Bickerstaff’s brainstem encephalitis, Miller Fisher syndrome and Guillain-Barré syndrome overlap in an asthma patient with negative anti-ganglioside antibodies
© Chongyu et al.; licensee BioMed Central Ltd. 2012
Received: 9 April 2012
Accepted: 14 June 2012
Published: 14 June 2012
Bickerstaff’s brainstem encephalitis (BBE), together with Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS) were considered to form a continuous clinical spectrum. An anti-GQ1b antibody syndrome has been proposed to underlie the common pathophysiology for the three disorders; however, other studies have found a positive anti-GM1 instead of anti-GQ1b antibody.
Here we report a 20-year-old male patient with overlapping BBE, MFS and GBS. The patient had a positive family history of bronchial asthma and had suffered from the condition for over 15 years. He developed BBE symptoms nine days after an asthma exacerbation. During the course of illness, he had significantly elevated IgE levels in both serum and cerebrospinal fluid. Serologic analysis of antibodies against ganglioside complexes (anti-GDIa, anti-GDIb, anti-GM1, anti-GM2, anti-GM3, anti-GQIb and anti-GTIb antibodies) showed negative results.
Since asthma has recently been related to autoimmune disease, our case supports an autoimmune mechanism underlying the clinical spectrum composed of BBE, MFS and GBS. However, contrary to a proposed anti-GQ1b antibody syndrome, we would suggest that pathogenesis of this clinical spectrum is not limited to anti-ganglioside antibodies.
KeywordsAsthma Autoimmune Bickerstaff’s brainstem encephalitis Miller Fisher syndrome Guillain-Barré syndrome
Patients with overlapping Bickerstaff’s brainstem encephalitis (BBE), Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS) were rarely reported outside of Japan. The three disorders have been considered part of a clinical spectrum, however, a common underlying pathophysiology is still being investigated . An anti-GQ1b antibody syndrome has been proposed to associate BBE, MFS, GBS and other similar conditions . Despite this proposed anti-GQ1b syndrome, a positive anti-GM1 antibody has also been demonstrated in an overlapping case of BBE, MFS and GBS rather than the expected anti-GQ1b . Here, we report a case of overlapping BBE, MFS and GBS, in which all tested ganglion nucleoside antibodies were negative, serum IgE showed significant elevation, and a positive family history of bronchial asthma was present. Most recently, studies have suggested that asthma has an autoimmune pathogenesis similar to various autoimmune diseases . The patient displayed BBE, MFS and GBS as a continuous clinical course related to an autoimmune response. Since various autoimmune mechanisms have been suggested for asthma  a clinical syndrome composed of BBE, MFS and GBS may have a broader immunologic basis rather than a single autoantibody-mediated response against a ganglioside complex.
The patient was diagnosed with BBE and concurrent MFS and GBS. The patient was in a hypersensitive state as evidenced by his increased serum and CSF IgE levels and precipitating asthma symptoms, thus intravenous dexamethasone (20 mg per day) was used. The dose of dexamethasone was reduced by half five days later, then after another five days, switched to oral prednisone and tapered. The patient improved gradually; by day 37, he could speak hoarsely and feed himself. His eye movements were sufficient, but demonstrated horizontal nystagmus. Symmetrical limb weakness registered 2–3 in the arms and 1–2 in the legs on the MRC scale. Deep tendon reflexes were present, but reduced in all 4 limbs. A follow-up visit by telephone, on day 132, found the patient still recovering. His nystagmus and ataxia had disappeared, the muscle strength of his arms had recovered, he could walk around with support, and the only problem remaining was bilateral leg weakness.
Diagnostic criteria for Bickerstaff’s brainstem encephalitis (BBE), Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS)
Acute ophthalmoplegia, ataxia, disturbed consc-iousness or hypereflexia
Abnormal lesions on brain MRI; EEG showing abnormal slow-wave activity; anti-GQ1b IgG antibody in serum; Albuminocytological dissociation in the CSF
Acute ophthalmoplegia, ataxia and areflexia
Albuminocytological dissociation in the CSF; anti-GQ1b IgG antibody in serum
Acute symmetrical limb weakness and areflexia
Albuminocytological dissociation in the CSF; relatively mild sensory loss; cranial neuropathy; EMG showing demyelination or axonal damage in peripheral nerves and spinal roots
Odaka and his colleagues  reviewed clinical profiles and laboratory findings in 62 cases of BBE, and found a high proportion (37 out of 62, 60%) of patients with concurrent GBS. These GBS syndromes were predominantly characterized by axonal damage. Some patients had additional MFS, suggesting that the three conditions are closely related. Our patient initially presented with ataxia and ophthalmoplegia, and later developed consciousness disturbances. As the disease progressed, his deep tendon reflexes reduced to areflexia, and he developed quadriplegia. At this time, the CSF began to show albuminocytologic dissociation. Based on the course of illness, the patient fits a diagnosis of a combined BBE, MFS and GBS syndrome. An axonal form of GBS revealed by electromyogram (EMG) in our patient supports the idea that a considerable number of BBE patients have a concurrent axonal Guillain-Barré syndrome .
Prior to the occurrence of BBE, our patient had a cough and rhinorrhea. These symptoms were quickly followed by wheezing and dyspnea, diagnosed as an episode of bronchial asthma. Further examinations of CMV, HSV-I, CV, MV and EBV in serum and CSF showed negative results, and serum antibodies against ganglioside complexes were also negative. Our findings support neither the proposal of BBE, MFS and GBS as an anti-GQ1b syndrome , nor the idea of an anti-GM1-mediated process for this clinical spectrum . A special phenomenon associated with our patient is his past history of bronchial asthma and positive family history. Twenty-one days after the onset of BBE, his serum and CSF immunoglobulin showed normal concentrations of IgA, IgM and IgG, but significantly elevated IgE levels. Fifteen-fold increase of serum IgE level in the patient suggests that the asthma episode precipitated the combined BBE, MFS and GBS syndrome. In fact, asthma patients usually have a higher serum IgE level at the remission stage compared with healthy people , and IgE mediated autoallergy has been implicated in various autoimmune disorders such as rheumatoid arthritis, bullous pemphigoid and chronic spontaneous urticaria [10, 11]. Most recently, Calenoff reported that IgE-mediated mast cell degranulation was possibly involved in the pathogenesis of multiple sclerosis, a well-known CNS autoimmune disease . The association of asthma with BBE in our patient was indirectly supported by his response to steroid treatment.
Recently, an intriguing development in the field of asthma is its relationship with autoimmune disease. Asthma had long been considered a classic allergy disorder, thought to be mechanistically, distinctly different from autoimmune disorders. However, during the past several years, multiple studies have reported a high proportion of asthma patients with coexisting autoimmune diseases: type 1 diabetes, rheumatoid arthritis, Crohn’s disease and Addison’s disease were most frequently reported . Based on these findings, a common pathogenetic effector pathway has been suggested, and mast cells, T cells, and cytokines are all potential candidates as key regulators of the immune response in both asthma and autoimmune conditions .
An autoimmune mechanism is most probably involved in the pathogenesis of asthma, and the present case suggests that the clinical spectrum composed of BBE, MFS and GBS is also associated with an autoimmune mechanism . Recently, increased incidence of antinuclear antibodies and autoantibodies against bronchial epithelial or endothelial antigens have been found in asthma patients, such as autoantibodies against cytokeratin-18, alpha-enolase and IgE [14, 15]. In addition, common loci of single nucleotide polymorphisms (SNPs) have been found to alter the risk for asthma, type 1 diabetes, primary biliary cirrhosis, and Crohn disease . Therefore, although serum antibodies against ganglioside complexes were negative in our patient, the possibility exists that other antibody-mediated autoimmune responses or SNPs facilitated susceptibility and induced a continuous morbidity of BBE, MFS and GBS.
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of written consent is available for review by the Editor-in-Chief of this journal.
Yuan Wang as co-first author.
Bickerstaff’s brainstem encephalitis
Miller Fisher syndrome
Medical Research Council
Herpes Simplex Virus I
Viral Capsid antigen
Nerve conduction study
Central nervous system
Peripheral nervous system
Magnetic resonance imaging
Single nucleotide polymorphisms.
The case report was supplied by Department of Neurology, You Anmen Hospital.
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