Published Phase III immunomodulatory treatment trials in relapsing and remitting multiple sclerosis have demonstrated a modest decline in attack rates, but only a minor effect on disability. As genuine disability progression is difficult to ascertain in relatively short studies with the conventional rating scales available, the acquisition and analysis of relapse data are critical. However, there are as yet unresolved questions related to the latter. We will first discuss the problems associated with relapse definitions by trial investigators, the paucity of the data collected (especially on the magnitude and duration of exacerbations) and statistical issues in their analysis. We will then suggest practical points for obtaining more accurate information on relapses and evaluating them meaningfully. While there is still general consensus among neurologists that primary endpoints for therapeutic trials should be clinical, improvements for future protocols are essential.

The treatment effects of recent immunomodulatory therapies on disease progression in relapsing-remitting multiple sclerosis (MS) have been mostly established from 'confirmed progression' endpoints. However, the reliability of this outcome measure is poor and a significant proportion of patients may be erroneously classified. We previously proposed the area under disability/time curves to quantify in-trial disability changes, but although these have advantages, they lack information on the direction of change. We have therefore performed disease trend analyses and categorical classifications using serial Expanded Disability Status Scale (EDSS) scores from the 533 complete datasets in a double-blind, randomized, placebo-controlled, phase III trial of subcutaneous interferon beta-1a (IFNbeta-1a) (PRISMS study). We found significant treatment benefits for IFNbeta-1a on in-trial disability course (P=0.002). Therapeutic advantages remained when relapse-related assessments were excluded (P=0.018). Post hoc analyses demonstrated that IFNbeta-1a was mainly effective in both increasing the proportion of patients with a 'stable' course and reducing those with prolonged, disabling deteriorations. Baseline disease duration and EDSS levels, but not MRI lesion load, predicted the subsequent disability trends. Mean 'numbers needed to treat' (NNTs) to obtain preferred disability courses were reduced in patients with shorter disease duration. These results have important implications for the targeting of immunomodulatory therapies in MS.

The mechanical properties of biological tissue provide information related to the strength and integrity of the cellular microstructure. Recently, mechanical properties of the brain have been visualized and measured non-invasively with magnetic resonance elastography (MRE). Virtual MRE (VMRE) is based on non-Gaussian distribution model, which can be regarded as an indicator to reflect the complexity and change of different brain microstructure. The purpose of this study is to explore the capability of diffusion–based VMRE in the characterization of the gray matter shear stiffness, discuss the cause of the differences of gray matter encephalic in normal human brains.

Magnetic resonance, magnetisation transfer, and diVusion weighted imaging correlates of optic nerve, brain, and cervical cord damage in Leber's hereditary optic neuropathyThe association between Leber's hereditary optic neuropathy and multiple sclerosis has encouraged the search for susceptibility genes in multiple sclerosis. This symbiotic relation is reversed in the paper by Inglese et al 1 (this issue, pp 444-449) in which magnetic resonance (MR) techniques originally developed for studying multiple sclerosis were applied to patients with Leber's hereditary optic neuropathy. The authors aimed to quantify the amount of optic nerve damage, and, more interestingly, detect the degree of pathological change in the brain, in a disease often thought in its isolated form to be highly tissue specific for the optic pathways.Leber's hereditary optic neuropathy is probably the most studied disease caused by mitochondrial DNA (mtDNA) mutations. It usually results in bilateral and severe visual loss in young adults, with a preponderance in men. It has been associated with other neurological syndromes, the best described as resembling multiple sclerosis and occurring mainly in female patients, often with a family history of Leber's hereditary optic neuropathy (also called Harding's disease).2 Advances in mitochondrial genetics have facilitated our knowledge of the disease. Most patients with Leber's hereditary optic neuropathy are linked to the "primary" mtDNA mutations at nucleotide positions 11 778, 3460, and 14 484, all located in genes encoding polypeptides found in complex I of the oxidative phosphorylation pathway. However, incomplete penetrance may occur and unaVected family members can be virtually homoplasmic (>95% mtDNA) for a particular mutation but remain asymptomatic in life. This may be explained by other aetiological influences including environmental factors (for example, tobacco and alcohol use) and the presence of "secondary" mtDNA mutations. Clinically, the primary mutations give rise to slightly diVerent phenotypes, with 11 778 (and rarely 3460) being associated with Harding's disease, whereas 14 484 is the most benign mutation with the best prognosis for visual recovery (40%). Recent in vitro functional experiments have perhaps complicated our understanding of the pathogenesis of Leber's hereditary optic neuropathy, with the mutations generating diVerent changes in biochemical markers. 3 In vivo MR studies have so far produced conflicting results regarding abnormalities within and outside the optic nerve.Inglese et al employed MR techniques developed in their earlier series on multiple sclerosis, including thin slice conventional MR, non-conventional imaging with magnetisation transfer (MT), and echo planar diVusion weighted imaging (DWI), to investigate a relatively heterogeneous cohort (10 patients with isolated Leber's hereditary optic neuropathy and four with Leber's hereditary optic neuropathy-multiple sclerosis). The first part of this study established the presence of optic nerve atrophy, as con...