Brain atrophy and lesion load predict long term disability in multiple sclerosis

Popescu, Veronica Adriana; Agosta, Federica; Hulst, Hanneke E.; Sluimer, Ingrid C.; Knol, Dirk L.; Sormani, Maria Pia; Enzinger, Christian; Ropele, Stefan; Alonso, Joan Nunes i; Sastre‐Garriga, Jaume; Rovira, Àlex; Montalbán, Xavier; Bodini, Benedetta; Ciccarelli, Olga; Khaleeli, Zhaleh; Chard, Declan; Matthews, Lucy; Palace, J; Giorgio, Antonio; Stefano, Nicola De; Eisele, Philipp; Gass, Achim; Polman, Chris H.; Uitdehaag, Bernard M. J.; Messina, M; Comi, Giancarlo; Filippi, Massimo; Barkhof, Frederik; Vrenken, Hugo

doi:10.1136/jnnp-2012-304094

Cited by 296 publications

(291 citation statements)

References 41 publications

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“…The clinical disease course was well reflected in the rate of brain volume loss, which was most rapid in the severe subgroup who experienced ≥2 confirmed progressions and least rapid in the stable subgroup who experienced no confirmed progressions. These results confirm a relationship between brain volume loss and disability worsening in PPMS, consistent with findings in RMS 2, 3, 4, 5. The relationship between brain volume loss and disability worsening was sustained even in the absence of on‐study inflammatory activity, defined as new or enlarging T2 lesions or relapses.…”

Section: Discussionsupporting

confidence: 88%

“…Many studies in relapse‐onset multiple sclerosis (RMS) found a relationship between brain volume loss and disability worsening 2, 3, 4, 5. Moreover, patients with RMS and a small normalized brain volume are significantly more likely to worsen over 4 years than patients with large normalized brain volume but otherwise similar baseline characteristics 6.…”

Section: Introductionmentioning

confidence: 99%

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Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study

Miller

Lublin

Sormani

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo investigate the relationship between brain volume and disability worsening over ≥3 years in the natural history of primary progressive multiple sclerosis using data from the placebo group of the INFORMS trial (n = 487; clinicaltrials.gov NCT00731692).MethodsMagnetic resonance imaging scans were collected annually. Brain volume loss was determined using SIENA. Patients were stratified by baseline normalized brain volume after adjusting for demographic and disease‐burden covariates.ResultsBaseline normalized brain volume was predictive of disability worsening: Risk of 3‐month confirmed disability progression was reduced by 36% for high versus low baseline normalized brain volume (Cox's model hazard ratio 0.64, P = 0.0339; log‐rank test: P = 0.0297). Moreover, on‐study brain volume loss was significantly associated with disability worsening (P = 0.012) and was evident in patients with or without new lesions or relapses. Brain volume loss depended significantly on baseline T2 lesion volume (P < 0.0001). Despite low inflammatory activity at baseline (13% of patients had gadolinium‐enhancing lesions) and throughout the study (mean 0.5 new/enlarging T2 lesions and 172 mm3 T2 lesion volume increase per year), baseline T2 lesion volume was substantial (mean 10 cm3). Lower normalized brain volume at baseline correlated with higher baseline T2 volume and older age (both P < 0.0001).InterpretationBaseline brain volume and the rate of ongoing brain atrophy are significantly associated with disability worsening in primary progressive multiple sclerosis. Brain volume loss is significantly related to baseline T2 lesion volume, but partially independent of new lesion activity, which might explain the limited efficacy of anti‐inflammatory treatment.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study

Miller

Lublin

Sormani

et al. 2018

Ann Clin Transl Neurol

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“…33,34 Generally speaking, brain volume changes can be an important measure of tissue damage in patients with MS. 32 Indeed, baseline atrophy and high rates of subsequent volume loss are associated with cognitive impairment, fatigue and disability progression over the long term. 32,[35][36][37][38][39][40][41] In a complex disease such as MS, brain volume loss results from the sum of and interactions between various destructive pathological processes, 42 including irrever sible demyelination, and axonal and/or neuronal loss. The neurodegenerative pathology that occurs in MS is an important target for treatment; thus, MRI brain volume measures have been used in randomized clinical trials to monitor the effects of disease modifying thera pies on these parameters.…”

Section: Focal Lesionsmentioning

confidence: 99%

MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis—establishing disease prognosis and monitoring patients

2015

Nat Rev Neurol

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“…1,2 Currently available disease-modifying therapies (DMTs) for relapsing-remitting MS (RRMS) modulate or suppress the immune system, reducing the risk for future inflammation and associated neurodegeneration. 3 Accordingly, the effect of DMTs on MRI-derived estimates of brain atrophy is a common outcome in MS trials.…”

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confidence: 99%

Disease-modifying therapies modulate retinal atrophy in multiple sclerosis

et al. 2017

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Objective: To retrospectively investigate whether disease-modifying therapies (DMTs) exert differential effects on rates of retinal atrophy in relapsing-remitting multiple sclerosis (RRMS), as assessed using optical coherence tomography (OCT).Methods: A total of 402 patients with RRMS followed at the Johns Hopkins MS Center who underwent Cirrus-HD OCT were assessed for eligibility. Inclusion criteria included at least 1 year of OCT follow-up and adherence to a single DMT during the period of follow-up. Combined thickness of the ganglion cell 1 inner plexiform (GCIP) and other retinal layers was computed utilizing automated macular segmentation. Retinal thickness changes were analyzed using mixed-effects linear regression.Results: The effects of glatiramer acetate (GA; n 5 48), natalizumab (NAT; n 5 46), and interferonb-1a subcutaneously (IFN SC ; n 5 35) and intramuscularly (IFN IM ; n 5 28) were assessed. Baseline analyses revealed no significant differences between groups in terms of age, sex, optic neuritis history, or follow-up duration. During follow-up, relative to NAT-treated patients, IFN SC -and GAtreated patients exhibited 0.37 mm/y (p , 0.001) and 0.14 mm/y (p 5 0.035) faster rates of GCIP thinning, respectively, adjusting for the interval between initiation of DMT and OCT monitoring (gap time), age, sex, relapses, and disease duration. In the IFN SC group, GCIP thinning was 1.53 mm/y faster during the first year of therapy vs during the time interval afterwards (p , 0.001).Conclusions: Rates of GCIP atrophy in patients with RRMS vary according to DMT utilization. Our findings support OCT for monitoring neurodegenerative treatment effects in the retina, an easily accessible tissue, and as a practical outcome measure in RRMS clinical trials. Neurology ® 2017;88:525-532 GLOSSARY AMT 5 average macular thickness; DMT 5 disease-modifying therapy; GA 5 glatiramer acetate; GCIP 5 ganglion cell 1 inner plexiform layer; HC 5 healthy control; IFN 5 interferon; IFN IM 5 intramuscular interferon-b-1a; IFN SC 5 subcutaneous interferon-b-1a; INL 5 inner nuclear layer; MME 5 microcystic macular edema; MS 5 multiple sclerosis; NAT 5 natalizumab; OCT 5 optical coherence tomography; ON 5 optic neuritis; ONL 5 outer nuclear layer; pRNFL 5 peripapillary retinal nerve fiber layer thickness; RRMS 5 relapsing-remitting multiple sclerosis.Although multiple sclerosis (MS) is conventionally regarded as an autoimmune, inflammatory, demyelinating disorder of the CNS, neurodegeneration resulting from these processes is recognized as the principal substrate of long-term disability.1,2 Currently available disease-modifying therapies (DMTs) for relapsing-remitting MS (RRMS) modulate or suppress the immune system, reducing the risk for future inflammation and associated neurodegeneration.3 Accordingly, the effect of DMTs on MRI-derived estimates of brain atrophy is a common outcome in MS trials. [4][5][6][7] Recent studies reveal that retinal atrophy mirrors brain atrophy over time in MS. 8 However, it remains unclear wh...

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Brain atrophy and lesion load predict long term disability in multiple sclerosis

Abstract: This large multicentre study points to the complementary predictive value of atrophy and lesion volumes for predicting long term disability in MS.

Cited by 296 publications

References 41 publications

Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study

Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study

MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis—establishing disease prognosis and monitoring patients

Disease-modifying therapies modulate retinal atrophy in multiple sclerosis

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