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Acute Disseminated Encephalomyelitis Associated With Hepatitis C Virus Infection
Sabrina Sacconi, MD;
Leonardo Salviati, MD;
Elisa Merelli, MD
Arch Neurol. 2001;58:1679-1681.
ABSTRACT
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Background Acute disseminated encephalomyelitis (ADEM) is an autoimmune demyelinating
disease of the central nervous system that is frequently preceded by an acute
viral infection. This is the first reported case of ADEM associated with hepatitis
C virus (HCV) infection.
Case Description A 46-year-old woman underwent a surgical procedure and received multiple
blood transfusions, at which time serologic testing for HCV was negative.
Fifty days later, she suddenly developed seizures, alteration of consciousness,
right hemiparesis, hemianopsia, and urinary retention. Magnetic resonance
imaging revealed symmetric multifocal changes on T2-weighted images in the
cerebral gray and white matter and in the cerebellar white matter with some
lesion enhancement after gadolinium administration. Blood testing showed a
recent HCV infection with high titer of IgM early antigens and a strongly
positive reaction for HCV RNA. All other microbiological and virological test
results were negative both in serum and in cerebrospinal fluid. Treatment
with high-dose dexamethasone was followed by a dramatic improvement of the
clinical and magnetic resonance picture. Within a few months the patient recovered
completely and there were no relapses during 2 years of follow-up.
Conclusions Infection with HCV is associated with several autoimmune neurological
manifestations. It is recommended the patients with ADEM be screened for HCV.
INTRODUCTION
ACUTE disseminated encephalomyelitis (ADEM) is an autoimmune demyelinating
disease of the central nervous system (CNS) that usually develops after acute
viral or bacterial infection or vaccination. It has also occurred after organ
transplantation or administration of drugs such as gold and streptomycin,
but in a few patients no precipitating cause could be found. Numerous infectious
agents have been linked to ADEM, including varicella, mumps, measles, rubella,
influenza, coxsackievirus B, human T-lymphotropic virus 1, human immunodeficiency
virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus 6, herpes simplex
virus, Legionella cincinnatiensis, Campylobacter, Borrelia burgdorferi, Salmonella typhi, Mycoplasma pneumoniae, and Chlamydia pneumoniae.1, 2, 3, 4
Thus far, however, no association of hepatitis C virus (HCV) with ADEM had
been reported. Acute disseminated encephalomyelitis is usually a monophasic
disease with acute onset characterized by multiple foci of CNS damage, predominantly
in the cerebral and cerebellar white matter, although basal ganglia and gray
matter may also be involved. Lesions are frequently bilateral, large, and
confluent.5
Effective therapy has included high-dose corticosteroids, and, more
recently, intravenous immunoglobulins6 and
plasmapheresis.7
REPORT OF A CASE
A 46-year-old woman was admitted to the Department of Neurology, Policlinico
of Modena, Modena, Italy, for the sudden onset of occipital headache and recurrent
generalized seizures. Fifty days earlier, during a Billroth II gastroresection
for a perforated duodenal ulcer, she had received multiple blood transfusions.
Serologic testing for HCV was negative at the time of the surgery.
On admission, the patient was somnolent but arousable, and showed mild
right hemiparesis and right hemianopsia. She had headache and vomiting, but
no evidence of meningeal irritation.
On the first day of admission she had alternating stupor and psychomotor
agitation and developed urinary retention. Routine blood screening was normal.
Findings of electrocardiographic and chest x-ray film examinations were normal.
Levels of anticardiolipin antibodies, antinuclear antibody, antineutrophil
cytoplasmic antibody, cryoglobulins, neoplastic markers ( -fetoprotein,
carcinoembryonic antigen, cancer antigen (CA) 125, CA 19.9, CA 15.5, and neuron-specific
enolase) were also normal. The CSF examination showed mild pleocytosis and
increased total protein (65 mg/dL [reference range, 15-45 mg/dL]). Isoelectrofocusing
of paired CSF and serum samples showed a "mirror pattern" with numerous IgG
oligoclonal bands in both CSF and serum.
Bacterial, mycobacterial, and fungal cultures from blood and CSF were
negative. Results of serologic testing and CSF–polymerase chain reaction
analysis for Borrelia burgdorferi, human immunodeficiency
virus, adenovirus, Enterovirus, HSV types 1 and 2,
cytomegalovirus, Epstein-Barr virus, human herpesvirus 6, polyomavirus JC,
and hepatitis B virus were also negative.
Anti-HCV IgG, tested by second-generation enzyme-linked immunosorbent
assay, was mildly positive; serum IgM antibodies to structural antigens (c33,
c22, NS5) were strongly positive; and HCV RNA, detected by reverse transcription–polymerase
chain reaction, was highly positive (2.800 MEq/mL), indicating recent HCV
infection.8
An electroencephalogram showed severe diffuse theta-delta activity,
predominantly on the right hemisphere. Magnetic resonance imaging (MRI) of
the brain revealed symmetrical multifocal changes on T2-weighted images that
involved gray and white matter in parieto-occipital regions, hemispheric white
matter in frontal and periventricular regions, and the cerebellar white matter.
Some lesions presented enhancement after gadolinium administration (Figure 1, A-B).
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T2-weighted magnetic resonance images obtained on admission (A, B)
and at follow-up 5 months later (C, D). A and B, Large confluent areas of
high-intensity signal in parieto-occipital regions involving gray and white
matter more prominently on the left; symmetric multifocal changes in frontal
and periventricular white matter. C and D, Complete recovery of abnormal signal
foci.
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Treatment with intravenous dexamethasone, 0.6 mg/kg (30 mg) daily for
15 days was instituted. In the following days, the seizures ceased, her alertness
increased, and both hemiparesis and hemianopsia improved. On the seventh day
after admission, the foci of abnormal signal on brain MRI were remarkably
reduced in number and size.
At discharge, 24 days after admission, neurological examination and
brain MRI (Figure 1, C-D) had improved
further. The intravenous dexamethasone regimen was tapered to a regimen of
oral prednisone, 25 mg for 2 weeks, and then to 12.5 mg for 2 months.
Five months later, the patient showed complete resolution of clinical
and neuroradiological signs. During the next 2 years, there were no relapses
and the patient led a usual life.
COMMENT
Infection with HCV is often associated with neurological complications
involving the peripheral nervous system9 and
less frequently the CNS.10 It has been shown
to cause profound alterations in the host immune system, resulting in immunological
abnormalities such as autoantibodies production, especially cryoglobulins,
immune complex formation, and deposition and development of collagen vascular
disorders.11 Complications of the CNS result
from direct action of the virus or from immune-mediated damage. However, CNS
involvement was reported only in 1 patient with progressive encephalomyelitis,
in whom HCV RNA was isolated from the CSF.12
To date, HCV-associated CNS vasculitis has been described in some patients.10, 11, 12, 13, 14, 15
This occurs late in the course of the disease, months or even years after
the infection, and is usually associated with cryoglobulinemia and accompanied
by multisystemic manifestations.
In our patient, CNS vasculitis was ruled out because she had no skin
lesions, kidney abnormalities, peripheral nervous system involvement, or other
signs of multisystemic disease. In addition, there were no cryoglobulins,
autoantibodies, or circulating immune complexes.16
Moreover, the disease developed shortly after the HCV infection, as indicated
by the fact that serologic test results were negative before the patient underwent
surgery and transfusion, and seroconversion was noted on admission, 50 days
later. Recent viral infection is typical of ADEM, whereas CNS vasculitis is
usually associated with chronic infection.
Central nervous system lymphoma or metastatic malignant neoplasms were
ruled out by clinical course and MRI, and acute CNS infections were excluded
by negative microbiological and virological data.
The diagnosis of multiple sclerosis was carefully considered, but the
sudden, multifocal clinical onset and the extensive, symmetric, and confluent
abnormalities on MRI, as well as the absence of clinical or neuroradiological
relapses after 2 years, made this diagnosis unlikely.5
Thus, it appears that our patient had immune-mediated CNS damage associated
with HCV infection, and directed mainly against myelin rather than against
blood vessels, as in the cases with vasculitis.
The pathogenetic mechanism of ADEM is still obscure, and both humoral
and cellular responses have been considered.1
A recent study identified TH2 cells reactive to myelin basic protein
in peripheral blood of patients with ADEM.17
The response to plasmapheresis and intravenous immunoglobulin administration
suggests a key role of autoantibodies, similar to other autoimmune neurological
diseases, such as Guillaine-Barrè syndrome or myasthenia gravis. Still,
it is unclear how so many different agents may activate a common cascade of
events leading to inflammation and demyelination in the CNS—further
data are needed to elucidate these mechanisms.
In conclusion, we emphasize the importance of HCV screening in patients
with ADEM because acute CNS demyelination might be the first manifestation
of HCV infection.
AUTHOR INFORMATION
Accepted for publication June 7, 2001.
From the Neurology Clinic, University of Modena, Modena, Italy (Drs
Sacconi and Merelli); the Department of Neurology, Columbia University, New
York, NY (Drs Sacconi and Salviati); and the Department of Pediatrics, University
of Padova, Padova, Italy (Dr Salviati).
Corresponding author and reprints: Sabrina Sacconi, MD, 630 W 168th
St, P&S 4-420, Columbia University, Department of Neurology, New York,
NY 10032.
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