Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy: Analysis of 102 patients

Eoin Flanagan, Shannon R. Hinson, Vanda A Lennon, Boyan Fang, Allen Jr. Aksamit, P. Pearse Morris, Eati Basal, Josephe A. Honorat, Nora B. Alfugham, Jenny J. Linnoila, Brian G Weinshenker, Sean J Pittock, Andrew McKeon

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Abstract

Objective: A novel autoimmune central nervous system (CNS) disorder with glial fibrillary acidic protein (GFAP)-IgG as biomarker was recently characterized. Here, 102 patients with GFAP-IgG positivity are described. Methods: The 102 included patients had: (1) serum, cerebrospinal fluid (CSF), or both that yielded a characteristic astrocytic pattern of mouse tissue immunostaining; (2) confirmation of IgG reactive with specific GFAP isoforms (α, ɛ, or κ) by cell-based assays; and (3) clinical data available. Control specimens (n = 865) were evaluated by tissue (n = 542) and cell-based (n = 323) assays. Results: Median symptom onset age was 44 years (range = 8–103), and 54% were women. The predominant phenotype (83 patients; 81%) was inflammation of meninges, brain, spinal cord, or all 3 (meningoencephalomyelitis). Among patients, highest specificity for those phenotypes was observed for CSF testing (94%), and highest sensitivity was for the GFAPα isoform (100%). Rare GFAP-IgG positivity was encountered in serum controls by tissue-based assay (0.5%) or cell-based assay (1.5%), and in CSF controls by cell-based assay (0.9%). Among patients, striking perivascular radial enhancement was found on brain magnetic resonance imaging in 53%. Although cases frequently mimicked vasculitis, angiography was uniformly negative, and spinal imaging frequently demonstrated longitudinally extensive myelitic lesions. Diverse neoplasms encountered were found prospectively in 22%. Ovarian teratoma was most common and was predicted best when both N-methyl-D-aspartate receptor–IgG and aquaporin-4–IgG coexisted (71%). Six patients with prolonged follow-up had brisk corticosteroid response, but required additional immunosuppression to overcome steroid dependency. Interpretation: GFAPα-IgG, when detected in CSF, is highly specific for an immunotherapy-responsive autoimmune CNS disorder, sometimes with paraneoplastic cause. Ann Neurol 2017;81:298–309.

Original languageEnglish (US)
Pages (from-to)298-309
Number of pages12
JournalAnnals of Neurology
Volume81
Issue number2
DOIs
StatePublished - Feb 1 2017

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Glial Fibrillary Acidic Protein
Immunoglobulin G
Biomarkers
Cerebrospinal Fluid
Central Nervous System Diseases
Protein Isoforms
Phenotype
Meninges
Aquaporins
Encephalitis
N-Methylaspartate
Vasculitis
Serum
Age of Onset
Immunotherapy
Immunosuppression
Spinal Cord
Angiography
Adrenal Cortex Hormones
Steroids

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy : Analysis of 102 patients. / Flanagan, Eoin; Hinson, Shannon R.; Lennon, Vanda A; Fang, Boyan; Aksamit, Allen Jr.; Morris, P. Pearse; Basal, Eati; Honorat, Josephe A.; Alfugham, Nora B.; Linnoila, Jenny J.; Weinshenker, Brian G; Pittock, Sean J; McKeon, Andrew.

In: Annals of Neurology, Vol. 81, No. 2, 01.02.2017, p. 298-309.

Research output: Contribution to journalArticle

Flanagan, Eoin ; Hinson, Shannon R. ; Lennon, Vanda A ; Fang, Boyan ; Aksamit, Allen Jr. ; Morris, P. Pearse ; Basal, Eati ; Honorat, Josephe A. ; Alfugham, Nora B. ; Linnoila, Jenny J. ; Weinshenker, Brian G ; Pittock, Sean J ; McKeon, Andrew. / Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy : Analysis of 102 patients. In: Annals of Neurology. 2017 ; Vol. 81, No. 2. pp. 298-309.
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abstract = "Objective: A novel autoimmune central nervous system (CNS) disorder with glial fibrillary acidic protein (GFAP)-IgG as biomarker was recently characterized. Here, 102 patients with GFAP-IgG positivity are described. Methods: The 102 included patients had: (1) serum, cerebrospinal fluid (CSF), or both that yielded a characteristic astrocytic pattern of mouse tissue immunostaining; (2) confirmation of IgG reactive with specific GFAP isoforms (α, ɛ, or κ) by cell-based assays; and (3) clinical data available. Control specimens (n = 865) were evaluated by tissue (n = 542) and cell-based (n = 323) assays. Results: Median symptom onset age was 44 years (range = 8–103), and 54{\%} were women. The predominant phenotype (83 patients; 81{\%}) was inflammation of meninges, brain, spinal cord, or all 3 (meningoencephalomyelitis). Among patients, highest specificity for those phenotypes was observed for CSF testing (94{\%}), and highest sensitivity was for the GFAPα isoform (100{\%}). Rare GFAP-IgG positivity was encountered in serum controls by tissue-based assay (0.5{\%}) or cell-based assay (1.5{\%}), and in CSF controls by cell-based assay (0.9{\%}). Among patients, striking perivascular radial enhancement was found on brain magnetic resonance imaging in 53{\%}. Although cases frequently mimicked vasculitis, angiography was uniformly negative, and spinal imaging frequently demonstrated longitudinally extensive myelitic lesions. Diverse neoplasms encountered were found prospectively in 22{\%}. Ovarian teratoma was most common and was predicted best when both N-methyl-D-aspartate receptor–IgG and aquaporin-4–IgG coexisted (71{\%}). Six patients with prolonged follow-up had brisk corticosteroid response, but required additional immunosuppression to overcome steroid dependency. Interpretation: GFAPα-IgG, when detected in CSF, is highly specific for an immunotherapy-responsive autoimmune CNS disorder, sometimes with paraneoplastic cause. Ann Neurol 2017;81:298–309.",
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T2 - Analysis of 102 patients

AU - Flanagan, Eoin

AU - Hinson, Shannon R.

AU - Lennon, Vanda A

AU - Fang, Boyan

AU - Aksamit, Allen Jr.

AU - Morris, P. Pearse

AU - Basal, Eati

AU - Honorat, Josephe A.

AU - Alfugham, Nora B.

AU - Linnoila, Jenny J.

AU - Weinshenker, Brian G

AU - Pittock, Sean J

AU - McKeon, Andrew

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N2 - Objective: A novel autoimmune central nervous system (CNS) disorder with glial fibrillary acidic protein (GFAP)-IgG as biomarker was recently characterized. Here, 102 patients with GFAP-IgG positivity are described. Methods: The 102 included patients had: (1) serum, cerebrospinal fluid (CSF), or both that yielded a characteristic astrocytic pattern of mouse tissue immunostaining; (2) confirmation of IgG reactive with specific GFAP isoforms (α, ɛ, or κ) by cell-based assays; and (3) clinical data available. Control specimens (n = 865) were evaluated by tissue (n = 542) and cell-based (n = 323) assays. Results: Median symptom onset age was 44 years (range = 8–103), and 54% were women. The predominant phenotype (83 patients; 81%) was inflammation of meninges, brain, spinal cord, or all 3 (meningoencephalomyelitis). Among patients, highest specificity for those phenotypes was observed for CSF testing (94%), and highest sensitivity was for the GFAPα isoform (100%). Rare GFAP-IgG positivity was encountered in serum controls by tissue-based assay (0.5%) or cell-based assay (1.5%), and in CSF controls by cell-based assay (0.9%). Among patients, striking perivascular radial enhancement was found on brain magnetic resonance imaging in 53%. Although cases frequently mimicked vasculitis, angiography was uniformly negative, and spinal imaging frequently demonstrated longitudinally extensive myelitic lesions. Diverse neoplasms encountered were found prospectively in 22%. Ovarian teratoma was most common and was predicted best when both N-methyl-D-aspartate receptor–IgG and aquaporin-4–IgG coexisted (71%). Six patients with prolonged follow-up had brisk corticosteroid response, but required additional immunosuppression to overcome steroid dependency. Interpretation: GFAPα-IgG, when detected in CSF, is highly specific for an immunotherapy-responsive autoimmune CNS disorder, sometimes with paraneoplastic cause. Ann Neurol 2017;81:298–309.

AB - Objective: A novel autoimmune central nervous system (CNS) disorder with glial fibrillary acidic protein (GFAP)-IgG as biomarker was recently characterized. Here, 102 patients with GFAP-IgG positivity are described. Methods: The 102 included patients had: (1) serum, cerebrospinal fluid (CSF), or both that yielded a characteristic astrocytic pattern of mouse tissue immunostaining; (2) confirmation of IgG reactive with specific GFAP isoforms (α, ɛ, or κ) by cell-based assays; and (3) clinical data available. Control specimens (n = 865) were evaluated by tissue (n = 542) and cell-based (n = 323) assays. Results: Median symptom onset age was 44 years (range = 8–103), and 54% were women. The predominant phenotype (83 patients; 81%) was inflammation of meninges, brain, spinal cord, or all 3 (meningoencephalomyelitis). Among patients, highest specificity for those phenotypes was observed for CSF testing (94%), and highest sensitivity was for the GFAPα isoform (100%). Rare GFAP-IgG positivity was encountered in serum controls by tissue-based assay (0.5%) or cell-based assay (1.5%), and in CSF controls by cell-based assay (0.9%). Among patients, striking perivascular radial enhancement was found on brain magnetic resonance imaging in 53%. Although cases frequently mimicked vasculitis, angiography was uniformly negative, and spinal imaging frequently demonstrated longitudinally extensive myelitic lesions. Diverse neoplasms encountered were found prospectively in 22%. Ovarian teratoma was most common and was predicted best when both N-methyl-D-aspartate receptor–IgG and aquaporin-4–IgG coexisted (71%). Six patients with prolonged follow-up had brisk corticosteroid response, but required additional immunosuppression to overcome steroid dependency. Interpretation: GFAPα-IgG, when detected in CSF, is highly specific for an immunotherapy-responsive autoimmune CNS disorder, sometimes with paraneoplastic cause. Ann Neurol 2017;81:298–309.

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