Morten Blinkenberg

Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis

We wanted to assess whether intravenous immunoglobulin G (IVIG) decreases disease activity on MRI in relapsing MS. Previous trials of IVIG in relapsing-remitting MS demonstrated a reduction of acute relapses, but these studies did not include MRI. We treated 26 patients in a randomized, double-blind, crossover study of IVIG 1 g/kg daily or placebo on 2 consecutive days every month during two 6-month treatment periods. The primary end point was the number of gadolinium-enhancing lesions on monthly serial MRI. Secondary efficacy variables were the occurrence of exacerbations, clinical neurologic ratings, total MS lesion load on T2-weighted MRI, and multimodal evoked potentials. Eighteen patients completed the entire trial; eight patients did not. Twenty-one patients completed the first treatment period and at least two MRI examinations in the second treatment period and were included in the intention-to-treat analysis. On serial MRI, we observed fewer enhancing lesions per patient per scan during IVIG treatment (median, 0.4; range, 0 to 9.3) than during placebo treatment (median, 1.3; range, 0.2 to 25.7; p = 0.03). During IVIG treatment, 15 patients were exacerbation free compared with only 7 on placebo (p = 0.02). The total number of exacerbations in the IVIG period was 11 and in the placebo period, 19 (not significant). None of the remaining secondary efficacy measures were significantly different between the two treatment periods. The number of adverse events, in particular eczema, was significantly higher during IVIG therapy than during placebo treatment. These results suggest that IVIG treatment is beneficial to patients with relapsing MS.

Rate Dependence of Regional Cerebral Activation During Performance of a Repetitive Motor Task: A PET Study

Using repeated positron emission tomography (PET) measures of regional cerebral counts, we investigated the regional cortical activations induced in eight normal subjects performing eight different frequencies of fingertapping (0.5–4 Hz) with the right index finger. The task was auditorially cued and the performance recorded during the scanning procedure. Performance evaluation showed increased error rates, during fingertapping, of high and low frequencies, and the best tapping performance was measured in the midrange of frequencies. Significantly activated areas (p < 0.05) of normalized cerebral counts were located in the left sensorimotor cortex (M1S1), right motor cortex, left thalamus, right insula, supplementary motor area (SMA), and bilaterally in the primary auditory cortex and the cerebellum. Statistical evaluation showed a significant (p < 0.01) and positive dependence of cerebral activation upon movement rate in the contralateral M1S1. There was no significant rate dependence of cerebral activation in other activated motor areas. The SMA and the right cerebellar hemisphere showed a more uniform activation throughout the tapping frequency range. Furthermore, we found a stimulus rate dependence of cerebral activation in the primary auditory cortex. We believe that the present data provide useful information for the preparation and interpretation of future motor activation studies of normal human subjects and may serve as reference points for studies of pathological conditions.

Regional differences in the CBF and BOLD responses to hypercapnia: a combined PET and fMRI study.

Previous fMRI studies of the cerebrovascular response to hypercapnia have shown signal change in cerebral gray matter, but not in white matter. Therefore, the objective of the present study was to compare (15)O PET and T *(2)-weighted MRI during a hypercapnic challenge. The measurements were performed under similar conditions of hypercapnia, which were induced by inhalation of 5 or 7% CO(2). The baseline rCBF values were 65.1 ml hg(-1) min(-1) for temporal gray matter and 28.7 ml hg(-1) min(-1) for white matter. By linear regression, the increases in rCBF during hypercapnia were 23.0 and 7. 2 ml hg(-1) min(-1) kPa(-1) for gray and white matter. The signal changes were 6.9 and 1.9% for the FLASH sequence and were 3.8 and 1. 7% for the EPI sequence at comparable echo times. The regional differences in percentage signal change were significantly reduced when normalized by regional flow values. A deconvolution analysis is introduced to model the relation between fMRI signal and end-expiratory CO(2) level. Temporal parameters, such as mean transit time, were derived from this analysis and suggested a slower response in white matter than in gray matter regions. It was concluded that the differences in the magnitude of the fMRI response can largely be attributed to differences in flow and that there is a considerable difference in the time course of the response between gray and white matter.

Cortical cerebral metabolism correlates with MRI lesion load and cognitive dysfunction in MS

Objective: To study the association between the cortical cerebral metabolic rate of glucose (CMRglc), MRI T2-weighted total lesion area (TLA), cognitive dysfunction, and neurologic disability in MS. Background: MRI lesion load is widely used in the clinical evaluation of the MS patient but little is known about the associated changes in cortical activation. Methods: Twenty-three patients with clinically definite MS underwent measurements of CMRglc, TLA, motor evoked potentials (MEPs), and cognitive and neurologic disability. CMRglc was calculated using PET and 18-F-deoxyglucose and compared with nine normal control subjects. Results: Reductions in CMRglc (p < 0.01) were found in the cortical global and regional lobar measurements. Furthermore, regional CMRglc (rCMRglc) was reduced in the dorsolateral prefrontal cortex, orbitofrontal cortex, caudate, putamen, thalamus, and hippocampus. Global cortical CMRglc correlated with TLA (Spearman rank correlation coefficient [SRCC] = −0.66, p = 0.001), and rCMRglc correlated with regional lesion load in all cerebral lobes (p ≤ 0.05). Global cortical CMRglc and cognitive disability also correlated (SRCC = 0.58, p = 0.015), and stepwise regression analysis showed a significant association between rCMRglc of the right thalamus and cognitive performance as well as TLA. There was no correlation between CMRglc and neurologic disability (Expanded Disability Status Scale) or MEP. Conclusion: Global and regional cortical CMRglc is reduced significantly in MS patients compared with normal control subjects. Furthermore, the CMRglc reductions correlate with TLA as well as with cognitive dysfunction, which indicates that MRI white matter lesion burden has a deteriorating effect on cortical cerebral neural function.

Apoliprotein E and multiple sclerosis: impact of the epsilon-4 allele on susceptibility, clinical type and progression rate

The purpose of this study was to investigate the relation between APOE genotype and Multiple Sclerosis (MS) in a genetically homogeneous population. We examined 240 patients consulting the MS-clinic during a period of 3 years (1996-1999). The mean age of the patients was 41.7 years (range 19-80 Y, SD 10.0 Y). As a measure of the progression rate (PR) the last registered Expanded Disability Status Scale (EDSS) score was divided by the time span (years) from disease onset until the latest assessment. The APOE genotype was determined from saliva and/or blood samples using PCR-techniques. The prevalence of different APOE genotypes was compared with the allele-distribution in a population of 361 persons from a Danish cross-sectional population study. The frequency of APOE-e4/e4 homozygotes was significantly higher in the MS-group as compared to controls (P<0.05, odds ratio: 2.3), whereas the frequency distribution of other genotypes did not differ significantly. The rate of progression was significantly faster in the APOE-e4/e4 homozygotes compared to other genotypes in the MS group (P<0.05). This study suggests that the APOE-e4/e4 homozygotes have an increased risk of developing MS. MS patients with the APOE-e4/e4 allele may also have an increased rate of disease progression.

Standardization of facilitation of compound muscle action potentials evoked by magnetic stimulation of the cortex. Results in healthy volunteers and in patients with multiple sclerosis

To establish the importance of standardization of the facilitation of central motor conduction measured by magnetic stimulation we studied the effect of increasing voluntary muscle contraction on the central motor conduction time (CMCT) and motor evoked potential (MEP) amplitudes for 3 upper and 2 lower limb muscles. MEPs were elicited by magnetic stimulation of the cortex and the spinal roots. Muscle force was indirectly assessed from the integrated electrical muscle activity and expressed as the root mean square (RMS) and was varied from 0 to 40% of maximal activity. The central motor conduction time (CMCT) decreased during increasing muscle contraction, reaching constant values at approximately 10-20% RMSmax. Similarly, the increases of MEP amplitude tapered off at about the same RMS level. For each muscle an optimal RMS level was defined. The shortening of the CMCTs at the optimal RMS levels were: the brachial biceps, 3.4 msec; the radial carpal flexor of the wrist, 2.7 msec; the first dorsal interosseus muscle of the hand, 2.9 msec; the anterior tibial, 4.2 msec; and the abductor hallucis, 2.4 msec. The standardizing procedure was applied to 10 patients with multiple sclerosis. The stimulus thresholds were higher in these patients compared with those of the normals. Only the CMCT reduction of the BB was significantly larger (8.1 msec) than in the controls. Using standardized facilitation the diagnostic value of the amplitudes seems to be only a little less than that of the CMCTs.

A longitudinal study of cerebral glucose metabolism, MRI, and disability in patients with MS

Objective: To study the time-related changes in cerebral metabolic rate of glucose (CMRglc) in MS patients and to correlate these with changes in MRI lesion load and disability. Background: Measurements of MRI lesion load and neurologic disability are used widely to monitor disease progression in longitudinal studies of MS patients, but little is known about the associated changes in cerebral neural function. Methods: The authors studied 10 patients with clinically definite MS who underwent serial measurements of CMRglc, MRI T2-weighted total lesion area (TLA), and clinical evaluation of disability (Expanded Disability Status Scale [EDSS]) over a period of approximately 2 years (three examinations). CMRglc was calculated using PET and 18-fluorodeoxyglucose (FDG). Results: The global cortical CMRglc decreased with time (p < 0.001) and the most pronounced reductions of CMRglc were detected in frontal and parietal cortical areas. There was a statistically significant increase of disability (p < 0.01) and TLA (p < 0.05) measurements during the study, but changes in CMRglc were not correlated to changes in TLA and EDSS. Conclusions: Global cortical cerebral metabolism in MS is decreased significantly during a 2-year observation period, suggesting a deterioration of cortical activity with disease progression. The time-related changes of cortical CMRglc are statistically stronger than changes in TLA measurements and neurologic disability, and might be a useful secondary measure of treatment efficacy.

The management of multiple sclerosis in children: a European view

About 3—5% of all patients with multiple sclerosis experience the onset of their disease under the age of 16. A significant proportion of paediatric multiple sclerosis patients develop significant cognitive disturbances and persistent physical disability. The high relapse rate and the morbidity in the paediatric multiple sclerosis population has triggered the use of disease-modifying therapies that have been shown to reduce relapse rate, disease progression and cognitive decline in adult patients with multiple sclerosis. Hard evidence for the right treatment and its appropriate timing is scarce in paediatric multiple sclerosis. Nevertheless, expertise in this field has grown thanks to recent open-label trials and experience generated in specialized centres. In spring 2009, a first meeting was held in Rotterdam with clinicians from 11 European countries (one from Canada) that are all active in the management of paediatric multiple sclerosis. One of the aims was to generate a common view on the management of paediatric multiple sclerosis patients. The result of this meeting is presented here to help standardize treatment and to support clinicians with less experience in this field.

The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects

B cells play a central role in the pathogenesis in multiple sclerosis (MS), being involved in the activation of proinflammatory T cells, secretion of proinflammatory cytokines, and production of autoantibodies directed against myelin. Hence, the usage of B-cell-depleting monoclonal antibodies as therapy for autoimmune diseases including MS lay near at hand. Rituximab was the first therapeutic B-cell-depleting chimeric monoclonal antibody to be used successfully in MS. Ocrelizumab, a second-generation humanized anti-CD20 antibody, was explored in a large phase II, randomized, placebo-controlled multicentre trial in patients with relapsing–remitting disease. Compared with placebo, two doses of ocrelizumab (600 and 2000 mg on days 1 and 15) showed a pronounced effect on disease activity seen in magnetic resonance imaging (MRI) as gadolinium-enhanced lesions (89% and 96% relative reduction, both p < 0.001) and also had a significant effect on relapses. In exploratory analyses, both doses of ocrelizumab had better effect on gadolinium-enhanced lesions than interferon beta-1a intramuscularly that was used as a reference arm. Adverse effects were mainly infusion-related reactions, in particular during the first infusion. Serious infections occurred at similar rates in ocrelizumab and placebo-treated patients, and no opportunistic infections were reported. However, progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with anti-CD20 monoclonal antibodies for other indications. Other anti-CD20 monoclonal antibodies have been tested as treatments for MS, including ofatumumab that has shown beneficial results in placebo-controlled phase II trials in patients with relapsing–remitting MS. Ocrelizumab is now in phase III development for the treatment of relapsing–remitting MS, as well as primary progressive MS, and the results of ongoing clinical trials are eagerly awaited and will determine the place of ocrelizumab in the armamentarium of MS therapies.

Correlations of brain MRI parameters to disability in multiple sclerosis

Objectives– The objective was to correlate magnetic resonance imaging (MRI) T2‐weighted lesion load and measures of white matter atrophy in the brain to disability in a population‐based sample of patients with multiple sclerosis (MS). Material and methods– A well defined cohort of patients was drawn at random from the general MS population by using the Danish Multiple Sclerosis Reigistry. A semi‐automated local thresholding technique was used to quantify T2‐weighted lesions on MRI; whereas manual tracing was applied to measure the corpus callosum brain ratio (CCR) and the ventricle brain ratio (VBR). Results– A sample of 86 patients with a mean age of 43.3 years (SD 4.3), mean disease duration of 13.6 years (SD 4.4) and a median Expanded Disability Status Score (EDSS) of 6.0 was identified. The correlation between total lesion area of the brain (TLA) and disability (EDSS) for the whole sample was moderate (Spearman rank correlation coefficient r=0.48, P<0.001). Also correlations of CCR and VBR to disability (r=0.32–0.46) were significant. Conclusions– Correlations of TLA and disability in this study were rather strong. Hence, T2‐weighted MRI lesion load in the brain still plays an important role as a surrogate marker of disease and as a secondary outcome measure in phase III treatment trials.