David H. Miller

Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain

Several quantitative magnetic resonance (MR) measures are used to investigate multiple sclerosis (MS) in vivo. Precise quantitative investigation of the histopathological correlates of such measures has, to date, been limited. This study investigates the relationship of quantitative measures of myelin content, axonal density, and gliosis with quantitative MR measures in postmortem (PM) MS tissue. MR imaging (MRI) was performed on a 1.5T scanner and T1‐relaxation time (T1‐RT) and magnetization transfer ratio (MTR) maps were acquired in fresh PM brain of 20 MS subjects. Myelin content, axonal counts, and the extent of gliosis all were quantified using morphometric and digital imaging techniques. MRI and pathological data were in most cases coregistered using stereotactic navigation. Using multiple regression analysis, we detected significant correlations between myelin content (Trmyelin) and MTR (r = −0.84, p < 0.001) and myelin content and axonal count (−0.80, p < 0.001); MTR correlated with T1‐RT (r = −0.79, p < 0.001). No association was detected between the extent of gliosis and either MR measure. MTR was significantly higher in remyelinated than demyelinated lesions (means: 30.0 [standard deviation, 2.9] vs 23.8 [standard deviation, 4.3], p = 0.008). In conclusion, MTR is affected by myelin content in MS white matter. Ann Neurol 2004

Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis.

Axonal loss is thought to be a likely cause of persistent disability after a multiple sclerosis relapse; therefore, noninvasive in vivo markers specific for axonal loss are needed. We used optic neuritis as a model of multiple sclerosis relapse to quantify axonal loss of the retinal nerve fiber layer (RNFL) and secondary retinal ganglion cell loss in the macula with optical coherence tomography. We studied 25 patients who had a previous single episode of optic neuritis with a recruitment bias to those with incomplete recovery and 15 control subjects. Optical coherence tomography measurement of RNFL thickness and macular volume, quantitative visual testing, and electrophysiological examination were performed. There were highly significant reductions (p < 0.001) of RNFL thickness and macular volume in affected patient eyes compared with control eyes and clinically unaffected fellow eyes. There were significant relationships among RNFL thickness and visual acuity, visual field, color vision, and visual‐evoked potential amplitude. This study has demonstrated functionally relevant changes indicative of axonal loss and retinal ganglion cell loss in the RNFL and macula, respectively, after optic neuritis. This noninvasive RNFL imaging technique could be used in trials of experimental treatments that aim to protect optic nerves from axonal loss. Ann Neurol 2005

Primary-progressive multiple sclerosis

About 10-15% of patients with multiple sclerosis (MS) present with gradually increasing neurological disability, a disorder known as primary-progressive multiple sclerosis (PPMS). Compared with relapse-onset multiple sclerosis, people with PPMS are older at onset and a higher proportion are men. Inflammatory white-matter lesions are less evident but diffuse axonal loss and microglial activation are seen in healthy-looking white matter, in addition to cortical demyelination, and quantitative MRI shows atrophy and intrinsic abnormalities in the grey matter and the white matter. Spinal cord atrophy corresponds to the usual clinical presentation of progressive spastic paraplegia. Although neuroaxonal degeneration seems to underlie PPMS, the pathogenesis and the extent to which immune-mediated mechanisms operate is unclear. MRI of the brain and spinal cord, and examination of the CSF, are important investigations for diagnosis; conventional immunomodulatory therapies, such as interferon beta and glatiramer acetate, are ineffective. Future research should focus on the clarification of the mechanisms of axonal loss, improvements to the design of clinical trials, and the development of effective neuroprotective treatments.

The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy.

AbstractFrom 1991–2002, we treated 58 patients with multiple sclerosis (MS) using the humanised monoclonal antibody, Campath–1H, which causes prolonged T lymphocyte depletion. Clinical and surrogate markers of inflammation were suppressed. In both the relapsing–remitting (RR) and secondary progressive (SP) stages of the illness, Campath–1H reduced the annual relapse rate (from 2.2 to 0.19 and from 0.7 to 0.001 respectively; both p < 0.001). Remarkably, MRI scans of patients with SP disease, treated with Campath–1H 7 years previously, showed no new lesion formation. However, despite these effects on inflammation, disability was differently affected depending on the phase of the disease. Patients with SPMS showed sustained accumulation of disability due to uncontrolled progression marked by unrelenting cerebral atrophy, attributable to ongoing axonal loss. The rate of cerebral atrophy was greatest in patients with established cerebral atrophy and highest inflammatory lesion burden before treatment (2.3 versus 0.7 ml/year; p = 0.04). In contrast, patients with RR disease showed an impressive reduction in disability at 6 months after Campath–1H (by a mean of 1.2 EDSS points) perhaps owing to a suppression of on–going inflammation in these patients with unusually active disease. In addition, there was a further significant, albeit smaller, mean improvement in disability up to 36 months after treatment.We speculate that this represents the beneficial effects of early rescue of neurons and axons from a toxic inflammatory environment, and that prevention of demyelination will prevent long–term axonal degeneration. These concepts are currently being tested in a controlled trial comparing Campath–1H and IFN–beta in the treatment of drug–naïve patients with early, active RR MS.

Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study

BACKGROUND Oral fumarate (BG00012) might have dual anti-inflammatory and neuroprotective effects. Our aim was to assess the efficacy and safety of BG00012 in patients with relapsing-remitting multiple sclerosis. METHODS 257 patients, aged 18-55 years, with relapsing-remitting multiple sclerosis were randomly assigned to receive 120 mg once daily (n=64), 120 mg three times daily (n=64), or 240 mg three times daily (n=64) BG00012, or placebo (n=65) for 24 weeks. During an extension period of 24 weeks for safety assessment, patients treated with placebo received BG00012 240 mg three times daily. The primary endpoint was total number of new gadolinium enhancing (GdE) lesions on brain MRI scans at weeks 12, 16, 20, and 24. Additional endpoints included cumulative number of new GdE lesions (weeks 4-24), new or enlarging T2-hyperintense lesions, new T1-hypointense lesions at week 24, and annualised relapse rate. Analysis was done on the efficacy-evaluable population. Safety and tolerability were also assessed. This study is registered with ClinicalTrials.gov, number NCT00168701. FINDINGS Treatment with BG00012 240 mg three times daily reduced by 69% the mean total number of new GdE lesions from week 12 to 24 compared with placebo (1.4 vs 4.5, p<0.0001). It also reduced number of new or enlarging T2-hyperintense (p=0.0006) and new T1-hypointense (p=0.014) lesions compared with placebo. BG00012 reduced annualised relapse rate by 32% (0.44 vs 0.65 for placebo; p=0.272). Adverse events more common in patients given BG00012 than in those given placebo included abdominal pain, flushing, and hot flush. Dose-related adverse events in patients on BG00012 were headache, fatigue, and feeling hot. INTERPRETATION The anti-inflammatory effects and favourable safety profile of BG00012 warrant further long-term phase III studies in large patient groups.

Brain structure and neurocognitive and behavioural function in adolescents who were born very preterm

BACKGROUND Infants born very preterm (<33 weeks) are at increased risk of neurocognitive deficits. Their neurodevelopmental outcome up to age 8 years can be predicted by neonatal ultrasonography, but little is known of their later function. We investigated the effect of very preterm birth on brain structure and neurocognitive and behavioural functioning in adolescence. METHODS A cohort of 105 infants born before 33 weeks of gestation in 1979-80 had ultrasonographic scans at University College Hospital, London, and were prospectively examined at 1, 4, and 8 years. At age 14-15 years, 72 of those who remained in UK (cases) and 21 age-matched full-term controls underwent brain magnetic resonance imaging (MRI), as well as neurological, cognitive, and behavioural assessment. MRI images were assessed by two neuroradiologists unaware of ultrasonographic findings or case or control status. FINDINGS Of the 72 cases, 40 had unequivocally abnormal MRI and 15 had equivocal scans. Of the 21 controls, one had abnormal and five equivocal MRI. Abnormalities of ventricles, corpus callosum, and white matter were especially common in cases. More brain lesions were identified by MRI than by neonatal ultrasonography. The cases had significantly more reading, adjustment, and neurological impairments than controls, but their behaviour was significantly related to MRI abnormality. INTERPRETATION Individuals born very preterm show an excess of neurocognitive and behavioural problems in adolescence, and more than half have abnormal MRI brain scans.

Magnetic resonance imaging in monitoring the treatment of multiple sclerosis: concerted action guidelines.

Serial gadolinium enhanced MRI of the brain detects much clinically silent disease activity in early relapsing-remitting and secondary progressive multiple sclerosis (MS), and thus has an important role in monitoring the effects of therapy. Based on the proceedings of a recent Commission of the European Communities (CEC) workshop and a review of the literature, guidelines are presented for using MRI to monitor treatment trials in MS. The guidelines consider: A) MRI system and techniques; B) patient selection; C) trial design; D) analysis of results. Priorities for future research are also indicated.

Gray matter atrophy is related to long‐term disability in multiple sclerosis

To determine the relation of gray matter (GM) and white matter (WM) brain volumes, and WM lesion load, with clinical outcomes 20 years after first presentation with clinically isolated syndrome suggestive of multiple sclerosis (MS).

Eight-year follow-up study of brain atrophy in patients with MS

Objective: To characterize whole-brain atrophy in relapsing-remitting MS (RRMS) patients over an 8-year period. The specific goals of this study were to determine if brain atrophy is related to subsequent disability status and to identify MRI correlates of atrophy progression. Methods: A follow-up study was conducted to reassess patients from a phase III trial of interferon β-1a (IFNβ-1a) 8 years after randomization. Clinical and MRI data from 172 patients followed over 2 years in the original trial were used as baseline data. Follow-up data were obtained on 160 patients, including 134 patients with follow-up MRI examinations. Brain atrophy was estimated by automated calculation of brain parenchymal fraction. The relation between atrophy during the original trial and disability status at follow-up was determined. Correlations were also determined between lesion measurements from the original trial and the brain parenchymal fraction at follow-up. Results: Brain atrophy was correlated with subsequent disability status. Atrophy rate during the original trial was the most significant MRI predictor of disability status at follow-up. Brain atrophy at follow-up was related to lesion volumes measured during the original trial. Conclusions: The relation between atrophy progression and subsequent neurologic disability status suggests that atrophy progression during RRMS is clinically relevant. Therefore, atrophy progression may be a useful marker for disease progression in clinical trials. The relation between lesions and subsequent atrophy indicates that brain atrophy may be related to focal tissue damage at earlier points in time, but important predisposing or other factors contributing to atrophy remain undefined.

Spinal cord MRI using multi-array coils and fast spin echo. II: Findings in multiple sclerosis

We performed MRI of brain and spinal cord on 80 patients with multiple sclerosis (MS). Using multi-array coils and fast spin echo, 139 intrinsic lesions were identified in 59 patients (74%). Lesions were more common in the cervical than in the thoracic cord. Cross-sectional areas of the cord, measured from axial images at four levels, showed atrophy in 40%. Clinical disability correlated with cord atrophy but not with cord lesion load. These results show that the use of multi-array coils and fast spin echo allows rapid and sensitive detection of spinal cord lesions in MS and that the cord is involved in the majority of patients. A lack of association between cord lesions and disability may relate to limitations in MR resolution but also suggests that the mechanisms of disability in MS are complex and multifactorial.