Brain atrophy in relapsing multiple sclerosis: relationship to relapses, EDSS, and treatment with interferon β-1a

2000 ◽  
Vol 6 (6) ◽  
pp. 365-372 ◽  
Author(s):  
Richard A Rudick ◽  
Elizabeth Fisher ◽  
Jar-Chi Lee ◽  
Jeffrey T Duda ◽  
Jack Simon
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trial ◽  
Brain Atrophy ◽  
Surrogate Marker ◽  
Phase Iii ◽  
Therapeutic Effects ◽  
Lesion Volume ◽  
Interferon Β ◽  
Brain Parenchymal ◽  
The Brain

Brain atrophy is a relevant surrogate marker of the disease process in multiple sclerosis (MS) because it represents the net effect of various pathological processes leading to brain tissue loss. There are various approaches to quantifying central nervous system atrophy in MS. We have focused on a normalized measure of whole brain atrophy, the brain parenchymal fraction (BPF). BPF is defined as the brain parenchymal volume, divided by the volume within the surface of the brain. We applied this method to an MRI data set generated during a phase III clinical trial of interferon β-1a (AVONEX). The purpose of the current study is to further explore clinical and MRI correlates of the BPF, particularly as they relate to relapse rate and Kurtzke's Expanded Disability Status Score (EDSS); and to further explore the therapeutic effects observed in interferon β-1a recipients. Of all demographic and disease measures in the clinical trial data base, T2 lesion volume most closely correlated with BPF in cross sectional studies, and was the baseline factor most closely correlated with progressive brain atrophy in the subsequent 2 years. We also observed that change in T2 lesion volume was the disease measure most closely correlated with change in BPF during 2 years of observation. Of interest, relapse number and EDSS change during 2 years were only weakly correlated with BPF change during the same period. Disability progression, defined as sustained worsening of at least 1.0 EDSS points from baseline, persisting at least 6 months, was associated with significantly greater brain atrophy progression. We observed a therapeutic effect of interferon β-1a in the second year of the clinical trial, and this beneficial effect was not accounted for by change in gadolinium enhanced lesion volume, or by corticosteroid medication within 40 days of the final MRI scan. The BPF is an informative surrogate marker for destructive pathological processes in relaping MS patients, and is useful in demonstrating treatment effects in controlled clinical trials. The significance of progressive brain atrophy during relapsing MS will be assessed by measuring clinical and MRI changes in prospective follow up studies.

Has your patient's multiple sclerosis lesion burden or brain atrophy actually changed?

2004 ◽  
Vol 10 (4) ◽  
pp. 402-406 ◽  
Author(s):  
Xingchang Wei ◽  
Charles RG Guttmann ◽  
Simon K Warfield ◽  
Michael Eliasziw ◽  
J Ross Mitchell
Keyword(s):  
Multiple Sclerosis ◽  
Measurement Error ◽  
Brain Tissue ◽  
Brain Atrophy ◽  
Multiple Sclerosis Lesion ◽  
Lesion Volume ◽  
Measurement Variability ◽  
Brain Parenchymal Fraction ◽  
Significant Change ◽  
Brain Parenchymal

Changes in mean magnetic resonance imaging (MRI)-derived measurements between patient groups are often used to determine outcomes in therapeutic trials and other longitudinal studies of multiple sclerosis (MS). However, in day-to-day clinical practice the changes withinindividual patients may also be of interest. In this paper, we estimated the measurement error of an automated brain tissue quantification algorithm and determined the thresholds for statistically significant change of MRI-derived T2 lesion volume and brain atrophy in individual patients. Twenty patients with MS were scanned twice within 30 min. Brain tissue volumes were measured using the computer algorithm. Brain atrophy was estimated by calculation of brain parenchymal fraction. The threshold of change between repeated scans that represented statistically significant change beyond measurement error with 95% certainty was 0.65 mL for T2 lesion burden and 0.0056 for brain parenchymal fraction. Changes in lesion burden and brain atrophy below these thresholds can be safely (with 95% certainty) explained by measurement variability alone. These values provide clinical neurologists with a useful reference to interpret MRI-derived measures in individual patients.

scholarly journals Influence of equipment changes on MRI measures of brain atrophy and brain microstructure in a placebo-controlled trial of ibudilast in progressive multiple sclerosis

2021 ◽  
Vol 7 (2) ◽  
pp. 205521732110108
Author(s):  
Ken Sakaie ◽  
Janel K Fedler ◽  
Jon W Yankey ◽  
Kunio Nakamura ◽  
Josef Debbins ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trial ◽  
Brain Atrophy ◽  
Controlled Trial ◽  
Progressive Multiple Sclerosis ◽  
Imaging Biomarkers ◽  
Imaging Data ◽  
Brain Microstructure ◽  
Brain Parenchymal ◽  
The Impact

Background Hardware changes can be an unavoidable confound in imaging trials. Understanding the impact of such changes may play an important role in the analysis of imaging data. Objective To characterize the effect of equipment changes in a longitudinal, multi-site multiple sclerosis trial. Methods Using data from a clinical trial in progressive multiple sclerosis, we explored how major changes in imaging hardware affected data. We analyzed the extent to which these changes affected imaging biomarkers and the estimated treatment effects by including such changes as a time-dependent covariate. Results Significant differences whole brain atrophy (brain parenchymal fraction, BPF) and microstructure (transverse diffusivity, TD) between scans with and without changes were found and depended on the type of hardware change. A switch from GE HDxt to Siemens Skyra led to significant shifts in BPF (p < 0.04) and TD (p < 0.0001). However, we could not detect the influence of hardware changes on overall trial outcomes– differences between placebo and treatment arms in change over time of BPF and TD (p > 0.5). Conclusions The results suggest that differences among hardware types should be considered when planning and analyzing brain atrophy and diffusivity in a longitudinal clinical trial.

Relationship between brain atrophy and disability: an 8-year follow-up study of multiple sclerosis patients

2000 ◽  
Vol 6 (6) ◽  
pp. 373-377 ◽  
Author(s):  
E Fisher ◽  
R A Rudick ◽  
G Cutter ◽  
M Baier ◽  
D Miller ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Progression ◽  
Brain Atrophy ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Follow Up Study ◽  
Relapsing Remitting ◽  
Brain Parenchymal Fraction ◽  
Brain Parenchymal

Brain atrophy measurement can provide an estimate of the amount of tissue destruction due to the pathologic processes in multiple sclerosis. The potential usefulness of atrophy as a marker of disease progression depends upon the concurrent and predictive relationships between atrophy and disability. A follow-up study was performed to measure atrophy and disability scores in patients from the Multiple Sclerosis Collaborative Research Group's phase III trial of IFNb-1a (Avonex) in relapsing-remitting multiple sclerosis. New data were obtained on 160 out of 172 eligible patients from the original trial were enrolled in the follow-up study approximately 8 years after randomization. The follow-up visit consisted of several tests and questionnaires including a clinical exam to determine Expanded Disability Status Score (EDSS) and Multiple Sclerosis Functional Composite (MSFC), and a magnetic resonance imaging exam to calculate the brain parenchymal fraction. Brain parenchymal fraction was correlated with both EDSS and MSFC at each of the four time points for which data were available (baseline 1, 2 and 8 years). Furthermore, the change in BPF was correlated with the changes in disability scores from the end of the phase III trial to the follow-up exam. These data suggest that brain atrophy may be a useful and clinically relevant marker of disease progression in relapsing-remitting MS.

scholarly journals Therapeutic effects of non-invasive, individualized, transcranial neuromodulation treatment for voiding dysfunction in multiple sclerosis patients: study protocol for a pilot clinical trial

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Khue Tran ◽  
Zhaoyue Shi ◽  
Christof Karmonik ◽  
Blessy John ◽  
Hamida Rajab ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trial ◽  
Urinary Tract ◽  
Functional Mri ◽  
Lower Urinary Tract ◽  
Voiding Dysfunction ◽  
Therapeutic Effects ◽  
Non Invasive ◽  
The Brain ◽  
Lower Urinary

Abstract Background Voiding dysfunction (VD) is a common neurogenic lower urinary tract dysfunction (NLUTD) in multiple sclerosis (MS) patients. Currently, the only effective management for VD and urinary retention in MS patients is catheterization, prompting us to look for novel therapeutic options beyond the bladder, such as the brain. Transcranial rotating permanent magnet stimulator (TRPMS) is a non-invasive, portable, multifocal neuromodulator that simultaneously modulates multiple cortical regions, enhancing or attenuating strengths of functional connections between these regions. The objective of this pilot clinical trial is to evaluate the feasibility of a TRPMS trial to address lower urinary tract symptoms in MS patients, through investigating the therapeutic effects of TRPMS in modulating brain regions during voiding initiation and mitigating VD in female MS individuals. Methods Ten adult female MS patients with VD (defined as having %post-void residual/bladder capacity (%PVR/BC) ≥ 40% or Liverpool nomogram percentile < 10%) will be recruited for this study. Concurrent urodynamic and functional MRI evaluation with a bladder filling/emptying task repeated three to four times will be performed at baseline and post-treatment. Predetermined regions of interest and their blood-oxygen-level-dependent (BOLD) activation at voiding initiation will be identified on each patient’s baseline anatomical and functional MRI scan, corresponding to the microstimulators placement on their individualized TRPMS treatment cap to either stimulate or inhibit these regions. Patients will receive 10 40-min treatment sessions. Non-instrumented uroflow and validated questionnaires will also be collected at baseline and post-treatment to evaluate clinical improvement. Discussion Despite the crucial role of the central nervous system in urinary control and its sensitivity to MS, there has been no treatment for urinary dysfunction targeting the brain centers that are involved in proper bladder function. This trial, to our knowledge, will be the first of its kind in humans to consider non-invasive and individualized cortical modulation for treating VD in MS patients. Results from this study will provide a better understanding of the brain control of neurogenic bladders and lay the foundation for a potential alternative therapy for VD in MS patients and other NLUTD in a larger neurogenic population in the future. Trial registration This trial is registered at ClinicalTrials.Gov (NCT03574610, 2 July 2018.) and Houston Methodist Research Institute IRB (PRO00019329)

scholarly journals Therapeutic Effects of Noninvasive, Individualized, Transcranial Neuromodulation Treatment for Voiding Dysfunction in Multiple Sclerosis Patients: Study Protocol for a Pilot Clinical Trial

2021 ◽  
Author(s):  
Khue Tran ◽  
Zhaoyue Shi ◽  
Christof Karmonik ◽  
Blessy John ◽  
Hamida Rajab ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trial ◽  
Functional Mri ◽  
Voiding Dysfunction ◽  
Post Treatment ◽  
Lower Urinary Tract Dysfunction ◽  
Therapeutic Effects ◽  
Functional Connections ◽  
Multiple Sclerosis Patients ◽  
The Brain

Abstract Background: Voiding dysfunction (VD) is a common neurogenic lower urinary tract dysfunction (NLUTD) in multiple sclerosis (MS) patients. Currently, the only effective management for VD and urinary retention in MS patients is catheterization, prompting us to look for novel therapeutic options beyond the bladder, such as the brain. Transcranial rotating permanent magnet stimulator (TRPMS) is a noninvasive, portable, multifocal neuromodulator that simultaneously modulates multiple cortical regions, enhancing or attenuating strengths of functional connections between these regions. The objective of this pilot clinical trial is to evaluate the therapeutic effects of TRPMS in modulating brain regions during voiding initiation and mitigating VD in female MS individuals.Methods: Ten adult female MS patients with VD (defined as having %post-void residual/bladder capacity (%PVR/BC) ≥ 40% or Liverpool nomogram percentile < 10%) will be recruited for this study. Concurrent urodynamic and functional MRI evaluation with a bladder filling/emptying task repeated three to four times will be performed at baseline and post-treatment. Predetermined regions of interest and their blood-oxygen-level-dependent (BOLD) activation at voiding initiation will be identified on each patient’s baseline anatomical and functional MRI scan, corresponding to the microstimulators placement on their individualized TRPMS treatment cap to either stimulate or inhibit these regions. Patients will receive ten 40-minute treatment sessions. Non-instrumented uroflow and validated questionnaires will also be collected at baseline and post-treatment to evaluate clinical improvement.Discussion: Despite the crucial role of the central nervous system in urinary control and its sensitivity to MS, there has been no treatment for urinary dysfunction targeting the brain centers that are involved in proper bladder function. This trial, to our knowledge, will be the first of its kind in humans to consider non-invasive and individualized cortical modulation for treating VD in MS patients. Results from this study will provide a better understanding of the brain control of neurogenic bladders and lay the foundation for a potential alternative therapy for VD in MS patients and other NLUTD in a larger neurogenic population in the future.Trial registration: This trial is registered at ClinicalTrials.Gov (NCT03574610, July 2, 2018, https://clinicaltrials.gov/ct2/show/NCT03574610) and Houston Methodist Research Institute IRB (PRO00019329).

scholarly journals Therapeutic Effects of Noninvasive, Individualized, Transcranial Neuromodulation Treatment for Voiding Dysfunction in Multiple Sclerosis Patients: Study Protocol for a Pilot Clinical Trial

2021 ◽  
Author(s):  
Khue Tran ◽  
Zhaoyue Shi ◽  
Christof Karmonik ◽  
Blessy John ◽  
Hamida Rajab ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trial ◽  
Functional Mri ◽  
Voiding Dysfunction ◽  
Post Treatment ◽  
Lower Urinary Tract Dysfunction ◽  
Therapeutic Effects ◽  
Functional Connections ◽  
Multiple Sclerosis Patients ◽  
The Brain

Abstract Background: Voiding dysfunction (VD) is a common neurogenic lower urinary tract dysfunction (NLUTD) in multiple sclerosis (MS) patients. Currently, the only effective management for VD and urinary retention in MS patients is catheterization, prompting us to look for novel therapeutic options beyond the bladder, such as the brain. Transcranial rotating permanent magnet stimulator (TRPMS) is a noninvasive, portable, multifocal neuromodulator that simultaneously modulates multiple cortical regions, enhancing or attenuating strengths of functional connections between these regions. The objective of this pilot clinical trial is to evaluate the therapeutic effects of TRPMS in modulating brain regions during voiding initiation and mitigating VD in female MS individuals.Methods: Ten adult female MS patients with VD (defined as having %post-void residual/bladder capacity (%PVR/BC) ≥ 40% or Liverpool nomogram percentile < 10%) will be recruited for this study. Concurrent urodynamic and functional MRI evaluation with a bladder filling/emptying task repeated three to four times will be performed at baseline and post-treatment. Predetermined regions of interest and their blood-oxygen-level-dependent (BOLD) activation at voiding initiation will be identified on each patient’s baseline anatomical and functional MRI scan, corresponding to the microstimulators placement on their individualized TRPMS treatment cap to either stimulate or inhibit these regions. Patients will receive ten 40-minute treatment sessions. Non-instrumented uroflow and validated questionnaires will also be collected at baseline and post-treatment to evaluate clinical improvement.Discussion: Despite the crucial role of the central nervous system in urinary control and its sensitivity to MS, there has been no treatment for urinary dysfunction targeting the brain centers that are involved in proper bladder function. This trial, to our knowledge, will be the first of its kind in humans to consider non-invasive and individualized cortical modulation for treating VD in MS patients. Results from this study will provide a better understanding of the brain control of neurogenic bladders and lay the foundation for a potential alternative therapy for VD in MS patients and other NLUTD in a larger neurogenic population in the future.Trial registration: This trial is registered at ClinicalTrials.Gov (NCT03574610, July 2, 2018, https://clinicaltrials.gov/ct2/show/NCT03574610) and Houston Methodist Research Institute IRB (PRO00019329).

scholarly journals Effect of fingolimod on MRI outcomes in patients with paediatric-onset multiple sclerosis: results from the phase 3 PARADIGMS study

2020 ◽  
Vol 91 (5) ◽  
pp. 483-492 ◽  
Author(s):  
Douglas L Arnold ◽  
Brenda Banwell ◽  
Amit Bar-Or ◽  
Angelo Ghezzi ◽  
Benjamin M Greenberg ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Early Treatment ◽  
Brain Atrophy ◽  
Treatment Discontinuation ◽  
Interferon Β ◽  
Phase 3 ◽  
Once Daily ◽  
T2 Lesions ◽  
Superior Efficacy

ObjectivePARADIGMS demonstrated superior efficacy and comparable safety of fingolimod versus interferon β-1a (IFN β-1a) in paediatric-onset multiple sclerosis (PoMS). This study aimed to report all predefined MRI outcomes from this study.MethodsPatients with multiple sclerosis (MS) (aged 10–<18 years) were randomised to once-daily oral fingolimod (n=107) or once-weekly intramuscular IFN β-1a (n=108) in this flexible duration study. MRI was performed at baseline and every 6 months for up to 2 years or end of the study (EOS) in case of early treatment discontinuation/completion. Key MRI endpoints included the annualised rate of formation of new/newly enlarging T2 lesions, gadolinium-enhancing (Gd+) T1 lesions, new T1 hypointense lesions and combined unique active (CUA) lesions (6 months onward), changes in T2 and Gd+ T1 lesion volumes and annualised rate of brain atrophy (ARBA).ResultsOf the randomised patients, 107 each were treated with fingolimod and IFN β-1a for up to 2 years. Fingolimod reduced the annualised rate of formation of new/newly enlarging T2 lesions (52.6%, p<0.001), number of Gd+ T1 lesions per scan (66.0%, p<0.001), annualised rate of new T1 hypointense lesions (62.8%, p<0.001) and CUA lesions per scan (60.7%, p<0.001) versus IFN β-1a at EOS. The percent increases from baseline in T2 (18.4% vs 32.4%, p<0.001) and Gd+ T1 (–72.3% vs 4.9%, p=0.001) lesion volumes and ARBA (–0.48% vs −0.80%, p=0.014) were lower with fingolimod versus IFN β-1a, the latter partially due to accelerated atrophy in the IFN β-1a group.ConclusionFingolimod significantly reduced MRI activity and ARBA for up to 2 years versus IFN β-1a in PoMS.

Treatment adherence and patient retention in the first year of a Phase-III clinical trial for the treatment of multiple sclerosis

1999 ◽  
Vol 5 (3) ◽  
pp. 192-197 ◽  
Author(s):  
David C Mohr ◽  
Donald E Goodkin ◽  
Lorianne Masuoka ◽  
Leah P Dick ◽  
David Russo ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trial ◽  
Patient Management ◽  
Phase Iii ◽  
Trial Participation ◽  
First Year ◽  
Adherence To Treatment ◽  
Specific Patient ◽  
Phase Iii Clinical Trial ◽  
Patient Retention

The purpose of this study was to examine the relationship between patient management strategies employed by study personnel, and patient retention and adherence to treatment in the first year of a Phase III clinical trial of interferon beta-1b for treatment of secondary progressive multiple sclerosis (MS). Study staff from each of 35 sites were interviewed regarding patient management practices. Sites which were rated as more empathetic, as instilling a sense of purpose in the patient, and promoting less formal relationships with patients had high rates of adherence to treatment. In addressing specific patient concerns, attention to patients' emotional status and patients' expectations of trial participation were related to better adherence.

Neutralising and binding anti-interferon-β-1 b (IFN-b-1 b) antibodies during IFN-β-1 b treatment of multiple sclerosis

1997 ◽  
Vol 3 (3) ◽  
pp. 184-190 ◽  
Author(s):  
P. Kivisäkk ◽  
GV Alm ◽  
WZ Tian ◽  
D. Matusevicius ◽  
S. Fredrikson ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Solid Phase ◽  
Inflammatory Diseases ◽  
Neurological Diseases ◽  
Resonance Imaging ◽  
Interferon Β ◽  
Lesion Load ◽  
Neutralising Antibodies ◽  
The Brain ◽  
Antibody Secreting Cells

Interferon-β-1b (IFN-β-1b) is an immunomodulatory therapy of multiple sclerosis (MS), reducing the numbers and severity of exacerbations and the total lesion load measured by magnetic resonance imaging of the brain. The benefits of IFN-β-1b could be hampered by the development of neutralising antibodies against the compound. Our results confirmed earlier studies, showing that 42% of MS patients treated with IFN-β-1b for more than 3 months had developed neutralising antibodies. The occurrence of binding anti-IFN-β-1b antibodies, presently not believed to impede the clinical efficacy of IFN-β-1b, were demonstrated by an immunoassay in some patients already after I month of treatment and in 78% after 3 months. The development of binding antibodies seemed to be an early phenomenon, preceding the appearance of neutralising antibodies. Antibodies crossreacting with IFN-β-1a and natural IFN-β were also found in a majority of IFN-β-1b treated patients with high titres of binding antibodies. Employing a solid-phase enzyme-linked immunospot (ELISPOT) assay, 68% of MS patients treated with IFN-β-1b for 1 -23 months had elevated numbers of anti-IFN-β-1b-antibody secreting cells in blood, compared to 18% of untreated MS patients and 20% among patients with other neurological diseases. Thus, our findings confirm that IFN-β-1 b is immunogenic in MS patients. High levels of anti-IFN-β-1b antibody secreting cells were, however, also found in two untreated control patients with inflammatory diseases, suggesting that anti-IFN-β-1b antibodies might also occur spontaneously.

Sign in / Sign up

Export Citation Format

Share Document