David G. MacManus

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.

Application of the new McDonald criteria to patients with clinically isolated syndromes suggestive of multiple sclerosis.

Traditionally, multiple sclerosis (MS) has been diagnosed on the basis of clinical evidence of dissemination in time and space. Previously, it could not be diagnosed in patients with single clinical episodes of demyelination known as clinically isolated syndromes. New diagnostic criteria from the International Panel of McDonald and colleagues incorporate MRI evidence of dissemination in time and space to allow a diagnosis of MS in patients with clinically isolated syndromes. From clinical and MRI examinations performed prospectively at baseline, 3 months, 1 year, and 3 years of follow‐up, the frequency of developing MS was ascertained by the application of both the new McDonald criteria and the Poser criteria for clinically definite MS. The specificity, sensitivity, positive and negative predictive value, and accuracy of the new criteria for the development of clinically definite MS were assessed. At 3 months, 20 of 95 (21%) patients had MS with the McDonald criteria, whereas only 7 of 95 (7%) had developed clinically definite MS. After 1 year, the corresponding figures were 38 of 79 (48%) and 16 of 79 (20%), and after 3 years, they were 29 of 50 (58%) and 19 of 50 (38%). The development of MS with the new MRI criteria after 1 year had a high sensitivity (83%), specificity (83%), positive predicative value (75%), negative predictive value (89%), and accuracy (83%) for clinically definite MS at 3 years. Use of the new McDonald criteria more than doubled the rate of diagnosis of MS within a year of presentation with a clinically isolated syndrome. The high specificity, positive predictive value, and accuracy of the new criteria for clinically definite MS support their clinical relevance.

MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS.

Background: In a 2-year, placebo-controlled trial (the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] study), involving 942 patients with relapsing multiple sclerosis (MS), natalizumab significantly reduced the relapse rate by 68% and progression of sustained disability by 42% vs placebo. We report the effect of natalizumab on MRI measures from the AFFIRM study. Methods: The number and volume of gadolinium (Gd)-enhancing, new or enlarging T2-hyperintense, and new T1-hypointense lesions and brain parenchymal fraction were measured from annual scans obtained at baseline, 1 year, and 2 years. Results: Compared with placebo, natalizumab produced a 92% decrease in Gd-enhancing lesions (means 2.4 vs 0.2; p < 0.001), an 83% decrease in new or enlarging T2-hyperintense lesions (means 11.0 vs 1.9; p < 0.001), and a 76% decrease in new T1-hypointense lesions (means 4.6 vs 1.1; p < 0.001) over 2 years. Median T2-hyperintense lesion volume increased by 8.8% in the placebo group and decreased by 9.4% in the natalizumab group (p < 0.001); median T1-hypointense lesion volume decreased by 1.5% in the placebo group and decreased by 23.5% in the natalizumab group (p < 0.001). Brain atrophy was greater in year 1 and less in year 2 in natalizumab-treated patients. Conclusion: Natalizumab has a sustained effect in preventing the formation of new lesions in patients with relapsing multiple sclerosis.

Head size, age and gender adjustment in MRI studies: a necessary nuisance?

Imaging studies of cerebral volumes often adjust for factors such as age that may confound between-subject comparisons. However the use of nuisance covariates in imaging studies is inconsistent, which can make interpreting results across studies difficult. Using magnetic resonance images of 78 healthy controls we assessed the effects of age, gender, head size and scanner upgrade on region of interest (ROI) volumetry, cortical thickness and voxel-based morphometric (VBM) measures. We found numerous significant associations between these variables and volumetric measures: cerebral volumes and cortical thicknesses decreased with increasing age, men had larger volumes and smaller thicknesses than women, and increasing head size was associated with larger volumes. The relationships between most ROIs and head size volumes were non-linear. With age, gender, head size and upgrade in one model we found that volumes and thicknesses decreased with increasing age, women had larger volumes than men (VBM, whole-brain and white matter volumes), increasing head size was associated with larger volumes but not cortical thickness, and scanner upgrade had an effect on thickness and some volume measures. The effects of gender on cortical thickness when adjusting for head size, age and upgrade showed some non-significant effect (women>men), whereas the independent effect of head size showed little pattern. We conclude that age and head size should be considered in ROI volume studies, age, gender and upgrade should be considered for cortical thickness studies and all variables require consideration for VBM analyses. Division of all volumes by head size is unlikely to be adequate owing to their non-proportional relationship.

Effect of natalizumab on conversion of gadolinium enhancing lesions to T1 hypointense lesions in relapsing multiple sclerosis

Abstract.Background:Natalizumab, a humanized monoclonal anti-adhesion molecule antibody, reduces the frequency of new gadolinium (Gd) enhancing lesions and relapses in multiple sclerosis (MS). Its effect on evolution of new Gd enhancing lesions to T1 hypointense lesions is unknown.Methods:213 patients were randomized to receive 3 mg/kg or 6 mg/kg natalizumab or placebo monthly for 6 months and then followed for a further 6 months. A subset of patients who had one or more new gadolinium enhancing lesions from Month 0 to Month 6 and available electronic data were analysed. Each new Gd enhancing lesion that developed during treatment (months 1–6) was investigated for conversion to a new T1 hypointense lesion at month 12. Lesions were classified as large or small if their cross-sectional area was greater or less than 20mm2. Because of the similarity of both doses of natalizumab on the frequency of new Gd enhancing lesions, the two natalizumab arms were combined in all analyses.Results:Compared with the placebo group, the natalizumab group exhibited significant decreases in: (i) the proportion of patients with new Gd enhancing lesions that evolved to T1-hypointense lesions (10/38 [26 %] versus 27/40 [68 %]; p < 0.01); (ii) the proportion of patients who developed large T1 hypointense lesions (2/38 [5 %] versus 16/40 [40 %]; p < 0.01); (iii) the proportion of new Gd enhancing lesions that became T1 hypointense (11/75 [15 %] versus 118/466 [25 %]; p = 0.045); (iv) the mean proportion per patient of new Gd enhancing lesions that converted to T1-hypointense lesions (0.15 versus 0.28; p = 0.005), and (v) the odds ratio (OR) of converting from Gd enhancing to T1-hypointense lesions (OR = 0.48; 95% CI = 0.24, 0.94, p = 0.031)).Conclusion:Natalizumab significantly suppresses the evolution of new Gd enhancing to T1-hypointense lesions. This may reflect several mechanisms including reduced cell migration across the blood brain barrier, reduced T cell activation within lesions, an inhibitory effect on subsequent axonal damage within the new central nervous system lesion, and a reduced likelihood of recurrent lesion inflammation.

Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy

Objective: Natalizumab is a humanized recombinant monoclonal antibody against very late activation antigen-4 approved for the treatment of patients with multiple sclerosis (MS). A phase II study failed to demonstrate a difference between natalizumab treatment groups and the placebo group with regard to gadolinium enhancing lesions on MRI 3 months after discontinuation of therapy. The objective of this study was to assess clinical MS disease activity, surrogate disease markers on MRI, immunologic parameters in peripheral blood and CSF, as well as safety in patients with MS after discontinuation of natalizumab therapy. Methods: This study is a longitudinal and serial cross-sectional assessment, in which 23 patients who were treated with natalizumab in the context of two phase III clinical trials were originally enrolled. A subgroup of patients was followed over 14 months. The annual relapse rate, neurologic disease progression assessed by the Expanded Disability Status Scale, disease surrogate markers on MRI, cellular and humoral immune markers in peripheral blood and CSF, and adverse events of the drug were monitored. Results: With regard to clinical disease activity, neuroimaging, and immune responses, the majority of patients in our cohort were stable. Decreased lymphocyte cell numbers and altered cell ratios returned to normal 14 months after cessation of natalizumab. No infectious complications were observed. Conclusion: This is the first long-term follow-up of patients who discontinued natalizumab. We did not observe a clinical, radiographic, or immunologic rebound phenomenon after discontinuation of natalizumab therapy.

Recollection and familiarity in dense hippocampal amnesia: a case study

In the amnesia literature, disagreement exists over whether anterograde amnesia involves recollective-based recognition processes and/or familiarity-based ones depending on whether the anatomical damage is restricted to the hippocampus or also involves adjacent areas, particularly the entorhinal and perirhinal cortices. So far, few patients with well documented anatomical lesions and detailed assessment of recollective and recognition performance have been described. We report a comprehensive neuroanatomical assessment and detailed investigation of the anterograde memory functions of a previously described severe amnesic patient (VC). The results of four previously published neuroradiological investigations (resting PET, qualitative MRIs, volumetric MRI and functional MRI) together with the results of two new investigations (voxel-based morphometry and magnetic resonance spectroscopy) are presented. The consistent finding across these different qualitative and quantitative examinations of VCs brain has shown that there is primarily structural and functional abnormality located selectively in the hippocampus bilaterally. Marked impairments in both verbal and non-verbal recall and recognition standardized memory tests were documented in the context of VCs intact cognitive profile and normal semantic memory. The results of five new experimental recognition memory tests tapping recollection and familiarity using verbal, topographical (buildings and landscapes) and unknown human faces memoranda revealed striking differential effects according to the type of stimuli used. A receiver operating characteristic analysis revealed that VCs recollective- and familiarity-based recognition processes were well preserved for unknown human faces. In contrast, recollective-based recognition for verbal and topographical material was at floor. Familiarity-based recognition was also impaired, significantly below controls for verbal and buildings memoranda and quite weak, although not reaching significance, for landscapes. These data suggest that the hippocampus is involved in recollective processes of verbal and topographical stimuli. It also plays an appreciable role in familiarity processes for these stimuli. However, recollection and familiarity of human faces appear not to depend on this region.

MRS shows abnormalities before symptoms in familial Alzheimer disease

Background: Pathologic change in Alzheimer disease (AD) begins some years before symptoms. MRS has the potential to detect metabolic abnormalities reflecting this early pathologic change. Presenilin 1 (PS1) and amyloid precursor protein (APP) mutation carriers have a nearly 100% risk of developing AD and may be studied prior to symptom onset. Methods: Short echo time proton MR spectra were acquired from a midline posterior cingulate voxel in presymptomatic carriers of PS1 or APP mutations (“presymptomatic mutation carriers” [PMCs]; n = 7) and age- and sex-matched control subjects (n = 6). Ratios of N-acetyl aspartate (NAA), myo-inositol (MI), and choline-containing compounds (Cho) to creatine (Cr) were measured and NAA/MI calculated. Regression analyses and t tests were performed after log transformation. Results: PMC and control subjects were matched for age and sex. PMC subjects were 1.7 to 21.6 years (mean 9.8 years) before expected symptom onset, predicted from family-specific mean age at onset. Age did not significantly affect metabolite ratios. Geometric mean ratios in control subjects were as follows: NAA/Cr = 1.75, MI/Cr = 0.59, and NAA/MI = 2.95. NAA/Cr and NAA/MI were significantly reduced in PMC relative to controls (NAA/Cr mean decrease 10% [95% CI 2 to 18%]; NAA/MI mean decrease 25% [95% CI 3 to 44%]). MI/Cr was increased in PMC, but the differences did not achieve significance (19% increase [95% CI 1% decrease to 41% increase]; p = 0.07)). In PMCs, reduction in NAA/MI (p = 0.001) and MI/Cr (p = 0.002) were related to proximity of expected age at onset. Conclusions: Metabolic changes are detectable in presymptomatic mutation carriers years before expected onset of Alzheimer disease. Their magnitude is related to proximity of expected age at onset.

Proton MR spectroscopy in clinically isolated syndromes suggestive of multiple sclerosis

The concentration of the metabolite N-acetyl aspartate (NAA), thought to be a marker of axonal loss or damage, has been shown to be reduced in lesions, as demonstrated by high signal areas on T2-weighted MRI, and in normal-appearing white matter (NAWM) in established multiple sclerosis (MS). The stage of the disease when these changes first appear is not known. To try to determine this we studied 20 patients with clinically isolated syndromes, many of whom will be at the earliest clinical stages of MS, and 20 age- and sex-matched controls with single-voxel proton magnetic spectroscopy (MRS). MRS was performed using a General Electric 1.5T Signa EchoSpeed scanner (TR 3000 ms, TE 30 ms, PRESS). Absolute metabolite concentrations were determined using the LCModel fitting software. No significant reduction of NAA concentration was evident in the NAWM of the patients (patients: median 7.3 mM; controls: median 7.7 mM; P=0.19). There was, however, a significantly lower concentration of NAA in lesions (median 6.6 mM, P=0.015). Absolute values of choline-containing compounds, creatine and myo-inositol were significantly raised in the lesions (P=0.007, P=0.011 and P=0.002 respectively). The low NAA in lesions is consistent with axonal loss, damage or dysfunction occurring focally at the earliest clinical phase of the disease. The lack of any significant reduction in NAA in patient NAWM demonstrates that more widespread axonal changes are not yet detectable at this early clinical stage. A larger cohort and follow-up will be necessary to determine whether or not MRS findings have any prognostic significance for individual patients or sub-groups. This will also enable the clarification of the time course, pathogenesis and pathophysiological significance of the development of the low NAA, which is found in the NAWM of many patients with established MS.

Continuing optic nerve atrophy following optic neuritis: a serial MRI study.

To investigate optic neuritis as a model for atrophy in multiple sclerosis (MS) lesions we performed serial magnetic resonance imaging (MRI) on 10 patients with a history of optic neuritis using a fat saturated short-echo fast fluid-attenuated inversion recovery (sTE fFLAIR) sequence. The first study was performed a median of 19.5 months after the onset of optic neuritis and the second 1 year later. Using a computer-assisted contouring technique, a blinded observer calculated the mean area of the intra-orbital optic nerves. The mean area of affected optic nerves decreased over 1 year by 0.9 mm2 from 11.1 to 10.2 mm2 (p=0.01). Poor visual acuity and decreased visual-evoked potential (VEP) amplitude were associated with atrophy. These findings suggest that atrophy is a feature of focal demyelinating lesions, it may evolve over several years, and may have functional significance. Optic neuritis provides a model to study the effect of inflammatory demyelination through the ability to accurately measure visual function and to visualize and measure the optic nerves using magnetic resonance imaging.