Sex bias in multiple sclerosis and neuromyelitis optica spectrum disorders: How it influences clinical course, MRI parameters and prognosis.

This review is a condensed summary of representative articles addressing the sex/gender bias in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). The strong effects of sex on the incidence and possibly also the activity and progression of these disorders should be implemented in the evaluation of any phase of clinical research and also in treatment choice consideration in clinical practice and evaluation of MRI parameters. Some relationships between clinical variables and gender still remain elusive but with further understanding of sex/gender-related differences, we should be able to provide appropriate patient-centered care and research.

Numeric, Agent-based or System Dynamics Model? Which Modeling Approach is the Best for Vast Population Simulation?

BACKGROUND: Alzheimer's disease is one of the most common mental illnesses. It is posited that more than 25% of the population is affected by some mental disease during their lifetime. Treatment of each patient draws resources from the economy concerned. Therefore, it is important to quantify the potential economic impact. METHODS: Agent-based, system dynamics and numerical approaches to dynamic modeling of the population of the European Union and its patients with Alzheimer's disease are presented in this article. Simulations, their characteristics, and the results from different modeling tools are compared. RESULTS: The results of these approaches are compared with EU population growth predictions from the statistical office of the EU by Eurostat. The methodology of a creation of the models is described and all three modeling approaches are compared. The suitability of each modeling approach for the population modeling is discussed. CONCLUSION: In this case study, all three approaches gave us the results corresponding with the EU population prediction. Moreover, we were able to predict the number of patients with AD and, based on the modeling method, we were also able to monitor different characteristics of the population.

Prediction of population with Alzheimer's disease in the European Union using a system dynamics model.

INTRODUCTION: Alzheimer's disease (AD) is a slowly progressing neurodegenerative brain disease with irreversible brain effects; it is the most common cause of dementia. With increasing age, the probability of suffering from AD increases. In this research, population growth of the European Union (EU) until the year 2080 and the number of patients with AD are modeled. AIM: The aim of this research is to predict the spread of AD in the EU population until year 2080 using a computer simulation. METHODS: For the simulation of the EU population and the occurrence of AD in this population, a system dynamics modeling approach has been used. System dynamics is a useful and effective method for the investigation of complex social systems. Over the past decades, its applicability has been demonstrated in a wide variety of applications. In this research, this method has been used to investigate the growth of the EU population and predict the number of patients with AD. The model has been calibrated on the population prediction data created by Eurostat. RESULTS: Based on data from Eurostat, the EU population until year 2080 has been modeled. In 2013, the population of the EU was 508 million and the number of patients with AD was 7.5 million. Based on the prediction, in 2040, the population of the EU will be 524 million and the number of patients with AD will be 13.1 million. By the year 2080, the EU population will be 520 million and the number of patients with AD will be 13.7 million. CONCLUSION: System dynamics modeling approach has been used for the prediction of the number of patients with AD in the EU population till the year 2080. These results can be used to determine the economic burden of the treatment of these patients. With different input data, the simulation can be used also for the different regions as well as for different noncontagious disease predictions.

Intravenous immunoglobulin treatment in chronic neurological diseases: do we have maintenance dose right?

Objectives. We tried to define, on individual basis, minimal effective maintenance dose of intravenous immunoglobulins (IVIG) in 26 patients with chronic neurological conditions requiring long-term IVIG treatment. Methods. Clinical criteria were reviewed in individual cases (Phase 1) followed by titration phase (Phase 2, 12 months) and posttitration/follow-up phase (Phase 3, 3 months). Objective neurological examination and patient self-reports were used for clinical follow-up. Results. 69.2% of patients reported condition as stable, 26.9% as better, and 3.9% as mildly worse. Original mean monthly dose was 1 g/kg; over the period of 12 months we reduced dose of IVIG to mean dose 0.67 g/kg (range 0.3-2.5 g/kg, P < 0.0001) which meant reduction by 36.4%. We identified 4 nonresponders and diagnosis in one case was reclassified to degenerative disease. In follow-up phase we reduced dose further to 0.60 g/kg. Cumulative monthly dose dropped from 2040 g to 1298 g and to 991 g, respectively. Financial expenses were reduced significantly (by -36.4% during titration phase and by -51.4% during follow-up phase) (comparing with baseline) (P < 0.0001). Conclusion. Individual dose titration leads to significant maintenance IVIG dose reduction with preserved clinical efficacy. Maintenance dose below 1 g/kg (in our study around 0.7 g/kg) has acceptable risk/benefit ratio.

Development of gray matter atrophy in relapsing-remitting multiple sclerosis is not gender dependent: results of a 5-year follow-up study.

OBJECTIVES: The aim of this study was to explore the evolution of MRI related gender differences in patients with relapsing-remitting (RR) multiple sclerosis (MS) who participated in a clinical trial over the 5 years. METHODS: 181 patients (39 males and 142 females) were assessed for clinical and neuroradiological disease activity over a period of 5 years. Clinical and MRI examination were performed at the baseline, 6, 12, 24, 36, 48 and 60 months. Longitudinal percentage volume changes in whole brain (PBVC), gray matter (PGMVC) white matter (PWMVC) cortex (PCVC), and lateral ventricles (PLVVC) were calculated by using direct methods (SIENA and SIENAX-multitimepoint). Absolute tissue volume changes of subcortical deep GM structures including caudate, putamen, globus pallidus, thalamus, hippocampus, amygdala and nucleus accumbens were estimated using FIRST, a model based segmentation/registration tool. T2 lesion volume (T2-LV) and lesion activity analyses were performed, using a contouring-threshold and subtraction techniques. All clinical and MRI variables were analyzed between males and females. RESULTS: Global (PBVC) and tissue specific (PGMVC, PWMVC, PCVC, PLVVC) brain volume changes showed no significant gender differences over the 5-year follow-up period. Although total subcortical deep GM, caudate, putamen, globus palidus, thalamus and nucleus accumbens normalized volumes were significantly larger in male subjects at baseline, the follow-up analysis showed no differences over the 5 years. There were no gender differences in lesion activity or T2-LV changes over the 5 years. CONCLUSION: No MRI lesion, global, tissue specific or regional brain volume gender change differences were found over the 5-year follow-up.

Bimonthly Evolution of Cortical Atrophy in Early Relapsing-Remitting Multiple Sclerosis over 2 Years: A Longitudinal Study.

We investigated the evolution of cortical atrophy in patients with early relapsing-remitting (RR) multiple sclerosis (MS) and its association with lesion volume (LV) accumulation and disability progression. 136 of 181 RRMS patients who participated in the Avonex-Steroids-Azathioprine study were assessed bimonthly for clinical and MRI outcomes over 2 years. MS patients with disease duration (DD) at baseline of ≤24 months were classified in the early group (DD of 1.2 years, n = 37), while patients with DD > 24 months were classified in the late group (DD of 7.1 years, n = 99). Mixed effect model analysis was used to investigate the associations. Significant changes in whole brain volume (WBV) (P < 0.001), cortical volume (CV) (P < 0.001), and in T2-LV (P < 0.001) were detected. No significant MRI percent change differences were detected between early and late DD groups over 2 years, except for increased T2-LV accumulation between baseline and year 2 in the early DD group (P < 0.01). No significant associations were found between changes in T2-LV and CV over the followup. Change in CV was related to the disability progression over the 2 years, after adjusting for DD (P = 0.01). Significant cortical atrophy, independent of T2-LV accumulation, occurs in early RRMS over 2 years, and it is associated with the disability progression.

Clinical correlates of grey matter pathology in multiple sclerosis.

Traditionally, multiple sclerosis has been viewed as a disease predominantly affecting white matter. However, this view has lately been subject to numerous changes, as new evidence of anatomical and histological changes as well as of molecular targets within the grey matter has arisen. This advance was driven mainly by novel imaging techniques, however, these have not yet been implemented in routine clinical practice. The changes in the grey matter are related to physical and cognitive disability seen in individuals with multiple sclerosis. Furthermore, damage to several grey matter structures can be associated with impairment of specific functions. Therefore, we conclude that grey matter damage - global and regional - has the potential to become a marker of disease activity, complementary to the currently used magnetic resonance markers (global brain atrophy and T2 hyperintense lesions). Furthermore, it may improve the prediction of the future disease course and response to therapy in individual patients and may also become a reliable additional surrogate marker of treatment effect.

Patients' stratification and correlation of brain magnetic resonance imaging parameters with disability progression in multiple sclerosis.

AIMS: The objective was to correlate the change in the lesion load (LL) and brain atrophy in patients with multiple sclerosis (MS) with progression of clinical disability, represented by the Expanded Disability Status Scale (EDSS), and to test if stratification of patients according to magnetic resonance imaging (MRI) criteria can increase the predictive ability of MRI for MS clinical development. METHODS: 181 patients with clinically definite relapsing-remitting MS underwent MRI for a period of up to 5 years. Grouping of patients according to the LL value at the study entry revealed a substantial increase in the Spearman rank correlation coefficient R. RESULTS: For the low LL cohort of patients, we found a statistically significant correlation (R up to -0.71 with p < 0.01) of a later increase in the EDSS score (years 4 and 5) with increased brain atrophy in the first 2 years. For the high LL group, we found a statistically significant correlation (R up to 0.72 with p < 0.01) of a later increase in the EDSS score (years 4 and 5) with an increase in the LL value in the first year. CONCLUSIONS: We conclude that stratification of patients according to the MRI criterion (LL) can increase the predictive ability of MRI.

Gray matter atrophy and disability progression in patients with early relapsing-remitting multiple sclerosis: a 5-year longitudinal study.

We assessed the relationship between gray matter (GM) and white matter (WM) atrophy and clinical status in early relapsing-remitting multiple sclerosis (MS) patients over 5 years. A group of 181 patients who participated in the ASA (Avonex-Steroid-Azathioprine) study and had complete clinical and MRI assessments over 2 and 5 years was investigated. One hundred seventy (170) patients completed the 12-month follow-up, 147 the 24-month, 98 the 36-month, 65 the 48-month and 47 the 60-month. Changes in GM (GMV), WM (WMV) and peripheral GM (PGV) volumes, whole brain volume (percentage brain volume change PBVC), lateral ventricle volume (LVV), third ventricle width (3VW) and T2-lesion volume (T2-LV) were measured. Patients were assigned according to their clinical status to one of two groups: the Stable group, and the Reached Confirmed Sustained Progression (RCSP) group (24-week interval). At 0-6 months PBVC and GMV, at 0-12 months PBVC, GMV and T2-LV, at 0-24 months PBVC and GMV, at 0-36 months PBVC, GMV and T2-LV, and at 0-48 PBVC predicted the differences between the RCSP and Stable groups. PBVC and LVV showed the strongest ability to differentiate patients who presented 0 or >or=3 relapses in the Stable group. Decline in PBVC and GMV were predictive markers of disability deterioration. Correlation of T2-LV with clinical status was weaker and decreased over time. Higher number of relapses was associated with faster decline in whole brain volume.

Detection of cortical lesions is dependent on choice of slice thickness in patients with multiple sclerosis.

Understanding the importance of cortical lesions in MS pathogenesis has changed. Histopathologic studies using new immunohistochemical methods show that cortical lesions can be detected more frequently than previously reported. Newer MRI sequences also detect cortical lesions more accurately. The aim of this study was to evaluate whether the effect of slice thickness (th) is an important factor for detection of cortical lesions in patients with multiple sclerosis (MS). We aimed also to investigate the relationship of cortical lesions with clinical status or other MRI variables. Forty-one patients with relapsing-remitting (RR) MS (11 males, 30 females with mean EDSS 2.3) underwent scans of Two-dimensional (2D)-fluid-attenuated inversion recovery (FLAIR) and 3D-T1-WI at 1.5-, 3-, and 5-mm slice thicknesses on 1.5-T MRI. Cortical and juxtacortical lesions were volumetrically assessed using a semiautomated method. 2D-FLAIR and 3D-T1-WI were coregistered and the matrix of the neocortical volume (NCV) segmentation mask (SIENAX-generated) was used to classify the location of the cortical-subcortical lesions. Cortical lesions fell into three classes: (1) class 1 were defined as lesions located in the NCV, (2) class 2 were juxtacortical lesions in contact with the NCV mask, and (3) class 3 were cortical-juxtacortical lesions situated in both regions. We measured NCV and normalized gray matter (GM) volume as well. We used partial correlation and multiple regressions to investigate the relationship between cortical lesions and other clinical and MRI variables. Of the total T2-lesion volume (T2-LV) measured on 1.5-mm th scans (mean 16108 mm(3)), cortical lesions represented 2.4% (276 mm(3)), juxtacortical lesions 6.1% (760 mm(3)), and cortical-juxtacortical 3.7% (491 mm(3)). Compared to 1.5-mm th scan, cortical LV was reduced by -28.3%, p < 0.001 on 3-mm th and by -40.78%, p < 0.001 on 5-mm th scans. Results for juxtacortical LV were for 3-mm th scans (-17.9%, p < 0.01) and for 5-mm th scans (-30.3%, p < 0.01). The figures for cortical-juxtacortical LV were also for 3-mm th scans (-16.2%, p < 0.01) and for 5-mm th scans (-26.7%, p < 0.01). We observed a significant correlation between T2-LV and GM atrophy in all slice thickness (r = -0.4 to -0.48, p = 0.001-0.003) and a modest relationship between cortical and cortical-juxtacortical LVs and disability, especially at 1.5-mm slice thickness (r = 0.35, p = 0.025). Use of thinner slices (1.5 mm) on 2D-FLAIR images can significantly increase the sensitivity and precision of detecting cortical and juxtracotical lesions in patients with MS. Cortical and juxtacortical lesions contribute more to disability development than total T2-LV alone.