Miller Fisher Syndrome vs Bickerstaff Brainstem Encephalitis:What Is the Difference?
By Michael Rubin, MD, Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Rubin reports no financial relationships relevant to this field of study.
Synopsis: Sera from patients with Bickerstaff brainstem encephalitis demonstrate the ability to disrupt the blood-brain barrier; sera from Miller Fisher syndrome do not.
Source: Saito K, et al. Blood-brain barrier destruction determines Fisher/Bickerstaff clinical phenotypes: An in vitro study. J Neurol Neurosurg Psychiatry 2013;84:756-765.
Characterized by ophthalmoplegia, ataxia, altered consciousness, and hyper-reflexia, Bickerstaff brainstem encephalitis (BBE) shares features with Miller Fisher syndrome (MFS), including a history of preceding infection, spontaneous recovery, response to plasma exchange or intravenous immunoglobulin, the presence of serum IgG anti-GQ1b antibodies, and cerebrospinal fluid cytoalbuminogenic dissociation. Could these disorders form a spectrum of an anti-GQ1b antibody syndrome, with MFS the peripheral nervous system analog and BBE the central nervous system counterpart, and if so, what might explain the variable clinical expression? Might differences in breakdown of the blood-brain and blood-nerve barriers be responsible?
To address these questions, acute-phase sera were obtained within 3 weeks of symptom onset, from hospitalized patients with MFS (n = 10) and BBE (n = 11) throughout Japan. Anti-GQ1b antibodies were detected in 8/11 BBE sera and 9/10 MFS sera. Sera of eight healthy individuals served as normal controls. Immortalized human brain microvascular endothelial cells and peripheral nerve microvascular endothelial cells were incubated with these sera to determine how blood-brain and blood-nerve barrier function was impaired as a consequence, by evaluating transendothelial electrical resistance and expression of tight junction proteins, including claudin-5 and occludin. Statistical analysis encompassed ANOVA and the Mann-Whitney U test, with P < 0.05 considered statistically significant.
Following exposure to BBE sera, but not MFS sera, human brain microvascular endothelial cells demonstrated significantly decreased transendothelial electrical resistance, not influenced by the presence or absence of anti-GQ1b antibodies. BBE sera, but not MFS sera, decreased claudin-5 protein expression, but not occludin, in brain microvascular endothelial cells, and increased mRNA expression of matrix metallopeptidase 9 (MMP-9) and matrix metallopeptidase 2 (MMP-2). MMP-9 secretion, but not MMP-2, was also increased by BBE sera, but not by MFS sera, in brain microvascular endothelial cells. No correlation was found between MMP-9 concentration and change in transendothelial electrical resistance. TNF-alpha neutralizing antibody reversed the blood-brain barrier disruption of brain microvascular endothelial cells induced by BBE sera. Blood-brain and blood-nerve barrier function were unaffected by purified IgG obtained from BBE or MFS sera, and peripheral nerve microvascular endothelial cells were similarly unaffected by MFS or BBE sera. Only BBE sera, and not MFS sera, disrupt and reduce blood-brain barrier function. Purified IgG from these sera does not cause blood-brain barrier disruption, and the presence of anti-GQ1b antibodies seems not to contribute to this disruption, suggesting that humoral factors other than IgG antibodies, including anti-GQ1b, play the significant role. Alteration of the blood-brain barrier may explain the central nervous system dysfunction in BBE and it may be mediated by upregulated matrix metallopeptidases.
Anti-GQ1b antibodies are also found in patients who do not fulfill criteria for MFS but who have either acute ataxia or ophthalmoparesis with cerebrospinal fluid cytoalbuminogenic dissociation. Isolated, unilateral cranial neuropathies are also reported, and in one study of 100 patients with isolated abducens palsy, 25% were positive for anti-GQ1b antibodies.1 Pharyngeal-cervical-brachial weakness, affecting oropharyngeal, neck, and shoulder muscles, associated with areflexia is another syndrome associated with anti-GQ1b antibodies. Recurrent episodes are rare but described.
1. Tatsumoto M, et al. Isolated abducens nerve palsy as a regional variant of Guillain-Barre syndrome. J Neurol Sci 2006;243: