Editorial commentary
Is ‘Bickerstaff brainstem encephalitis’ really encephalitis? Satoshi Kuwabara, Sonoko Misawa, Masahiro Mori Bickerstaff brainstem encephalitis (BBE) is characterised by acute ophthalmoplegia, ataxia, and some features suggesting CNS involvement such as consciousness disturbance. In 1951, Bickerstaff and Cloake described three patients in their original report entitled ‘Mesencephalitis and rhomboencephalitis’, and in 1957 Bickerstaff expanded his series to eight patients and proposed the condition ‘brainstem encephalitis’, subsequently termed ‘BBE’. Between the two publications, in 1956 Miller Fisher described three patients with “an unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia and areflexia)”; this condition has been widely recognised as Fisher syndrome (FS). A detailed historical perspective of BBE and FS was presented in a review article recently published in this journal.1 Each disorder was initially considered mutually exclusive. Bickerstaff and colleagues believed that BBE is a purely CNS disease, whereas FS as a variant of Guillain-Barré syndrome is therefore an inflammatory ‘neuropathy’. However, in addition to the common major manifestations of ophthalmoplegia and ataxia, BBE and FS have striking similarities: preceding infection, CSF albuminocytological dissociation, spontaneous recovery, and association with Guillain-Barré syndrome. Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan Correspondence to Dr Satoshi Kuwabara, Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;
[email protected]
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Serum IgG anti-GQ1b antibodies were discovered in FS patients in 1992, and in BBE patients in 1993.1 The immunological profile suggests that both conditions are part of the same spectrum of disease,2 raising a new fundamental question concerning the pathophysiology of BBE: is BBE really encephalitis? Assuming that anti-GQ1b is very likely responsible for ophthalmoplegia and ataxia in FS, the same cardinal clinical features in BBE could be caused by the same mechanism.2 3 Cumulative data suggest that BBE is a variant of FS with CNS involvement, and that BBE and FS share a common peripheral pathogenesis for ophthalmoplegia/ ataxia. If that is the case, the next task is to elucidate the mechanism for additional CNS dysfunction in BBE. Saito et al4 investigates the effects of sera from BBE and FS patients on the blood– brain barrier using cultured human brain microvascular endothelial cells. The results show that sera from BBE patients decreased the electrical resistance and expression of tight junction protein in the cultured cells. Matrix metalloproteinase-9 secretion by the cells was also significantly increased by BBE sera. However , application of FS sera did not result in similar effects. The authors propose that breakdown of the blood–brain barrier mediated by upregulated matrix metalloproteinases in BBE sera may explain CNS dysfunction in BBE. The findings suggest that differences in the extent of activation of humoral factors determine blood–brain barrier dysfunction and subsequent additional CNS lesions in BBE. This observation could be
of clinical significance in the treatment of BBE. The natural course of typical FS is generally good, and no specific immunomodulating therapy is required.3 For BBE associated with more prominent inflammatory responses than FS, inhibition of matrix metalloproteinases or proinflammatory cytokines may be a therapeutic option. Acknowledgements This work was supported in part by a Health and Labour Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labour and Welfare of Japan. Contributors SK, SM and MM prepared the manuscript, and contributed equally to the article. Competing interest None. Provenance and peer review Commissioned; internally peer reviewed. To cite Kuwabara S, Misawa S, Mori M. J Neurol Neurosurg Psychiatry 2013;84:712. Received 22 December 2012 Accepted 27 December 2012 Published Online First 20 April 2013
▸ http://dx.doi.org/10.1136/jnnp-2012-304306 J Neurol Neurosurg Psychiatry 2013;84:712. doi:10.1136/jnnp-2012-304655
REFERENCES 1
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Shahrizaila N, Yuki N. Bickerstaff brainstem encephalitis and Fisher syndrome: anti-GQ1b antibody syndrome. J Neurol Neurosurg Psychiatry 2013;84:576–83. Odaka M, Yuki N, Hirata K. Anti-GQ1b IgG antibody syndrome: clinical and immunological range. J Neurol Neurosurg Psychiatry 2001;70:50–5. Ito M, Kuwabara S, Odaka M, et al. Bickerstaff’s brainstem encephalitis and Fisher syndrome form a continuous spectrum: clinical analysis of 581 cases. J Neurol 2008;255:674–82. Saito S, Shimizu F, Koga M, et al. Blood-brain barrier destruction determines Fisher/Bickerstaff clinical phenotypes: an in vitro study. J Neurol Neurosurg Psychiatry 2013;84:756–65.
Kuwabara S, et al. J Neurol Neurosurg Psychiatry July 2013 Vol 84 No 7
