Background:Acute monosymptomatic optic neuritis (ON) may be the earliest manifestation of multiple sclerosis (MS). Atrophy has been shown to be a prominent feature of MS with great impact on disability.
Objectives:The objectives of this study were to evaluate retinal and brain atrophy and possible associations at the earliest possible stages of MS.
Methods:In a prospective observational cohort study we included 60 untreated patients with monosymptomatic ON and 19 healthy volunteers. Unaffected fellow eyes were examined with optical coherence tomography (OCT) and normalized brain volumes were calculated based on MRI. Additionally, visual evoked potentials (VEPs) were recorded.
Results:Neither OCT measurements nor brain volume measures revealed signs of localized or generalized atrophy in patients compared with healthy volunteers. Stratification of patients into high risk based on the presence of white matter lesions did not reveal differences. The association between OCT measures and brain volumes previously found could not be confirmed at the time of the first clinical event. VEP latency was significantly prolonged in patients with white matter lesions compared to those without lesions. A trend towards a relationship between VEP amplitude of fellow eyes and brain volumes was noted.
Conclusions:In this cohort we were not able to show atrophic features in the retina or the brain, and the association between structural measures of the retina and the brain as indicated in the later stages of MS could not be reproduced. These findings suggest that atrophy does require time to evolve and indicate the complexity of the relationship between local and general structural measures.
TrappBDPetersonJRansohoffRMRudickRMörkSBöL. Axonal transection in the lesions of multiple sclerosis. N Engl J Med1998; 338: 278–285.
2.
LassmannHSuchanekGOzawaK. Histopathology and the blood-cerebrospinal fluid barrier in multiple sclerosis. Ann Neurol1994; 36(Suppl): S42–S46.
3.
RovarisMAgostaFSormaniMP. Conventional and magnetization transfer MRI predictors of clinical multiple sclerosis evolution: a medium-term follow-up study. Brain2003; 126: 2323–2332.
4.
GeYGrossmanRIUdupaJK. Brain atrophy in relapsing–remitting multiple sclerosis and secondary progressive multiple sclerosis: longitudinal quantitative analysis. Radiology2000; 214: 665–670.
5.
RudickRAFisherELeeJCDudaJTSimonJ. Brain atrophy in relapsing multiple sclerosis: relationship to relapses, EDSS, and treatment with interferon beta-1a. Mult Scler2000; 6: 365–372.
6.
SørensenTLFrederiksenJLBrønnum-HansenHPetersenHC. Optic neuritis as onset manifestation of multiple sclerosis: a nationwide, long-term survey. Neurology1999; 53: 473–478.
7.
BeckRWTrobeJDMokePS. High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial. Arch Ophthalmol2003; 121: 944–949.
8.
O'RiordanJIThompsonAJKingsleyDP. The prognostic value of brain MRI in clinically isolated syndromes of the CNS. A 10-year follow-up. Brain1998; 121(Pt 3): 495–503.
9.
ParisiVManniGSpadaroM. Correlation between morphological and functional retinal impairment in multiple sclerosis patients. Invest Ophthalmol Vis Sci1999; 40: 2520–2527.
10.
TripSASchlottmannPGJonesSJ. Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis. Ann Neurol2005; 58: 383–391.
11.
SergottRC. Optical coherence tomography: measuring in-vivo axonal survival and neuroprotection in multiple sclerosis and optic neuritis. Curr Opin Ophthalmol2005; 16: 346–350.
12.
CostelloFCouplandSHodgeW. Quantifying axonal loss after optic neuritis with optical coherence tomography. Ann Neurol2006; 59: 963–969.
13.
FisherJBJacobsDAMarkowitzCE. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology2006; 113: 324–332.
14.
RebolledaGNovalSContrerasIArnalich-MontielFGarcía-PerezJLMuñoz-NegreteFJ. Optic disc cupping after optic neuritis evaluated with optic coherence tomography. Eye (Lond)2009; 23: 890–894.
15.
PulickenMGordon-LipkinEBalcerLJFrohmanECutterGCalabresiPA. Optical coherence tomography and disease subtype in multiple sclerosis. Neurology2007; 69: 2085–2092.
16.
DaltonCMBrexPAJenkinsR. Progressive ventricular enlargement in patients with clinically isolated syndromes is associated with the early development of multiple sclerosis. J Neurol Neurosurg Psychiatry2002; 73: 141–147.
17.
TripSASchlottmannPGJonesSJ. Optic nerve atrophy and retinal nerve fibre layer thinning following optic neuritis: evidence that axonal loss is a substrate of MRI-detected atrophy. Neuroimage2006; 31: 286–293.
18.
GrazioliEZivadinovRWeinstock-GuttmanB. Retinal nerve fiber layer thickness is associated with brain MRI outcomes in multiple sclerosis. J Neurol Sci2008; 268: 12–17.
19.
SepulcreJMurie-FernandezMSalinas-AlamanAGarcía-LayanaABejaranoBVillosladaP. Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS. Neurology2007; 68: 1488–1494.
20.
Gordon-LipkinEChodkowskiBReichDS. Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis. Neurology2007; 69: 1603–1609.
21.
SigerMDziegielewskiKJasekL. Optical coherence tomography in multiple sclerosis: thickness of the retinal nerve fiber layer as a potential measure of axonal loss and brain atrophy. J Neurol2008; 255: 1555–1560.
22.
FrohmanEMDwyerMGFrohmanT. Relationship of optic nerve and brain conventional and non-conventional MRI measures and retinal nerve fiber layer thickness, as assessed by OCT and GDx: a pilot study. J Neurol Sci2009; 282: 96–105.
23.
KallenbachKSimonsenHSanderB. Retinal nerve fiber layer thickness is associated with lesion length in acute optic neuritis. Neurology2010; 74: 252–258.
24.
AnonX. The clinical profile of optic neuritis. Experience of the Optic Neuritis Treatment Trial. Optic Neuritis Study Group. Arch Ophthalmol1991; 109: 1673–1678.
25.
SmithSMZhangYJenkinsonM. Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage2002; 17: 479–489.
26.
SmithSMJenkinsonMWoolrichMW. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage2004; 23(Suppl 1): S208–S219.
27.
NeacsuVJasperseBKortewegT. Agreement between different input image types in brain atrophy measurement in multiple sclerosis using SIENAX and SIENA. J Magn Reson Imaging2008; 28: 559–565.
28.
MillerDHBarkhofFFrankJAParkerGJThompsonAJ. Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain2002; 125: 1676–1695.
29.
IshikawaHSteinDMWollsteinGBeatonSFujimotoJGSchumanJS. Macular segmentation with optical coherence tomography. Invest Ophthalmol Vis Sci2005; 46: 2012–2017.
30.
BrexPAJenkinsRFoxNC. Detection of ventricular enlargement in patients at the earliest clinical stage of MS. Neurology2000; 54: 1689–1691.
31.
PaolilloAPiattellaMCPantanoP. The relationship between inflammation and atrophy in clinically isolated syndromes suggestive of multiple sclerosis: a monthly MRI study after triple-dose gadolinium-DTPA. J Neurol2004; 251: 432–439.
32.
GalloARovarisMRivaR. Diffusion-tensor magnetic resonance imaging detects normal-appearing white matter damage unrelated to short-term disease activity in patients at the earliest clinical stage of multiple sclerosis. Arch Neurol2005; 62: 803–808.
33.
HenryRGShiehMOkudaDTEvangelistaAGorno-TempiniMLPelletierD. Regional grey matter atrophy in clinically isolated syndromes at presentation. J Neurol Neurosurg Psychiatry2008; 79: 1236–1244.
34.
RoccaMAAgostaFSormaniMP. A three-year, multi-parametric MRI study in patients at presentation with CIS. J Neurol2008; 255: 683–691.
35.
CeccarelliARoccaMAPaganiE. A voxel-based morphometry study of grey matter loss in MS patients with different clinical phenotypes. Neuroimage2008; 42: 315–322.
36.
CalabreseMAtzoriMBernardiV. Cortical atrophy is relevant in multiple sclerosis at clinical onset. J Neurol2007; 254: 1212–1220.
37.
GoodCDJohnsrudeISAshburnerJHensonRNFristonKJFrackowiakRS. A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage2001; 14: 21–36.
38.
OutteryckOZephirHDefoortS. Optical coherence tomography in clinically isolated syndrome: no evidence of subclinical retinal axonal loss. Arch Neurol2009; 66: 1373–1377.
39.
PueyoVMartinJFernandezJ. Axonal loss in the retinal nerve fiber layer in patients with multiple sclerosis. Mult Scler2008; 14: 609–614.
40.
ThurtellMJBalaEYaniglosSSRuckerJCPeacheyNSLeighRJ. Evaluation of optic neuropathy in multiple sclerosis using low-contrast visual evoked potentials. Neurology2009; 73: 1849–1857.
41.
PueyoVAraJRAlmarceguiC. Sub-clinical atrophy of the retinal nerve fibre layer in multiple sclerosis. Acta Ophthalmol2009[Epub ahead of print].
42.
NovalSContrerasIRebolledaGMuñoz-NegreteFJ. Optical coherence tomography versus automated perimetry for follow-up of optic neuritis. Acta Ophthalmol Scand2006; 84: 790–794.
43.
GundoganFCDemirkayaSSobaciG. Is optical coherence tomography really a new biomarker candidate in multiple sclerosis? – A structural and functional evaluation. Invest Ophthalmol Vis Sci2007; 48: 5773–5781.
44.
NaismithRTTutlamNTXuJ. Optical coherence tomography is less sensitive than visual evoked potentials in optic neuritis. Neurology2009; 73: 46–52.
