Nikos Evangelou

Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis.

We assessed axonal loss in the normal appearing white matter of the corpus callosum in postmortem brains of patients with multiple sclerosis, using quantitative measures of both axonal density and white matter atrophy. The calculated total number of axons was reduced significantly (mean ± SD, 5.4 × 107 ± 3.1 × 107) compared with normal controls (11.6 × 107 ± 2.2 × 107, p = 0.001) with a reduction both in axonal density (median, 34%; range, 16–56%; p = 0.004) and area (mean ± SD: multiple sclerosis, 584 ± 170 mm2; controls, 871 ± 163 mm2; p = 0.004). These results confirm substantial axonal loss in the normal appearing white matter and demonstrate that measures of both axonal density and white matter volume are necessary to appreciate the full extent of axonal loss. Ann Neurol 2000;47:391–395

Association between pathological and MRI findings in multiple sclerosis

The identification of pathological processes that could be targeted by therapeutic interventions is a major goal of research into multiple sclerosis (MS). Pathological assessment is the gold standard for such identification, but has intrinsic limitations owing to the limited availability of autopsy and biopsy tissue. MRI has gained a leading role in the assessment of MS because it allows doctors to obtain an ante mortem picture of the degree of CNS involvement. A number of correlative pathological and MRI studies have helped to define in vivo the pathological substrates of MS in focal lesions and normal-appearing white matter, not only in the brain, but also in the spinal cord. These studies have resulted in the identification of aspects of pathophysiology that were previously neglected, including grey matter involvement and vascular pathology. Despite these important achievements, numerous open questions still need to be addressed to resolve controversies about how the pathology of MS results in fixed neurological disability.

MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines

Summary In patients presenting with a clinically isolated syndrome (CIS), magnetic resonance imaging (MRI) can support and substitute clinical information for multiple sclerosis (MS) diagnosis demonstrating disease dissemination in space (DIS) and time (DIT) and helping to rule out other conditions that can mimic MS. From their inclusion in the diagnostic work-up for MS in 2001, several modifications of MRI diagnostic criteria have been proposed, in the attempt to simplify lesion-count models for demonstrating DIS, change the timing of MRI scanning for demonstrating DIT, and increase the value of spinal cord imaging. Since the last update of these criteria, new data regarding the application of MRI for demonstrating DIS and DIT have become available and improvement in MRI technology has occurred. State-of-the-art MRI findings in these patients were discussed in a MAGNIMS workshop, the goal of which was to provide an evidence-based and expert-opinion consensus on diagnostic MRI criteria modifications.

Regional variations in the extent and pattern of grey matter demyelination in Multiple Sclerosis: a comparison between the cerebral cortex, cerebellar cortex, deep grey matter nuclei and the spinal cord

Background: Substantial grey matter (GM) demyelination occurs in both the cerebral cortex and spinal cord in multiple sclerosis (MS). GM demyelination also occurs in the cerebellar cortex and the deep GM nuclei of the brain. However, no study has made a direct “within subject” comparison of the extent of GM pathology between these regions. Aim: To examine the extent and pattern of GM demyelination in the motor cortex, cingulate gyrus, cerebellum, thalamus and spinal cord in MS. Methods: Postmortem study using material from 14 MS cases and three controls. Sections were taken from the five predetermined areas and stained for proteolipid protein. The extent of GM and white matter (WM) demyelination was assessed in each region. Results and conclusion: Overall, 28.8% of the GM was demyelinated compared with 15.6% of the WM (p<0.001), with demyelination being greater in the GM than in the WM at each of the anatomical sites. There was substantial variation in the extent of demyelination between the different CNS regions. GM demyelination was most extensive in the spinal cord and cerebellum while WM demyelination was most prominent in the spinal cord.

DEMONSTRATING THE PERIVASCULAR DISTRIBUTION OF MS LESIONS IN VIVO WITH 7-TESLA MRI

While most white matter (WM) demyelinating lesions in multiple sclerosis (MS) have a perivascular distribution, heterogeneity in lesion pathology has been shown to include a variable relationship between lesions and parenchymal blood vessels.1 Reports that such lesion characteristics at brain biopsy predict treatment response suggest that identifying perivascular lesions in vivo could be clinically relevant.2 It is unclear, however, to what extent the age and topographic location of a lesion influence its vascular anatomy. This pilot study aimed to develop an imaging technique capable of defining the relationship between demyelination and small parenchymal blood vessels in MS. Comparison between T2-weighted MR images at 1.5 tesla with subsequent venography has previously been used to determine the relationship of lesions to blood vessels.3 While this technique can demonstrate an MS lesion and a blood vessel in close proximity, the inability to demonstrate both structures simultaneously means the exact spatial relationship cannot be defined or followed longitudinally. Ultra-high field human MRI offers an increased signal to noise ratio and enhanced spatial resolution compared to clinical MRI scanners, at the expense of increased radiofrequency and static field inhomogeneity which result in a (smooth) variation of intensity across the image and distortions at structural boundaries. T2* contrast observed at ultra high field strengths …

Ultra-high-field imaging distinguishes MS lesions from asymptomatic white matter lesions

Objectives: To investigate whether multiple sclerosis (MS) and non-MS white matter brain lesions can be distinguished by their appearance on 7 T T2*-weighted MRI. Methods: This was an observational study of 28 patients with MS and 17 patients with cerebral white matter lesions who did not have MS. Subjects were imaged using 7 T T2*-weighted imaging. White matter lesions were identified and analyzed for volume, location, and perivenous appearance. Results: Out of 901 lesions identified in patients with MS, 80% were perivenous. In comparison, 19% of 428 lesions identified in patients without MS had a perivenous appearance. Seven-Tesla T2*-weighted MRI reliably distinguished all patients with clinically definite MS (>40% lesions appeared perivenous) from those without clinical MS (<40% lesions appeared perivenous). Perivenous lesion appearance was more predictive of MS (odds ratio [OR] 14, p < 0.001) than subcortical or periventricular lesion location (OR 4.5, p < 0.001, and OR 2.4, p = 0.009). Perivenous lesion appearance was observed with a similar frequency in patients with clinically isolated syndrome of demyelination and in early (gadolinium-enhancing) MS lesions. Conclusion: Perivenous lesion location on 7 T T2*-weighted imaging is predictive of the presence of demyelination. Optimization of this imaging technique at lower magnetic resonance field strengths would offer benefit for the diagnosis of MS.

A Comparison of 3T and 7T in the Detection of Small Parenchymal Veins Within MS Lesions

Objective:Histologic examination of multiple sclerosis (MS) brain lesions reveals heterogeneity including the presence or absence of a central blood vessel. Recent work has shown that T2* weighted magnetic resonance imaging at 7T allows the identification of small parenchymal veins within MS lesions. The aims of this study were (1) to compare whether a comparable sequence at 3T was also capable of demonstrating parenchymal veins within MS brain lesions, and (2) to investigate the potential of 7T T2* weighted imaging to differentiate between MS white matter lesions and age-related vascular lesions seen in controls. Materials and Methods:Seven patients with demyelinating brain disease and 7 healthy volunteers were scanned at 3T and 7T. Fluid attenuated inversion recovery (FLAIR) images acquired at 3T were used to identify each brain lesion in each patient. A comparison of images from both field strengths was then made to determine whether white matter lesions seen in 3T FLAIR images could be identified in T2*-weighted images, and whether a central vein could be detected. Results:A total of 358 brain lesions were identified in the brains of the 7 patients using 3T FLAIR images. The 3T T2* sequence detected 89% of FLAIR lesions compared with 94% using the 7T T2* sequence (P = 0.0002). A central vessel could be identified in 45% of visible lesions using 3T T2* and 87% of visible lesions using 7T T2* (P < 0.0001). Using 7T T2* imaging, a central vein was evident in only 8% of the discrete white matter lesions found in the brains of healthy volunteers. Discussion:This study suggests that ultra high field imaging is advantageous in demonstrating detailed structural anatomy of MS lesions. 7T T2* imaging can be used in the future to investigate the pathogenesis of MS lesions. The potential for ultra high field imaging to discriminate between MS white matter lesions and microangiopathic lesions warrants further investigation as this would represent a clinically useful application.

Spinal cord gray matter demyelination in multiple sclerosis : A novel pattern of residual plaque morphology

The extent and pattern of gray matter (GM) demyelination in the spinal cord in multiple sclerosis (MS) has not been examined in detail. Human autopsy material was obtained from 36 MS cases and 12 controls. Transverse sections were taken from five levels of the spinal cord (upper cervical, lower cervical, upper thoracic, lower thoracic and lumbar levels) and the extent of GM and white matter (WM) demyelination evaluated using proteolipid protein immunohistochemistry (IHC). The proportion of the GM that was demyelinated (33%) was significantly greater than the proportion of demyelinated WM (20%) (P < 0.0001). Similarly, demyelination was more extensive in the GM than in the WM at each of the five cord levels. The extent of GM demyelination was not significantly different between the five cord levels while WM demyelination was greatest at the upper cervical level. Morphologically, the borders of a proportion of the GM plaques show a strict respect for the GM/WM boundary. We demonstrate that extensive demyelination occurs in the GM of the spinal cord in MS. Myelin protein IHC reveals a novel pattern of residual plaque morphology challenging previous work suggesting that MS plaques display a total disregard for anatomical boundaries.

Association of the APOE epsilon4 allele with disease activity in multiple sclerosis.

OBJECTIVES Allelic variants of the APOE gene are known to influence the course of many neurological diseases and there is increasing evidence that apolipoprotein E (APOE) is a pivotal component in reinnervation and dendritic remodelling after neuronal injury. Previous studies did not show significant differences in the APOE allele frequencies in multiple sclerosis compared with controls but did not examine for correlation with disease severity. This study explores the relation of APOE genotypes with the disease severity. METHODS Ninety five patients with multiple sclerosis were studied. Age of onset, type, and activity of the disease were recorded prospectively and genotyping was performed according to standard protocols. RESULTS APOE allele frequencies of the group as a whole, the relapsing group, or the primary progressive group were not significantly different from those reported from matched historical controls. The ε4 allele was found to be more common in patients with a more aggressive type of multiple sclerosis (odds ratio=2.95, p=0.03). CONCLUSIONS Although APOE does not seem to be implicated in the early pathogenesis of the disease, patients possessing the ε4 allele might have a reduced capacity for neuronal remodelling after relapses.

Distinction of seropositive NMO spectrum disorder and MS brain lesion distribution

Objective: Neuromyelitis optica and its spectrum disorder (NMOSD) can present similarly to relapsing-remitting multiple sclerosis (RRMS). Using a quantitative lesion mapping approach, this research aimed to identify differences in MRI brain lesion distribution between aquaporin-4 antibody–positive NMOSD and RRMS, and to test their diagnostic potential. Methods: Clinical brain MRI sequences for 44 patients with aquaporin-4 antibody–positive NMOSD and 50 patients with RRMS were examined for the distribution and morphology of brain lesions. T2 lesion maps were created for each subject allowing the quantitative comparison of the 2 conditions with lesion probability and voxel-wise analysis. Results: Sixty-three percent of patients with NMOSD had brain lesions and of these 27% were diagnostic of multiple sclerosis. Patients with RRMS were significantly more likely to have lesions adjacent to the body of the lateral ventricle than patients with NMOSD. Direct comparison of the probability distributions and the morphologic attributes of the lesions in each group identified criteria of “at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or the presence of a subcortical U-fiber lesion; or a Dawsons finger-type lesion,” which could distinguish patients with multiple sclerosis from those with NMOSD with 92% sensitivity, 96% specificity, 98% positive predictive value, and 86% negative predictive value. Conclusion: Careful inspection of the distribution and morphology of MRI brain lesions can distinguish RRMS and NMOSD.