A study of subtle blood brain barrier disruption in a placebo-controlled trial of natalizumab in relapsing remitting multiple sclerosis.

Natalizumab, an anti-alpha4 integrin antibody, significantly reduces the number of visibly enhancing multiple sclerosis (MS) lesions. In this substudy of a 2-year trial of natalizumab monotherapy versus placebo, contrast-enhanced imaging investigated for subtle blood brain barrier (BBB) leakage in relapsing remitting (RRMS) patients, and whether such leakage is modified by natalizumab. After 24 weeks on treatment, 40 patients from 3 centres (27 on natalizumab and 13 on placebo) were studied. T1 weighted images were obtained before and at set timepoints up to 46 minutes after gadolinium (Gd)-DTPA (0.3 mmol/kg to 18 patients, 0.15 mmol/kg to 22). Paired regions of interest were placed around non-enhancing lesions and contralateral normal appearing white matter (NAWM). BBB leakage was inferred through post-Gd T1 weighted signal intensity (SI) change. SI change was greater in T2 non-enhancing lesions than paired NAWM at all timepoints (P<0.005), indicating BBB leakage in lesions. No significant difference in inferred BBB leakage was observed between treatment arms as measured by SI change of lesions (P>0.05 for all timepoints, joint test P=0.24), or in SI change of NAWM (joint test P=0.37). T1 hypointense and isointense lesions exhibited similar SI changes (joint test P=0.12). There is evidence of a subtle BBB leakage within visibly non-enhancing lesions in RRMS that was not modified by alpha4 integrin blockade in this substudy cohort.

Selective magnetization transfer ratio decrease in the visual cortex following optic neuritis.

Patients with clinically isolated syndromes suggestive of multiple sclerosis have evidence for abnormality in normal appearing grey matter detected using the magnetization transfer ratio (MTR), a quantitative MRI measure. One potential mechanism for the decreased grey matter MTR (GM MTR) observed is trans-synaptic morphological abnormality secondary to demyelinating lesions that are in an anatomically linked pathway but remote location. We investigated this potential association by studying the location of abnormalities using voxel-based analysis of GM MTR maps in a group of 80 patients studied within 6 months of presenting with isolated optic neuritis and compared the findings with those seen in 50 age- and sex-matched healthy controls. Occipital cortex and whole brain analysis comparing all optic neuritis patients and controls revealed a selective decrease of MTR bilaterally in the visual cortex in patients [Brodmann area (BA) 17]. Whole brain analysis of patients fulfilling the McDonald criteria for multiple sclerosis (n = 20) showed a lower MTR compared to controls bilaterally in the visual cortex (BA 17/18), left hippocampus, bilateral superior temporal gyrus, bilateral lenticular nuclei and the right cerebellum. There was no significant difference in the percentage of grey matter between patients and controls in the regions of abnormal MTR detected in the visual cortex. The intrinsic MTR decrease seen in patients suggests that there are structural changes in the visual cortex following an attack of optic neuritis. Potential mechanisms for this include trans-synaptic neuronal degeneration and cortical synaptic morphological changes; such abnormalities may also contribute to MTR abnormalities observed in the normal appearing grey matter in multiple sclerosis.

Cerebral atrophy measurement in clinically isolated syndromes and relapsing remitting multiple sclerosis: a comparison of registration-based methods.

BACKGROUND AND PURPOSE: Brain atrophy is a proposed marker of disease progression in multiple sclerosis (MS). Many magnetic resonance imaging-based methods of atrophy quantification exist, but their relative sensitivity and precision is unclear. Our aim was to compare atrophy rates from the brain boundary shift integral (BBSI), structural image evaluation, using normalization of atrophy (SIENA) (both registration-based methods) and segmented brain volume difference, in patients with clinically isolated syndromes (CIS), relapsing remitting MS (RRMS), and controls. METHODS: Thirty-seven CIS patients, 30 with early RRMS and 16 controls had T1-weighted volumetric imaging at baseline and 1 year. Brain atrophy rates were determined using segmented brain volume difference, BBSI, and SIENA. RESULTS: BBSI and SIENA were more precise than subtraction of segmented brain volumes and were more sensitive distinguishing RRMS subjects from controls. A strong correlation was observed between BBSI and SIENA. Atrophy rates were greater in CIS and RRMS subjects than controls (RRMS P < .001). With all methods, significantly greater atrophy rates were observed in CIS patients who developed clinically definite MS relative to subjects who did not. CONCLUSION: Registration-based techniques are more precise and sensitive than segmentation-based methods in measuring brain atrophy, with BBSI and SIENA providing comparable results.

Early predictors of rapidly evolving multiple sclerosis: A case report.

Objective The aim of this case report is to highlight some important features of rapidly evolving Multiple Sclerosis. BACKGROUND: In a small proportion of patients, Multiple Sclerosis (MS) can present as a fulminant disease characterised by severe and frequent relapses. This form of rapidly evolving MS is associated with significant morbidity and mortality. It is therefore important to identify these patients as early as possible, so that they can be managed effectively. However, due to the rarity of fulminant forms of MS, there is limited data on the natural history and management of this condition. CASE REPORT: We present a young man with rapidly evolving Multiple Sclerosis (MS) who had 2 disabling relapses within 14weeks. He had an unusually high CSF white cell count at presentation (86per mm3; 100% lymphocytes, 97% T cells, 3% B cells), with positive oligoclonal bands. Brain MRI showed large, cavitating lesions, with no enhancement. He required a prolonged course of intravenous methyl-prednisolone and plasma exchange. CONCLUSIONS: This case suggests that male gender, young age at onset, time to second relapse, relapse severity, high CSF white cell count at presentation, large and cavitating lesions on MRI may be early predictors of rapidly evolving MS. It also highlights the therapeutic value of plasma exchange and longer courses of intravenous methylprednisolone in managing severe MS relapses. Enhancement may not always be a reliable indicator of disease activity, particularly in clinical settings where single dose gadolinium is used, due to its low sensitivity in detecting blood brain barrier leakage.