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Stiff-Person Syndrome Following West Nile Fever
Sharon Hassin-Baer, MD; Eilon D. Kirson, MD, PhD; Lester Shulman, PhD; Aron S. Buchman, MD; Hanna Bin, PhD;Musa Hindiyeh, PhD; Lea Markevich; Ella Mendelson, PhD Background: Stiff-person syndrome is a rare autoim-
Result: The search revealed a stretch of 12 amino acids
mune disorder associated with antibodies against glu- in the NS1 protein of West Nile virus with a high degree tamic acid decarboxylase (GAD), the key enzyme in of homology to the GAD65 region (an isoform of GAD) ␥-aminobutyric acid synthesis. In most cases, a trigger Objective: To describe a 41-year-old man who devel-
Conclusion: Cross-reactivity between antibodies di-
oped stiff-person syndrome and antibodies to GAD fol- rected against West Nile virus and GAD may have con- lowing acute West Nile virus infection.
tributed to the development of stiff-person syndrome inthis patient.
Design: A case report and a search in GenBank for com-
mon epitopes.
STIFF-PERSONSYNDROME(SPS) REPORTOFACASE
is a rare disorder that is char-acterized by progressivemuscle stiffness, rigidity, and interfering with central ␥-aminobutyric steroidal anti-inflammatory agents. A few sion.2-4 In most cases of SPS, no specific oped blurring of vision, a feeling of neck and upper back heaviness, and muscle stiff- ness at the base of the neck and upper ex- flavivirus maintained in nature through a tremities. This was followed by motor dys- function of his left arm and right leg. There Central Virology Laboratory,Public Health Laboratories, gitis and encephalitis.5-8 Israel is endemic several deaths and significant morbidity9 oped anti–GAD-positive SPS following se- shoulder girdle region and arms. There was stiffness and limitation in the range of ac- and left arm. There was also slowing of fin- (Dr Mendelson); and theDepartment of Neurological the left than on the right side. Hyperre- flexia was noted in the arms, more on the (REPRINTED) ARCH NEUROL / VOL 61, JUNE 2004 2004 American Medical Association. All rights reserved.
Figure 1. IgM and IgG antibodies to West Nile virus (WNV) in the patient’s
Figure 2. Anti–glutamic acid decarboxylase (GAD) IgG titers in the patient’s
serum and cerebrospinal fluid (CSF) were noted. Plasma exchange (PE) was serum and cerebrospinal fluid (CSF). Plasma exchange (PE) was performed performed 16 weeks after the acute WNV infection, and intravenous 16 weeks after the acute West Nile virus (WNV) infection, and intravenous immunoglobulins (IVIGs) were administered for 5 days after 28 weeks and immunoglobulins (IVIGs) were administered for 5 days after 28 weeks and then once monthly for 4 months. OD indicates optic density.
then once monthly for 4 months. OD indicates optic density.
left than on the right side, and in the legs, more on the creased (to 105 U/mL in serum and 84 U/mL in CSF) when right than on the left side. Tone was increased in the left he first complained of stiffness (Figure 2).
arm and both legs. Plantar responses were extensor bi- Given a tentative diagnosis of SPS, the patient was laterally. The patient seemed stiff when walking, and his treated with clonazepam. After a couple of weeks, action- arm swing was decreased with posturing of both arms.
induced muscle spasms developed involving the shoul- The results of routine blood work, including the de- der girdle muscles, and clonazepam was replaced by di- termination of antinuclear antibody levels, were nor- azepam, 15 mg/d, and baclofen, 75 mg/d, with partial mal, except for the levels of creatine kinase (242 IU/L; improvement. The increased intracranial pressure was upper limit, 190 IU/L) and thyrotropin (6.39 mIU/mL).
treated with acetazolamide, 250 mg, 3 times a day for 3 The patient also displayed mild eosinophilia (14.6%).
weeks, with resolution of the blurring of the optic disc The results of cervical and cranial magnetic reso- margins. He received 5 courses of plasma exchange 4 nance imaging were normal. The opening pressure of his months after the onset of his symptoms, with some im- first lumbar puncture was normal, as were cerebrospi- nal fluid (CSF) chemistry, cytology, and culture results.
When examined 3 months after the onset of his IgM and IgG antibodies to WNV in serum and CSF symptoms, his pyramidal signs were no longer present were noted (Figure 1), as were trace oligoclonal IgG
and the stiffness in his right leg was nearly resolved.
antibodies in the CSF. Test results were also positive for A third lumbar puncture performed 7 months after the onset of his symptoms showed a normal opening pres- The results of nerve conduction studies, repetitive sure and normal cytologic and chemistry results. At this nerve stimulation, and electromyography were normal, time, the WNV IgM level was low in the serum, but still with the exception that it took longer for the patient to relatively high in the CSF. Serum and CSF IgG titers for relax and discontinue voluntary recruitment of motor unit WNV remained high. The anti–GAD antibody level in the serum and CSF decreased following plasma ex- A month later, the results of a neurological exami- nation were unchanged except for blurring of the bor- Because of insufficient improvement 7 months af- ders of the optic discs. The results of a computerized vi- ter the onset of his symptoms, he was treated with in- sual field examination were normal. The results of a travenous immunoglobulins (Omr-IgG-am; Omrix Bio- computed tomographic scan of the head were normal as pharmaceutical Ltd, Tel Hashomer). He received well. A second lumbar puncture demonstrated an el- preparations from donors in Israel, containing high ti- evated opening pressure of 290 mm H2O, with normal ters (1:1600) of antibodies against WNV.11 The initial dos- CSF glucose and protein levels and 6 polymorpho- age was 0.4 g/kg of body weight once daily for 5 days.
He received additional treatment with intravenous im- The result of a polymerase chain reaction for WNV munoglobulins, 0.4 g/kg of body weight, once a month was negative, but test results were still positive for IgM for 3 more months.12-15 Following treatment with intra- and IgG antibodies to WNV in the serum and CSF (Fig- venous immunoglobulins, there was marked improve- ure 1). Retrospectively, serum anti–GAD antibody lev- els (CIS bio international, France [subsidiary of Three years following WNF, the patient is much im- SCHERING SA]) were elevated during the initial short- proved, although still minimally symptomatic. He still term phase of his infection (level, 71 U/mL) and in- has mild stiffness of his left upper limb and rare spasms (REPRINTED) ARCH NEUROL / VOL 61, JUNE 2004 2004 American Medical Association. All rights reserved.
reported,8 and serves as a model for the development of postinfectious immune-mediated disorders after infec- Recent evidence23 suggests that SPS is caused by an autoimmune process. Genetic and environmental factors are involved in the cause of autoimmune diseases, and vi-ral infections have been implicated as nongenetic triggers Figure 3. Amino acid similarity of a motif of the NS1 protein of West Nile
of autoimmune reactions to self antigens. Type 1 diabetes virus (WNV) with the PEVKEK epitope region of human glutamic acid mellitus is an immune-mediated disease that results from decarboxylase (GAD) isoforms 65 and 67 using a computer program selective loss of the insulin-producing pancreatic (BESTFIT program of the GCG Software Package using blosum62). The merous epidemiological and clinical studies24 have linkedenteroviral infections, particularly infections with coxsack- in his shoulders and neck. He has been able to resume ievirus B4, with a progression to type 1 diabetes mellitus.
his professional and leisure activities. He still takes ba- Except for the rare case of SPS as a paraneoplastic syn- clofen, 75 mg/d. His serum anti-GAD titers remain el- drome, no specific triggers for the onset of clinical symp- toms are usually present. Rarely have infectious processes A search of GenBank for an amino acid homology been associated with SPS. Two atypical cases of SPS were between WNV and GAD65 revealed a possible common reported to occur after Lyme borreliosis.25,26 Two cases of epitope to GAD65 and the viral NS1 protein, which sur- fulminant progressive encephalomyelitis with rigidity have rounds and partially overlaps the GAD65-PEVKEK epi- been reported, one in a patient coinfected with human im- tope (Figure 3).
munodeficiency virus type 1 and Epstein-Barr virus27 andthe other in a patient after hepatitis C virus infection.28 The natural history of SPS is usually a slowly pro- gressive course without rapid declines or spontaneous In this report, we describe a patient with SPS following remissions. Most patients respond to a combination of WNF. The diagnosis of WNV infection was based on the therapy with diazepam and baclofen. There have been development of a febrile illness during a known local epi- several reports of improvement with immunomodula- demic of WNV; the patient had positive serological re- tory therapies, such as corticosteroids,29,30 plasma ex- sults. Although the patient’s clinical course of WNF lasted change,31-34 and intravenous immunoglobulins.13-15,35 In only a few weeks, the serological data (Figure 1) indi- this patient, although plasma exchange was followed by cated a long-lasting immunological response to the virus, decreased serum levels of anti–GAD antibodies, the clini- including IgM and IgG in the serum and CSF. Infection cal response was suboptimal. Only after treatments with with flaviviruses can induce a long-term virus-specific IgM intravenous immunoglobulins, enriched with anti– response in the serum and CSF.16,17 Long-term sequelae WNV antibodies, was a significant clinical improve- following acute WNV CNS infection were recently re- ment noted, lasting a couple of years. There has not been ported,18 as was increased mortality (M. Green, MD, PhD, a clinical worsening since then, but serum anti–GAD an- MPH, unpublished data, 2002). The reason for these phe- nomena is not known, but virus persistence is a possible We suggest that following acute WNV infection, this mechanism.19 Indeed, flavivirus persistence in cell cul- patient developed a postinfectious immune-mediated pro- tures, animals, and humans has been described.20-22 Thus, cess affecting mainly GABAergic neurons in the brain and we raise the possibility of long-term subclinical infection spinal cord. In this case, the patient had a propensity for with WNV in the patient with SPS; although the results autoimmune diseases based on his history of immune- of the polymerase chain reaction studies for WNV in the mediated thyroid disease with the presence of serum an- serum and CSF in this patient were negative, the sensi- tithyroglobulin antibodies. The presence of the putative tivity of polymerase chain reaction testing for WNV has autoimmune homologous epitope between WNV and not been defined, so this possibility is not ruled out.
GAD65 is supportive of this hypothesis.
The neurological symptoms of SPS began a few weeks Human type 1 diabetes mellitus is also associated following incomplete recovery from acute WNV infec- with anti–GAD65 antibodies and with infection with en- tion. While WNV is known to cause meningitis and en- teroviruses.24 A mechanism of molecular mimicry has been cephalitis, there was no conclusive evidence that this pa- suggested because the PEVKEK motif, which was re- tient had meningitis or encephalitis because a lumbar cently recognized as a dominant B-cell epitope for type puncture was not performed during the short-term phase 1 diabetes mellitus, was also found in coxsackievirus B4 The development of neurological abnormalities Further investigation of the cross-reactivity be- within weeks after acute WNF is suggestive of a postin- tween anti-WNV and anti-GAD65, identification of the fectious process, although we have no evidence that anti– oligoclonal bands in the patient’s CSF, and functional GAD65 antibodies were absent before the viral infec- analysis of the common epitope are required to estab- tion. The development of mild papilledema, increased CSF pressure, and 6 cells in the CSF with elevated antibod-ies is suggestive of ongoing central nervous system in- Accepted for publication December 9, 2003. fection or an inflammatory process. The development of Author contributions: Study concept and design (Drs
acute idiopathic polyneuritis following WNF has been Hassin-Baer, Kirson, Buchman, and Mendelson); acqui- (REPRINTED) ARCH NEUROL / VOL 61, JUNE 2004 2004 American Medical Association. All rights reserved.
sition of data (Drs Hassin-Baer, Kirson, Shulman, Bin, 15. Khanlou H, Eiger G. Long-term remission of refractory stiff-man syndrome after Hindiyeh, and Mendelson and Ms Markevich); analysis treatment with intravenous immunoglobulin. Mayo Clin Proc. 1999;74:1231-1232.
and interpretation of data (Drs Hassin-Baer, Kirson, 16. Roehrig JT, Nash D, Maldin B, et al. Persistence of virus-reactive serum immu- Shulman, Buchman, Bin, and Mendelson); drafting of the noglobulin M antibody in confirmed West-Nile virus encephalitis cases. Emerg manuscript (Drs Hassin-Baer, Kirson, Shulman, Buch- man, Bin, and Mendelson and Ms Markevich); critical re- 17. Gunther G, Haglund M, Lindquist L, Skoldenberg B, Forsgren M. Intrathecal IgM, vision of the manuscript for important intellectual content IgA and IgG antibody response in tick-borne encephalitis: long-term follow-uprelated to clinical course and outcome. Clin Diagn Virol. 1997;8:17-29.
(Drs Hassin-Baer, Buchman, Hindiyeh, and Mendel- 18. Sejvar JJ, Haddad MB, Tierney BC, et al. Neurologic manifestations and out- son); obtained funding (Dr Mendelson); administrative, come of West Nile virus infection. JAMA. 2003;290:511-515.
technical, and material support (Drs Hassin-Baer, Bin, and 19. Schneider-Schaulies J, Dorries R, Meulen VT. Establishment and control of viral Mendelson); study supervision (Drs Kirson, Buchman, Bin, infections of the central nervous system. In: Keane RW, Hickey WF, eds. Immu- nology of the Nervous System. New York, NY: Oxford University Press Inc; 1997:576-610.
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(REPRINTED) ARCH NEUROL / VOL 61, JUNE 2004 2004 American Medical Association. All rights reserved.

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