Athina Papadopoulou

Contribution of cortical and white matter lesions to cognitive impairment in multiple sclerosis

Background: Cortical lesions (CLs) have been reported to be a better predictor for cognitive impairment than white matter (WM) lesions in relapsing–remitting multiple sclerosis (RRMS). Objectives: The objectives of this article are to investigate the contribution of CLs and WM lesions to cognitive impairment in 91 patients with MS and clinically isolated syndrome, and to test potential associations of CLs and WM lesions with fatigue and depression. Methods: Lesions were scored and segmented on 3D double inversion recovery sequences, according to their location (cortical, WM). Normalised grey matter volume was also determined. Cognitive performance was assessed with the SDMT and PASAT-3, fatigue with the FSMC and depression with the German version of the CES-D. Results: CL volume did not correlate with fatigue or depression, but correlated significantly with both neuropsychological outcome measures: PASAT-3 (r = −0.275, p = 0.009) and SDMT (r = −0.377, p < 0.001). Multiple regression analyses with age, WM lesions, CLs and GM volume as independent variables, however, did not reveal CL volume as a significant predictor of neuropsychological outcomes, whereas WM lesion volume significantly predicted SDMT and by trend PASAT performance. Conclusions: These findings suggest a role of WM lesions in the development of cognitive deficits, especially information-processing speed, which may be higher than previously assumed. Abbreviations: CES-D: Center for Epidemiologic Studies Depression scale (ADS-L: Allgemeine Depressions Skala-L, German version of CES-D), CIS: clinically isolated syndrome, CL: cortical lesion, DIR: double inversion recovery, EDSS: Expanded Disability Status Scale, FSMC: fatigue scale for motor and cognitive functions, GM: grey matter, MRI: magnetic resonance imaging, MS: multiple sclerosis, PASAT-3: paced auditory serial addition test 3s, PPMS: primary progressive multiple sclerosis, RRMS: relapsing–remitting multiple sclerosis, SDMT: symbol digit modalities test, SPM: statistical parametric mapping, SPMS: secondary progressive multiple sclerosis, WM: white matter

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.

Dimethyl fumarate for multiple sclerosis

Importance of the field: One of the disadvantages of currently available disease-modifying drugs (DMDs) for multiple sclerosis (MS) is their parenteral administration. Moreover, efficacy is only partial. Most patients treated with first-line DMDs do not remain relapse-free. There is a need for new oral drugs that are more effective than currently available compounds. Innovative oral drugs with new mechanisms of action showed promising results in clinical trials. One of these emerging drugs is BG00012 (BG-12), a fumaric acid ester (FAE). Its active agent, dimethyl fumarate had first been included in FAE treatments for psoriasis. Areas covered in this review: Results that highlight the potential role of BG-12 in MS treatment. We focus on findings of experimental studies and current results of clinical studies with FAE in MS. What the reader will gain: An overview of the immunomodulatory and neuroprotective effects of FAE, their effect in animal models of MS and their short-term efficacy and safety profile in a Phase IIb clinical trial. Take home message: BG-12 is a promising emerging treatment for relapsing–remitting MS, combining anti-inflammatory and possibly clinically relevant neuroprotective effects with the convenience of oral administration. However, the future role of BG-12 in treatment of MS will have to be determined after the completion of ongoing Phase III studies.

Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis

The SENTINEL study showed that the addition of natalizumab improved outcomes for patients with relapsing multiple sclerosis (MS) who had experienced disease activity while receiving interferon beta-1a (IFNbeta-1a) alone. Previously unreported secondary and tertiary magnetic resonance imaging (MRI) measures are presented here. Patients received natalizumab 300 mg (n=589) or placebo (n=582) intravenously every 4 weeks plus IFNbeta-1a 30 microg intramuscularly once weekly. Annual MRI scans allowed comparison of a range of MRI end points versus baseline. Over 2 years, 67% of patients receiving natalizumab plus IFNbeta-1a remained free of new or enlarging T2-lesions compared with 30% of patients receiving IFNbeta-1a alone. The mean change from baseline in T2 lesion volume over 2 years decreased in patients receiving natalizumab plus IFNbeta-1a and increased in those receiving IFNbeta-1a alone (-277.5mm(3) versus 525.6mm(3); p<0.001). Compared with IFNbeta-1a alone, add-on natalizumab therapy resulted in a smaller increase in mean T1-hypointense lesion volume after 2 years (1821.3mm(3) versus 2210.5mm(3); p<0.001), a smaller mean number of new T1-hypointense lesions over 2 years (2.3 versus 4.1; p<0.001), and a slower rate of brain atrophy during the second year of therapy (-0.31% versus -0.40%; p=0.020). Natalizumab add-on therapy reduced gadolinium-enhancing, T1-hypointense, and T2 MRI lesion activity and slowed brain atrophy progression in patients with relapsing MS who experienced disease activity despite treatment with IFNbeta-1a alone.

Safety of teriflunomide for the management of relapsing-remitting multiple sclerosis

Introduction: Teriflunomide is a new oral disease-modifying drug (DMD), recently approved for the first-line treatment of relapsing multiple sclerosis (MS). Since MS is a chronic disease, which often necessitates long-term treatment, data not only on efficacy but also on long-term safety, including pregnancy-related issues, are very important. Areas covered: In this review article, we outline the key preclinical and clinical data on teriflunomide with a focus on its safety profile. We summarize adverse events observed in the Phase II and III clinical trials and the safety data from the long-term extension phases as well as the > 15-year post-marketing experience with the parent drug, leflunomide. We also consider the evidence regarding immune competence and potential fetal risks of the drug. Expert opinion: Teriflunomide has the advantage of a convenient once-daily oral administration scheme and a large body of evidence suggesting a manageable safety profile (clinical development program with > 6800 patient-years of exposure and post-marketing experience with leflunomide). Further post-marketing data, especially regarding pregnancy outcomes and risks of infections, will help to define the exact place of teriflunomide in the treatment of MS in the future, especially compared with the other oral DMDs.

Lesion-to-ventricle distance and other risk factors for the persistence of newly formed black holes in relapsing–remitting multiple sclerosis

Background: Progenitor cells from the subventricular zone (SVZ) of the lateral ventricles are assumed to contribute to remyelination and resolution of black holes (BHs) in multiple sclerosis (MS). This process may depend on the distance between the lesion and the SVZ. Objective: The objective of this paper is to investigate the relationship between lesion-to-ventricle (LV) distance and persistence of new BHs. Methods: We analysed the magnetic resonance images (MRIs) of 289 relapsing–remitting (RR) MS patients, obtained during a multi-centre, placebo-controlled phase II trial over one year. Results: Overall, 112/289 patients showed 367 new BHs at the beginning of the trial. Of these, 225 were located in 94/112 patients at the level of the lateral ventricles on axial MRIs and included in this analysis. In total, 86/225 (38%) BHs persisted at month 12. LV distance in persistent BHs (PBHs) was not longer than in transient BHs. In fact PBHs tended to be closer to the SVZ than transient BHs. A generalised linear mixed multivariate model adjusted for BHs clustered within a patient and including patient- as well as lesion-specific factors revealed size, ring contrast enhancement, and shorter LV distance as independent predictors for BH persistence. Conclusion: Location of BHs close to the lateral ventricles does not appear to favourably influence the resolution of new BHs in RRMS.

MRI characteristics of periaqueductal lesions in multiple sclerosis

BACKGROUND In multiple sclerosis (MS), periaqueductal lesions (PAL) have been described histopathologically. OBJECTIVES We sought to investigate the frequency and characteristics of PAL on magnetic resonance images (MRIs) in patients with MS or clinically isolated syndrome (CIS). METHODS We analyzed proton density (PD)-weighted MRIs of 247 MS and 10 CIS patients. PAL were identified based on their abnormal hyperintensity and lesion shape on at least two consecutive slices. Patients with and without PAL were compared for clinical characteristics in a propensity score weighted analysis. RESULTS We identified PAL in 48/257 patients (18.7%), 34 of which had CIS or relapsing-remitting MS and 14 a progressive disease course. The shape of PAL was often circular (65%), or/and wedge-like (42%). Multi-planar image analysis in a subgroup of patients with double inversion recovery sequences revealed that 36% of PAL were periventricular lesions of the third ventricle extending towards the aqueduct. We found an association of PAL and brainstem functional system. CONCLUSIONS Although PAL may be underreported in MS, they are relatively frequent and found at all clinical stages and in CIS. They could be considered as a variant of periventricular lesions in the supratentorial midbrain and thus be useful in the diagnosis of MS.

Detection of Cerebrospinal Fluid Leaks by Intrathecal Contrast-Enhanced Magnetic Resonance Myelography

A 70-year-old woman had double vision, nausea, neck pain, and acute bilateral hypacusis. The neurological examination showed nerve VI palsy on the right. There was no history of trauma. Brain magnetic resonance (MR) imaging was indicative of intracranial hypotension, with diffuse pachymeningeal thickening, strong dural enhancement, and frontoparietal subdural hygromas. A radioisotope cisternography, performed in the search for a potential spinal cerebrospinal fluid (CSF) leak, was inconclusive. Thus, intrathecal gadolinium-enhanced MR myelography was considered as a possible alternative. Before intrathecal gadolinium administration, an MR image of the spinal cord showed a small perineural cyst at the level of L2 on the right but no evidence of a CSF leakage. The intrathecal gadolinium-enhanced MR myelography provided clear-cut evidence of dural leaks along the right L2 and L3 nerve roots (Figure). According to these findings, targeted epidural blood patching was performed and the patient’s symptoms gradually improved during the following month. At 1-year follow-up, she was asymptomatic.

Association of clinical headache features with stroke location: An MRI voxel-based symptom lesion mapping study.

Background We have recently shown that the presence of headache in ischemic stroke is associated with lesions of the insular cortex. The aim of this post-hoc subgroup analysis was to investigate the association of specific headache features with stroke location in patients with acute ischemic stroke. Methods In this observational study, patients (mean age: 61.5, 58% males) with ischemic stroke and acute headache (n = 49) were investigated. Infarcts were manually outlined on 3D diffusion weighted magnetic resonance imaging (MRI) scans and transformed into standard stereotaxic space; lesions of the left hemisphere were mirrored in the x-axis to allow a voxel-wise group analysis of all patients. We analyzed the association of lesion location and the following phenotypical characteristics by voxel-based symptom lesion mapping: Headache intensity, different qualities of headache (pulsating, tension-type like and stabbing), and the presence of nausea, of cranial autonomic symptoms and of light or noise sensitivity. Results Headache intensity was associated with lesions of the posterior insula, the operculum and the cerebellum. “Pulsating” headache occurred with widespread cortical and subcortical strokes. The presence of “tension-like” and “stabbing” headache was not related to specific lesion patterns. Nausea was associated with lesions in the posterior circulation territory. Cranial-autonomic symptoms were related to lesions of the parietal lobe, the somatosensory cortex (SI) and the middle temporal cortex. The presence of noise sensitivity was associated with cerebellar lesions, whereas light sensitivity was not related to specific lesions in our sample. Conclusion Headache phenotype in ischemic stroke appears to be related to specific ischemic lesion patterns.

Decision for intravenous thrombolysis in a young patient with acute vertical gaze palsy

any vascular risk factors. The neurological examination revealed a skew deviation with complete vertical gaze palsy involving both upward and downward gaze, while horizontal gaze was intact. The calculated National Institute of Health Stroke Scale (NIHSS) was two. Since magnetic resonance imaging (MRI) was not available in this emergency setting, a non-enhanced brain computed tomography (CT) was performed, which did not show any signs of hemorrhage or infarction. Moreover, the CTarteriography was normal. However, dynamic perfusion CT showed a small area of delayed perfusion (abnormally prolonged time to peak, TTP) in the right paramedian thalamus, while cerebral blood volume (CBV) was only slightly reduced, revealing a TTP-CBV mismatch (Fig. 1).