views & reviews

Hepatitis C infection,
cryoglobulinemia, and vasculitic
neuropathy. Treatment with
interferon alfa:
Case report and literature review
S.L. Khella, MD; S. Frost, MD; G.A. Hermann, MD; L. Leventhal, MD;
S. Whyatt, BA; M.A. Sajid, PhD; and S.S. Scherer, MD, PhD

Article abstract-A patient with mononeuropathy multiplex, hepatitis C viral infection, and mixed cryoglobulinemia
had axonal degeneration by EMG and vasculitis of the epineurial vessels on sural nerve biopsy. There was no evidence
of viral particles in the nerve by immunofluorescence.Treatment with interferon alfa improved the patients symptoms
and cleared the hepatitis C viral RNA and cryoglobulins from the serum.
NEUROLOGY 1995;45:407-411

Mononeuropathy multiplex is a multifocal periph-
eral neuropathy often caused by vasculitis and
sometimes by cry~globulinemia.~-~ We present a pa-
tient with a cryoglobulinemic vasculitic neuropathy
that appeared secondary to hepatitis C viral infec-
tion and review the literature.
Cryoglobulins are immunoglobulins that precipi-
tate at low temperatures and dissolve at higher
temperatures. They are associated with a variety of
systemic illnesses including infections, malignan-
cies, and immune disorders. Brouet et a16 classified
86 patients as having three patterns or types of
cryoglobulinemia: type I were patients who had
monoclonal immunoglobulins, type I1 had a combi-
nation of polyclonal and monoclonal immunoglobu-
lins, and type I11 had polyclonal immunoglobulins.
Types I1 and I11 were termed mixed. When types
I1 or I11 are not associated with an underlying dis-
order, they are termed essential. Essential cryo-
globulinemia may be associated with a systemic
vasculitis involving the peripheral nerves and
other ~ r g a n s . ~ - l ~
Hepatitis C viral infection is considered to be the
major cause of non-A, non-B hepatitis contracted
sporadically, sexually, post-transfusion, or by other
means.15J6This infection may be especially com-
mon in inner-city patients,16 but its frequency in
the general population remains unknown. Hepati-
tis C viral infection appears to be the most common
cause of essential mixed ~ryoglobulinernia.~~-~~
Case report. A previously healthy 40-year-old man de-
veloped new-onset Raynauds phenomenon and numb-
ness and toe stiffness of the right foot in June 1992. Sev-
eral weeks later, the ball of the left foot became numb
and an extensive purpuric rash erupted on the legs and
buttocks, which was diagnosed as leukocytoclastic vas-
culitis by skin biopsy.
On October 9, 1992, the patient presented to Presbyte-
rian Medical Center of Philadelphia for neurologic evalu-
ation. He had no risk factors of known causes of a periph-
eral neuropathy. On general physical examination, the
rash was the only notable finding. On neurologic exami-
nation, there was diminution to pinprick and tempera-
ture sensation to the right knee and the left ankle, with
a Tinels sign over the right superficial peroneal and
sural nerves. The ankle jerks were hyporeflexic bilater-
ally. On the right, ankle and great toe dorsiflexion and
ankle plantar flexion were 4/5 (by t h e MRC scale).
Strength in the right four small toes was 0 to 1/5. Two
weeks later, the rash and left foot paresthesias wors-
ened, and a patch of numbness developed in the distribu-
tion of the left anterior and medial femoral cutaneous
nerves. Twenty-six days after presentation, a patch of

From the Departments of Neurology (Dr. Khella), Medicine (Drs. Frost and Leventhal), and Pathology (Drs. Hermann and Sajid), University of Pennsyl-
vania School of Medicine and Presbyterian Medical Center of Philadelphia, and the Department of Neurology (A. Whyatt and Dr. Scherer), Hospital of
the University of Pennsylvania, Philadelphia, PA.
Supported by the Harry and Joan Kahn Fund (to the Department of Neurology, Presbyterian Medical Center of Philadelphia).
Presented in part a t the XVth World Congress of Neurology, Vancouver, BC, Canada, September 1993.
Received January 5, 1994.Accepted in final form August 18,1994.
Address correspondence and reprint requests to Dr. Sami L. Khella, Presbyterian Medical Center of Philadelphia, 39th and Market Streets, Philadel-
phia, PA 19104.

March 1996 NEUROLOGY 45 407

Table 1. Nerve conduction studies ~~

Dietal latency. Conduction velocity Amplitudet

Normal 11/82 4/83 9/83 3194 Normal 11/92 4/99 9/83 3/94 Normal llE82 4/83 9/83 3194
Motor
Left peroneal <6.0msec 9.3 NR NR NR >38 31.1 NR NR NR ~ 0 . 8 m V 1.8 mV NR NR NR
msec dsec dsec
Right peroneal 8.0 ND 9.6 9.1 40.8 ND 40.3 41 0.8 mV ND 0.6 mV 0.7 niV
msec msec msec dsec dsec dsec
Left posterior ~ 6 . 0 m s e c 5.0 6.7 5.0 6.1 ~ 3 8 37.8 31.5 31.7 36 21.0 mV 3.6 mV 3.0mV 2.4 mV 3.8 mV
tibial msec msec msec msec dsec dsec dsec dsec dsec
Right posterior 9.3 ND 12.2 11.2 43.0 ND 42.7 35 0.8 mV ND 0.6 mV 0.52 mV
tibial msec msec msec dsec dsec dsec
Right median <4.8 msec >49 60.2 >5.0 mV 10.0 mV
d S e C dsec
Right ulnar ~ 3 . msec
4 3.2 >47 65.0 >3.0 mV 9.0 mV
msec dsec dsec
Sensory
Left sural NR
Right sural NR
Right radial ~ 3 . msec
4 2.9 >50 59.0 >15.0 pV 32.0 pV
msec dWC dsec
Right median ~ 4 . 0 m s e c 3.8 >45 60.0 >10.0 pV 30.0 pV
meec dsec dsee
Right ulnar ~ 3 . msec
2 2.9 >45 51.7 >7.0 pV 32.0 pV
msec dsec dsec
Right MCF NR
Left MCF NR

Skin surface temperature was maintained a t 32 "C

*
Distal motor latency is measured from onset of the response. Distal sensory latency is measured from the peak of the response.
t
Motor amplitudes represent the distal compound muscle action potential, which in all instances varied from the proximal response by 4%
MCF Medial cutaneous nerve of the forearm.
NR No response.
ND Notdone.

numbness developed in the territory of the right medial
antebrachial cutaneous nerve. Hypesthesia in these
anatomic distributions was found on clinical examina-
tion, and strength in the left small toes was 2/5.
Laboratory evaluation. Electrodiapnosis. The first
nerve conduction/EMG examination, performed on
November 5, 1992, demonstrated an acute asymmetric
sensory motor polyneuropathy (table 1).On concentric
needle examination, fibrillation potentials and sharp pos-
itive waves were found in the right abductor hallucis, ex-
tensor hallucis longus, and tibialis anterior and poste-
rior. The motor unit morphology was normal, the recruit-
ment ratio increased, and the interference pattern re-
duced.
Serial concentric needle examinations suggested re-
innervation because of the appearance of a mixture of
large and small polyphasic motor units in the previously
denervated right leg muscles. In those muscles, large
motor units fired early and rapidly.
S e r o l o a On presentation, serologic evaluation re-
vealed an erythrocyte sedimentation rate of 3 mm/hr,
alanine aminotransferase 42 IUA (0to 45 IUA), aspartate
aminotransferase 25 IU/1 ( 3 to 4 1 IU/l), gamma-
glutamyltranspeptidase 71 IUA (20 to 58 IUA), and lac-
tate dehydrogenase 175 IUA (111to 217 IUA). Cryoglobu-
lin concentrations were IgG 10 mg/dl and IgM 29 mg/dl.
The rheumatoid factor was 1:640. Anti-hepatitis C anti-
bodies were positive by recombinant immunoblot assay
and polymerase chain reaction (PCR) detected hepatitis
C viral RNA. The hepatitis B surface antigen was nega-
tive. The following studies were negative or normal: elec-
trolytes, CBC count, urine analysis, HIV antibodies,
upper and lower endoscopy, chest x-ray, gallium-67
whole-body scan, and CT of the abdomen and pelvis.
Nerve histolow. Biopsy of the right sural nerve was
performed in November 1992 to further evaluate the
cause of this patient's mononeuropathy multiplex. There
was evidence of an acute and chronic axonal neuropathy
with vasculitis of the epineurial blood vessels (figure).
408 NEUROLOGY 45 March 1996
Fibrinoid necrosis was not found. Immunofluorescence,
performed by Dr. K. Krawczynski at the Centers for Dis-
ease Control and Prevention, showed no evidence of the
hepatitis C virus in the nerve or its blood vessels. Stain-
ing of the nerve with IgM, IgG, and complement C3 and
C4 did not show focal immunoreactivity.
Treatment and clinical course. On October 23, 1992,
the patient was started on prednisone 80 mg/d (1mg/kg)
for 3 months, and the dose was then tapered over 4
months. Also in October, he underwent plasmapheresis
every other day over a n &day period. A total of 15 liters
was exchanged using 5% albumin for replacement fluid.
There was minimal symptomatic improvement.
The prednisone was stopped. One week later, inter-
feron alfa was started a t a dose of 3 million IU three
times per week. The rash and paresthesias diminished
within a few weeks, and within several months his right
leg strength became 5/5. Also, his ability to walk in-
creased from one-half a street block before and during
prednisone therapy to 5 miles, his premorbid exercise
level.
Nine months after treatment with interferon alfa, the
patient was free of the paresthesias affecting the proxi-
mal left leg and right forearm. Clinical examination
showed mild hypesthesia to pinprick in the distal legs
and none in the distribution of the previously affected
proximal cutaneous nerves of the left leg and right arm.
Strength continued to be 5/51 in all muscle groups. The
rash was present when the legs were dependent for
hours. The hepatitis C virus became undetectable by
PCR 9 months after therapy with interferon alfa.
Discussion. This report confirms the existence of a
peripheral neuropathy previously described in pa-
tients with hepatitis C viral infection and cryoglob-
ulinemia (table 2). This is the first carefully docu-
mented case of cryoglobulinemia-related neuropa-
thy responsive to treatment with interferon alfa.
Figure. Sural nerve biopsy. (A) Mononuclear cells have infiltrated an epineurial arteriole, disrupting the integrity of the
vessel wall. (B)A fascicle of nerve adjacent to the abnormal arteriole shows moderately severe loss of the myelinated
fibers, myelin debris (arrowheads), and endoneurial edema. The nerve was fixed in 3% phosphate-buffered
glutaraldehyde, osmicated, and embedded in epoxy. One-micron-thicksections were stained with methylene blue-azure
11-basic fuchsin. Scale bar = 10 p m .

Our patient appeared to have a primarily ax-
onal neuropathy because of vasculitic destruction
of the epineurial vessels. There was neither elec-
trophysiologic nor biopsy evidence of demyelina-
tion. The patient had no risk factors for hepatitis C
viral infection, and he improved when therapy
with interferon alfa was directed at the hepatitis C
virus rather than the cryoglobulinemia. Hepatitis
C virus and cryoglobulins persisted for almost 1
year after initiation of therapy with interferon
alfa.
Ferri et a120 described 52 patients with hepatitis
C viral infection and cryoglobulinemia. Sixty-nine
percent of these patients had a peripheral neuropa-
thy, but these authors did not give further details
regarding the possible causes or the type of neu-
ropathy. Whether there are patients with hepatitis
C viral infection who do not have measurable cryo-
globulins and a vasculitic polyneuropathy remains
unknown but seems unlikely; Merican et a1,22in a
series of 102 patients with hepatitis C, made no
mention of either cryoglobulinemia or peripheral
neuropathy .
Because hepatitis C viral infection appears to be
a common cause of essential mixed cryoglob-
~linemia,'~ some
- ~ ~patients previously diagnosed
with essential mixed cryoglobulinemia and periph-
eral neuropathy may have had hepatitis C viral in-
fection.21In several series of patients with essential
mixed cryoglobulinemia, the neuropathy was most
often characterized by axonal degeneration, and an
e p i n e u r i a l vasculitis w a s a common find-
ing.1J2J3,23,24 The vasculitis is thought to cause fasci-
cular ischemia that results in axonal degeneration.
As in many vasculitic neuropathies, the presenta-
tion may be either a distal symmetric polyneuropa-
thy or mononeuropathy multiple^.'-^ In a few pa-
tients with cryoglobulinemia, demyelination either
was present as the primary process or occurred
with axonal degeneration.'J5
The absence of hepatitis C virus particles from
our patient's nerve supports the hypothesis of indi-
rect damage to the nerve, perhaps by the cryoglob-
ulins or the inflammatory cells. Clones of B lym-
phocytes produce cryoglobulins, which form com-
plexes, especially after cold exposure, that deposit
March 1995 NEUROLOGY 45 409
Table 2. Patients with hepatitis C infection and Acknowledgments
neuropathy
Thanks are due to Mrs. Patricia Duda and Mrs. Ruth Sheehan
for their secretarial skills.
Age (yrV Cryoglobulin
Report Sex/No. pts typeloompodtione Associated findings

Taillan et aP* Not 11-IgMk. IgG Chronic active

mentioned hepatitis
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