Brain leakiness predicts conversion to MS

Permeability of the blood-brain barrier predicts conversion from optic neuritis to multiple sclerosis.Cramer SP, Modvig S, Simonsen HJ, Frederiksen JL, Larsson HB. Brain. 2015. pii: awv203. [Epub ahead of print]

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. 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. 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. 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.

Maybe of interest to CISers.  Dr. K may wish to comment

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  • Interesting but I’m somehow unimpressed by these findings. Evidence for BBB leakage independent of lesions, i.e. in brain tissue that appears normal on standard MRI, has long been out there. Here, the authors are trying to translate this knowledge into a clinical set-up, and one must ask what it delivers in day-to-day practise. The answer at the moment is virtually zero. With a specificity of 72% the suggested set of criteria misses significantly more MSers compared to say the latest version of “McDonald” criteria with a specificity close to 90% (Swanton, et al. Lancet Neurol 2007;6:677–86). And how do these indices stand up in the differential diagnosis of MS? Let’s hope they keep their good work going!

  • I am part of a Brazilian group of MS in facebook in which most reports have optic neuritis have had a first demyelinating event to the optic nerve, many even negative for the OCBs in the cerebrospinal fluid, but between 05, 07 years later had another outbreak which confirmed the diagnosis of MS, and in this second event those who claim to have repeated examination of cerebrospinal fluid have tested positive for OCBs …

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