WEST NILE VIRUS INFECTION AND MYASTHENIA GRAVIS
A. ARTURO LEIS, MD,1 GABRIELLA SZATMARY, MD, PhD,2 MARK A. ROSS, MD,3 and DOBRIVOJE S. STOKIC, MD, DSc1
1
Center for Neuroscience and Neurological Recovery, Methodist Rehabilitation Center, 1350 East Woodrow Wilson, Suite 2, Jackson,
Mississippi, 39216, USA
2
Hattiesburg Clinic, Hattiesburg, Mississippi, USA
3
Mayo Clinic, Scottsdale, Arizona
Accepted 27 March 2013
ABSTRACT: Introduction: Viruses are commonly cited as trig-
gers for autoimmune disease. It is unclear if West Nile virus
(WNV) initiates autoimmunity. Methods: We describe 6 cases of
myasthenia gravis (MG) that developed several months after
WNV infection. All patients had serologically confirmed WNV
neuroinvasive disease. None had evidence of MG before WNV.
Results: All patients had stable neurological deficits when they
developed new symptoms of MG 3 to 7 months after WNV
infection. However, residual deficits from WNV confounded or
delayed MG diagnosis. All patients had elevated acetylcholine
receptor (AChR) antibodies, and 1 had thymoma. Treatment
varied, but 4 patients required acetylcholinesterase inhibitors,
multiple immunosuppressive drugs, and intravenous immune
globulin or plasmapheresis for recurrent MG crises. Conclu-
sions: The pathogenic mechanism of MG following WNV
remains uncertain. We hypothesize that WNV-triggered autoim-
munity breaks immunological self-tolerance to initiate MG, pos-
sibly through molecular mimicry between virus antigens and
AChR subunits or other autoimmune mechanisms.
Muscle Nerve 49:26–29, 2014
Infectious agents typically trigger an immune
response and occasionally initiate autoimmune dis-
eases. In particular, viruses are cited commonly as
triggers for autoimmune disease.1 West Nile virus
(WNV) is a neurotropic flavivirus that causes
human disease, ranging from a relatively benign
febrile illness (WNV fever) to neuroinvasive disease
characterized by meningitis, encephalitis, or polio-
myelitis.2 The question of whether WNV can trig-
ger autoimmune disease has previously been
raised.3,4 Support for this contention arises from
reports of WNV patients who present with various
neuromuscular diseases that presumably involve
autoimmune mechanisms (e.g., Guillian–Barre syn-
drome,5 other demyelinating neuropathies,6,7
brachial plexopathies,8 stiff-person syndrome9) and
persistent or recurrent symptoms. We describe 6
cases of myasthenia gravis (MG) that developed
several months after acute WNV neuroinvasive dis-
ease and discuss possible mechanisms involved.
This work was supported in part by the Wilson Research Foundation,
Jackson, Mississippi.
Abbreviations: AChR, acetylcholine receptor; CT, computed tomogra-
phy; EMG, electromyography; IV, intravenous; IVIG, intravenous immune
globulin; MG, myasthenia gravis; WNV, West Nile virus
Key words: autoimmunity; molecular mimicry; myasthenia gravis;
poliomyelitis; neuromuscular junction; West Nile virus
Correspondence to: A. Arturo Leis; e-mail: aleis@mmrcrehab.org
C 2013 Wiley Periodicals, Inc.
V
Published online 5 April 2013 in Wiley Online Library (wileyonlinelibrary.
com). DOI 10.1002/mus.23869
26 Myasthenia Gravis and WNV Infection
METHODS
This retrospective case series was approved by
the Institutional Review Board for Human
Research at Methodist Rehabilitation Center. From
2002 to 2011, we performed comprehensive neuro-
logical and electrodiagnostic evaluations on 107
patients with serologically confirmed WNV infec-
tion. Five patients (3 men, 2 women, ages 56 to
76) developed MG following acute WNV infection
classified as neuroinvasive disease according to
clinical features based on criteria established by
the Centers for Disease Control and Prevention.2
An additional patient (a 74 year old man) also
developed MG following acute WNV neuroinvasive
disease, but he was evaluated at an out-of-state
institution. None had clinical evidence of MG
before WNV infection. All had a computed tomog-
raphy (CT) scan of the chest to look for thymoma.
RESULTS
Patient 1. A 56-year-old man developed neuroinva-
sive WNV with encephalitis and asymmetric flaccid
paralysis involving all limbs. Electromyography
(EMG) suggested WNV poliomyelitis, and baseline
repetitive stimulation studies showed no pre- or
postsynaptic defect of neuromuscular transmission.
Neurological deficits stabilized, but 4 months later,
he developed classic symptoms of MG, including
fluctuating ptosis, diplopia, dysarthria, dysphagia,
increased fatigue, and generalized weakness.
Repeat repetitive nerve stimulation showed a post-
synaptic defect in neuromuscular transmission
(12% and 57% decrement in ulnar and facial
nerves, respectively). The acetylcholine receptor
(AChR) binding antibody was elevated at 58 (nor-
mal <0.4 nmol/L). The patient was treated with
pyridostigmine and prednisone for control of MG.
Patient 2. A 65-year-old woman with a history of
breast cancer, mastectomy, and chemotherapy
developed encephalitis and asymmetric flaccid pa-
ralysis in both legs and the right arm (triparesis).
EMG suggested WNV poliomyelitis. The weakness
stabilized. Five months later, she noted classic
symptoms of bulbar MG, beginning with diplopia,
late afternoon ptosis, dysarthria, dysphagia, and
worsening fatigue. Repetitive nerve stimulation
showed a postsynaptic defect in neuromuscular
transmission (10% and 23% decrement in ulnar
MUSCLE & NERVE January 2014
and facial nerves, respectively). The AChR binding
antibody was markedly elevated at 135
(<0.4 nmol/L). Symptoms of MG were controlled
with pyridostigmine. The patient’s aunt also had
MG.
Patient 3. A 64-year-old woman developed neuro-
invasive WNV with encephalitis and asymmetric
flaccid paralysis involving the left arm and leg.
Outside EMG suggested WNV-associated “motor
neuron disease.” Neurological deficits stabilized,
but 3 months later, she developed bulbar symp-
toms including dysphagia, ptosis, dysarthria, diplo-
pia, and new weakness (“trouble lifting my head”).
She reported that “doctors thought it was related
to WNV,” so she was not hospitalized. She pro-
gressed to respiratory failure and required pro-
longed mechanical ventilation. Repetitive
stimulation studies confirmed a defect in neuro-
muscular transmission. AChR binding antibody was
markedly elevated at 201 (<0.4 nmol/L). Chest
CT showed a 5 3 3 cm thymoma. The patient’s
course was characterized by recurrent MG crises
despite thymectomy and treatment with pyridostig-
mine, prednisone, intravenous (IV) methylpredni-
solone, intravenous immune globulin (IVIG),
mycophenolate mofetil, and plasmapheresis.
Patient 4. A 76-year-old man developed neuroinva-
sive WNV with asymmetric flaccid paralysis involv-
ing both legs and weakness in the arms. EMG
suggested WNV poliomyelitis. Neurological deficits
stabilized with no new symptoms until 5 months
later, when he was hospitalized for “post-viral neu-
ropathy secondary to WNV,” attributed to Guil-
lian–Barre syndrome or chronic immune
demyelinating polyneuropathy. However, the new
symptoms included classic symptoms of MG (e.g.,
“slurred and muffled speech,” “difficulty sucking
from a straw,” “difficulty swallowing,” “droopy eye-
lids”), and neurological examination confirmed
dysarthria, ptosis, dysphagia, and bilateral facial
weakness. AChR binding antibody was elevated at
35 (<0.4 nmol/L). His course was characterized by
recurrent MG crises, despite treatment with pyri-
dostigmine, prednisone, IV methylprednisolone,
IVIG, and mycophenolate mofetil.
Patient 5. A 64-year-old man developed neuroinva-
sive WNV with asymmetric paralysis in the proxi-
mal right arm and both legs (left more than
right). EMG suggested a “moderate to severe
motor neuropathy of lower limbs.” Neurological
deficits stabilized; 4 months later, he developed
symptoms of MG, including intermittent diplopia,
ptosis, more weakness in the legs, and increased fa-
tigue and generalized weakness. An edrophonium
test was positive, and AChR binding antibody was
Myasthenia Gravis and WNV Infection
elevated at 43 (<0.4 nmol/L). The patient had
recurrent MG crises, despite treatment with pyri-
dostigmine, prednisone, azathioprine, IVIG, and
plasmapheresis.
Patient 6. A 74-year-old man developed neuroinva-
sive WNV with encephalitis, quadriparesis, and re-
spiratory failure requiring prolonged mechanical
ventilation. After recovering from the acute illness,
he completed inpatient and outpatient rehabilita-
tion with stable neurologic deficits. Seven months
later, he developed new symptoms of dysarthria,
dysphagia, and left eyelid ptosis. Repetitive nerve
stimulation studies revealed an 11% decrement in
the right facial nerve. AChR binding antibody was
markedly elevated at 6 (<0.02 nmol/L, Mayo
Clinic). The patient responded to initial treatment
with pyridostigmine and plasmapheresis. He was
also treated with prednisone and mycophenolate
mofetil and developed pharmacologic remission.
Nine months later, he experienced a relapse of
dysarthria and dysphagia related to prednisone
tapering.
DISCUSSION
We report 6 cases of MG following acute WNV
neuroinvasive disease. All patients initially pre-
sented with WNV neuroinvasive disease with polio-
myelitis based on clinical features (asymmetric
flaccid paralysis) and electrodiagnostic findings
(reduced or absent compound muscle action
potentials in affected limbs, relatively preserved
sensory nerve action potentials, and asymmetric
acute denervation on needle EMG examination).
None had the relatively benign form of WNV infec-
tion, known as WNV fever. This observation sug-
gests that neuroinvasive disease, and poliomyelitis
in particular, may be a precondition that triggers
autoimmunity to break immunological self-toler-
ance and initiate MG. All patients also had stable
neurological deficits before developing classic
symptoms of MG (e.g., fluctuating ptosis, diplopia,
dysarthria, dysphagia, worsening fatigue, general-
ized weakness, or new respiratory distress). MG
symptoms developed 3 to 7 months after the acute
WNV infection. However, residual deficits from
neuroinvasive WNV (e.g., fatigue, persistent asym-
metric weakness) confounded or delayed the diag-
nosis of MG. In patient 3, the delay resulted in
acute respiratory failure and prolonged mechanical
ventilation. All patients had elevated AChR anti-
bodies, and 1 had thymoma. Treatment varied: 1
patient was managed with only acetylcholinesterase
inhibitors (pyridostigmine); 1 with pyridostigmine
and prednisone; and 4 with pyridostigmine, multi-
ple immunosuppressive drugs, and IVIG or plasma-
pheresis for recurrent MG crises. The 4 patients
with relapsing MG suggest that, in some cases of
MUSCLE & NERVE January 2014 27
WNV-related MG, it may be difficult to
achieve pharmacologic remission. Although no
patient had clinical evidence of MG before WNV
infection, 1 had a family history of MG (aunt), and
another had thymoma, raising the question
of underlying predisposing factors to WNV-
associated MG.
The pathogenic mechanism of MG following
WNV infection remains to be elucidated. There is
no evidence that this neurotropic virus causes mor-
phological damage to AChR subunits or the neuro-
muscular junction. Rather, the defect in
neuromuscular transmission appears to be medi-
ated indirectly by host factors induced by virus.
Several mechanisms have been proposed for patho-
gen-triggered autoimmunity, including molecular
mimicry, cryptic antigens, epitope spreading,
bystander activation, and polyclonal activation.10
Examples of viruses that have been implicated in
human autoimmune diseases include coxsackievi-
rus (implicated in type I diabetes, Sj€ ogren syn-
drome, and myocarditis),11 rubella virus (type I
diabetes),12 Epstein–Barr virus (systemic lupus ery-
thematosus, rheumatoid arthritis, Sj€ ogren syn-
drome, and multiple sclerosis),13,14 human
cytomegalovirus (multiple sclerosis, lupus),15 and
parvovirus B19 (systemic lupus erythematosus,
rheumatoid arthritis).16 Herpes simplex virus has
also been implicated in MG through the mecha-
nism of molecular mimicry.17 An autoantigenic site
of the AChR alpha-subunit has been shown to
have biologic activity and react immunochemically
with herpes simplex virus.17 In addition to WNV, 2
other flaviviruses have been implicated in human
autoimmune diseases: hepatitis C virus18 and den-
gue virus.10,19 Hepatitis C virus has been reported
commonly in association with Sj€ ogren syndrome
(483 cases), rheumatoid arthritis (150 cases), sys-
temic lupus erythematosus (129 cases), polyarteritis
nodosa (78 cases), antiphospholipid syndrome (59
cases), inflammatory myopathies (39 cases), and
sarcoidosis (28 cases).18 In these patients, antinu-
clear antibody, rheumatoid factor, and mixed cryo-
globulinemia are the predominant immunological
features. In the case of dengue virus, the mecha-
nism of the pathogenesis of dengue hemorrhagic
syndrome and dengue shock syndrome are not
resolved fully, but studies suggest possible molecu-
lar mimicry in which antibodies directed against
dengue virus nonstructural protein-1 cross-react
with human platelets and endothelial cells to cause
damage and dysfunction.10,19 This results in the
clinical features of hemorrhagic fever and shock
syndrome.10,19
The prevalence of MG among patients with
neuroinvasive WNV disease that we examined from
2002 to 2011 is 5 per 107 cases (4.7%). In contrast,
28 Myasthenia Gravis and WNV Infection
the prevalence of MG in the United States is esti-
mated by the Myasthenia Gravis Foundation of
America to be 14 to 20 per 100,000 population
(.014 to .02%).20 The relatively high prevalence of
4.7% is likely biased by referral patterns and
patients who came to our attention through the
local WNV Support Group meetings. During this
10-year period, however, a total of 412 cases of
neuroinvasive WNV disease were reported to the
Mississippi State Health Department. Hence, the
prevalence of MG among all neuroinvasive WNV
cases in Mississippi from 2002 to 2011 is estimated
at 5 per 412 cases (1.2%). This rate is also biased,
because it is unlikely that we saw all MG cases dur-
ing this period, and some cases in the community
probably remained undiagnosed. Nevertheless, the
1.2% rate is still 100-fold higher than the estimated
prevalence of MG in the general US population,
supporting the proposed link between WNV infec-
tion and development of MG.
Future studies are warranted to determine
pathophysiologic mechanisms involved, for exam-
ple, if human antibodies directed against WNV
proteins cross-react with AChR subunits. Such
cross-reactivity would provide immunologic evi-
dence that WNV can initiate MG in humans. It is
also important to determine risk factors for devel-
oping MG after WNV infection. It seems plausible
that patients with thymoma (patient 3) may be at
higher risk, because thymic abnormalities com-
monly precede MG. Thymoma is found in approxi-
mately 10% of MG patients and is often associated
with more fulminant MG disease.21 Similarly at
higher risk may be people with a family history of
MG (patient 2) in whom the WNV trigger may
superimpose on already existing predisposition to
initiate MG.
REFERENCES
1. Vogel A, Manns MP, Strassburg CP. Autoimmunity and viruses. Clin
Liver Dis 2002;6:739–753.
2. Centers for Disease Control and Prevention (CDC). West Nile virus
infection: clinical description. http://www.cdc.gov/ncidod/dvbid/
westnile/clinicians/clindesc.htm.
3. Leis AA, Stokic DS. Neuromuscular manifestations of human West
Nile virus infection. Curr Treat Options Neurol 2005;7:15–22.
4. Leis AA, Stokic DS. Neuromuscular manifestations of West Nile virus
infection. Front Neuromuscul Med 2012;37:1–10.
5. Ahmed S, Libman R, Wesson K, Ahmed F, Einberg K. Guillain-Barre
syndrome: an unusual presentation of West Nile virus infection. Neu-
rology 2000;55:144–146.
6. Pepperell C, Rau N, Krajden S, Kern R, Humar A, Mederski B, et al.
West Nile virus infection in 2002: morbidity and mortality among
patients admitted to hospital in southcentral Ontario. CMAJ 2003;
168:1399–1405.
7. Sumner N, Jones L. Multifocal neuropathy associated with West Nile
virus infection. Neurology 2008;71:1123.
8. Almhanna K, Palanichamy N, Sharma M, Hobbs R, Sil A. Unilateral
brachial plexopathy associated with West Nile virus meningoencepha-
litis. Clin Infect Dis 2003;36:1629–1630.
9. Hassin-Baer S, Kirson ED, Shulman L, Buchman AS, Bin H, Hindiyeh
M, et al. Stiff-person syndrome following West Nile fever. Arch Neu-
rol 2004;61:938–941.
10. Lin YS, Yeh TM, Lin CF, Wan SW, Chuang YC, Hsu TK, et al. Molec-
ular mimicry between virus and host and its implications for dengue
disease pathogenesis. Exp Biol Med (Maywood) 2011;236:515–523.
MUSCLE & NERVE January 2014
11. Stathopoulou EA, Routsias JG, Stea EA, Moutsopoulos HM, Tzioufas
AG. Cross-reaction between antibodies to the major epitope of Ro60
kD autoantigen and a homologous peptide of Coxsackie virus 2B
protein. Clin Exp Immunol 2005;141:148–154.
12. Ou D, Mitchell LA, Metzger DL, Gillam S, Tingle AJ. Cross-reactive
rubella virus and glutamic acid decarboxylase (65 and 67) protein
determinants recognized by T cells of patients with type I diabetes
mellitus. Diabetologia 2000;43:750–762.
13. Toussirot E, Roudier J. Epstein–Barr virus in autoimmune diseases.
Best Pract Res Clin Rheumatol 2008;22:883–896.
14. McClain MT, Heinlen LD, Dennis GJ, Roebuck J, Harley JB, James
JA. Early events in lupus humoral autoimmunity suggest initiation
through molecular mimicry. Nat Med 2005;11:85–89.
15. Varani S, Frascaroli G, Landini MP, Soderberg-Naucler C. Human cy-
tomegalovirus targets different subsets of antigen-presenting cells
with pathological consequences for host immunity: implications for
immunosuppression, chronic inflammation and autoimmunity. Rev
Med Virol 2009;19:131–145.
Myasthenia Gravis and WNV Infection
16. Meyer O. Parvovirus B19 and autoimmune diseases. Joint Bone Spine
2003;70:6–11.
17. Schwimmbeck PL, Dyrberg T, Drachman DB, Oldstone MB. Molecu-
lar mimicry and myasthenia gravis. An autoantigenic site of the ace-
tylcholine receptor alpha-subunit that has biologic activity and reacts
immunochemically with herpes simplex virus. J Clin Invest 1989;84:
1174–1180.
18. Ramos-Casals M, Munoz S, Medina F, Jara LJ, Rosas J, Calvo-Alen J,
et al. Systemic autoimmune diseases in patients with hepatitis C virus
infection: characterization of 1020 cases (The HISPAMEC Registry).
J Rheumatol 2009;36:1442–1448.
19. Liu IJ, Chiu CY, Chen YC, Wu HC. Molecular mimicry of human en-
dothelial cell antigen by autoantibodies to nonstructural protein 1 of
dengue virus. J Biol Chem 2011;286:9726–9736.
20. Myasthenia Gravis Foundation of America, 2006. http://www.my
asthenia.org/healthprofessionals/clinicaloverviewofmg.aspx.
21. Vern CJ, Massey JM. Autoimmune myasthenia gravis: recommenda-
tions for treatment and immunologic modulation. Curr Treat
Options Neurol 2005;7:3–14.
MUSCLE & NERVE January 2014 29