Ondrej Dolezal

Subcortical and Cortical Gray Matter Atrophy in a Large Sample of Patients with Clinically Isolated Syndrome and Early Relapsing-Remitting Multiple Sclerosis

Brain atrophy is commonly seen in patients with chronic MS. Here, the authors assessed 212 patients with clinically isolated syndrome and early RRMS for atrophy of gray matter. In both groups the cortex displayed no significant atrophy but the deep gray matter nuclei (caudate, thalamus, globus pallidus, putamen, and hippocampus) showed significant atrophy during the first 4 years of the disease. Deep gray matter atrophy may play a relevant role in patient symptoms and seems to appear and progress from the earliest stages of the disease. BACKGROUND AND PURPOSE: Recent studies have shown that selective regional, but not global, GM atrophy occurs from clinical onset to conversion to clinically definite MS. Our aim was to investigate the difference in the extent of SDGM and cortical atrophy in a large sample of patients with CIS and early RRMS and to explore the relationship between SDGM and cortical atrophy and other MR imaging and clinical outcomes. MATERIALS AND METHODS: Two hundred twelve patients with CIS recruited at the first clinical event (mean age, 29.3 years; median EDSS, 1.5; median disease duration, 3 months) and 177 patients with early RRMS (mean age, 30.7 years; median EDSS, 2.0; median disease duration, 47 months) were imaged on a 1.5T scanner by using a high-resolution 3D T1 spoiled gradient-recalled sequence. Volumetric data for SDGM structures were obtained by using FSL FIRST, while whole-brain, GM, white matter, cortical, and lateral ventricle volumes were estimated by using SIENAX software. Comparisons between the groups were adjusted for age and sex. RESULTS: Patients with early RRMS showed significantly lower SDGM but not cortical volumes compared with patients with CIS. The most apparent SDGM differences were evident in the caudate and thalamus (P < .0001), total SDGM (P = .0001), and globus pallidus (P = .01). Patients with CIS with a median T2 lesion volume >4.49 mL showed lower total SDGM, caudate, thalamus (P < .001), globus pallidus (P = .007), hippocampus (P = .004), and putamen (P = .01) volumes and higher lateral ventricle volume (P = .001) than those with a median T2 lesion volume <4.49 mL. Decreased thalamic volume showed the most consistent relationship with MR imaging outcomes (P < .0001) in patients with CIS. CONCLUSIONS: Significant SDGM, but not cortical, atrophy develops during the first 4 years of the RRMS. GM atrophy is relevant for disease progression from the earliest clinical stages.

Evolution of different MRI measures in patients with active relapsing-remitting multiple sclerosis over 2 and 5 years: a case–control study

Background: There is growing evidence for the concept of multiple sclerosis (MS) as an inflammatory neurodegenerative disease, with a different pattern of atrophy evolution in grey matter (GM) and white matter (WM) tissue compartments. Objective: We aimed to investigate the evolution of different MRI measures in early relapsing-remitting patients with MS and in normal controls (NCs) over 2 years. We also evaluated the progression of these MRI measures in a subset of patients who were followed for up to 5 years. Methods: Included in this study were 147 patients who participated in the combination ASA (Avonex Steroids Azathioprine) study and completed full treatment, clinical and MRI assessment at 0, 12 and 24 months. A subgroup of 66 patients was followed for 36 months, 51 patients for 48 months and 43 patients for 60 months. Mean age at baseline was 30.7 years, mean disease duration was 5.5 years, mean EDSS was 1.8 and mean annualised relapse rate before study entry was 1.7. MRI scans were performed on a 1.5T scanner every 2 months for the first 2 years and thereafter once yearly for up to 5 years. In addition to the MS group, 27 NCs were examined at months 0, 12 and 24 using the same MRI protocol. Percentage brain volume change (PBVC), GM volume (GMV), WM volume (WMV) and peripheral grey volume (PGV) were measured annually using SIENA/X software. T2-hyperintense lesion volume (LV), lateral ventricle volume (LVV) and third ventricle width (3VW) were also assessed annually. Results: Over the period of 0–24 months, patients with MS lost significantly more GMV (−2.6% vs −0.72%, p<0.001), PGV (−2.4% vs −1.03%, p<0.001) and PBVC (−1.2% vs −0.22%, p<0.001), and increased in LVV (+16.6% vs +0.55%, p<0.003) and 3VW (+9.3% vs 0%, p = 0.003), when compared with NCs. Within-person change in MRI measures for patients with MS over 5 years was −4.2% for PBVC, −6.2% for GMV, −5.8% for PGV, −0.5% for WMV (all p<0.001), +68.7 for LVV (p<0.001), +4% for 3VW (p<0.001) and +42% for T2-LV (p<0.001). Conclusions: Our study confirmed a different pattern of GM, WM and central atrophy progression over 2 years between patients with MS and NCs. The study showed a different evolution of tissue compartment atrophy measures in patients with MS, with faster decline in cortical and deep GM regions, as well as periventricular WM regions, over a 5-year period.

Randomized study of interferon beta-1a, low-dose azathioprine,and low-dose corticosteroids in multiple sclerosis

Background Studies evaluating interferon beta (IFNβ) for multiple sclerosis (MS) showed only partial efficacy. In many patients, IFNβ does not halt relapses or disability progression. One strategy to potentially enhance efficacy is to combine IFNβ with classical immunosuppressive agents, such as azathioprine (AZA) or corticosteroids, commonly used for other autoimmune disorders. Objective The Avonex–Steroids–Azathioprine study was placebo-controlled trial and evaluated efficacy of IFNβ-1a alone and combined with low-dose AZA alone or low-dose AZA and low-dose corticosteroids as initial therapy. Methods A total of 181 patients with relapsing–remitting MS (RRMS) were randomized to receive IFNβ-1a 30 μg intramuscularly (IM) once weekly, IFNβ-1a 30 μg IM once weekly plus AZA 50 mg orally once daily, or IFNβ-1a 30 μg IM once weekly plus AZA 50 mg orally once daily plus prednisone 10 mg orally every other day. The primary end point was annualized relapse rate (ARR) at 2 years. Patients were eligible for enrollment in a 3-year extension. Results At 2 years, adjusted ARR was 1.05 for IFNβ-1a, 0.91 for IFNβ-1a plus AZA, and 0.73 for combination. The cumulative probability of sustained disability progression was 16.8% for IFNβ-1a, 20.7% for IFNβ-1a plus AZA, and 17.5% for combination. There were no statistically significant differences among groups for either measure at 2 and 5 years. Percent T2 lesion volume change at 2 years was significantly lower for combination (+14.5%) versus IFNβ-1a alone (+30.3%, P < 0.05). Groups had similar safety profiles. Conclusion In IFNβ-naïve patients with early active RRMS, combination treatment did not show superiority over IFNβ-1a monotherapy.

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.

Evolution of Cortical and Thalamus Atrophy and Disability Progression in Early Relapsing-Remitting MS during 5 Years

BACKGROUND AND PURPOSE: Pathologic changes in GM have an important role in MS. We investigated the association between SDGM and cortical volume changes and disability progression in early RRMS. MATERIALS AND METHODS: One hundred eighty patients with RRMS had clinical assessment during 5 years and were divided into those with or without SDP at 5 years by the usual definition in treatment trials. The number of available MR imaging scans at various time points was the following: at baseline, 178; and at 6 months, 172; at 12 months, 175; at 24 months, 155; at 36 months, 160; at 48 months, 158; and at 60 months, 162, respectively. Longitudinal changes in cortical, GM, and WM volume were calculated by using the direct method. RESULTS: At 5 years, 90 patients with RRMS experienced SDP and 90 had stable disease. At baseline, patients with SDP had longer disease duration, greater T2-lesion volume, and smaller whole-brain, WM, cortical, and SDGM volume (P < .01). At 5 years, patients with SDP had significantly greater percentage decreases from baseline compared with those without SDP in the volume of the whole brain (P < .0001), cortex (P = .001), GM (P = .003), and thalamus (P = .01). In patients who developed SDP at 5 years and those who did not, mixed-effect models, adjusted for age, disease duration, and change of the treatment status, showed significant interactions between SDP status at 5 years and changes with time in whole-brain, cortical, lateral ventricle (all P < .001), thalamus (P = .006), and total SDGM (P = .0095) volume. CONCLUSIONS: SDP is associated with progression of cortical, central, and thalamic atrophy in early RRMS during 5 years.

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.

Early predictors of non-response to interferon in multiple sclerosis

To identify early clinical and MRI predictors of non‐response to interferon (IFN) treatment in multiple sclerosis (MS).

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.

Interferon, azathioprine and corticosteroids in multiple sclerosis: 6-year follow-up of the ASA cohort

OBJECTIVE To evaluate long-term effects of 2-year treatment with interferon beta combined with low-dose azathioprine and prednisone in multiple sclerosis. METHODS In the original 2-year ASA study, 181 patients with early relapsing-remitting multiple sclerosis were randomised into 3 treatment arms: those treated with interferon beta (n=60), with interferon beta and low-dose azathioprine (n=58), and interferon beta, azathioprine and low-dose prednisone (n=63). Of these, 172 were included in this 4-year non-study extension. Three monthly clinical controls and annual MRI scans were carried out. The primary endpoint was annual relapse activity. The secondary endpoints were disability and quantitative MRI parameters. RESULTS Nine patients were lost to follow-up and 172 were included in the analyses. None of relapse activity, disability accumulation or MRI parameters differed significantly between the groups over 6 years. Only 5.5% and 0.6% of patients were free from disease activity at year 2 and year 6 of the treatment initiation. CONCLUSION The tested combined therapeutic regimen does not improve long-term outcomes in patients with multiple sclerosis. Furthermore, interferon is not able to completely abolish disease activity.

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.