title: Permeability of the blood-brain barrier predicts conversion from optic neuritis to multiple sclerosis.
abstract: Optic neuritis is an acute inflammatory condition that is highly associated with multiple sclerosis. Currently, the best predictor of future development of multiple sclerosis is the number of T2 lesions visualized by magnetic resonance imaging. Previous research has found abnormalities in the permeability of the blood-brain barrier in normal-appearing white matter of patients with multiple sclerosis and here, for the first time, we present a study on the capability of blood-brain barrier permeability in predicting conversion from optic neuritis to multiple sclerosis and a direct comparison with cerebrospinal fluid markers of inflammation, cellular trafficking and blood-brain barrier breakdown. To this end, we applied dynamic contrast-enhanced magnetic resonance imaging at 3 T to measure blood-brain barrier permeability in 39 patients with monosymptomatic optic neuritis, all referred for imaging as part of the diagnostic work-up at time of diagnosis. Eighteen healthy controls were included for comparison. Patients had magnetic resonance imaging and lumbar puncture performed within 4 weeks of onset of optic neuritis. Information on multiple sclerosis conversion was acquired from hospital records 2 years after optic neuritis onset. Logistic regression analysis showed that baseline permeability in normal-appearing white matter significantly improved prediction of multiple sclerosis conversion (according to the 2010 revised McDonald diagnostic criteria) within 2 years compared to T2 lesion count alone. There was no correlation between permeability and T2 lesion count. An increase in permeability in normal-appearing white matter of 0.1 ml/100 g/min increased the risk of multiple sclerosis 8.5 times whereas having more than nine T2 lesions increased the risk 52.6 times. Receiver operating characteristic curve analysis of permeability in normal-appearing white matter gave a cut-off of 0.13 ml/100 g/min, which predicted conversion to multiple sclerosis with a sensitivity of 88% and specificity of 72%. We found a significant correlation between permeability and the leucocyte count in cerebrospinal fluid as well as levels of CXCL10 and MMP9 in the cerebrospinal fluid. These findings suggest that blood-brain barrier permeability, as measured by magnetic resonance imaging, may provide novel pathological information as a marker of neuroinflammation related to multiple sclerosis, to some extent reflecting cellular permeability of the blood-brain barrier, whereas T2 lesion count may more reflect the length of the subclinical pre-relapse phase.See Naismith and Cross (doi:10.1093/brain/awv196) for a scientific commentary on this article.
authors.affiliation: 1 Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Nordre Ringvej 57, 2600 Glostrup, Denmark stig.praestekjaer.cramer@regionh.dk.
authors.forename: Stig P
authors.initials: SP
authors.lastname: Cramer
authors.affiliation: 2 Department of Neurology, Rigshospitalet, Nordre Ringvej 57, 2600 Glostrup, Denmark.
authors.forename: Signe
authors.initials: S
authors.lastname: Modvig
authors.affiliation: 1 Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Nordre Ringvej 57, 2600 Glostrup, Denmark.
authors.forename: Helle J
authors.initials: HJ
authors.lastname: Simonsen
authors.affiliation: 2 Department of Neurology, Rigshospitalet, Nordre Ringvej 57, 2600 Glostrup, Denmark 3 Institute of Clinical Medicine, The Faculty of Health Science, University of Copenhagen, Blegdamsvej 3B, 2200 København N, Denmark.
authors.forename: Jette L
authors.initials: JL
authors.lastname: Frederiksen
authors.affiliation: 1 Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Nordre Ringvej 57, 2600 Glostrup, Denmark 3 Institute of Clinical Medicine, The Faculty of Health Science, University of Copenhagen, Blegdamsvej 3B, 2200 København N, Denmark.
authors.forename: Henrik B W
authors.initials: HB
authors.lastname: Larsson
mesh_terms: D000293:Adolescent; D000328:Adult; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001921:Brain / Q000473:pathology; D002199:Capillary Permeability / Q000502:physiology*; D018925:Chemokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000134:cerebrospinal fluid; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000503:physiopathology*; D043025:Oligoclonal Bands / Q000134:cerebrospinal fluid; D009902:Optic Neuritis / Q000134:cerebrospinal fluid / Q000503:physiopathology*; D011237:Predictive Value of Tests; D012372:ROC Curve; D012307:Risk Factors; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: D018925:Chemokines; D007074:Immunoglobulin G; D043025:Oligoclonal Bands
keywords: DCE-MRI; blood–brain barrier; multiple sclerosis; optic neuritis; perfusion MRI