Semin Neurol 2008; 28(1): 046-055
DOI: 10.1055/s-2007-1019127
© Thieme Medical Publishers

Recent Advances in Neuroimaging of Multiple Sclerosis

Waqar Rashid1 , David H. Miller1
  • 1MS NMR Research Unit, Department of Neuroinflammation, Institute of Neurology, University College London, London, United Kingdom
Further Information

Publication History

Publication Date:
07 February 2008 (online)

ABSTRACT

Conventional magnetic resonance imaging (MRI) is sensitive in detecting abnormalities in multiple sclerosis (MS), but these tend not to be pathologically specific. The visible T2 lesions are diagnostically valuable and may allow earlier diagnosis of the disease and more accurate prognostication. Quantitative MR techniques such as volume measurement can reveal pathology in nonlesional tissue with some clinical correlation; however, accurate pathological interpretation at a cellular level is problematic given the current resolution of MRI. In this update, recent studies using conventional and quantitative MR techniques are discussed and new, promising non-MRI methodologies highlighted, including retinal nerve fiber layer estimation. The role of MRI in measuring metabolic function, such as functional measures and investigating nonlocomotor symptoms such as cognition, is also discussed as are future improvements to the techniques currently employed in research studies. With increased sophistication and improved analysis of these techniques, understanding of the pathology underlying MS may increase, and objective quantification of the natural history of MS is possible.

REFERENCES

  • 1 Ormerod I E, Miller D H, McDonald W I et al.. The role of NMR imaging in the assessment of multiple sclerosis and isolated neurological lesions: a quantitative study.  Brain. 1987;  110 1579-1616
  • 2 Miller D H, Grossman R I, Reingold S C, McFarland H F. The role of magnetic resonance techniques in understanding and managing multiple sclerosis.  Brain. 1998;  121 3-24
  • 3 Miller D H, Rudge P, Johnson G et al.. Serial gadolinium enhanced magnetic resonance imaging in multiple sclerosis.  Brain. 1988;  111 927-939
  • 4 McDonald W I, Compston A, Edan G et al.. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis.  Ann Neurol. 2001;  50 121-127
  • 5 Lassmann H. Multiple sclerosis pathology: evolution of pathogenic concepts.  Brain Pathol. 2005;  15 217-222
  • 6 Kurtzke J F. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).  Neurology. 1983;  33 1444-1452
  • 7 IFNB Multiple Sclerosis Study Group, and the University of British Columbia MS/MRI Analysis Group . Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial.  Neurology. 1995;  45 1277-1285
  • 8 Truyen L, van Waesberghe J H, van Waldervenn M A et al.. Accumulation of hypointense lesions (“black holes”) on T1 spin-echo MRI correlates with disease progression in multiple sclerosis.  Neurology. 1996;  47 1469-1476
  • 9 Kappos L, Moeri D, Radue E W et al.. Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis.  Lancet. 1999;  353 964-969
  • 10 Charil A, Yousry T A, Rovaris M et al.. MRI and the diagnosis of multiple sclerosis: expanding the concept of “no better explanation..”  Lancet Neurol. 2006;  5 841-852
  • 11 Nijeholt G J, van Walderveen M A, Castelijns J A et al.. Brain and spinal cord abnormalities in multiple sclerosis: correlations between MRI parameters, clinical subtypes and symptoms.  Brain. 1998;  121 687-697
  • 12 Oppenheimer D R. The cervical cord in multiple sclerosis.  Neuropathol Appl Neurobiol. 1978;  4 151-162
  • 13 Kidd D, Thorpe J W, Thompson A J et al.. Spinal cord MRI using multi-array coils and fast spin echo. II: findings in multiple sclerosis.  Neurology. 1993;  43 2632-2637
  • 14 Bot J C, Barkhof F, Polman C H et al.. Spinal cord abnormalities in recently diagnosed MS patients: added value of spinal MRI examination.  Neurology. 2004;  62 226-233
  • 15 Bot J C, Barkhof F, Lycklama à Nijeholt G et al.. Differentiation of multiple sclerosis from other inflammatory disorders and cerebrovascular disease: value of spinal MR imaging.  Radiology. 2002;  223 46-56
  • 16 Fazekas F, Offenbacher H, Fuchs S et al.. Criteria for an increased specificity of MRI interpretation in elderly subjects with suspected multiple sclerosis.  Neurology. 1988;  38 1822-1825
  • 17 Dalton C M, Brex P S, Miszkel K M et al.. New T2 lesions enable an earlier diagnosis of multiple sclerosis in clinically isolated syndromes.  Ann Neurol. 2003;  53 673-676
  • 18 Barkhof F, Filippi M, Miller D H et al.. Comparison of MR imaging criteria at first presentation to predict conversion to clinically definite multiple sclerosis.  Brain. 1997;  120 2059-2069
  • 19 Tintoré M, Rovira A, Martínez M et al.. Isolated demyelinating syndromes: comparison of different MR imaging criteria to predict conversion to clinically definite multiple sclerosis.  AJNR Am J Neuroradiol. 2000;  21 702-706
  • 20 Dalton C M, Brex P A, Miszkel K A et al.. Application of the new McDonald criteria to patients with clinically isolated syndromes suggestive of multiple sclerosis.  Ann Neurol. 2002;  52 47-53
  • 21 Tintoré M, Rovira A, Rio J et al.. New diagnostic criteria for multiple sclerosis: application in first demyelinating episode.  Neurology. 2003;  60 27-30
  • 22 Poser C M, Paty D W, Scheinberg L et al.. New diagnostic criteria for multiple sclerosis: guidelines for research protocols.  Ann Neurol. 1983;  13 227-231
  • 23 Polman C H, Reingold S C, Edan G et al.. Diagnostic criteria for multiple sclerosis: 2005 revisions to the ‘McDonald criteria’.  Ann Neurol. 2005;  58 840-846
  • 24 Thompson A J, Montalban X, Barkhof F et al.. Diagnostic criteria for primary progressive multiple sclerosis: a position paper.  Ann Neurol. 2000;  47 831-835
  • 25 Swanton J K, Fernando K, Dalton C M et al.. Modification of MRI criteria for multiple sclerosis patients with clinically isolated syndromes.  J Neurol Neurosurg Psychiatry. 2006;  77 830-833
  • 26 Wingerchuk D M, Lennon V A, Pittock S J, Lucchinetti C F, Weinshenker B G. Revised diagnostic criteria for neuromyelitis optica.  Neurology. 2006;  66 1485-1489
  • 27 Pittock S J, Lennon V A, Krek K et al.. Brain abnormalities in neuromyelitis optica.  Arch Neurol. 2006;  63 390-396
  • 28 Lennon V A, Wingerchuk D M, Kryzer T J et al.. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis.  Lancet. 2004;  364 2106-2112
  • 29 Weinshenker B G, Ebers G C. The natural history of multiple sclerosis.  Can J Neurol Sci. 1987;  14 255-261
  • 30 Weinshenker B G, Bass B, Rice G P et al.. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability.  Brain. 1989;  112 133-146
  • 31 Brex P A, Ciccarelli O, O'Riordan J I, Sailer M, Thompson A J, Miller D H. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis.  N Engl J Med. 2002;  346 158-164
  • 32 Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process.  Brain. 2003;  126 770-782
  • 33 Minneboo A, Barkhof F, Polman C H et al.. Infratentorial lesions predict long-term disability in patients with initial findings suggestive of multiple sclerosis.  Arch Neurol. 2004;  61 217-221
  • 34 Tintoré M, Rovira A, Rio J et al.. Baseline MRI predicts future attacks and disability in clinically isolated syndromes.  Neurology. 2006;  67 968-972
  • 35 Barkhof F, Brück W, De Groot C JA et al.. Remyelinated lesions in multiple sclerosis. Magnetic resonance image appearance.  Arch Neurol. 2003;  60 1073-1081
  • 36 Allen I V, McKeown S R. A histological, histochemical and biochemical study of the macroscopically normal white matter in multiple sclerosis.  J Neurol Sci. 1979;  41 81-91
  • 37 Allen I V, Glover G, Anderson R. Abnormalities in the macroscopically normal white matter in cases of mild or spinal multiple sclerosis.  Acta Neuropathol Suppl. 1981;  7 176-178
  • 38 Evangelou N, Esiri M M, Smith S, Palace J, Matthews P M. Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis.  Ann Neurol. 2000;  47 391-395
  • 39 Peterson J W, Bo L, Monk S, Chang A, Trapp B D. Transected neuritis, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions.  Ann Neurol. 2001;  50 389-400
  • 40 Morgen K, Sammer G, Courtney S M et al.. Evidence for direct association between cortical atrophy and cognitive impairment in relapsing-remitting MS.  Neuroimage. 2006;  30 891-898
  • 41 Filippi M, Horsfield M A, Ader H J et al.. Guidelines for using quantitative measures of brain magnetic resonance imaging abnormalities in monitoring the treatment of multiple sclerosis.  Ann Neurol. 1998;  43 499-506
  • 42 Rovaris M, Judica E, Gallo A et al.. Grey matter predicts the evolution of primary progressive multiple sclerosis at 5 years.  Brain. 2006;  129 2628-2634
  • 43 Rovaris M, Gallo A, Valsasina P et al.. Short-term accrual of gray matter pathology in patients with progressive multiple sclerosis: an in vivo study using diffusion tensor MRI.  Neuroimage. 2005;  24 1139-1146
  • 44 Agosta F, Rovaris M, Pagani E, Sormani M P, Comi G, Filippi M. Magnetization transfer MRI metrics predict the accumulation of disability 8 years later in patients with multiple sclerosis.  Brain. 2006;  129 2620-2627
  • 45 Sastre-Garriga J, Ingle G T, Chard D T et al.. Metabolite changes in normal-appearing gray and white matter are linked with disability in early primary progressive multiple sclerosis.  Arch Neurol. 2005;  62 569-573
  • 46 Tiberio M, Chard D T, Altmann D R et al.. Gray and white matter volume changes in early RRMS: a 2-year longitudinal study.  Neurology. 2005;  64 1001-1007
  • 47 Schmierer K, Scaravilli F, Altmann D R et al.. Magnetization transfer ratio and myelin in post-mortem multiple sclerosis brain.  Ann Neurol. 2004;  56 407-415
  • 48 Schmierer K, Wheeler-Kingshott C A, Boulby P A et al.. Diffusion tensor imaging of post mortem multiple sclerosis brain.  Neuroimage. 2006;  35 467-477
  • 49 Dalton C M, Miszkiel K A, O'Connor P W, Plant G T, Rice G S, Miller D H. Ventricular enlargement in MS: one-year change at various stages of disease.  Neurology. 2006;  66 693-698
  • 50 Chard D T, Brex P A, Ciccarelli O et al.. The longitudinal relation between brain lesion load and atrophy in multiple sclerosis: a 14 year follow up study.  J Neurol Neurosurg Psychiatry. 2003;  74 1551-1554
  • 51 Rashid W, Davies G R, Chard D T et al.. Increasing cord atrophy in early relapsing-remitting multiple sclerosis: a 3 year study.  J Neurol Neurosurg Psychiatry. 2006;  77 51-55
  • 52 Marrie R A, Fisher E, Miller D M, Lee J C, Rudick R A. Association of fatigue and brain atrophy in multiple sclerosis.  J Neurol Sci. 2005;  228 161-166
  • 53 Brex P A, Jenkins R, Fox N C et al.. Detection of ventricular enlargement in patients at the earliest clinical stage of MS.  Neurology. 2000;  54 1689-1691
  • 54 Dalton C M, Brex P A, Jenkins R et al.. Progressive ventricular enlargement in patients with clinically isolated syndromes is associated with the early development of multiple sclerosis.  J Neurol Neurosurg Psychiatry. 2002;  73 141-147
  • 55 Dalton C M, Chard D T, Davies G R et al.. Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes.  Brain. 2004;  127 1101-1107
  • 56 Bakshi R, Benedict R H, Bermel R A, Jacobs L. Regional brain atrophy is associated with physical disability in multiple sclerosis: semiquantitative magnetic resonance imaging and relationship to clinical findings.  J Neuroimaging. 2001;  11 129-136
  • 57 Lin X, Blumhardt L D. Inflammation and atrophy in multiple sclerosis: MRI associations with disease course.  J Neurol Sci. 2001;  189 99-104
  • 58 Kalkers N F, Ameziane N, Bot J C, Minneboo A, Polman C H, Barkhof F. Longitudinal brain volume measurement in multiple sclerosis: rate of brain atrophy is independent of the disease subtype.  Arch Neurol. 2002;  59 1572-1576
  • 59 Turner B, Lin X, Calmon G, Roberts N, Blumhardt L D. Cerebral atrophy and disability in relapsing-remitting and secondary progressive multiple sclerosis over four years.  Mult Scler. 2003;  9 21-27
  • 60 Pagani E, Rocca M A, Gallo A et al.. Regional brain atrophy evolves differently in patients with multiple sclerosis according to clinical phenotype.  AJNR Am J Neuroradiol. 2005;  26 341-346
  • 61 Tedeschi G, Lavorgna L, Russo P et al.. Brain atrophy and lesion load in a large population of patients with multiple sclerosis.  Neurology. 2005;  65 280-285
  • 62 Chard D T, Griffin C M, Parker G JM, Kapoor R, Thompson A J, Miller D H. Brain atrophy in clinically early relapsing-remitting multiple sclerosis.  Brain. 2002;  125 327-337
  • 63 Chard D T, Griffin C M, Rashid W et al.. Progressive grey matter atrophy in clinically early relapsing-remitting multiple sclerosis.  Mult Scler. 2004;  10 387-391
  • 64 Sailer M, Fischl B, Salat D et al.. Focal thinning of the cerebral cortex in multiple sclerosis.  Brain. 2003;  126 1734-1744
  • 65 Audoin B, Davies G R, Finisku L, Chard D T, Thompson A J, Miller D H. Localization of grey matter atrophy in early RRMS: a longitudinal study.  J Neurol. 2006;  253 1495-1501
  • 66 Carone D A, Benedict R H, Dwyer M G et al.. Semi-automatic brain region extraction (SABRE) reveals superior cortical and deep gray matter atrophy in MS.  Neuroimage. 2006;  29 505-514
  • 67 Prinster A, Quarantelli M, Orefice G et al.. Grey matter loss in relapsing-remitting multiple sclerosis: a voxel-based morphometry study.  Neuroimage. 2006;  29 859-867
  • 68 Liu C, Edwards S, Gong Q, Roberts N, Blumhardt L D. Three dimensional MRI estimates of brain and spinal cord atrophy in multiple sclerosis.  J Neurol Neurosurg Psychiatry. 1999;  66 323-330
  • 69 Rudick R A, Fisher E, Lee J C, Duda J T, Simon J. Brain atrophy in relapsing multiple sclerosis: relationship to relapses, EDSS and treatment with interferon beta-1a.  Mult Scler. 2000;  6 365-372
  • 70 Zivadinov R, Locatelli L, Stival B et al.. Normalized regional brain atrophy measurements in multiple sclerosis.  Neuroradiology. 2003;  45 793-798
  • 71 Quarantelli M, Ciarmiello A, Morra V B et al.. Brain tissue volume changes in relapsing-remitting multiple sclerosis: correlation with lesion load.  Neuroimage. 2003;  18 360-366
  • 72 Sastre-Garriga J, Ingle G T, Chard D T, Ramio-Torrenta L, Miller D H, Thompson A J. Grey and white matter atrophy in early clinical stages of primary progressive multiple sclerosis.  Neuroimage. 2004;  22 353-359
  • 73 Simon J H. From enhancing lesions to brain atrophy in relapsing MS.  J Neuroimmunol. 1999;  98 7-15
  • 74 Fisher E, Rudick R A, Simon J H et al.. Eight-year follow-up study of brain atrophy in patients with MS.  Neurology. 2002;  59 1412-1420
  • 75 Richert N D, Howard T, Frank J A et al.. Relationship between inflammatory lesions and cerebral atrophy in multiple sclerosis.  Neurology. 2006;  66 551-556
  • 76 Benedict R H, Bruce J M, Dwyer M G et al.. Neocortical atrophy, third ventricular width, and cognitive dysfunction in multiple sclerosis.  Arch Neurol. 2006;  63 1301-1306
  • 77 Simon J H, Jacobs L D, Campion M K et al.. A longitudinal study of brain atrophy in relapsing multiple sclerosis.  The Multiple Sclerosis Collaborative Research Group (MSCRG) . Neurology. 1999;  53 139-148
  • 78 Fisher E, Rudick R A, Cutter G et al.. Relationship between brain atrophy and disability: an 8-year follow-up study of multiple sclerosis patients.  Mult Scler. 2000;  6 373-377
  • 79 Zivadinov R, Sepcic J, Nasuelli D et al.. A longitudinal study of brain atrophy and cognitive disturbances in the early phase of relapsing-remitting multiple sclerosis.  J Neurol Neurosurg Psychiatry. 2001;  70 773-780
  • 80 Paolillo A, Pozzilli C, Giugni E et al.. A 6-year clinical and MRI follow-up study of patients with relapsing-remitting multiple sclerosis treated with Interferon-beta.  Eur J Neurol. 2002;  9 645-655
  • 81 Zivadinov R, Bakshi R. Central nervous system atrophy and clinical status in multiple sclerosis.  J Neuroimaging. 2004;  14 27S-35S
  • 82 Sanfilipo M P, Benedict R H, Sharma J, Weinstock-Guttman B, Bakshi R. The relationship between whole brain volume and disability in multiple sclerosis: A comparison of normalized gray vs. white matter with misclassification correction.  Neuroimage. 2005;  26 1068-1077
  • 83 Sanfilipo M P, Benedict R H, Weinstock-Guttman B, Bakshi R. Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis.  Neurology. 2006;  66 685-692
  • 84 Lin X, Tench C R, Evangelou N, Jaspan T, Constantinescu C S. Measurement of spinal cord atrophy in multiple sclerosis.  J Neuroimaging. 2004;  14 20S-26S
  • 85 Losseff N A, Webb S L, O'Riordan J I et al.. Spinal cord atrophy and disability in multiple sclerosis: a new reproducible and sensitive MRI method with potential to monitor disease progression.  Brain. 1996;  119 701-708
  • 86 Stevenson V L, Leary S M, Losseff N A et al.. Spinal cord atrophy and disability in MS: A longitudinal study.  Neurology. 1998;  51 234-238
  • 87 Rovaris M, Bozzali M, Santuccio G et al.. In vivo assessment of the brain and cervical cord pathology with primary progressive multiple sclerosis.  Brain. 2001;  124 2540-2549
  • 88 Vaithianathar L, Tench C R, Morgan P S, Constantinescu C S. Magnetic resonance imaging of the cervical spinal cord in multiple sclerosis. A quantitative T1 relaxation time mapping approach.  J Neurol. 2003;  250 307-315
  • 89 Lin X, Tench C R, Turner B, Blumhardt L D, Constantinescu C S. Spinal cord atrophy and disability in multiple sclerosis over four years: application of a reproducible automated technique in monitoring disease progression in a cohort of the interferon β-1a (Rebif) treatment trial.  J Neurol Neurosurg Psychiatry. 2003;  74 1090-1094
  • 90 Rashid W, Davies G R, Chard D T et al.. Upper cervical cord area in early relapsing-remitting multiple sclerosis: cross-sectional study of factors influencing cord size.  J Magn Reson Imaging. 2006;  23 473-476
  • 91 Edwards S GM, Gong Q Y, Lui C et al.. Infratentorial atrophy on magnetic resonance imaging and disability in multiple sclerosis.  Brain. 1999;  122 291-301
  • 92 Anderson V M, Fox N C, Miller D H. Magnetic resonance imaging measures of brain atrophy in multiple sclerosis.  J Magn Reson Imaging. 2006;  23 605-618
  • 93 Zivadinov R, Grop A, Sharma J et al.. Reproducibility and accuracy of quantitative magnetic resonance imaging techniques of whole-brain atrophy measurement in multiple sclerosis.  J Neuroimaging. 2005;  15 27-36
  • 94 Anderson V M, Fernando K T, Davies G R et al.. Cerebral atrophy measurement in clinically isolated syndromes and relapsing remitting multiple sclerosis: a comparison of registration-based methods.  J Neuroimaging. 2007;  17 61-68
  • 95 Lycklama G, Thompson A, Filippi M et al.. Spinal-cord MRI in multiple sclerosis.  Lancet Neurol. 2003;  2 555-562
  • 96 Tench C R, Morgan P S, Constantinescu C S. Measurement of cervical spinal cord cross-sectional area by MRI using edge detection and partial volume correction.  J Magn Reson Imaging. 2005;  21 197-203
  • 97 Rudick R A, Fischer E, Lee J-C, Simon J, Jacobs L. Use of brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS.  Neurology. 1999;  53 1698-1704
  • 98 Hardmeier M, Freitag P, Wagenpfeil S et al.. Short and long term brain volume changes after initiation of treatment with rIFN-beta-1A in multiple sclerosis (MS).  J Neurol. 2002;  249(suppl 1) 20 , (abstract)
  • 99 Filippi M, Rovaris M, Inglese M et al.. Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomized, double-blind, placebo-controlled trial.  Lancet. 2004;  364 1489-1496
  • 100 Leary S M, Miller D H, Stevenson V L, Brex P A, Chard D T, Thompson A J. Interferon β-1a in primary progressive MS: an exploratory, randomized, controlled trial.  Neurology. 2003;  60 44-51
  • 101 Jones C K, Riddehough A, Li D KB et al.. MRI cerebral atrophy in relapsing-remitting MS: results from the PRISMS trial.  Neurology. 2001;  56(suppl 3) A379
  • 102 Gasperini C, Paolillo A, Giugni E et al.. MRI brain volume changes in relapsing-remitting multiple sclerosis patients treated with interferon beta-1a.  Mult Scler. 2002;  8 119-123
  • 103 Anderson V M, Bartlett J W, Fox N C, Fisniku L, Miller D H. Detecting treatment effects on brain atrophy in relapsing remitting multiple sclerosis: sample size estimates.  J Neurol. 2007;  254 1588-1594
  • 104 Furby J, Hayton T, Smith K J et al.. A randomised controlled trial of neuroprotection with lamotrigine in secondary progressive multiple sclerosis.  Mult Scler. 2006;  12(suppl 228) 794
  • 105 Ogawa S, Menon R S, Tank D W et al.. Functional brain mapping by blood oxygenation level-dependent contrast magnetic resonance imaging. A comparison of signal characteristics with a biophysical model.  Biophys J. 1993;  64 803-812
  • 106 Toosy A T, Hickman S J, Miszkiel K A et al.. Adaptive cortical plasticity in higher visual areas after acute optic neuritis.  Ann Neurol. 2005;  57 622-633
  • 107 Rocca M A, Colombo B, Falini A et al.. Cortical adaptation in patients with MS: a cross-sectional functional MRI study of disease phenotypes.  Lancet Neurol. 2005;  4 618-626
  • 108 Rosen B R, Belliveau J W, Vevea J M, Brady T J. Perfusion imaging with NMR contrast agents.  Magn Reson Med. 1990;  14 249-265
  • 109 Rashid W, Parkes L M, Ingle G T et al.. Abnormalities of cerebral perfusion in multiple sclerosis.  J Neurol Neurosurg Psychiatry. 2004;  75 1288-1293
  • 110 Wuerfel J, Bellmann-Strobl J, Brunecker P et al.. Changes in cerebral perfusion precede plaque formation in multiple sclerosis: a longitudinal perfusion MRI study.  Brain. 2004;  127 111-119
  • 111 Law M, Saindane A M, Ge Y et al.. Microvascular abnormality in relapsing-remitting multiple sclerosis: perfusion MR imaging findings in normal-appearing white matter.  Radiology. 2004;  231 645-652
  • 112 Bagert B, Camplair P, Bourdette D. Cognitive dysfunction in multiple sclerosis: natural history, pathophysiology and management.  CNS Drugs. 2002;  16 445-455
  • 113 Audoin B, Ibarrola D, Ranjeva J P et al.. Compensatory cortical activation observed by fMRI during a cognitive task at the earliest stage of MS.  Hum Brain Mapp. 2003;  20 51-58
  • 114 Audoin B, Au Duong M V, Ranjeva J P et al.. Magnetic resonance study of the influence of tissue damage and cortical reorganization on PASAT performance at the earliest stage of multiple sclerosis.  Hum Brain Mapp. 2005;  24 216-228
  • 115 Trip S A, Schlottmann P G, Jones S J et al.. Retinal nerve fibre layer axonal loss and visual dysfunction in optic neuritis.  Ann Neurol. 2005;  58 383-391
  • 116 Quigley H A, Davis E B, Anderson D R. Descending optic nerve degeneration in primates.  Invest Ophthalmol Vis Sci. 1977;  16 841-849
  • 117 Huang D, Swanson E A, Lin C P et al.. Optical coherence tomography.  Science. 1991;  254 1178-1181
  • 118 Fercher A F, Hitzenberger C K, Drexler W et al.. In vivo optical coherence tomography.  Am J Ophthalmol. 1993;  116 113-114
  • 119 Trip S A, Schlottmann P G, Jones S J et al.. Optic nerve atrophy and retinal nerve fibre layer thinning following optic neuritis: evidence that axonal loss is a substrate of MRI-detected atrophy.  Neuroimage. 2006;  31 286-293
  • 120 Costello F, Coupland S, Hodge W et al.. Qualifying axonal loss after optic neuritis with optical coherence tomography.  Ann Neurol. 2006;  59 963-969
  • 121 Debruyne J C, Versijpt J, van Laere K J et al.. PET visualisation of microglia in multiple sclerosis patients using [11C]PK11195.  Eur J Neurol. 2003;  10 257-264
  • 122 Banati R B, Newcombe J, Gunn R N et al.. The peripheral benzodiazepine binding site in the brain in multiple sclerosis. Quantitative in vivo imaging of microglia as a measure of disease activity.  Brain. 2000;  123 2321-2337
  • 123 Keiper M D, Grossman R I, Hirsch J A et al.. MR identification of white matter abnormalities in multiple sclerosis: a comparison between 1.5T and 4T.  AJNR Am J Neuroradiol. 1998;  19 1489-1493
  • 124 Wattjes M P, Harzheim M, Kuhl C K et al.. Does high-field MR imaging have an influence on the classification of patients with clinically isolated syndromes according to current diagnostic MR imaging criteria for multiple sclerosis?.  AJNR Am J Neuroradiol. 2006;  27 1794-1798
  • 125 Inglese M, Park S J, Johnson G et al.. Deep gray matter perfusion in multiple sclerosis: dynamic susceptibility contrast perfusion magnetic resonance imaging at 3T.  Arch Neurol. 2007;  64 196-202
  • 126 Mottershead J P, Schmierer K, Clemence M et al.. High field MRI correlates of myelin content and axonal density in multiple sclerosis: a post-mortem study of the spinal cord.  J Neurol. 2003;  250 1293-1301
  • 127 Srinivasan R, Sailasuta N, Hurd R et al.. Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3T.  Brain. 2005;  128 1016-1025
  • 128 Kidd D, Barkhof F, McConnell R, Algra P R, Allen I V, Revesz T. Cortical lesions in multiple sclerosis.  Brain. 1999;  122 17-26
  • 129 Geurts J J, Bö L, Pouwels P J, Castelijns J A, Polman C H, Barkhof F. Cortical lesions in multiple sclerosis: combined post-mortem MR imaging and histopathology.  AJNR Am J Neuroradiol. 2005;  26 572-577
  • 130 Geurts J J, Pouwels P J, Uitdehaag B M, Polman C H, Barkhof F, Castelijns J A. Intracortical lesions in multiple sclerosis: improved detection with 3D double inversion-recovery MR imaging.  Radiology. 2005;  236 254-260
  • 131 Goodin D S. Magnetic resonance imaging as a surrogate outcome measure of disability in multiple sclerosis: have we been overly harsh in our assessment?.  Ann Neurol. 2006;  59 597-605

Professor David H MillerF.R.C.P. 

MS NMR Research Unit, Department of Neuroinflammation, Institute of Neurology

University College London, Queen Square, London WC1N 3BG, United Kingdom

Email: d.miller@ion.ucl.ac.uk