Highlights
- •Follow-up tools of disease progression in RRMS lack relevance to the neurodegenerative aspects.
- •Brain volumetric MRI has yet to be translated into clinical practice.
- •Symbol Digit Modalities Test may be capable of replacing brain atrophy rate in NEDA-4.
Abstract
Background
: In relapsing-remitting multiple sclerosis (RRMS), no evidence of disease activity-3
(NEDA-3) is defined as the absence of: (1) relapses; (2) disability progression; (3)
MRI activity (new/enlarged T2 lesions and/or gadolinium-enhanced T1 lesions). NEDA-4
status is defined as meeting all NEDA-3 criteria plus having an annualized percentage brain volume change (a-PBVC)
>-0.4%. In individual patients, brain volume assessment is confounded with normal
aging, methodological limitations and fluid-shift related fluctuations in brain volume.
Cognitive impairment has been proposed as another component that should be integrated
into therapeutic algorithms for RRMS. We aim to determine the proportion of patients
failing to meet NEDA-4 criteria and to appraise whether the Symbol Digit Modalities
Test (SDMT) is capable of replacing a-PBVC as one of the components of NEDA-4. We
hypothesize that NEDA-4 has the potential to capture the impact of DMT therapies in
RRMS.
Methods
: Forty-five patients were prospectively followed 1 and 2 years after their baseline
assessment at the University of Chile Hospital. SIENA software was used to assess
a-PBVC.
Results
: At baseline, the patients had a mean age of 33.0 years (range 18–57), disease duration
of 1.9 years (0.4–4), Expanded Disability Status Scale score of 1.3 (0–4), and 67%
were female. The majority had RRMS (91% while 9% had clinically isolated syndrome
(CIS)). Seventy-three percent were on the so-called first line DMTs such as interferons
(53%), glatiramer acetate (13%), teriflunomide (9%), and 18% were on fingolimod. There
was a serial decline in the proportion of NEDA: after 1 and 2 years of follow-up 60%
and 47% met NEDA-3 status, and 38% and 27% met NEDA-4, respectively. At the last follow-up
21% remained on interferons, 47% were now on fingolimod, 4% on alemtuzumab and 2%
on natalizumab. At year 1 and year 2, with the replacement of a-PBVC by SDMT, 53%
and 40% of patients achieved a putative NEDA-4 status, respectively.
Conclusion
: Brain volumetric MRI has yet to be translated into clinical practice and SDMT may
qualify as the fourth component of NEDA-4 definition. NEDA-4 has the potential to
capture the impact of DMT therapies in RRMS earlier in the disease course of RRMS.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Multiple Sclerosis and Related DisordersAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Detecting treatment effects on brain atrophy in relapsing remitting multiple sclerosis: sample size estimates.J. Neurol. 2007; 254: 1588-1594https://doi.org/10.1007/s00415-007-0599-3
- Evolving role of MRI in optimizing the treatment of multiple sclerosis: Canadian consensus recommendations.Mult. Scler. J. Exp. Transl. Clin. 2015; 1https://doi.org/10.1177/2055217315589775
- Manifestations of early brain recovery associated with abstinence from alcoholism.Brain. 2007; 130: 36-47https://doi.org/10.1093/brain/awl303
- Evaluating and reducing the impact of white matter lesions on brain volume measurements.Hum. Brain Mapp. 2012; 33: 2062-2071https://doi.org/10.1002/hbm.21344
- Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis.Mult. Scler. 2017; 23: 721-733https://doi.org/10.1177/1352458517690821
- Brief international cognitive assessment for MS (BICAMS): international standards for validation.BMC Neurol. 2012; 12https://doi.org/10.1186/1471-2377-12-55
- Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS.Neurol. Neuroimmunol. Neuroinflamm. 2016; 3: e271https://doi.org/10.1212/NXI.0000000000000271
- No evidence of disease activity (NEDA) in MS should include CSF biology - towards a “Disease-free status score”.Mult. Scler. Relat. Disord. 2017; https://doi.org/10.1016/j.msard.2016.12.001
- The natural history of multiple sclerosis: a geographically based study. 5. The clinical features and natural history of primary progressive multiple sclerosis.Brain. 1999; 122: 625-639https://doi.org/10.1093/brain/122.4.625
- Multiple sclerosis epidemiology in Latin America: an updated survey.Mult. Scler. J. Exp. Transl. Clin. 2017; 3https://doi.org/10.1177/2055217317715050
- Clinical relevance of brain volume measures in multiple sclerosis.CNS Drugs. 2014; 28: 147-156https://doi.org/10.1007/s40263-014-0140-z
- Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis.J. Neurol. Neurosurg. Psychiatry. 2016; 87: 93-99https://doi.org/10.1136/jnnp-2014-309903
- Incidence of multiple sclerosis in Chile. A hospital registry study.Acta Neurol. Scand. 2012; 125: 71-75https://doi.org/10.1111/j.1600-0404.2011.01571.x
- Risk factors for progression of brain atrophy in aging: six-year follow-up of normal subjects.Neurology. 2005; 64: 1704-1711https://doi.org/10.1212/01.WNL.0000161871.83614.BB
- Efficacy and safety of alemtuzumab in a real-life cohort of patients with multiple sclerosis.J. Neurol. 2019;
- Gene geography of Chile: regional distribution of American, European and African genetic contributions.Rev. Med. Chile. 2014; 142: 281-289https://doi.org/10.4067/S0034-98872014000300001
- Measurement and clinical effect of grey matter pathology in multiple sclerosis.Lancet Neurol. 2012; https://doi.org/10.1016/S1474-4422(12)70230-2
- ‘No evidence of disease activity’ – is it an appropriate surrogate in multiple sclerosis?.Eur. J. Neurol. 2018; https://doi.org/10.1111/ene.13669
- Gray matter atrophy and disability progression in patients with early relapsing-remitting multiple sclerosis: a 5-year longitudinal study.J. Neurol. Sci. 2009; 282: 112-119https://doi.org/10.1016/j.jns.2008.12.005
- No evidence of disease activity status over 3 years in a real-world cohort of relapsing remitting MS patients in Germany.Mult. Scler. Relat. Disord. 2019; 27: 133-138
- Recommendations for cognitive screening and management in multiple sclerosis care.Mult. Scler. 2018; 24: 1665-1680https://doi.org/10.1177/1352458518803785
- Inclusion of brain volume loss in a revised measure of “no evidence of disease activity” (NEDA-4) in relapsing-remitting multiple sclerosis.Mult. Scler. 2016; 22: 1297-1305https://doi.org/10.1177/1352458515616701
- A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.N. Engl. J. Med. 2010; 362: 387-401https://doi.org/10.1056/NEJMoa0909494
- Effects of acute dehydration on brain morphology in healthy humans.Hum. Brain Mapp. 2009; 30: 291-298https://doi.org/10.1002/hbm.20500
- Multiple sclerosis in US minority populations: clinical practice insights.Neurol. Clin. Pract. 2015; 5: 132-142https://doi.org/10.1212/CPJ.0000000000000112
- Real-World Effectiveness of Disease-Modifying Therapies in Korean Patients with Relapsing Multiple Sclerosis.J. Clin. Neurol. 2019; 15: 20-26
- Brain atrophy in mild or moderate traumatic brain injury: a longitudinal quantitative analysis.Am. J. Neuroradiol. 2002; 23: 1509-1515
- Advances in spinal cord imaging in multiple sclerosis.Ther. Adv. Neurol. Disord. 2019; https://doi.org/10.1177/1756286419840593
- Diurnal fluctuations in brain volume: statistical analyses of MRI from large populations.Neuroimage. 2015; 118: 126-132https://doi.org/10.1016/j.neuroimage.2015.05.077
- A longitudinal study of disability, cognition and gray matter atrophy in early multiple sclerosis patients according to evidence of disease activity.PLoS One. 2015; 10
- Early disease stage of Multiple Sclerosis in Chilean patients: cognitive impairment is a key domain and does not relate to MRI measures.Neurology. 2018; 90: 1.412
- Outcomes of natalizumab treatment within 3 years of relapsing-remitting multiple sclerosis diagnosis: A prespecified 2-year interim analysis of STRIVE.BMC Neurol. 2019; 19
- Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria.Ann. Neurol. 2011; 69: 292-302https://doi.org/10.1002/ana.22366
- No evidence of disease activity (NEDA-3) and disability improvement after alemtuzumab treatment for multiple sclerosis: a 36-month real-world study.J. Neurol. 2018; 265: 2851-2860
- Brain volume loss and no evidence of disease activity over 3 years in multiple sclerosis patients under interferon beta 1a subcutaneous treatment.J. Clin. Neurosci. 2019; 59: 175-178
- Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort.JAMA Neurol. 2015; 72: 152-158https://doi.org/10.1001/jamaneurol.2014.3537
- An epidemiological study on the course of disease and therapeutic considerations in relapsing-remitting multiple sclerosis patients receiving injectable first-line disease-modifying therapies in Germany (EPIDEM).Ther. Adv. Neurol. Disord. 2018; 11https://doi.org/10.1177/1756285617749802
- Normalized accurate measurement of longitudinal brain change.J. Comput. Assist. Tomogr. 2001; 25: 466-475https://doi.org/10.1097/00004728-200105000-00022
- Accurate, robust, and automated longitudinal and cross-sectional brain change analysis.Neuroimage. 2002; 17: 479-489https://doi.org/10.1006/nimg.2002.1040
- Including blood neurofilament light chain in the NEDA concept in relapsing–remitting multiple sclerosis trials (S24.007).Neurology. 2018; 90 (S24): 007
- Towards the implementation of “no evidence of disease activity” in multiple sclerosis treatment: the multiple sclerosis decision model.Ther. Adv. Neurol. Disord. 2015; 8: 3-13https://doi.org/10.1177/1756285614560733
- Measurement of whole-brain and gray matter atrophy in multiple sclerosis: assessment with MR Imaging.Radiology. 2018; 288: 554-564https://doi.org/10.1148/radiol.2018172468
- Symbol Digit Modalities Test: a valid clinical trial endpoint for measuring cognition in multiple sclerosis.Mult. Scler. 2019; 25: 1781-1790https://doi.org/10.1177/1352458518808204
- Assessing treatment outcomes in multiple sclerosis trials and in the clinical setting.Nat. Rev. Neurol. 2018; https://doi.org/10.1038/nrneurol.2017.171
- A new assessment tool for patients with multiple sclerosis from Spanish-speaking countries: validation of the brief international cognitive assessment for MS (BICAMS) in Argentina.Clin. Neuropsychol. 2016; 30: 1023-1031https://doi.org/10.1080/13854046.2016.1184317
- Global, regional, and national burden of multiple sclerosis 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet. Neurol. 2019; 18: 269-285
- Assessing ‘No Evidence of Disease Activity’ Status in Patients with Relapsing-Remitting Multiple Sclerosis Receiving Fingolimod in Routine Clinical Practice: A Retrospective Analysis of the Multiple Sclerosis Clinical and Magnetic Resonance Imaging Outcom.CNS Drugs. 2018; 32: 75-84
- Brain volume loss is present in Japanese multiple sclerosis patients with no evidence of disease activity.Neurol. Sci. 2018; 39: 1713-1716
- No evidence of disease activity in patients receiving fingolimod at private or academic centers in clinical practice: a retrospective analysis of the multiple sclerosis, clinical, and magnetic resonance imaging outcomes in the USA (MS-MRIUS) study.Curr. Med. Res. Opin. 2018; 34: 1431-1440
Article info
Publication history
Published online: April 26, 2020
Accepted:
March 27,
2020
Received in revised form:
February 23,
2020
Received:
November 12,
2019
Identification
Copyright
© 2020 Elsevier B.V. All rights reserved.
