Carsten Lukas

Oral fumaric acid esters for the treatment of active multiple sclerosis: an open‐label, baseline‐controlled pilot study

An exploratory, prospective, open‐label study of fumaric acid esters (FAE, Fumaderm®) was conducted in patients with relapsing–remitting multiple sclerosis (RRMS). The study consisted of the following four phases: 6‐week baseline, 18‐week treatment (target dose of 720 mg/day), 4‐week washout, and a second 48‐week treatment phase (target dose of 360 mg/day). Ten patients with an Expanded Disability Status Scale (EDSS) score of 2.0–6.0 and at least one gadolinium‐enhancing (Gd+) lesion on T1‐weighted magnetic resonance imaging (MRI) brain scans participated in the study. Safety was assessed by adverse events (AEs), blood chemistry/hematology, electrocardiogram, and urinalysis. The primary efficacy outcomes were number and volume of Gd+ lesions. Other clinical outcomes included EDSS score, ambulation index (AI), and nine‐hole peg test (9‐HPT). Effects of FAE on intracellular cytokine profiles, T‐cell apoptosis, and soluble adhesion molecules were also assessed. Three patients withdrew during the first 3 weeks of the study because of side effects, non‐compliance, and follow‐up loss. The most common AEs were gastrointestinal symptoms and flushing; all AEs were reported as mild and reversible. FAE produced significant reductions from baseline in number (P < 0.05) and volume (P < 0.01) of Gd+ lesions after 18 weeks of treatment; this effect persisted during the second treatment phase at half the target dose after the 4‐week washout period. EDSS scores, AI, and 9‐HPT remained stable or slightly improved from baseline in all patients. Measures of T‐cell function demonstrated alterations in cytokines and circulating tumor necrosis factor. The results of this exploratory study suggest that further studies of FAE in patients with MS are warranted.

Improved in vivo detection of cortical lesions in multiple sclerosis using double inversion recovery MR imaging at 3 Tesla

ObjectiveTo investigate the impact of a higher magnetic field strength of 3 Tesla (T) on the detection rate of cortical lesions in multiple sclerosis (MS) patients, in particular using a dedicated double inversion recovery (DIR) pulse sequence.MethodsThirty-four patients with clinically isolated syndromes or definite MS were included. All patients underwent magnetic resonance imaging (MRI) at 1.5 T and 3 T, including T2-weighted turbo spin echo (TSE), fluid-attenuated inversion recovery (FLAIR) and DIR sequences. All images were analysed for focal lesions categorised according to their anatomical location.ResultsThe total number of detected lesions was higher at 3 T across all pulse sequences. We observed significantly higher numbers of lesions involving the cortex at 3 T using a DIR sequence. DIR at 3 T showed 192% more pure intracortical (p < 0.001) and 30% more mixed grey matter-white matter lesions (p = 0.008). No significant increase in cortical lesions could be detected on the FLAIR and T2-weighted images. Using the T2-weighted and FLAIR sequences, significantly more lesions could be detected at 3 T in the infratentorial, periventricular and juxtacortical white matter.ConclusionDIR brain MR imaging at 3 T substantially improves the sensitivity of the detection of cortical lesions compared with the standard magnetic field strength of 1.5 T.

Towards the implementation of ‘no evidence of disease activity’ in multiple sclerosis treatment: the multiple sclerosis decision model

Objective: The introduction of new and potent therapies for the treatment of relapsing remitting multiple sclerosis (MS) has increased the desire for therapeutic success. There is growing doubt that the mere reduction of relapse rate, Expanded Disability Status Scale (EDSS) progression and magnetic resonance imaging (MRI) markers are exclusive and appropriate factors to monitor the new aim of ‘no evidence of disease activity’ (NEDA). However, there is no generally accepted definition so far. Methods: To achieve the therapeutic aim of NEDA, a panel of MS experts searched the available literature on clinical and paraclinical outcomes to propose a test battery that is sensitive to detect disease activity in an everyday clinical setting. Results: The panel proposed to include, besides relapse rate, disability progression and MRI, neuropsychological outcome measures such as cognitive status, fatigue, depression and quality of life. To standardize the examinations in an economic and schematic way, a multifactorial model [multiple sclerosis decision model (MSDM)] that includes the domains ‘relapse’, ‘disability progression’, ‘MRI’, and ‘neuropsychology’ is proposed. The scheme reflects the complexity of the disease even in the early stages when scales such as the EDSS are not able to distinguish low levels of progression. Conclusion: The MSDM aims to support early treatment decisions and uncover timely treatment failure. Prospective investigations are required to prove that such a disease-monitoring concept leads to an early and effective silencing of disease activity.

Relevance of Spinal Cord Abnormalities to Clinical Disability in Multiple Sclerosis: MR Imaging Findings in a Large Cohort of Patients

PURPOSE To determine whether spinal cord atrophy differs among disease subtypes in multiple sclerosis (MS) and whether it offers diagnostic and clinical correlative information beyond that provided by other magnetic resonance (MR) imaging markers. MATERIALS AND METHODS The institutional review board approved the study; all subjects gave written informed consent. Upper cervical cord cross-sectional area (UCCA), brain and spinal cord lesion loads, and brain atrophy were measured in 440 patients with MS (311 with relapsing-remitting [RR] MS, 92 with secondary-progressive [SP] MS, and 37 with primary-progressive [PP] MS) studied in two centers. Disability was scored with the Expanded Disability Status Scale (EDSS), the timed 25-foot walk test (TWT), and the nine-hole peg test. UCCA was compared between groups with the Mann-Whitney U test. Correlations were assessed with the Spearman ρ test. Multivariate associations between UCCA and clinical and other MR imaging parameters, including number of hypointense brain lesions on T1-weighted MR images, presence of diffuse abnormalities, and number of involved segments in the spinal cord, were assessed by using multiple linear regression, adjusted for study center site. RESULTS The UCCA in patients with SP MS (median, 79 mm(2); interquartile range, 72.4-84.9 mm(2)) and PP MS (median, 77.3 mm(2); interquartile range, 69-82.5 mm(2)) was significantly smaller (P < .001) than that in patients with RR MS (median, 84 mm(2); interquartile range, 78.7-89.3 mm(2)). UCCA was inversely correlated with EDSS score, TWT, and nine-hole peg test findings (ρ ≤ -0.29, P < .001 for all comparisons). UCCA, number of hypointense brain lesions on T1-weighted MR images, presence of diffuse abnormalities, and number of involved segments in the spinal cord were found to be significant explanatory factors for clinical disability (R(2) = 0.564). The UCCA and the number of hypointense brain lesions on T1-weighted images were the strongest MR imaging parameters for explaining physical disability, as measured with the EDSS. CONCLUSION Spinal cord abnormalities have a strong effect on clinical disability in MS. MR imaging-derived UCCA was found to be the most significant spinal cord parameter for explaining EDSS score.

Disease course and outcome of 15 monocentrically treated natalizumab-associated progressive multifocal leukoencephalopathy patients

Objective Although the prognosis of natalizumab-associated progressive multifocal leukoencephalopathy (PML) seems to be better than HIV-associated PML, little is known about the long-term functional outcome in multiple sclerosis (MS) patients and the subsequent return of MS disease activity. We evaluated retrospectively 15 patients with natalizumab-associated PML treated at our centre. Patients and methods Fifteen MS-PML patients (nine women, six men) were referred to us from adjacent local centres. The patients had a median natalizumab exposure of 34 months at PML diagnosis. They received standardised treatment as described in previous work. Expanded Disability Status Scale (EDSS) and Karnofsky score in the year pre-PML, at PML-diagnosis (pre-immune reconstitution inflammatory syndrome (IRIS)) and post-PML were determined in 3–6 monthly intervals. Results The median follow-up of these 15 patients was 21.5 months. None of the 15 patients died. Three patients had a Karnofsky score of 80 or higher, nine patients between 50–70 and three patients of 40 or lower at latest examination. Eight of the 15 patients developed seizures during acute PML phase. Fifty percent of those patients were not seizure-free one year post PML, despite continuation of antiepileptic treatment. The median EDSS in the year pre-PML was 2.5, 4.5 at PML diagnosis, 6.5 post-IRIS and 5.5 at latest examination. CSF became virus-free in eight of the 15 patients after a median time of 4.5 months. In nine patients, disease reappeared after a median time of seven months from PML diagnosis. Conclusions Although the clinical outcome of natalizumab-treated PML patients is much better than in patients with HIV-associated PML, this may be further improved by treatment at reference centres using standardised therapy regimens and transient intensive care if needed. Systematic studies of appropriate MS immunotherapies after PML are critically needed.

Mechanisms mediating parallel action monitoring in fronto-striatal circuits.

Flexible response adaptation and the control of conflicting information play a pivotal role in daily life. Yet, little is known about the neuronal mechanisms mediating parallel control of these processes. We examined these mechanisms using a multi-methodological approach that integrated data from event-related potentials (ERPs) with structural MRI data and source localisation using sLORETA. Moreover, we calculated evoked wavelet oscillations. We applied this multi-methodological approach in healthy subjects and patients in a prodromal phase of a major basal ganglia disorder (i.e., Huntingtons disease), to directly focus on fronto-striatal networks. Behavioural data indicated, especially the parallel execution of conflict monitoring and flexible response adaptation was modulated across the examined cohorts. When both processes do not co-incide a high integrity of fronto-striatal loops seems to be dispensable. The neurophysiological data suggests that conflict monitoring (reflected by the N2 ERP) and working memory processes (reflected by the P3 ERP) differentially contribute to this pattern of results. Flexible response adaptation under the constraint of high conflict processing affected the N2 and P3 ERP, as well as their delta frequency band oscillations. Yet, modulatory effects were strongest for the N2 ERP and evoked wavelet oscillations in this time range. The N2 ERPs were localized in the anterior cingulate cortex (BA32, BA24). Modulations of the P3 ERP were localized in parietal areas (BA7). In addition, MRI-determined caudate head volume predicted modulations in conflict monitoring, but not working memory processes. The results show how parallel conflict monitoring and flexible adaptation of action is mediated via fronto-striatal networks. While both, response monitoring and working memory processes seem to play a role, especially response selection processes and ACC-basal ganglia networks seem to be the driving force in mediating parallel conflict monitoring and flexible adaptation of actions.

Successful Management of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy and Immune Reconstitution Syndrome in a Patient With Multiple Sclerosis

OBJECTIVE To describe a case of successful clinical management of natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution syndrome (IRIS) in a patient with multiple sclerosis. DESIGN Case report. SETTING University hospital. PATIENT A 41-year-old woman with relapsing-remitting multiple sclerosis developed PML after 29 natalizumab infusions. INTERVENTIONS Immediate plasma exchange was combined for removal of natalizumab with application of mefloquine and mirtazapine to limit viral replication and oligodendrocyte infection. A subsequent IRIS was treated with glucocorticosteroids. RESULTS After 3 months of treatment, cerebrospinal fluid tested negative for JC virus. There was a favorable outcome, and the Expanded Disability Status Scale score remained stable at 3.5 compared with before PML. CONCLUSIONS In the setting of early diagnosis and consequent treatment, natalizumab-associated PML can be well managed in some cases. This situation differs from the course of PML in other conditions, eg, after the application of depleting monoclonal antibodies, in which irreversible cellular effects are associated with very high mortality.

Cervical spinal cord volume loss is related to clinical disability progression in multiple sclerosis

Objective To examine the temporal evolution of spinal cord (SC) atrophy in multiple sclerosis (MS), and its association with clinical progression in a large MS cohort. Methods A total of 352 patients from two centres with MS (relapsing remitting MS (RRMS): 256, secondary progressive MS (SPMS): 73, primary progressive MS (PPMS): 23) were included. Clinical and MRI parameters were obtained at baseline, after 12 months and 24 months of follow-up. In addition to conventional brain and SC MRI parameters, the annualised percentage brain volume change and the annualised percentage upper cervical cord cross-sectional area change (aUCCA) were quantified. Main outcome measure was disease progression, defined by expanded disability status scale increase after 24 months. Results UCCA was lower in SPMS and PPMS compared with RRMS for all time points. aUCCA over 24 months was highest in patients with SPMS (−2.2% per year) and was significantly higher in patients with disease progression (−2.3% per year) than in stable patients (−1.2% per year; p=0.003), while annualised percentage brain volume change did not differ between subtypes (RRMS: −0.42% per year; SPMS −0.6% per year; PPMS: −0.46% per year) nor between progressive and stable patients (p=0.055). Baseline UCCA and aUCCA over 24 months were found to be relevant contributors of expanded disability status scale at month-24, while baseline UCCA as well as number of SC segments involved by lesions at baseline but not aUCCA were relevant contributors of disease progression. Conclusions SC MRI parameters including baseline UCCA and SC lesions were significant MRI predictors of disease progression. Progressive 24-month upper SC atrophy occurred in all MS subtypes, and was faster in patients exhibiting disease progression at month-24.

Early central atrophy rate predicts 5 year clinical outcome in multiple sclerosis

Objective To examine the predictive value of central atrophy in early multiple sclerosis (MS) patients, for medium term clinical outcome. Methods In 54 patients with recently diagnosed MS, clinical and MRI parameters were obtained at baseline, and after 2 and 5.5 years of follow-up. In addition to conventional MRI parameters and the annualised percentage brain volume change (aPBVC), the annualised percentage ventricular volume change (aPVVC) was quantified. Main outcome measure was disease progression, defined by an increase in Expanded Disability Status Scale of ≥1 after 5.5 years. Results Disease progression occurred in 29 patients. aPVVC within the first two years was significantly higher in these progressing patients (median 4.76%; IQR 3.05–9.17) compared with stable patients (median 3.23%; IQR −0.1–6.02) (p=0.02). A logistic regression model selected aPVVC within the first 2 years as the only MRI marker predicting progression after 5.5 years (OR 1.17, 95% CI 1.02 to 1.35). When entering all MRI and clinical markers, again aPVVC within the first 2 years was the only MRI marker selected. While aPVVC was correlated between the two consecutive time intervals (ρ=0.41, p<0.01), aPBVC was not. Furthermore, baseline T2 lesion load and gadolinium enhancing lesion load were correlated with aPVVC in the second time interval (2–5.5 years) but not with aPBVC. Conclusion The rate of ventricular enlargement seems to be even more strongly predictive of disease progression after medium term follow-up than whole brain atrophy rate, and also outperforms lesion measures. Central atrophy rate could therefore be an important prognostic marker, especially in the early stages of MS.

Dissociation of grey and white matter reduction in spinocerebellar ataxia type 3 and 6: A voxel-based morphometry study

The aim of this study was to examine the different patterns of cerebellar and/or brainstem atrophy in spinocerebellar ataxia (SCA) type 3 and 6. Eighteen patients (SCA3 n=9, SCA6 n=9) and 15 healthy volunteers were studied. Voxel-based morphometry (VBM) was applied to segmented grey matter (GM) and white matter (WM) of high-resolution T1-weighted brain volumes of each group. We found reduction of grey matter in the pons as well as in the vermis in SCA3 as compared to control subjects. In SCA6 significant grey matter loss was found in hemispheric lobules bilaterally as well as in the vermis. White matter analysis revealed significant changes in SCA3, especially in the pons, in the white matter surrounding the dentate nucleus (DN) and in the cerebellar peduncles, whereas no significant white matter reduction was found in SCA6 patients. Our results demonstrate different patterns of grey and white matter affection detected by magnetic resonance imaging (MRI) in SCA3 and SCA6 patients, confirming the pathological concept of cortical cerebellar atrophy in SCA6. In contrast, SCA3 represents a form of ponto-cerebellar atrophy with predominant affection of pontine nuclei and fibre tracts.