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Cited by 94Multiple Sclerosis Research StudiesBarrier Structure and Function StudiesGlaucoma and retinal disorders

Permeability of the blood–brain barrier predicts conversion from optic neuritis to multiple sclerosis

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Cramer, Stig P., Modvig, Signe, Simonsen, Helle J., Frederiksen, Jette L., Larsson, Henrik B. W.·2015·Brain
DOI 10.1093/brain/awv203PMC PMC4547053
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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.

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  • In multiple sclerosis patients, increased blood-brain barrier permeability has been shown by DCE-MRI in the cortex and adjacent white matter, corpus callosum and internal capsule, and thalamic gray matter.

    “More recently, an increase in BBB permeability has been shown in MS patients by DCE-MRI in the cortex and adjacent white matter (392), corpus callosum and internal capsule (121-123, 421, 574), as well as thalamic gray matter (123).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [122]

    The Imaging methods describe DCE-MRI measurements in periventricular normal-appearing white matter and thalamic grey matter, and the Discussion reports that permeability in both regions predicted conversion from optic neuritis to MS. The paper does not identify the corpus callosum or internal capsule as measured regions. It also says thalamic permeability was not higher in the optic-neuritis group as a whole than in healthy controls, so its finding does not establish a general increase in thalamic permeability among MS patients. (LLM, conf=0.84)

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  • In multiple sclerosis patients at different stages of the disease, elevated Qalb values, increased MMP-9 activity in CSF and serum, and increased CSF leukocyte count have been shown, all indicative of blood-brain barrier breakdown.

    “Elevated Qalb values (355), increased MMP-9 activity in CSF and serum (122, 168), and increased CSF leukocyte count (122), all indicative of BBB breakdown, have been shown in MS patients at different stages of the disease.”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [122]

    The Results (Table 1; page unavailable) show higher CSF leucocyte counts in optic neuritis patients than in healthy controls, and the Results subsection on CSF biomarkers links leucocyte count and CSF MMP9 concentration to measured BBB permeability. However, this study measured MMP9 concentration in CSF, not MMP9 activity in both CSF and serum, and studied optic neuritis patients followed for MS conversion rather than MS patients at different disease stages. The Qalb claim is cited to a different reference (355), not this paper. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Global blood-brain barrier disruption occurs at the onset of optic neuritis in patients who go on to develop multiple sclerosis.

    “as suggested by findings of global BBB disruption at the onset of optic neuritis in patients who go on to develop MS (122).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [122]

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Research works printed but not linked: 1

  1. van Osch MJ Vonken EJ Bakker CJ Viergever MA Correcting partial volume artifacts of the arterial input function in quantitative cerebral perfusion MRI. Magn Reson Med 2001; 45: 477– 85. 11241707

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Authors
Cramer, S. P., Modvig, S., Simonsen, H. J., Frederiksen, J. L., & Larsson, H. B. W.
Affiliations
  • Rigshospitalet (DK)
  • University of Copenhagen (DK)
Corresponding author
Cramer, Stig P.
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2015-07-17
Volume
138
Issue
9
Pages
2571-2583
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awv203
PMC
PMC4547053
OpenAlex
W1805190614
Cited by
94
References
33
Citations by year
2026: 5 · 2025: 5 · 2024: 8 · 2023: 8 · 2022: 6 · 2021: 8 · 2020: 12 · 2019: 8 · 2018: 11 · 2017: 9 · 2016: 10 · 2015: 3 · 2012: 1
FWCI
8.74
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Brain (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
  • Biogen
  • Scleroseforeningen (14588)
  • Multiple Sclerosis Society (14588)
  • Rigshospitalet
  • Region Hovedstaden
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
Keywords
blood-brain barrier permeability, optic neuritis, conversion to multiple sclerosis, normal-appearing white matter, dynamic contrast-enhanced MRI, cerebrospinal fluid biomarkers, CXCL10, MMP-9, white blood cell count, neuroinflammation, disease progression prediction, blood-brain barrier disruption, cell trafficking
MeSH terms
Adolescent, Adult, Blood-Brain Barrier, Brain, Capillary Permeability, Female, Humans, Immunoglobulin G, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, Optic Neuritis, Predictive Value of Tests, Risk Factors, ROC Curve, Statistics, Nonparametric, Chemokines, Oligoclonal Bands, Young Adult

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