J Neurol (2005) 252 [Suppl 5]: V/16–V/24 DOI 10.1007/s00415-005-5004-5 Massimo Filippi Maria Assunta Rocca MRI evidence for multiple sclerosis as a diffuse disease of the central nervous system JON 5004 ■ Abstract The classical view of MS as a chronic inflammatory de- myelinating disease leading to the formation of focal central nervous system (CNS) white matter (WM) lesions has been recently chal- lenged by pathological studies and by the extensive application of modern MRI-based techniques. There is now overwhelming evi- dence supporting the following statements:  MS causes widespread tissue damage in the normal-appear- ing white matter (NAWM) of the brain and spinal cord, whose ex- tent and severity is more strictly associated to the clinical mani- festations of the disease than the extent of focal pathology. Dis- crete, macroscopic lesions are just the tip of the iceberg of MS pathology. Dr. M. Filippi () · M. A. Rocca, MD Neuroimaging Research Unit Dept. of Neurology Scientific Institute and University Ospedale San Raffaele Via Olgettina 60 20132 Milan, Italy Tel.: + 39-02/26433054 Fax: +39-02/26433054 E-Mail: filippi.massimo@hsr.it  Grey matter (GM) damage is a consistent feature of all MS phe- notypes, which is progressive from the start of the relapsing- remitting phase of the disease. As is the case for WM, GM dam- age is also a mixture of focal lesions and diffuse pathology. High-field strength MR scan- ners are improving our ability to image focal GM lesions and modern MR-based techniques are enabling us to quantify in vivo the extent and severity of GM pathology, which have been shown to correlate only moder- ately with the amount of WM changes. At least part of GM pathology in MS is not sec- ondary to retrograde degenera- tion of fibers traversing WM lesions.  The neurodegenerative compo- nent of the disease is not a late phenomenon and it is not com- pletely driven by inflammatory demyelination. In fact, neurode- generation occurs very early in the course of MS and the corre- lation between MRI measures of inflammation and neurodegen- eration is weak in all disease phases. The interplay of inflam- mation and neurodegeneration is a complex and still poorly un- derstood phenomenon. At least part of MS-related neurodegen- eration is not directly driven by Wallerian degeneration.  Functional cortical changes can be seen in virtually all MS pa- tients and are likely to play a central role in the ability of the MS brain to respond to tissue injury and, hence, limit the functional consequences of structural damage. MS disability is not just the result of tissue de- struction but rather a balance between tissue destruction, tis- sue repair and adaptive cortical reorganization. All of this calls for the concept of MS as a focal, inflammatory de- myelinating, WM disease to be re- examined and to start viewing MS as a diffuse CNS disease with an important neurodegenerative com- ponent. This is central for identify- ing novel and effective treatment strategies. ■ Key words multiple sclerosis · normal-appearing white matter · grey matter · neurodegeneration · cortical adaptation