresthesia,
and fatigue, but no signs of peripheral nerve involvement,
were not considered as affected by clinical PN.
Abbreviations: CG, cryoglobulinaemia; CMAP, compound motor
action potential; DL, distal latency; HCV, hepatitis C virus; MCV, motor
conduction velocity; NCS, nerve conduction study; PCR, polymerase
chain reaction; PN, peripheral neuropathy; SAP, sensory action
potential; SCV, sensory nerve conduction velocity.
HCV infection was assessed by ELISA and recombinant
immunoblot; quantitative assays of hepatitis C virus level was
performed in 113 patients by polymerase chain reaction
(PCR). Routine blood and serum chemical tests including
serum thyroid hormones, vitamins (B12 and E), tumoral
markers, and (when indicated) toxicological investigations,
were run for all patients.13Screening for CG was done in 191
unselected patients; blood samples were kept at 37˚C until
complete coagulation and analysed for the presence of CG.
All patients underwent an electrophysiological examination
according to a simplified nerve conduction study (NCS)
protocol to define the presence of distal symmetrical
neuropathy.14Motor conduction velocity (MCV), compound
motor action potential (CMAP) amplitude, and distal latency
(DL) of the right median, right ulnar, and left peroneal nerves
were recorded. To detect changes in nerve conduction in
proximal nerve segments, the F-wave from median, ulnar,
and deep peroneal nerves was recorded at wrist and ankle.
Antidromic sensory nerve conduction velocity (SCV) was
measured along the right median, right ulnar, and left sural
nerves, and sensory action potential (SAP) amplitude was
evaluated. If a response was absent for any of the explored
nerves (sensory or motor) or clinical examination suggested
an asymmetrical involvement, NCS was repeated in the
contralateral nerves. All nerve conduction studies were done
using surface electrodes and skin limb temperature was kept
at least 32˚C. For each nerve, the electrophysiological values
were considered abnormal if more than 2.5 standard
deviations (SD) from the means for healthy age matched
controls in each laboratory.
A peripheral nerve was electrophysiologically defined as
affected when at least two parameters were found to be
abnormal (prolonged DL, reduced MCV and/or SCV, reduc-
tion of SAP and/or CMAP amplitude, prolonged F-wave
latency). Distal symmetric PN was diagnosed when all
explored nerves or when both lower limb nerves were
affected.14Mononeuropathy and mononeuropathy multiplex
were diagnosed when one nerve or two non-contiguous
nerves with asymmetrical distribution were affected. The
neuropathy was considered subclinical when the patient had
no symptoms nor clinical signs of peripheral nerve involve-
ment. Isolated mononeuropathies of the median nerve were
also checked but were excluded from further analysis because
of their high prevalence in the general population.
The results were analysed using the x2test and Student’s t
test for unpaired data. Multivariate analysis (conditional
stepwise backward logistic regression) was also done to
assess the association of PN with CG after adjusting for age,
sex, duration of HCV infection, and centre. The limit of
statistical significance was set at 5%.
Two hundred and thirty four patients—120 women and 114
men—were studied. Mean age (SD) was 52.3 (13.7) years
(range 18–89). Median duration of HCV infection was
36 months (range 1–156). CG were detectable in the serum
of 56/191 patients (29.3%) and CG typing, performed in 28%
of them, showed in all a type II mixed cryoglobulinaemia.
The main demographic, clinical, and laboratory features of
patients with and without electrophysiologically defined PN
are shown in table 1.
Clinical PN was diagnosed in 25 out of 234 patients
(10.6%). All these patients had electrophysiological evidence
of PN. Moreover, electrophysiological examination disclosed
a subclinical PN in 11 additional patients (4.7%). In
summary, electrophysiological examination detected PN in
36 out of 234 patients (15.3%). An axonal sensory-motor
polyneuropathy or mononeuropathy multiplex was diag-
nosed in 19/36 (52.8%) and 17/36 patients (47.2%), respec-
tively. No electrophysiological signs of demyelination or
cranial nerve involvement was found.
Thirty patients complained of symptoms consisting of pain,
burning paresthesiae, and fatigue but did not show any
clinical or electrophysiological signs of PN.
The patients tested for CG did not differ significantly from
those who were not tested, for age, sex, centre, duration of
infection, and electrophysiological findings. The prevalence of
CG tended to increase significantly with age. CG was present
in 15.5% of patients aged ,45 years, and in 25%, 35.4%, and
51.6% of those aged 45–54 years, 55–64 years, and .65 years
(Mantel-Haenszel x2, 14.7; p,0.001). CG was also related to
disease duration; CG was present in 15% of patients with
disease duration ,12 months, and in 32% and 40% of those
with 12–60 or more than 60 months (Mantel-Haenszel x2,
PN was present in 12/56 patients with CG (21%) as
compared to 18/135 (13%) without CG (Pearson x2, 1.9;
p=NS). PN was also unrelated to sex and centre, but tended
to increase significantly with age; it was present in 4.4% of
patients aged ,45 years, and in 8.6%, 28.1%, and 22.7% of
those aged 45–54 years, 55–64 years, and .65 years (Mantel-
Haenszel x2, 18.1; p,0.001). PN was unrelated to duration of
infection (Pearson x2, 2.8; p=NS). Logistic regression
analysis confirmed age as the only independent predictor of
PN (OR 1.10 for each year; 95% CI 1.04 to 1.15; p,0.001).
The median HCV RNA level in the blood was 1.8 million of
copies/ml (range 1800–42 000 000). No correlation was
found between HCV-RNA levels and the presence of PN
(Pearson x2, 0.9; p=NS) or CG (Pearson x2, 2.2; p=NS).
The current study is the first large prospective survey of a
fairly unselected consecutive series of untreated patients with
HCV infection which underwent systematically both clinical
and electrophysiological investigation to assess the preva-
lence and the characteristics of PN and the correlation
between PN and CG.
of patients with and without electrophysiologically defined
Demographic, clinical, and laboratory features
Duration of infection (months)
*Mantel-Haenszel x2, 18.1; p,0.001.
Peripheral neuropathy in HCV population627
The prevalence of electrophysiological PN in this popula-
tion was 15.3% and the prevalence of CG was 29.3%. Clinical
PN was present in 10.6% of all enrolled patients (25/234) and
in 69% (25/36) of patients with electrophysiological evidence
Only two similar studies have been published, so far. In the
first, only 36 patients were clinically and electrophysiologi-
cally investigated and PN was detected in 8% of them11; in the
other large prospective study, Cacoub and colleagues diag-
nosed a peripheral neuropathy in 9% of 321 HCV patients on
the basis of clinical symptoms only.12The prevalence of PN in
our study (10.6%), if based on clinical assessment only, is
very close to that of Cacoub and colleagues.12However, the
electrophysiological examination revealed a subclinical neuro-
pathy in 11 additional patients (4.7%). Therefore, pure clinical
assessment tends to underestimate peripheral nervous system
involvement in the HCV general population. As pointed out by
England and colleagues,14polyneuropathy occurs with a
combination of multiple symptoms, signs, and abnormal
electrodiagnostic studies, whereas symptoms alone have
relatively poor diagnostic accuracy in predicting the presence
ofpolyneuropathy. According to these criteria, PN could not be
confirmed in the 30 patients complaining of pain, burning
paresthesiae, and fatigue in the absence of electrophysiological
abnormalities. On the other hand, these symptoms are
frequently described in HCV patients and they can be due to
non-neurological (for example, rheumatological) causes or to
a small fibre neuropathy. A small fibre neuropathy could not
beruled outin ourpatients eitherby clinicalexamination orby
conventional nerve conduction studies, but this was not an
aim of the present study.
The prevalence of CG in our neuropathic patients was
lower than in other series.5 10 15The simplest explanation of
this difference may be the modality of the enrollment, which
in our study was based on the presence of HCV infection,
independently of the signs or symptoms of PN and CG,
duration of infection, severity of liver disease, and HCV viral
load. However, the prevalence of CG in the present study is
half of that reported by Cacoub (29% v 56%).12We do not
have an exhaustive explanation of this difference, though a
wide variability of CG prevalence in the HCV patients has
been well documented.16
As in Cacoub’s study, we found no significant association
between PN and CG. Vice versa an association between PN
and CG was found in two other studies. However, in both
studies patients were selected according to the presence of
neuropathy or CG.5 15Moreover the absence of CG related
symptoms in one third of neuropathic patients,15or the
similar neuropathological features in nerve biopsy specimens
in both CG+ and CG2 patients,5made questionable the direct
role of CG in the pathogenesis of neuropathy.15In fact,
different mechanisms unrelated to the presence of CG, but
possibly due to the direct or indirect effects of HCV infection,
have been largely proposed in the pathogenesis of nerve
damage.7–10Inflammatory vascular lesions and axonal degen-
eration, supporting an ischaemic mechanism of nerve
damage more than a direct role of the virus in HCV related
PN, have been described in sural nerve biopsy of HCV
patients both with and without CG.5 10Under this assump-
tion, the lack of correlation between type of PN and CG is also
in keeping with the current hypothesis that HCV related
vascular nerve damage could be due to virus triggered
immune mediated mechanisms rather than longstanding
CG precipitation.10The lack of correlation between HCV viral
load and PN or CG further supports this hypothesis.
Statistical analysis showed a strong correlation between
older age and PN but not between PN and the known
duration of HCV positivity. At first sight, this latter
observation might seem contradictory but the duration of
HCV positivity was assessed from the first laboratory
detection of HCV infection and it is likely different from
the true duration of HCV infection, which might have
actually occurred several years earlier.
Some authors have already noted that older age is a major
risk factor for the clinical and biological extrahepatic
manifestations of HCV.15 17In keeping with these data, we
found a strong correlation between older age and both PN
and CG, which may be interpreted in the light of the
emerging hypothesis of an immune mediated pathological
mechanism of HCV related clinical manifestations.10
The study has several limitations. Firstly, although we
elected to enroll consecutive patients regardless of the
presence of CG to prevent selection bias towards more severe
infection and patients with neurological complications, this is
not a population based study. For this reason, our findings
cannot be extended to HCV patients who do not seek care in
secondary and tertiary centres. Secondly, although we
screened all patients to detect other causes of PN, CG was
tested only in 82%. Although there were no significant
differences between patients tested and not tested, we cannot
exclude that their physicians decided to test patients at
higher risk for PN. Thirdly, although our sample is fairly
large, it may still be too small to detect a difference in the risk
of PN between CG+ and CG2 patients. Even with these
limitations, however, we can conclude that in our fairly
unselected, untreated HCV referral population the prevalence
of PN is lower than that observed in the diabetic population
(overall prevalence of distal symmetric polyneuropathy of
34%)18and higher than that reported in neoplastic patients
Moreover, we can also conclude that CG is not a risk factor
for neuropathy. However, an electrophysiological examina-
tion should always be done to avoid underestimating PN,
particularly in older HCV patients.
We are now organising a prospective study of HCV patients
to assess the incidence of neuropathy, its outcome, and the
effects of specific therapies.
L Santoro, F Manganelli, Department of Neurological Sciences,
University of Naples ‘‘Federico II’’, Napoli, Italy
C Briani, Department of Neurosciences, University of Padova, Italy
F Giannini, Department of Neurosciences, University of Siena, Italy
L Benedetti, Department of Neurosciences, Ophthalmology and Genetic,
and Centre for Biomedical Research, University of Genova, Italy
E Vitelli, Department of Neurology, Hospital ‘‘Maggiore’’, Lodi, Italy
A Mazzeo, Department of Neurosciences, Psychiatric and
Anaesthesiological Sciences, University of Messina, Italy
E Beghi, Department of Neurology, University of Milano-Bicocca,
Competing interests: none declared
*Members of HCV Peripheral Nerve Study Group are (alphabetical
order): F Bassi, MD; G. Bibbo `, MD; L Cavaletto, MD; L Chemello, MD;
L Cimino, MD; G Bogliun, MD; L M Faggi, MD; E Ghiglione, MD;
R Iodice, MD; P Girlanda, MD; A Schenone, MD; G Vita, MD; and
G Zara, MD.
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