Painful Peripheral Neuropathy Associated with Hepatitis C Infection
Jeffrey Spina, M. D.
Case Report :
A 49-year-old male with a history of multiple cere-brovascular
events over the past 5 years presented with the relatively acute onset of pain
and numbness in his feet and shins. Coincident with this, he noticed a rash
on the dorsal surface of his feet, extending midway up his legs. These symptoms
began approxi-mately three weeks prior to presentation and were gradually worsening.
He denied any fevers, chills, arthralgias or abdominal pain. He was on no medica-tion
at the time of presentation. He had taken warfarin for several years after
having multiple transient ischemic attacks associated with ongoing cocaine
use, but he had stopped the medication on his own over one year before presentation.
His TIA work-up had been negative for a hypercoagulable state, with the only
remarkable finding being a positive rheumatoid factor. He denied any drug use
over the past year, denied alcohol use for the past two years, and admitted
to smoking one pack of cigarettes per day. The patient was married and stated
that his wife had recently been diagnosed with hepatitis C.
On physical exam,
his vital signs were normal. The exam was remarkable for a dense sensory
deficit to touch, pain, proprioception and vibration ascending symmetrically
to his shins. His Achilles\' reflexes were absent bilaterally. A non-blanching,
purpuric rash was noted on the dorsal aspect of his feet and shins. His neurologic
exam was otherwise normal, as was the rest of his physical exam. He had no
hepatosplenomegaly. Peripheral pulses were palpable in both feet.
laboratory evaluation, he was found to have a mildly elevated AST of 42,
an ALT of 61, and a GGT of 85, with a normal bilirubin of 0.7. His hepa-titis
serology was positive for hepatitis C antibody and RNA and negative for hepatitis
Aand B. His CBC was normal, as were his electrolytes and renal function.
His sedimentation rate was 13, an ANA was negative, and his rheumatoid factor
was 365. His SPEP was normal and his serum cryoglobulins were 4%. A urinalysis
showed 6 RBCs and 5 WBCs, trace protein, no casts were noted. Subsequent
studies showed decreased serum complement levels and a
negative anti-phospholipid antibody titer. Electromyography was unremarkable,
and a sural nerve biopsy demonstrated perineuronal inflamma-tion with chronic
damage to the vasa nervorum.
The patient was diagnosed with mixed cryoglob-ulinemia
secondary to hepatitis C infection. He was started on alpha interferon (mg/
kg/ wk) and ribavirin. Within several weeks he became extremely depressed,
and the therapy was discontinued until psychiatric evaluation could be obtained.
He was ulti-mately restarted on interferon and ribavirin, but failed to clear
HCV RNA. After two years of treatment, his cryoglobulins were undetectable,
but he had only slight improvement in his paresthesias and neuropathy, continuing
to require long acting morphine for pain control.
Since its discovery in the late 1980\'s, hepatitis
C has emerged as a serious health concern, affecting millions of people. A
majority of those positive for HCV antibody are asymptomatic, though signs
and symptoms may range from fatigue and mild transam-inase elevations to cirrhosis
and end-stage liver disease. As our experience with hepatitis C has increased
over the past decade, so has our knowledge of the extra-hepatic conditions
associated with chronic HCV infection. One of the most common, peripheral neuropathy,
can be extremely debilitating, causing significant morbidity and loss of productivity
even in the absence of serious liver damage.
The peripheral neuropathy associated
with HCV infection is strongly linked to the presence of serum cryoglobulins.
As many as 80% of patients with chronic HCV have detectable cryoglobulin
levels. 1,2 Numbers have ranged from 20% in the United States to over 90% in
Europe and Asia -this discrepancy may be more reflective of differences in
assay sensi-tivity rather than true differences in incidence. 1 Cryoglobulinemia
is no more prevalent in one HCV subtype than another, though genotype does
influence response to therapy. 1 Of those patients with detectable cryoglobulins,
approximately 20% will experience symptoms directly related to them -i. e.
the syndrome of mixed cryoglobulinemia. 1 Peripheral neuropathy is the most
common symptom in patients with HCV-associated mixed cryoglobulinemia.
are monoclonal and polyclonal IgM and IgG antibodies, so called because they
precipitate in cooled serum. Cryoglobulinemia is termed essential if it occurs
outside the setting of
another identifiable disease process. Three types of cryoglobulinemia are described.
Type I is associated with lymphoproliferative disorders, is monoclonal, and
is rheumatoid factor negative. Type II and III, the mixed cryoglobulinemias,
are polyclonal and rheuma-toid factor positive. Other serologic findings in
mixed cryoglobulinemia may include reduced complement levels, a polyclonal
gamma spike on serum elec-trophoresis, and an elevated sedimentation rate.
The mixed cryoglobulinemias are associated with a wide range of diseases. Type
II cryoglobulinemia is most highly associated with hepatitis C infection.
pathophysiology of cryoglobulin production in the setting of HCV is not entirely
understood. Presumably, chronic immune stimulation by the virus leads to the
production of IgG immune complexes. Monoclonal rheumatoid factors made up of
IgG are subsequently produced against these immune complexes. The immune complexes
may then deposit in capillary walls, causing small vessel vasculitis, and leading
to the most common symptoms and signs of mixed cryoglobulinemia: glomerulonephritis,
arthral-gias, vasculitic skin lesions, and neuropathy. Other neurologic syndromes
including multineuropathy and encephalopathy have also been linked to HCV-associ-ated
mixed cryoglobulinemia. 2,3,4
The patient described above demonstrates three
features of the classic symptom tetrad of cryoglobu-linemia: sensory neuropathy,
palpable purpura, and urinalysis evidence of glomerular injury. These symptoms
in association with a positive HCV RNA, detectable cryglobulins, and biopsy
evidence of small vessel vasculitis confirm his diagnosis. A normal nerve conduction
study is not unexpected in this setting, as NCV measures conduction along myelinated
fibers and the initial site of injury in these patients is generally the small
non-myelinated sensory nerve fibers. An abnormal EMG/ NCV in this setting could
result from vasculitic injury to larger nerve fibers as well as another process
such as Guillain-Barre -a syndrome associated with HCV infection but not related
to cryo-globulinemia. This patient\'s history of transient ischemic attacks
in 1997 with a positive rheumatoid factor at that time raise the question of
whether he had symptomatic cryoglobulinemia with vasculitis prior to this presentation,
which simply went undetected.
HCV may also have a more direct role in the development
of neuropathy independent of the presence of cryoglobulins. Typically inflammatory
changes and perineuronal small vessel vasculitis are found on nerve biopsy.
This patient\'s biopsy was
entirely consistent with the diagnosis. Several recent studies have described
patients with HCV and peripheral neuropathy who are cryoglobulin negative.
5,6 In a study of five patients with chronic hepatitis C infection and negative
cryoglobulins, Bonetti et al detected HCV RNA by polymerase chain reaction
in nerve biopsy homogenates, raising the possibility of direct axonal injury
by HCV, unrelated to vasculitis. 6 Other studies have confirmed the presence
of HCV in nerve cells, but exactly what effect, if any, HCV has in this setting
Treatment is indicated for symptomatic cryoglob-ulinemia even in
the absence of significant liver injury. Treatment is aimed at reducing cryoglobulin
levels, thereby causing resolution of vasculitis. Interferon-alpha combined
with ribavirin has shown efficacy in reducing cryoglobulins to undetectable
levels with concomitant relief of neuropathic pain symptoms in some patients.
A fall in hepatitis C RNA and an improvement in transaminase levels generally
mirror this response. Naarendorp, et al reported on 11 patients with HCV-associated
cryoglobulinemia with extra-hepatic manifestations treated with alpha-inter-feron
alone. 7 Three of the eleven patients were deemed complete responders based
upon resolution of symptoms and disappearance of cryoprecipitates and HCV
RNA, but only one successfully tapered off of interferon after 3 years of treatment
with sustained resolution of HCV and cryoglobulinemia. 7 Better results with
combination alpha interferon and ribavirin were obtained by Zuckerman et
al with significant improvement in cryoglobulinemia-related signs in all 9
patients treated, even those patients who did not show a complete virologic
response to therapy. 8 Despite clearance of cryoglobulins, however, they found
the polyneuropathy-related symptoms relatively resistant to treatment, and
no follow-up data was provided regarding long-term response after discontinuation
of therapy. 8 Others have reported similar results with combination therapy,
but rising cryoglobulin levels with recurrence of symptoms after cessation
of therapy occurs in a majority of patients. The higher response rates and
lower side effect profile seen with the newer pegy-lated interferon may improve
The side effects of interferon therapy may limit its use in
many patients. In addition to potentially exac-erbating the symptoms of mixed
cryoglobulinemia, interferon may also cause myalgias and arthralgias, with
cases of bone marrow dyscrasia, severe depres-sion, and worsening of hepatitis
requiring cessation of
therapy occurring less commonly. Other treatment options include alternative
immunosuppressive agents, such as cyclophosphamide and plasma-pheresis. These
have shown variable success in case reports, and as they do not lead to clearance
of HCV, their effect is presumably temporary.
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2. Trejo O, Ramos-Casals M, Garcia-Carrasco M, et
al. Cryoglobulinemia: study of etiologic factors and clinical and immunologic
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