Ernst W. Radü

Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring.

Natalizumab, a highly specific α4-integrin antagonist, is approved for treatment of patients with active relapsing-remitting multiple sclerosis (RRMS). It is generally recommended for individuals who have not responded to a currently available first-line disease-modifying therapy or who have very active disease. The expected benefits of natalizumab treatment have to be weighed against risks, especially the rare but serious adverse event of progressive multifocal leukoencephalopathy. In this Review, we revisit and update previous recommendations on natalizumab for treatment of patients with RRMS, based on additional long-term follow-up of clinical studies and post-marketing observations, including appropriate patient selection and management recommendations.

Analysis of Impairment Related Functional Architecture in MS Patients during Performance of Different Attention Tasks

Abstract. More than 50 % of patients with multiple sclerosis (MS) suffer from cognitive deficits. Attention is one of the most frequently affected cognitive functions. It has been shown that MS patients suffer from a specific but not necessarily from a generalized decrease in performance and that different severity grades of impaired attentional processing can be distinguished. Little is known about patterns of brain activation in MS patients with different grades of attentional deficits. The objective was to examine if different severity grades in attentional impairment are reflected by altered patterns of brain activation in specific attention tasks. In the present study cerebral activation induced by three attention tasks of different complexity was assessed in 14 MS patients and seven healthy controls by functional MRI (fMRI). Based on their performance on the tests recorded off-line with a computerized test battery and during the fMRI investigation, patients were classified as mildly and severely impaired. MS patients with mild impairment showed increased and additional activation of brain areas which were in part not activated in normal subjects. Those were located mainly in the frontal cortex and posterior parietal cortex. This effect decreased with increasing task complexity and was strongest for the alertness task. In MS patients with severe impairment no additional activation was found in prefrontal structures and activation in the premotor cortex was not significantly different from controls. These findings suggest that compensation in MS patients is in part achieved by functional integration of frontal and parietal association areas. The extent of compensation seems to depend on the brains capacity to access additional brain structures. Exhaustion of this capacity may finally lead to severe cognitive impairment.

Dynamic patterns of USPIO enhancement can be observed in macrophages after ischemic brain damage

Cells of the mononuclear phagocytotic system (MPS) are often found near to or within ischemic tissue and can potentially aggravate cellular damage. Hence, visualization of those cells would allow demarcation of putatively affected from intact tissue. Experimental MRI studies have shown that ultrasmall particles of dextran‐coated iron oxide (USPIO) are internalized into cells of the MPS. To test if this cell tagging method may be also applied to cerebral infarction, USPIOs were administered to Fisher rats 5.5 h after permanent occlusion of the middle cerebral artery (pMCAO). During the first 2 days USPIO were preferentially found in patches within the lesion and in surrounding areas. On day 4, USPIOs expanded within the core of the lesion. On day 7 they were found predominantly within the boundary area. Histological analysis showed large populations of macrophages containing iron particles in the infarcted tissue. We conclude, therefore, that it is possible to monitor MPS activity after focal cerebral ischemia using USPIOs. Magn Reson Med 46:1018–1022, 2001.

Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial

BACKGROUND Depletion of B lymphocytes is associated with suppression of inflammatory activity in multiple sclerosis. We aimed to assess the safety and efficacy of atacicept, a recombinant fusion protein that suppresses B-cell function and antibody production. METHODS In this placebo-controlled, double-blind, 36-week, phase 2 trial (ATAMS) in Australia, Canada, Europe, and the USA, patients aged 18-60 years with relapsing multiple sclerosis were randomly assigned via an interactive voice response system in a 1:1:1:1 ratio, stratified by geographical region, to receive weekly subcutaneous injections with atacicept (25, 75, or 150 mg) or placebo. Both patients and study personnel were masked to treatment assignment. The primary endpoint was the change in mean number of gadolinium-enhancing lesions on T1-weighted MRI per patient per scan between weeks 12 and 36. Efficacy endpoints were analysed in the intention-to-treat population. Patients who completed week 36 were eligible to participate in a long-term extension study (ATAMS EXT), consisting of a double-blind phase followed by an open-label phase, for a total study time of up to 5 years. The study was terminated early after the independent data and safety monitoring board noted an increased annualised relapse rate with atacicept. The protocol was subsequently amended to include a 60-week safety follow-up, to allow treatment with approved multiple sclerosis drugs, and to change the primary endpoint to gadolinium-enhancing T1 lesions per scan during the entire double-blind period of ATAMS. Both the trial and the extension are registered with ClinicalTrials.gov, numbers NCT00642902 (ATAMS) and NCT00853762 (ATAMS EXT). FINDINGS Between April 23, 2008, and early study termination on Sept 11, 2009, 255 patients were randomly assigned: 63 to placebo, 63 to atacicept 25 mg, 64 to 75 mg, and 65 to 150 mg. 90 (35%) patients completed the week 36 treatment visit, 26 (10%) discontinued before study termination (including one who dropped out before receiving study treatment), and 139 (55%) discontinued because of study termination. During the double-blind period of ATAMS, annualised relapse rates were higher in the atacicept groups than in the placebo group (atacicept 25 mg, 0·86, 95% CI 0·43-1·74; 75 mg, 0·79, 0·40-1·58; 150 mg, 0·98, 0·52-1·81; placebo, 0·38, 0·17-0·87). Mean numbers of gadolinium-enhancing T1 lesions per scan were similar in all groups (25 mg, 2·26, 0·97-5·27; 75 mg, 2·30, 1·08-4·92; 150 mg, 2·49, 1·18-5·27; placebo, 3·07, 1·40-6·77). Seven patients (one taking placebo and six atacicept) discontinued treatment because of adverse events. One death occurred in the placebo group. During the safety follow-up, immunoglobulin concentrations and B-cell counts returned towards predose values and annualised relapse rates in the atacicept groups decreased until they were similar to that of the placebo group INTERPRETATION Increased clinical disease activity associated with atacicept suggests that the role of B cells and humoral immunity in multiple sclerosis is complex. For studies that explore therapeutic immunomodulation in multiple sclerosis, rigorous monitoring for negative effects on clinical and MRI outcomes is warranted. FUNDING Merck Serono (Merck KGaA) and EMD Serono (Merck KGaA).

Dynamic susceptibility contrast MR imaging of plaque development in multiple sclerosis: application of an extended blood-brain barrier leakage correction.

Since the pathogenesis of multiple sclerosis (MS) lesions is not yet fully understood, we investigated the potential of dynamic susceptibility contrast (DSC) magnetic resonance (MR) perfusion imaging for a better characterization of lesion pathology. Twenty‐five MS patients were examined on a 1.5 T scanner. A single dose of gadolinium (Gd)‐DOTA contrast agent was injected, and echoplanar images were acquired every 0.5 seconds for 1 minute. From the signal intensity‐versus‐time curves, the relative cerebral blood volume (rCBV) was evaluated for regions in plaques and in gray and white matter. The rCBV calculated for acute, Gd‐enhancing plaques was corrected for the effects of blood‐brain barrier leakage, using a new correction algorithm. Acute plaques had significantly higher blood volumes than normal‐appearing white matter (P < = 0.01). Chronic plaques that appeared hypointense on T1‐weighted images had lower rCBV than T1‐isointense plaques (P < = 0.03). Our results indicate that the acute phase in MS is accompanied by vasodilation. In later stages of gliosis, the perfusion decreases with increasing axonal injury. Although the DSC technique is less sensitive than conventional MR imaging, the information provided is essentially different from that obtained with any other MR method. J. Magn. Reson. Imaging 2000;11:495–505.

The relationship between total and regional corpus callosum atrophy, cognitive impairment and fatigue in multiple sclerosis patients

Objective: The objective of this paper is to investigate the relationship between total and regional corpus callosum (CC) atrophy, neuropsychological test performance and fatigue in multiple sclerosis (MS) patients. Methods: We conducted a cross-sectional study in 113 MS patients: mean age 48±11 years, 75/113 women, 84/113 relapsing–remitting MS, mean disease duration 21±9 years, mean Expanded Disability Status Scale (EDSS) score 3.2±1.7. All patients underwent brain magnetic resonance imaging, standardised neurological assessment and comprehensive cognitive testing including assessments for fatigue and depression. Total and regional CC atrophy was assessed using the corpus callosum index (CCI). Results: CCI correlated more strongly with T2- and T1-lesion volume and whole brain volume than with disease duration or EDSS score. CCI correlated strongly with the verbal fluency test (VFT), Symbol Digit Modalities Test (SDMT) and Paced Auditory Serial Addition Test (PASAT). Multivariate regression analysis revealed that atrophy of the posterior CC segment was significantly associated with poor outcome in the PASAT, VFT and SDMT. In contrast, atrophy of the anterior CC segment was significantly associated with fatigue severity and poor outcome in the long-term memory test. Conclusions: Atrophy of the CC is associated with cognitive impairment and fatigue. Regional CCI results indicate that these associations are partially spatially segregated.

Sex and side differences of cerebral arterial caliber.

SummaryThe diameter of 261 middle cerebral and 225 anterior cerebral arteries was measured on half axial antero-posterior (ap) view, and the diameter of 217 internal carotid arteries on side view angiograms. Mean diameter was significantly larger by 9.3%, 8.8% and 9.7% respectively in males than in females. In the females the vessels of the left hemisphere were wider but not significantly so than those of the right hemisphere, and the contrary was true for the males. In both sexes the side difference was reversed in the eighth decennium. There was no correlation of vessel diameter with age except for a statistically significant increase by 7.8% of right middle cerebral artery diameter in males from the fifth to the sixth decennium.

Therapy-induced plasticity of cognitive functions in MS patients : insights from fMRI

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system whose pathological mechanisms are still not completely understood. Physical as well as cognitive deterioration are consequences within the disease process that have an extensive impact on the patients quality of life. Therefore, understanding the functional background of spontaneous as well as induced remission is of high relevance. Studies on visualization of therapeutic effects of pharmacological or cognitive treatment by functional magnetic resonance imaging (fMRI) are still rare. From fMRI studies on focal brain lesions hypotheses on mechanisms of brain reorganization can be derived. This contribution will first give an overview of the existing studies using fMRI in MS, on cognitive decline, on cognitive treatment studies and its therapeutic effects on behavioural readouts in MS, and on therapy-induced brain plasticity and its possible visualization by fMRI. Results of a study on correlating the effects of cognitive training with changes in brain organization in patients with mild to severe cognitive impairment will be reported.

Operated low grade astrocytomas: a long term PET study on the effect of radiotherapy

The role of postoperative radiotherapy in patients with low grade gliomas is not established yet. PET with 11C methionine (MET) and 18F fluorodeoxyglucose (FDG) was used to perform cross sectional comparisons as well as within patient follow up studies in 30 operated patients with fibrillary astrocytoma WHO II. Uptake of tracer by tumour was quantified by radioactivity concentration ratios in tumour over contralateral brain (T/C). Comparing patients who did (n=13) or did not (n=17) receive external radiotherapy subsequent to first tumour resection, no differences in MET and FDG T/C between both groups were found during a postoperative period of 94 months (when recurrence and malignant progression of low grade astrocytomas are expected). Malignant progression occurred at a similar rate in both patient groups at a mean (SD) postoperative interval of 46 (26) months. Irrespective of whether radiotherapy was applied or not, malignant tumour recurrences showed higher T/C values (MET: 1.70 (0.64), FDG: 0.98 (0.23)) than recurrences without signs of malignancy (MET: 1.21 (0.21), FDG: 0.82 (0.08)) (Mann-Whitney: MET p=0.086, FDG p=0.035). The data show a relative lack of radiotherapy administered immediately after first tumour resection. In the course of disease, patients with tumours undergoing malignant progression may be identified with PET tracer methods.

Spatio-temporal Segmentation of Active Multiple Sclerosis Lesions in Serial MRI Data

This paper presents a new approach for the automatic segmentation and characterization of active MS lesions in 4D data of multiple sequences. Traditional segmentation of 4D data applies individual 3D spatial segmentation to each image data set, thus not making use of correlation over time. More recently, a time series analysis has been applied to 4D data to reveal active lesions [3]. However, misregistration at tissue borders led to false positive lesion voxels. Lesion development is a complex spatio-temporal process, consequently methods concentrating exclusively on the spatial or temporal aspects of it cannot be expected to provide optimal results. Active MS lesions were extracted from the 4D data in order to quantify MR-based spatio-temporal changes in the brain. A spatio-temporal lesion model generated by principal component analysis allowed robust identification of active MS lesions overcoming the drawbacks of traditional purely spatial or purely temporal segmentation methods.