Objective: To investigate how monophasic acquired demyelinating syndromes (ADS) affect age-expected brain growth over time. Methods: We analyzed 83 pediatric patients imaged serially from initial demyelinating attack: 18 with acute disseminated encephalomyelitis (ADEM) and 65 with other monophasic ADS presentations (monoADS). We further subdivided the monoADS group by the presence (n = 33; monoADSlesion) or absence (n = 32; monoADSnolesion) of T2 lesions involving the brain at onset. We used normative data to compare brain volumes and calculate age- and sex-specific z scores, and used mixed-effect models to investigate their relationship with time from demyelinating illness. Results: Children with monophasic demyelination (ADEM, non-ADEM with brain lesions, and those without brain involvement) demonstrated reduced age-expected brain growth on serial images, driven by reduced age-expected white matter growth. Cortical gray matter volumes were not reduced at onset but demonstrated reduced age-expected growth afterwards in all groups. Brain volumes differed from age- and sex-expected values to the greatest extent in children with ADEM. All patient groups failed to recover age-expected brain growth trajectories. Conclusions: Brain volume, and more importantly age-expected brain growth, is negatively affected by acquired demyelination, even in the absence of chronicity, implicating factors other than active inflammation as operative in this process.

Spinal cord (SC) atrophy is an important contributor to the development of disability in many neurological disorders including multiple sclerosis (MS). To assess the spinal cord atrophy in clinical trials and clinical practice, largely automated methods are needed due to the sheer amount of data. Moreover, using these methods in longitudinal trials requires them to deliver highly reliable measurements, enabling comparisons of multiple data sets of the same subject over time. We present a method for SC volumetry using 3D MRI data providing volume measurements for SC sections of fixed length and location. The segmentation combines a continuous max flow approach with SC surface reconstruction that locates the SC boundary based on image voxel intensities. Two cutting planes perpendicular to the SC centerline are determined based on predefined distances to an anatomical landmark, and the cervical SC volume (CSCV) is then calculated in-between these boundaries. The development of the method focused on its application in MRI follow-up studies; the method provides a high scan–rescan reliability, which was tested on healthy subject data. Scan–rescan reliability coefficients of variation (COV) were below 1 %, intra- and interrater COV were even lower (0.1–0.2 %). To show the applicability in longitudinal trials, 3-year follow-up data of 48 patients with a progressive course of MS were assessed. In this cohort, CSCV loss was the only significant predictor of disability progression (p = 0.02). We are, therefore, confident that our method provides a reliable tool for SC volumetry in longitudinal clinical trials.

Background: Acquired demyelinating syndromes (ADS) have the potential to negatively impact cerebellar growth, given the proclivity for infratentorial lesions in pediatric-onset multiple sclerosis (MS) and ADS.Objective: To investigate cerebellar growth longitudinally in pediatric ADS.Methods: Cerebellar volumes from 472 magnetic resonance imaging (MRI) scans of 98 patients with monophasic ADS (monoADS), monophasic acute disseminated encephalomyelitis (ADEM), and MS (49 girls; mean age: 11.4years at first scan, mean follow-up: 3.1years) imaged serially from onset and 897 MRI scans of 418 healthy children (223 girls, mean age: 11.3years, mean follow-up: 2.9years) were segmented automatically, analyzed with mixed-effect models, and compared with cerebral volume.Results: Cerebellar developmental trajectories followed a U-shaped curve, showing larger volumes in boys (p<0.001). Cerebellar volumes in all three patient groups failed to reach age-expected trajectories, leading to significantly smaller volumes, notably in the posterior lobes. Cerebellar volume reductions were of a similar magnitude to cerebral volume reductions. Cerebellar white matter volume declined in MS and ADEM patients over time, while in monoADS patients it remained similar to controls. Cerebellar volumes did not correlate either with lesion volumes at onset or with physical disability.Conclusion: MonoADS, ADEM, and MS in childhood lead to impaired age-expected growth of the cerebellum.

We performed voxel-guided morphometry (VGM) investigating the mechanisms of brain atrophy in multiple sclerosis (MS) related to focal lesions. VGM maps detect regional brain changes when comparing 2 time points on high resolution T1-weighted (T1w) magnetic resonace imaging (MRI). Two T1w MR datasets from 92 relapsing-remitting MS patients obtained 12 months apart were analysed with VGM. New lesions and volume changes of focal MS lesions as well as in the surrounding tissue were identified by visual inspection on colour coded VGM maps. Lesions were dichotomized in active and inactive lesions. Active lesions, defined by either new lesions (NL) (volume increase >5% in VGM), chronic enlarging lesions (CEL) (pre-existent T1w lesions with volume increase >5%), or chronic shrinking lesions (CSL) (pre-existent T1w lesions with volume reduction >5%) in VGM, were accompanied by tissue shrinkage in surrounding and/ or functionally related regions. Volume loss within the corpus callosum was highly correlated with the number of lesions in its close proximity. Volume loss in the lateral geniculate nucleus was correlated with lesions along the optic radiation. VGM analysis provides strong evidence that all active lesion types (NL, CEL, and CSL) contribute to brain volume reduction in the vicinity of lesions and/ or in anatomically and functionally related areas of the brain.

We present an automatic three-dimensional segmentation approach based on continuous max flow that targets tubular structures in medical images. Our method uses second-order derivative information provided by Frangi et al.’s vesselness feature and exploits it twofold: First, the vesselness response itself is used for localizing the tubular structure of interest. Second, the eigenvectors of the Hessian eigendecomposition guide our anisotropic total variation–regularized segmentation. In a simulation experiment, we demonstrate the superiority of anisotropic as compared to isotropic total variation–regularized segmentation in the presence of noise. In an experiment with magnetic resonance images of the human cervical spinal cord, we compare our automated segmentations to those of two human observers. Finally, a comparison with a dedicated state-of-the-art spinal cord segmentation framework shows that we achieve comparable to superior segmentation quality.

A first episode of acute demyelination of the central nervous system may be a monophasic transient illness or represent the first attack of multiple sclerosis (MS). This study investigates if it is possible to distinguish these two groups of patients retrospectively at the time of the first episode, in a pediatric population. For each patient, the method consists in fitting an individual brain growth curve using multiple follow-up time-points, and using this curve to predict 4 metrics at the first attack: brain volume, brain growth rate, thalamus volume normalized by the brain volume (called normalized thalamus) and normalized thalamus growth rate. These metrics were compared to age-and-sex matched healthy controls by computing z-scores.In this study, 85 patients were scanned up to 8 years after the first attack. During this follow-up period, 23 patients were subsequently diagnosed with MS (MS group). Among the 62 patients with a transient illness, 9 suffered from monophasic acute disseminated encephalomyelitis (ADEM group). The 53 remaining formed the non-ADEM monophasic (MONO) group.The normalized thalamus growth rate was the only metric that distinguished patient groups: the z-scores were significantly smaller for MS than for the MONO group (p<0.01). Whereas 93% of monophasic subjects were correctly classified with a linear discriminant analysis, only 13% of the MS subjects were correctly classified, due to a large inter-individual variability in this group.

Background: In relapsing-remitting multiple sclerosis (RRMS), the cerebellum is a known predilection site for atrophy. Neuromyelitis optica (NMO) is characterized by extensive lesions in the spinal cord and optic nerve; however, cerebellar involvement has been less studied. Secondary degeneration of the spinocerebellar tract could impact the cerebellum in NMO.Objective: We aimed to investigate whether spinal cord and cerebellar volume measures differ between patients with NMO and RRMS.Methods: Volumetric analyses of the cerebellum (TCV), the upper cervical cord (UCV) as well as the whole brain (NBV) of age- and gender-matched patients with NMO (n=30; 56% AQP4 +ve) and RRMS (n=25) were performed on 3T brain magnetic resonance imaging (MRI) and compared with 34 healthy controls (HC).Results: UCV was significantly reduced in NMO patients (6.3 cm(3)) as compared with HC (6.7 cm(3)), while patients with MS had reduced brain volumes compared with HC (NBV=1482 cm(3); p<0.001; TCV=188 cm(3); p=0.042), but UCV close to normal values. Patients with RRMS and NMO differed in NBV (p=0.001; lower in RRMS) and by trend (towards reduction in RRMS) in cerebellar volume (p=0.06).Conclusions: While atrophy seems to be diffuse in MS patients, a rather focussed pattern with predominant involvement of the UCV was observed in NMO patients.

In multiple sclerosis (MS), cerebellar signs and symptoms as well as cognitive dysfunction are frequent and contribute to clinical disability with only poor response to symptomatic treatment. The current consensus paper highlights the broad range of clinical signs and symptoms of MS patients, which relate to cerebellar dysfunction. There is considerable evidence of cerebellar involvement in MS based on clinical, histopathological as well as structural and functional magnetic resonance imaging (MRI) studies. The review of the recent literature, however, also demonstrates a high variability of results. These discrepancies are, at least partially, caused by the use of different techniques and substantial heterogeneity among the patient cohorts in terms of disease duration, number of patients, and progressive vs. relapsing disease courses. Moreover, the majority of studies were cross-sectional, providing little insight into the dynamics of cerebellar involvement in MS. Some links between the histopathological changes, the structural and functional abnormalities as captured by MRI, cerebellar dysfunction, and the clinical consequences are starting to emerge and warrant further study. A consensus is formed that this line of research will benefit from advances in neuroimaging techniques that allow to trace cerebellar involvement at higher resolution. Using a prospective study design, multimodal high-resolution cerebellar imaging is highly promising, particularly in patients who present with radiologically or clinically isolated syndromes or newly diagnosed MS.

BACKGROUND:Cognitive decline in multiple sclerosis (MS) negatively impacts patients' everyday functioning and quality of life. Since symptomatic pharmacological treatment is not yet available alternative treatment strategies such as cognitive rehabilitation are of particular interest.OBJECTIVES:To analyse the ways in which MS patients respond to cognitive training, by combining behavioral and fMRI data in a case-based triangulation approach.METHODS:Ten relapsing-remitting (RR) MS patients aged between 39 and 58 years and between 1 and 8 years post MS diagnosis were included. EDSS ranged from 1 to 3.5. Participants had normal to high intelligence levels. Six patients were assigned to the training group (TG) and four to the control group (CG) without intervention. The TG received a 4-week computerized working memory (WM) training, consisting of 16 training sessions of 45 min duration each. Before and after the training a neuropsychological examination and fMRI investigation by using an N-back task of different complexity was applied.RESULTS:Patients in the TG responded differently to cognitive training. Four participants did not meet the triangulation criteria for being treatment responders. The two responders showed two distinct changes regarding activation patterns after training: (I) decreased brain activation associated with increased processing speed and (II) increased brain activation associated with higher processing speed and WM performance.CONCLUSION:The occurrence of different and opposed response patterns after the same training indicates a risk in applying classical group statistics. Different and especially opposed patterns within the same sample may distort results of classical statistical comparisons. Thus, underlying processes may not be discovered and lead to misinterpretation of results.

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. (C) 2014 Elsevier B.V. All rights reserved.

The cerebellum is known to be involved not only in motor but also cognitive and affective processes. Structural changes in the cerebellum in relation to cognitive dysfunction are an emerging topic in the field of neuro-psychiatric disorders. In Multiple Sclerosis (MS) cerebellar motor and cognitive dysfunction occur in parallel, early in the onset of the disease, and the cerebellum is one of the predilection sites of atrophy. This study is aimed at determining the relationship between cerebellar volumes, clinical cerebellar signs, cognitive functioning and fatigue in MS. Cerebellar volumetry was conducted using T1-weighted MPRAGE magnetic resonance imaging of 172 MS patients. All patients underwent a clinical and brief neuropsychological assessment (information processing speed, working memory), including fatigue testing. Patients with and without cerebellar signs differed significantly regarding normalized cerebellar total volume (nTCV), normalized brain volume (nBV) and whole brain T2 lesion volume (LV). Patients with cerebellar dysfunction likewise performed worse in cognitive tests. A regression analysis indicated that age and nTCV explained 26.3% of the variance in SDMT (symbol digit modalities test) performance. However, only age, T2 LV and nBV remained predictors in the full model (r(2) = 0.36). The full model for the prediction of PASAT (Paced Auditory Serial Addition Test) scores (r(2) = 0.23) included age, cerebellar and T2 LV. In the case of fatigue, only age and nBV (r(2) = 0.17) emerged as significant predictors. These data support the view that cerebellar abnormalities contribute to disability, including cognitive impairment in MS. However, this contribution does not seem to be independent of, and may even be dominated by wider spread MS pathology as reflected by nBV and T2 LV.

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.

Due to its high flexibility, the spinal cord is a particularly challenging part of the central nervous system for the quantification of nervous tissue changes. In this paper, a novel semi-automatic method is presented that reconstructs the cord surface from MR images and reformats it to slices that lie perpendicular to its centerline. In this way, meaningful comparisons of cord cross-sectional areas are possible. Furthermore, the method enables to quantify the complete upper cervical cord volume. Our approach combines graph cut for presegmentation, edge detection in intensity profiles for segmentation refinement, and the application of starbursts for reformatting the cord surface. Only a minimum amount of user input and interaction time is required. To quantify the limits and to demonstrate the robustness of our approach, its accuracy is validated in a phantom study and its precision is shown in a volunteer scan–rescan study. The method’s reproducibility is compared to similar published quantification approaches. The application to clinical patient data is presented by comparing the cord cross-sections of a group of multiple sclerosis patients with those of a matched control group, and by correlating the upper cervical cord volumes of a large MS patient cohort with the patients’ disability status. Finally, we demonstrate that the geometric distortion correction of the MR scanner is crucial when quantitatively evaluating spinal cord atrophy.

Deep gray matter (DGM) atrophy has been reported in patients with multiple sclerosis (MS) already at early stages of the disease and progresses throughout the disease course. We studied DGM volume and shape and their relation to disability in a large cohort of clinically well-described MS patients using new subcortical segmentation methods and shape analysis. Structural 3D magnetic resonance images were acquired at 1.5 T in 118 patients with relapsing remitting MS. Subcortical structures were segmented using a multiatlas technique that relies on the generation of an automatically generated template library. To localize focal morphological changes, shape analysis was performed by estimating the vertex-wise displacements each subject must undergo to deform to a template. Multiple linear regression analysis showed that the volume of specific thalamic nuclei (the ventral nuclear complex) together with normalized gray matter volume explains a relatively large proportion of expanded disability status scale (EDSS) variability. The deformation-based displacement analysis confirmed the relation between thalamic shape and EDSS scores. Furthermore, white matter lesion volume was found to relate to the shape of all subcortical structures. This novel method for the analysis of subcortical volume and shape allows depicting specific contributions of DGM abnormalities to neurological deficits in MS patients. The results stress the importance of ventral thalamic nuclei in this respect.

Objective: To investigate the impact of a monophasic acquired demyelinating syndrome (monoADS) and pediatric-onset MS on the cerebellum in a longitudinal cohort of pediatric patients.Background: Recent studies have shown that in comparison to adult-onset multiple sclerosis (MS) there are more inflammatory lesions in the posterior fossa of pediatric-onset patients.Methodology: A newly developed automatic segmentation pipeline for cerebellum, using a template library and patch-based label-fusion, was used to segment cerebellar grey (CGV) and white matter volumes (CWV) from 449 longitudinal MRI scans (3m to 2y intervals) from 69 CIS and 24 MS patients (53 girls; mean age at onset 11.2 ± SD 3.4 years; mean follow-up 2.99 years). Mixed effect models were calculated using age, sex and diagnosis as well as presence of infratentorial lesions as fixed effects, and using random intercept and slope terms to account for within-subject variability of volumes.Results: MonoADS and MS patients, all showed inverted u-shaped developmental trajectories for total cerebellar volume (TCV) and CGV, peaking around 13y for girls and 17y for boys and then declining. In all cases, males had significantly larger volumes compared to females (p < 0.01). Significant age-by-gender effect was seen for CGV (p=0.001). Furthermore, a significant age-by-diagnosis interaction (p=0.005) was found for CWV, showing a reduction of CWV in MS patients, whereas the CWV plateaus in monoADS patients over time. The effect of infratentorial lesions was significantly different between groups (p=0.04), with CWV affected only in the MS group. Conclusion: MonoADS and MS in childhood leads to impaired age-expected growth of the cerebellum and atrophy possibly influencing sensori-motor and cognitive development. The presence of infratentorial lesions at this stage influences white matter growth in MS patients. Disclosure: Dr. Weier has nothing to disclose. Dr. Fonov has nothing to disclose. Dr. Aubert-Broche has nothing to disclose. Dr. Arnold has received personal compensation for activities with Acorda Therapeutics, Bayer Pharmaceuticals Corporation, Biogen Idec, Coronado Biosciences, EMD Serono, Genentech Inc., Genzyme Corporation, GlaxoSmithKline Inc., MedImmune, NeuroRx Research. Dr. Arnold has received research support from Bayer Pharmaceuticals Corporation. Dr. Banwell has received personal compensation in an editorial capacity for Multiple Sclerosis and Related Disorders. Dr. Banwell9s institution has received research support from the Multiple Sclerosis Society of Canada, the Canadian Multiple Sclerosis Scientific Research Foundation, and Canadian Institute of Health Research. Dr. Collins has received personal compensation for activities with NeuroRx Research.

Reliable and fast segmentation of the human cerebellum with its complex architecture of lobes and lobules has been a challenge for the past decades. Emerging knowledge of the functional integration of the cerebellum in various sensori‐motor and cognitive‐behavioral circuits demands new automatic segmentation techniques, with accuracies similar to manual segmentations, but applicable to large subject numbers in a reasonable time frame. This article presents the development and application of a novel pipeline for rapid automatic segmentation of the human cerebellum and its lobules (RASCAL) combining patch‐based label‐fusion and a template library of manually labeled cerebella of 16 healthy controls from the International Consortium for Brain Mapping (ICBM) database. Leave‐one‐out experiments revealed a good agreement between manual and automatic segmentations (Dice kappa = 0.82). Intraclass correlation coefficients (ICC) were calculated to test reliability of segmented volumes and were highest (ICC > 0.9) for global measures (total and hemispherical grey and white matter) followed by larger lobules of the posterior lobe (ICC > 0.8). Further we applied the pipeline to all 152 young healthy controls of the ICBM database to look for hemispheric and gender differences. The results demonstrated larger native space volumes in men then women (mean (± SD) total cerebellar volume in women = 217 cm3 (± 26), men = 259 cm3 (± 29); P < 0.001). Significant gender‐by‐hemisphere interaction was only found in stereotaxic space volumes for white matter core (men > women) and anterior lobe volume (women > men). This new method shows great potential for the precise and efficient analysis of the cerebellum in large patient cohorts. Hum Brain Mapp 35:5026–5039, 2014. © 2014 Wiley Periodicals, Inc.

Cerebellar dysfunction is an important contributor to disability in patients with multiple sclerosis (MS), however, few in vivo studies focused on cerebellar volume loss so far. This relates to technical challenges regarding the segmentation of the cerebellum. In this study, we evaluated the semi-automatic ECCET software for performing cerebellar volumetry using high-resolution 3D T1-MR scans in patients with MS and healthy volunteers. We performed test–retest as well as inter-observer reliability testing of cerebellar segmentation and compared the ECCET results with a fully automatic cerebellar segmentation using the FreeSurfer software pipeline in 15 MS patients. In a pilot matched-pair analysis with another data set from 15 relapsing–remitting MS patients and 15 age- and sex-matched healthy controls (HC), we assessed the feasibility of the ECCET approach to detect MS-related cerebellar volume differences. For total normalized cerebellar volume as well as grey and white matter volumes, intrarater (intraclass correlation coefficient (ICC) = 0.99, 95 % CI = 0.98–0.99) and interobserver agreement (ICC = 0.98, 95 % CI = 0.74–0.99) were strong. Comparison between ECCET and FreeSurfer results likewise yielded a good intraclass correlation (ICC = 0.86, 95 % CI = 0.58–0.95). Compared to HC, MS patients had significantly reduced normalized total brain, total cerebellar, and grey matter volumes ( p ≤ 0.05). ECCET is a suitable tool for cerebellar segmentation showing excellent test–retest and inter-observer reliability. Our matched-pair analysis between MS patients and healthy volunteers suggests that the method is sensitive and reliable in detecting cerebellar atrophy in MS.

WM: normal-appearing white matter, GM: normal appearing grey matter MAGNETIZATION TRANSFER RATIO OF NORMAL APPEARING SUBCORTICAL BRAIN STRUCTURES IN MS PATIENTS MEASURED WITH BALANCED STEADY STATE FREE PRECESSION IMAGING Michael Amann, Michaela Andelova, Athina Papadopoulou, Yvonne Naegelin, Julia Reinhardt, Katrin Weier, Ernst-Wilhelm Radue, Ludwig Kappos, Oliver Bieri, Christoph Stippich, and Till Sprenger Neurology/Neuroradiology, Universitätsspital Basel, Basel, BS, Switzerland, Neurology, Universitätsspital Basel, Basel, BS, Switzerland, Medical Image Analysis Centre, Basel, BS, Switzerland, Neuroradiology, Universitätsspital Basel, Basel, BS, Switzerland, Medical Physics, Universitätsspital Basel, Basel, BS, Switzerland