Guillain–Barré Syndrome Associated with Japanese Encephalitis Virus Infection in China

Introduction

Guillain–Barré syndrome (GBS), the most important cause of flaccid paralysis worldwide, is a clinical syndrome consisting of acute weakness and reduced or absent tendon reflexes, with or without sensory loss, that is often preceded by an infectious disease (4,5). Typical infectious agents associated with subsequent GBS include Campylobacter jejuni, Mycoplasma pneumoniae, cytomegalovirus, and Epstein–Barr virus. Associations with the arboviruses Dengue and West Nile have also been described (1). Japanese encephalitis virus (JEV) is transmitted to humans through the bite of an infected mosquito, and is the most common cause of encephalitis in Asia (2,11). JE typically presents with a Parkinson-like syndrome consisting of masklike facies, tremor, cogwheel rigidity, and choreoathetoid movements (8). Acute flaccid paralysis, with clinical and pathological features similar to those of poliomyelitis, has also been associated with JEV infection (8). JE is preventable with vaccination (3).

GBS secondary to JEV infection has been reported only in India (9). Here, we report a case of GBS preceded by JEV infection in China.

Case Report

A 23-year-old male had symptoms of generalized weakness and numbness in the extremities, and bilateral facial nerve paralysis. One week before, he had a high fever with headache, and several days later developed facial diplegia and sensory disturbances. He complained of a choking cough while drinking water, and slight difficulty in breathing. He denied any medical problems, and had not received JE vaccination. The patient was a farmer from a rural area in the southern Yunnan province of China where JEV is endemic, and had not received the JE vaccination. On physical examination, he was apyretic, had facial diplegia and a weak gag reflex, quadriparesis that was more pronounced distally, generalized hyporeflexia, and no Babinski sign. Superficial sensation was reduced in all extremities. JEV IgM (IgM-capture ELISA Kit; Beixi, Shanghai, China) and hepatitis B surface antibody (HbsAb) tests were positive. Other tests for hepatitis B infection were negative. Testing for autoimmune antibodies (antinuclear antibodies, antithyroglobulin), and antibodies against HIV, mycoplasma, herpes simplex virus, cytomegalovirus, and Epstein–Barr virus and rapid plasma reagin (RPR) for detection of syphilis were negative.

Electroencephalography (EEG) was normal. Magnetic resonance imaging (MRI) of the brain revealed symmetrical bilateral cerebral hemispheres and no gray matter abnormalities. The size and shape of each ventricle and cistern were normal; the central line structure, cerebellum, and brainstem were normal; and no abnormal focal signals were seen. Enhanced MRI for nerve roots was not performed. Electromyography revealed acute demyelinating and sensorimotor polyradiculoneuropathy of the four limbs. Nerve conduction velocity studies indicated motor potentials were absent and the sensory potentials were decreased for the bilateral median nerves, and the motor potentials were decreased and the latent phase was prolonged for ulnar, tibial, and peroneal nerves. The F waves of the left median nerve and the left tibial nerve were absent, and the F wave of the left ulnar nerve was decreased. Neurogenic damage in the anterior muscle of the right tibia was also noted.

On day 1 after admission, the cerebrospinal fluid (CSF) was clear and colorless, and the leukocyte count was 5×10⁶/L (normal range: 0–5×10⁶), protein 0.62 g/L (normal range: 0.15–0.45), and JEV IgM was weakly positive. On day 7, the CSF was clear and colorless, the leukocyte count was 2×10⁶/L, protein 0.81 g/L, and JEV IgM was positive.

He was diagnosed with GBS associated with a recent JEV infection. Intravenous immunoglobulin combined with intravenous methylprednisone was administered for 5 days. He made a rapid recovery with resolution of the numbness in the extremities. At discharge 2 weeks later, he was able to walk without difficulty, although left facial diplegia was still present. He underwent rehabilitation after discharge, and at the 3-month follow-up, a complete neurological recovery was noted.

Discussion

Guillain–Barré syndrome is preceded by an infection in two-thirds of patients, but the pathological organism is often not identified (4,6,7). It has been proposed that infection may elicit an immune response that cross-reacts with axolemmal or Schwann cell antigens, thereby damaging the peripheral nerves (5).

Our patient was a farmer from a rural area of China where JEV is endemic, and thus had risk factors for JE and had not been vaccinated for JEV. After admission, JEV IgM was detected in his serum and twice in the CSF by IgM capture enzyme-linked immunosorbent assay (ELISA) (10). These results, combined with a history of fever and headache, confirmed a diagnosis of JEV infection. He had involvement of several cranial nerves and areflexic paralysis, and the results of nerve electrophysiological examination and albuminocytologic dissociation in the CSF (i.e., increased CSF protein in the absence of increased white blood cells) were consistent with a diagnosis of GBS (1). Negative laboratory results (autoimmune antibodies, HIV, etc.) for other possible etiologies support the presumption that GBS was triggered by the recent JEV infection, although detection of C. jejuni antibody could not be performed (C. jejuni infection often precedes acute motor axonal neuropathy [AMAN], a subtype of GBS) (5). In addition, only HbsAb was positive; other tests for hepatitis B virus were negative, suggesting that a simultaneous hepatitis B virus infection was not present. Furthermore, the incidence of GBS and JEV infection are both low. Therefore, the possibility of both diseases occurring completely independently is extremely low. Also, Ravi et al. (9) reported that JEV infection may predispose to GBS in JE endemic areas, which suggests a probable connection between these entities.

While the clinical and laboratory data are all consistent with JEV infection, other testing such as the observation of JEV-IgG-seroconversion in two sequential serum samples, JEV-RNA-PCR on CSF, or measurement of JEV antigen level would have strengthened the diagnosis. It is possible, though unlikely, that an IgM test may be affected by cross-reactions. Regrettably, these tests were not performed.

The main pathological change seen with GBS is demyelination of nerve fibers, and in severe cases, axonal degeneration may be seen (5). These changes are characterized by slower nerve conduction velocity, decreased compound muscle action potential (CMAP) amplitude, and/or an abnormal F wave on electromyography, as seen in this case. Thus, electromyography is important for the diagnosis of GBS. Acute flaccid paralysis can be seen with a number of diseases, and is seen in JEV infection due to damage to the anterior horn cells of the spinal cord. Electrophysiological findings include slowed nerve conduction velocity and decreased CMAP amplitude, with or without a decreased sensory nerve action potential (SNAP) amplitude (8). This testing can also differentiate it from poliomyelitis. At the initial stage of poliomyelitis, most patients have a fever and limb paralysis, which is asymmetrically distributed and typically limited to a unilateral lower limb. There is usually no sensory disturbance, and neurogenic damage is typically limited to the anterior horn of the spinal cord. Electrophysiologic studies with show a normal nerve condition velocity, normal or decreased CMAP amplitude, and normal SNAP amplitude. At the acute or subacute onset of GBS, the initial symptoms of most patients are symmetrical limb weakness accompanied with acroparesthesia.

Distinguishing GBS from JEV is important because GBS shows a good response to intravenous immunoglobulin or plasma exchange and has a good prognosis (5), whereas treatment of acute flaccid paralysis in JEV infection is mainly symptomatic and supportive (11).

In summary, GBS can occur after JEV infection. Diagnosis of GBS is important as the condition exhibits a good response to prompt treatment.