Tarek A. Yousry

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.

The Microbleed Anatomical Rating Scale (MARS): Reliability of a tool to map brain microbleeds

Objective: Brain microbleeds on gradient-recalled echo (GRE) T2*-weighted MRI may be a useful biomarker for bleeding-prone small vessel diseases, with potential relevance for diagnosis, prognosis (especially for antithrombotic-related bleeding risk), and understanding mechanisms of symptoms, including cognitive impairment. To address these questions, it is necessary to reliably measure their presence and distribution in the brain. We designed and systematically validated the Microbleed Anatomical Rating Scale (MARS). We measured intrarater and interrater agreement for presence, number, and anatomical distribution of microbleeds using MARS across different MRI sequences and levels of observer experience. Methods: We studied a population of 301 unselected consecutive patients admitted to our stroke unit using 2 GRE T2*-weighted MRI sequences (echo time [TE] 40 and 26 ms). Two independent raters with different MRI rating expertise identified, counted, and anatomically categorized microbleeds. Results: At TE = 40 ms, agreement for microbleed presence in any brain location was good to very good (intrarater κ = 0.85 [95% confidence interval (CI) 0.77–0.93]; interrater κ = 0.68 [95% CI 0.58–0.78]). Good to very good agreement was reached for the presence of microbleeds in each anatomical region and in individual cerebral lobes. Intrarater and interrater reliability for the number of microbleeds was excellent (intraclass correlation coefficient [ICC] = 0.98 [95% CI 0.97–0.99] and ICC = 0.93 [0.91–0.94]). Very good interrater reliability was obtained at TE = 26 ms (κ = 0.87 [95% CI 0.61–1]) for definite microbleeds in any location. Conclusion: The Microbleed Anatomical Rating Scale has good intrarater and interrater reliability for the presence of definite microbleeds in all brain locations when applied to different MRI sequences and levels of observer experience.

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.

MRI criteria for MS in patients with clinically isolated syndromes

In recent years, criteria for the diagnosis of multiple sclerosis (MS) have changed, mainly due to the incorporation of new MRI criteria. While the new criteria are a logical step forward, they are complex and—not surprisingly—a good working knowledge of them is not always evident among neurologists and neuroradiologists. In some circumstances, several MRI examinations are needed to achieve an accurate and prompt diagnosis. This provides an incentive for continued efforts to refine the incorporation of MRI-derived information into the diagnostic workup of patients presenting with a clinically isolated syndrome. Within the European multicenter collaborative research network that studies MRI in MS (MAGNIMS), a workshop was held in London in November 2007 to review information that may simplify the existing MS diagnostic criteria, while maintaining a high specificity that is essential to minimize false positive diagnoses. New data that are now published were reviewed and discussed and together with a new proposal are integrated in this position paper.

Quantitative magnetic resonance of postmortem multiple sclerosis brain before and after fixation

Unfixed and fixed postmortem multiple sclerosis (MS) brain is being used to probe pathology underlying quantitative MR (qMR) changes. Effects of fixation on qMR indices in MS brain are unknown. In 15 postmortem MS brain slices T1, T2, MT ratio (MTR), macromolecular proton fraction (fB), fractional anisotropy (FA), and mean, axial, and radial diffusivity (MD, Dax, and Drad) were assessed in white matter (WM) lesions (WML) and normal appearing WM (NAWM) before and after fixation in formalin. Myelin content, axonal count, and gliosis were quantified histologically. Students t‐test and regression were used for analysis. T1, T2, MTR, and fB obtained in unfixed MS brain were similar to published values obtained in patients with MS in vivo. Following fixation T1, T2 (NAWM, WML) and MTR (NAWM) dropped, whereas fB (NAWM, WML) increased. Compared to published in vivo data all diffusivity measures were lower in unfixed MS brain, and dropped further following fixation (except for FA). MTR was the best predictor of Tmyelin (inversely related to myelin) in unfixed MS brain (r = −0.83; P < 0.01) whereas postfixation T2 (r = 0.92; P < 0.01), T1 (r = 0.89; P < 0.01), and fB (r = −0.86; P < 0.01) were superior. All diffusivity measures (except for Dax in unfixed tissue) were predictors of myelin content. Magn Reson Med 59:268–277, 2008.

Consensus recommendations for MS cortical lesion scoring using double inversion recovery MRI

Background: Different double inversion recovery (DIR) sequences are currently used in multiple sclerosis (MS) research centers to visualize cortical lesions, making it difficult to compare published data. This study aimed to formulate consensus recommendations for scoring cortical lesions in patients with MS, using DIR images acquired in 6 European centers according to local protocols. Methods: Consensus recommendations were formulated and tested in a multinational meeting. Results: Cortical lesions were defined as focal abnormalities on DIR, hyperintense compared to adjacent normal-appearing gray matter, and were not scored unless ≥3 pixels in size, based on at least 1.0 mm2 in-plane resolution. Besides these 2 obligatory criteria, additional, supportive recommendations concerned a priori artifact definition on DIR, use of additional MRI contrasts to verify suspected lesions, and a constant level of displayed image contrast. Robustness of the recommendations was tested in a small dataset of available, heterogeneous DIR images, provided by the different participating centers. An overall moderate agreement was reached when using the proposed recommendations: more than half of the readers agreed on slightly more than half (54%) of the cortical lesions scored, whereas complete agreement was reached in 19.4% of the lesions (usually larger, mixed white matter/gray matter lesions). Conclusions: Although not designed as a formal interobserver study, the current study suggests that comparing available literature data on cortical lesions may be problematic, and increased consistency in acquisition protocols may improve scoring agreement. Sensitivity and specificity of the proposed recommendations should now be studied in a more formal, prospective, multicenter setting using similar DIR protocols.

Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis - Establishing disease prognosis and monitoring patients

The role of MRI in the assessment of multiple sclerosis (MS) goes far beyond the diagnostic process. MRI techniques can be used as regular monitoring to help stage patients with MS and measure disease progression. MRI can also be used to measure lesion burden, thus providing useful information for the prediction of long-term disability. With the introduction of a new generation of immunomodulatory and/or immunosuppressive drugs for the treatment of MS, MRI also makes an important contribution to the monitoring of treatment, and can be used to determine baseline tissue damage and detect subsequent repair. This use of MRI can help predict treatment response and assess the efficacy and safety of new therapies. In the second part of the MAGNIMS (Magnetic Resonance Imaging in MS) networks guidelines on the use of MRI in MS, we focus on the implementation of this technique in prognostic and monitoring tasks. We present recommendations on how and when to use MRI for disease monitoring, and discuss some promising MRI approaches that may be introduced into clinical practice in the near future.

Magnetic resonance imaging pattern in natalizumab-associated progressive multifocal leukoencephalopathy

Natalizumab is an effective treatment for patients with multiple sclerosis (MS) that is associated with a risk of progressive multifocal leukoencephalopathy (PML). Recommendations were published in 2006 to improve early diagnosis of PML using magnetic resonance imaging (MRI). However, due to the small number of MS patients initially diagnosed with PML, the imaging criteria could only be derived from PML lesions in patients with human immunodeficiency virus. Therefore, there is an urgent need to assess the MRI characteristics of PML in MS patients to update the existing recommendations.

Prospective evaluation of neurological complications after allogeneic bone marrow transplantation

Objective: To determine the spectrum and frequency of neurologic sequelae after allogeneic bone marrow transplantation (BMT) and to define a risk profile of the patients. Methods: A prospective follow-up of 71 allogeneic bone marrow recipients 14 ± 3 months after transplantation. Patients underwent a neurologic examination, a neuropsychological test battery, and cranial MRI before and after BMT. Results: A large proportion of patients (65%) developed sequelae after BMT. Acute complications of defined etiology occurred in 18% of the patients and led to death in 9% of the study population. A total of 47% of the patients developed new neurologic abnormalities of undefined origin that were mild and subacute and predominantly affected the peripheral nervous system. The cognitive and neuroradiologic outcome was favorable in a majority of these patients, but a small subgroup exhibited cognitive deterioration and white matter lesions. Risk factor analysis identified acute graft-versus-host disease (GvHD) and other variables partly related to GvHD such as long-lasting immunosuppression as the main predictors of sequelae after allogeneic BMT. The authors have established an association with various factors but, owing to the observational character of this study, conclusions about the etiology of the findings are unclear. Conclusion: Neurologic complications significantly contribute to the morbidity and mortality of patients receiving allogeneic BMT. Subclinical abnormalities, cognitive deficits, and white matter lesions detected 1 year after BMT in a subgroup of patients may be related to more extensive CNS changes observed after transplantation in an earlier retrospective study and may be associated with the risk factor chronic GvHD/immunosuppression.

Intra-operative recordings of local field potentials can help localize the subthalamic nucleus in Parkinson's disease surgery

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can be a highly effective treatment for Parkinsons disease (PD). However, therapeutic efficacy is limited by difficulties in consistently and correctly targeting this nucleus. Increasing evidence suggests that there is abnormal synchronization of beta frequency band activity (approximately 20 Hz) in the STN of PD patients, as reflected in the oscillatory nature of the local field potential (LFP). We hypothesized that an increase in the power of the LFP beta activity may provide intra-operative confirmation of STN targeting in patients undergoing STN implantation for the treatment of advanced PD. Accordingly, we recorded LFPs from the four contacts of DBS electrodes as the latter were advanced in 2 mm steps from a point 4-6 mm above the intended surgical target point in the STN, to a point 4 mm below this. Contacts were configured to give three bipolar recordings of LFPs. These were analyzed on 16 sides in 9 patients. The power in the 13-35 Hz band recorded at the lowest contact pair underwent a steep but focal increase during electrode descent. The depth of the peak beta activity showed excellent agreement with the level of the intra-operative clinical stun effect (k coefficient = 0.792). The depth of peak beta activity also showed 100% specificity and 100% sensitivity for placement within STN in comparison to pre- and Post-operative stereotactic MRI. Functional physiological localization of STN by the on-line spectral analysis of LFPs is quick to perform and may provide information directly relevant to the position of the electrode contact actually used for DBS.