Michaela Andelova

Cerebellar abnormalities contribute to disability including cognitive impairment in multiple sclerosis.

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 (r2 = 0.36). The full model for the prediction of PASAT (Paced Auditory Serial Addition Test) scores (r2 = 0.23) included age, cerebellar and T2 LV. In the case of fatigue, only age and nBV (r2 = 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.

Label-fusion-segmentation and deformation-based shape analysis of deep gray matter in multiple sclerosis: The impact of thalamic subnuclei on disability

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. Hum Brain Mapp 35:4193–4203, 2014.

Efficacy and Safety of Fingolimod in an Unselected Patient Population

Background Fingolimod is a first in class oral compound approved for the treatment of relapsing-remitting multiple sclerosis (RR-MS). The aim of this study was to evaluate clinical and neuroradiological responses to fingolimod as well as the safety and tolerability in RR-MS patients in clinical practice. In addition, a panel of pro-inflammatory serum cytokines was explored as potential biomarker for treatment response. Methods We conducted a retrospective, non-randomized, open-label, observational study in 105 patients with RR-MS and measured cytokines in longitudinal serum samples. Results Compared to the year before fingolimod start the annualized relapse rate was reduced by 44%. Also, the percentage of patients with a worsening of the EDSS decreased. Accordingly, the fraction of patients with no evidence of disease activity (no relapse, stable EDSS, no new active lesions in MRI) increased from 11% to 38%. The efficacy and safety were comparable between highly active patients or patients with relevant comorbidities and our general patient population. Conclusions The efficacy in reducing relapses was comparable to that observed in the phase III trials. In our cohort fingolimod was safe and efficacious irrespective of comorbidities and previous treatment.

Is the migrainous brain normal outside of acute attacks? Lessons learned from psychophysical, neurochemical and functional neuroimaging studies.

Migraine is a largely inherited disorder of the brain with recurrent head pain attacks. There is an increasing awareness, however, that the manifestation of migrainous biology is not restricted to such acute head pain attacks, but that migraine is rather a disorder with a continuous complex and broad sensory processing dysfunction in which normal sensory stimuli (somatosensory, visual, auditory and olfactory) are misinterpreted by the brain. This dysfunction is most prominent during attacks, but there are more and more evidences that the processing and perception of stimuli is abnormal also outside of attacks to a varying degree. In this topical review, we will summarize and discuss the current clinical, neurochemical and functional neuroimaging literature on this paradigm shift from a strictly episodic head pain disorder to migraine as a more general dysfunction of sensory processing.

Neurostatus e-Scoring improves consistency of Expanded Disability Status Scale assessments: A proof of concept study:

Background: To improve the consistency of standardized Expanded Disability Status Scale (EDSS) assessments, an electronic data capture tool and analysis tool was developed, Neurostatus e-Scoring (NESC). This tool allows real-time feedback by comparing entries with established scoring rules. Objective: To test whether using NESC reduces inconsistencies as compared to the paper-and-pencil version of the Expanded Disability Status Scale (pEDSS). Methods: In all, 100 multiple sclerosis (MS) patients were assessed in random order on the same day by pairs of neurologists, one using pEDSS and one NESC. We compared inter-rater reliability and frequency of inconsistencies in Neurostatus subscores, functional system (FS) scores, ambulation and EDSS steps. Results: Inconsistencies of any type were more likely to occur when using pEDSS (mean odds ratio (95% confidence interval (CI)) = 2.93 (1.62; 5.29)). This was also the case for FS score inconsistencies (2.54 (1.40; 4.61)) and more likely for patients in the lower EDSS range (⩽3.5 vs >3.5) (5.32 (1.19; 23.77)). Overall, inter-rater agreement for the assessed Neurostatus subscores was high (median and inter-quartile range = 0.84 (0.73, 0.81)). Conclusion: Our data provide class II evidence that the use of NESC increases consistency of standardized EDSS assessments, and may thus have the potential to decrease noise and increase power of MS clinical trials.

The role of cerebellar abnormalities in neuromyelitis optica – a comparison with multiple sclerosis and healthy controls:

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 cm3) as compared with HC (6.7 cm3), while patients with MS had reduced brain volumes compared with HC (NBV=1482 cm3; p<0.001; TCV=188 cm3; 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.

Impact of 3 Tesla MRI on interobserver agreement in clinically isolated syndrome: A MAGNIMS multicentre study

Background: Compared to 1.5 T, 3 T magnetic resonance imaging (MRI) increases signal-to-noise ratio leading to improved image quality. However, its clinical relevance in clinically isolated syndrome suggestive of multiple sclerosis remains uncertain. Objectives: The purpose of this study was to investigate how 3 T MRI affects the agreement between raters on lesion detection and diagnosis. Methods: We selected 30 patients and 10 healthy controls from our ongoing prospective multicentre cohort. All subjects received baseline 1.5 and 3 T brain and spinal cord MRI. Patients also received follow-up brain MRI at 3–6 months. Four experienced neuroradiologists and four less-experienced raters scored the number of lesions per anatomical region and determined dissemination in space and time (McDonald 2010). Results: In controls, the mean number of lesions per rater was 0.16 at 1.5 T and 0.38 at 3 T (p = 0.005). For patients, this was 4.18 and 4.40, respectively (p = 0.657). Inter-rater agreement on involvement per anatomical region and dissemination in space and time was moderate to good for both field strengths. 3 T slightly improved agreement between experienced raters, but slightly decreased agreement between less-experienced raters. Conclusion: Overall, the interobserver agreement was moderate to good. 3 T appears to improve the reading for experienced readers, underlining the benefit of additional training.

Three-Tesla MRI does not improve the diagnosis of multiple sclerosis: A multicenter study

Objective In the work-up of patients presenting with a clinically isolated syndrome (CIS), 3T MRI might offer a higher lesion detection than 1.5T, but it remains unclear whether this affects the fulfilment of the diagnostic criteria for multiple sclerosis (MS). Methods We recruited 66 patients with CIS within 6 months from symptom onset and 26 healthy controls in 6 MS centers. All participants underwent 1.5T and 3T brain and spinal cord MRI at baseline according to local optimized protocols and the MAGNIMS guidelines. Patients who had not converted to MS during follow-up received repeat brain MRI at 3–6 months and 12–15 months. The number of lesions per anatomical region was scored by 3 raters in consensus. Criteria for dissemination in space (DIS) and dissemination in time (DIT) were determined according to the 2017 revisions of the McDonald criteria. Results Three-Tesla MRI detected 15% more T2 brain lesions compared to 1.5T (p < 0.001), which was driven by an increase in baseline detection of periventricular (12%, p = 0.015), (juxta)cortical (21%, p = 0.005), and deep white matter lesions (21%, p < 0.001). The detection rate of spinal cord lesions and gadolinium-enhancing lesions did not differ between field strengths. Three-Tesla MRI did not lead to a higher number of patients fulfilling the criteria for DIS or DIT, or subsequent diagnosis of MS, at any of the 3 time points. Conclusion Scanning at 3T does not influence the diagnosis of MS according to McDonald diagnostic criteria.