title: Hypoxia-like tissue injury and glial response contribute to Balo concentric lesion development.
abstract: OBJECTIVE
  To clarify the pathogenic factors and mechanisms underlying the development of concentric demyelinating lesions in Balo disease.
  
  
  METHODS
  We conducted serial clinical, MRI, and histopathologic assessments of concentric lesion formation in a case of relapsing Balo disease.
  
  
  RESULTS
  The patient experienced 2 attacks caused by left parietal and left frontal lesions in 5 years. In MRI findings from both episodes of expanding lesions, there were diffusion-restricted rings that antedated the appearance of gadolinium enhancement; subsequently, typical concentric T2 lesions appeared concurrently with the disappearance of this enhancement. Histopathologic examinations of biopsied brain tissues revealed definite concentric demyelinating layers typical of Balo disease with massive macrophage infiltration but preserved axons. Numerous hypertrophic astrocytes were observed beyond the edges of and within the demyelinating layers. The expression of hypoxia-inducible factor-1α, a protein related to hypoxia-induced tissue preconditioning that contributes to survival and protection against further hypoxia-like injury, was upregulated primarily in glial cells located beyond the edge of the demyelinating layers but was also elevated in hypertrophic astrocytes on the inner sides of resected lesions and in oligodendrocytes in nondemyelinating layers. In addition, these astrocytes expressed CC motif chemokine 2 and/or interleukin-1β, which are inducible by hypoxia-inducible factor-1α and potentially promote demyelination.
  
  
  CONCLUSIONS
  Our study suggests that a unique interplay between hypoxia-induced tissue preconditioning and proinflammatory cytokines derived from glial cells may contribute to the development of concentric demyelinating lesions in Balo disease.
authors.affiliation: From the Departments of Neurology (Y.T., T.M., S.N., H.O., H.K., I.N., M.A., K.F.), Multiple Sclerosis Therapeutics (T.M., K.F.), Neurosurgery (R.S., M.K.), Diagnostic Radiology (S.M.), and Pathology (M.W.), Tohoku University Graduate School of Medicine, Sendai; Department of Neurology (T.M.), National Hospital Organization Hachinohe National Hospital; Department of Neurosurgery (Y.S.), Yamagata University School of Medicine; and Department of Neurosurgery (T.K.), Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Takai
authors.affiliation: From the Departments of Neurology (Y.T., T.M., S.N., H.O., H.K., I.N., M.A., K.F.), Multiple Sclerosis Therapeutics (T.M., K.F.), Neurosurgery (R.S., M.K.), Diagnostic Radiology (S.M.), and Pathology (M.W.), Tohoku University Graduate School of Medicine, Sendai; Department of Neurology (T.M.), National Hospital Organization Hachinohe National Hospital; Department of Neurosurgery (Y.S.), Yamagata University School of Medicine; and Department of Neurosurgery (T.K.), Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Misu
authors.affiliation: From the Departments of Neurology (Y.T., T.M., S.N., H.O., H.K., I.N., M.A., K.F.), Multiple Sclerosis Therapeutics (T.M., K.F.), Neurosurgery (R.S., M.K.), Diagnostic Radiology (S.M.), and Pathology (M.W.), Tohoku University Graduate School of Medicine, Sendai; Department of Neurology (T.M.), National Hospital Organization Hachinohe National Hospital; Department of Neurosurgery (Y.S.), Yamagata University School of Medicine; and Department of Neurosurgery (T.K.), Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Nishiyama
authors.affiliation: From the Departments of Neurology (Y.T., T.M., S.N., H.O., H.K., I.N., M.A., K.F.), Multiple Sclerosis Therapeutics (T.M., K.F.), Neurosurgery (R.S., M.K.), Diagnostic Radiology (S.M.), and Pathology (M.W.), Tohoku University Graduate School of Medicine, Sendai; Department of Neurology (T.M.), National Hospital Organization Hachinohe National Hospital; Department of Neurosurgery (Y.S.), Yamagata University School of Medicine; and Department of Neurosurgery (T.K.), Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Ono
authors.affiliation: From the Departments of Neurology (Y.T., T.M., S.N., H.O., H.K., I.N., M.A., K.F.), Multiple Sclerosis Therapeutics (T.M., K.F.), Neurosurgery (R.S., M.K.), Diagnostic Radiology (S.M.), and Pathology (M.W.), Tohoku University Graduate School of Medicine, Sendai; Department of Neurology (T.M.), National Hospital Organization Hachinohe National Hospital; Department of Neurosurgery (Y.S.), Yamagata University School of Medicine; and Department of Neurosurgery (T.K.), Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kuroda
authors.affiliation: From the Departments of Neurology (Y.T., T.M., S.N., H.O., H.K., I.N., M.A., K.F.), Multiple Sclerosis Therapeutics (T.M., K.F.), Neurosurgery (R.S., M.K.), Diagnostic Radiology (S.M.), and Pathology (M.W.), Tohoku University Graduate School of Medicine, Sendai; Department of Neurology (T.M.), National Hospital Organization Hachinohe National Hospital; Department of Neurosurgery (Y.S.), Yamagata University School of Medicine; and Department of Neurosurgery (T.K.), Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakashima
authors.affiliation: From the Departments of Neurology (Y.T., T.M., S.N., H.O., H.K., I.N., M.A., K.F.), Multiple Sclerosis Therapeutics (T.M., K.F.), Neurosurgery (R.S., M.K.), Diagnostic Radiology (S.M.), and Pathology (M.W.), Tohoku University Graduate School of Medicine, Sendai; Department of Neurology (T.M.), National Hospital Organization Hachinohe National Hospital; Department of Neurosurgery (Y.S.), Yamagata University School of Medicine; and Department of Neurosurgery (T.K.), Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Saito
authors.affiliation: From the Departments of Neurology (Y.T., T.M., S.N., H.O., H.K., I.N., M.A., K.F.), Multiple Sclerosis Therapeutics (T.M., K.F.), Neurosurgery (R.S., M.K.), Diagnostic Radiology (S.M.), and Pathology (M.W.), Tohoku University Graduate School of Medicine, Sendai; Department of Neurology (T.M.), National Hospital Organization Hachinohe National Hospital; Department of Neurosurgery (Y.S.), Yamagata University School of Medicine; and Department of Neurosurgery (T.K.), Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kanamori
authors.affiliation: From the Departments of Neurology (Y.T., T.M., S.N., H.O., H.K., I.N., M.A., K.F.), Multiple Sclerosis Therapeutics (T.M., K.F.), Neurosurgery (R.S., M.K.), Diagnostic Radiology (S.M.), and Pathology (M.W.), Tohoku University Graduate School of Medicine, Sendai; Department of Neurology (T.M.), National Hospital Organization Hachinohe National Hospital; Department of Neurosurgery (Y.S.), Yamagata University School of Medicine; and Department of Neurosurgery (T.K.), Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sonoda
authors.affiliation: From the Departments of Neurology (Y.T., T.M., S.N., H.O., H.K., I.N., M.A., K.F.), Multiple Sclerosis Therapeutics (T.M., K.F.), Neurosurgery (R.S., M.K.), Diagnostic Radiology (S.M.), and Pathology (M.W.), Tohoku University Graduate School of Medicine, Sendai; Department of Neurology (T.M.), National Hospital Organization Hachinohe National Hospital; Department of Neurosurgery (Y.S.), Yamagata University School of Medicine; and Department of Neurosurgery (T.K.), Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kumabe
authors.affiliation: From the Departments of Neurology (Y.T., T.M., S.N., H.O., H.K., I.N., M.A., K.F.), Multiple Sclerosis Therapeutics (T.M., K.F.), Neurosurgery (R.S., M.K.), Diagnostic Radiology (S.M.), and Pathology (M.W.), Tohoku University Graduate School of Medicine, Sendai; Department of Neurology (T.M.), National Hospital Organization Hachinohe National Hospital; Department of Neurosurgery (Y.S.), Yamagata University School of Medicine; and Department of Neurosurgery (T.K.), Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Mugikura
authors.affiliation: From the Departments of Neurology (Y.T., T.M., S.N., H.O., H.K., I.N., M.A., K.F.), Multiple Sclerosis Therapeutics (T.M., K.F.), Neurosurgery (R.S., M.K.), Diagnostic Radiology (S.M.), and Pathology (M.W.), Tohoku University Graduate School of Medicine, Sendai; Department of Neurology (T.M.), National Hospital Organization Hachinohe National Hospital; Department of Neurosurgery (Y.S.), Yamagata University School of Medicine; and Department of Neurosurgery (T.K.), Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: From the Departments of Neurology (Y.T., T.M., S.N., H.O., H.K., I.N., M.A., K.F.), Multiple Sclerosis Therapeutics (T.M., K.F.), Neurosurgery (R.S., M.K.), Diagnostic Radiology (S.M.), and Pathology (M.W.), Tohoku University Graduate School of Medicine, Sendai; Department of Neurology (T.M.), National Hospital Organization Hachinohe National Hospital; Department of Neurosurgery (Y.S.), Yamagata University School of Medicine; and Department of Neurosurgery (T.K.), Kitasato University School of Medicine, Kanagawa, Japan. aokim@med.tohoku.ac.jp.
authors.forename: Masashi
authors.initials: M
authors.lastname: Aoki
authors.affiliation: From the Departments of Neurology (Y.T., T.M., S.N., H.O., H.K., I.N., M.A., K.F.), Multiple Sclerosis Therapeutics (T.M., K.F.), Neurosurgery (R.S., M.K.), Diagnostic Radiology (S.M.), and Pathology (M.W.), Tohoku University Graduate School of Medicine, Sendai; Department of Neurology (T.M.), National Hospital Organization Hachinohe National Hospital; Department of Neurosurgery (Y.S.), Yamagata University School of Medicine; and Department of Neurosurgery (T.K.), Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Fujihara
mesh_terms: D016207:Cytokines / Q000378:metabolism; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000150:complications* / Q000000981:diagnostic imaging / Q000473:pathology*; D038524:Diffusion Magnetic Resonance Imaging; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D008875:Middle Aged; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism*
chemical_list: D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004676:Myelin Basic Protein