white matter. cortical lesions are inflammatory (immune mediated) and can present relapses cortex lesions are disposed around the principal cortical veins and the majority enter the terrain of the white matter, and have been classified into seven types some research groups have proposed that cortical lesions are the origin of the nawm areas in the white matter and 7 tesla scanners seem to confirm this hypothesis, showing that cortical pathology starts in the pial surface (external layer of the brain), which is in contact with the csf, and extends later into the brain inner layers. lesions in the cortex have been classified by the area they affect into four groups: type i (leukocortical), type ii (intracortical), type iii (subpial), and type iv (subpial extending through the whole cortical width but not to subcortical wm). this classification is not related to the white matter lesions classification. normal appearing cortex as with normal appearing white matter (nawm) and gray matter (nagm), there is a normal appearing cortex (nac) in which no lesions have developed, but with abnormal microscopical properties. the nac shows extensive rna oxidation. recently it has been found that normal appearing cortex presents primary neurodegenerative damage in the dendritic spines of the neurons, with no demyelination nor autoimmune infiltrates. for some authors this constitutes a proof to state that ms is a primary neurodegenerative condition. motor cortex fibrinogen is deposited in ms motor cortex and associates with neurodegeneration. olfactory bulb the olfactory nerve, similar to the optic nerve, is part of the central nervous system. this nerve terminates in the olfactory bulb, which also belongs to the central nervous system. both develop from the cns embrion, and recently it has been shown, by autopsies, that they are affected by the same diseases than the rest of the cns. in particular, they are damaged during the multiple sclerosis course. related to this, the csf of patients with disease activity show high levels of "lateral olfactory tract usher substance" (lotus) retina and optic nerve damage the eye's retina in ms is also damaged. given that retina cells have no myelin, damage must be different from the autoimmune attack of the brain. the underlying condition in the retina produces pure neurodegeneration. the retina and the optic nerve originate as outgrowths of the brain during embryonic development, so they are considered part of the central nervous system (cns). it is the only part of the cns that can be imaged non-invasively in the living organism. the retina nerve fiber layer (rnfl) is thinner than normal in ms patients the procedure by which the ms underlying condition attacks the retina is currently unknown, but seems mediated by human leukocyte antigen-dr positive cells with the phenotype of microglia. ms patients show axonal loss in the retina and optic nerve, which can be measured by optical coherence tomography or by scanning laser polarimetry. this measure can be used to predict disease activity and to establish a differential diagnosis from neuromyelitis optica about antibodies in the retina, tissue-bound igg was demonstrated on retinal ganglion cells in six of seven multiple sclerosis cases but not in controls. two eye problems, uveitis and retinal phlebitis are manifestations of ms. proposed procedures for the neurodegeneration are than narrower arterioles and wider venules have been reported. also rigidity has been noticed degenerative process in the optic nerve and retina human retina is devoid of myelin, but inflammation is prominent in ms even at late stages of disease, showing prominent gliosis and inflammation surrounding the vessels of the inner retina. some results suggest the presence of trans-synaptic degeneration as a contributor to chronic axon damage in the optic nerve and retina nevertheless, the authors of the paper were unable to identify whether the degeneration condition spreads from the anterior part or from the rear. the optic radiation (or), which is a set of axons that lead to the visual cortex, is more similar to the rest of the brain because it contains myelin. it is also damaged. in this area nawm areas (see below) appear. the optic radiation damage is composed by two factors: trans-synaptic degeneration, and wallerian degeneration respect the theory about the role of the meninges in ms evolution, it is important to notice that the optic nerve in its intraorbital part has the tree meninges and it is tightly coupled with the pia mater. neural and axonal damage two different mechanisms of axon destruction are acting in ms. first of all, there is a diffuse axon degeneration, probably related to the nawm appearance. later, there is a second axonal damage mechanism localized in old demyelinating lesions, probably produced by b-cells. this second damage is related to the t1-hypointense lesions (mri black holes) which appear when a demyelinating lesion is not remyelinated. the axons of the neurons are damaged probably by b-cells, though currently no relationship has been established with the relapses or the attacks. it seems that this damage is a primary target of the immune system, i.e. not secondary damage after attacks against myelin, though this has been disputed proton magnetic resonance spectroscopy has shown that there is widespread neuronal loss even at the onset of ms, largely unrelated to inflammation. a relationship between neural damage and n-acetyl-aspartate concentration has been established, and this could lead to new methods for early ms diagnostic through magnetic resonance spectroscopy. axonal degeneration at cns can be estimated by n-acetylaspartate to creatine (naa/cr) ratio, both measured by with proton magnetic resonance spectroscopy. the meninges in multiple sclerosis drawing of the three meninges the meninges are three layers that protect the brain and the spinal cord. they are called (from the outside to the inside) the dura mater, the arachnoid mater and the pia mater. the cerebrospinal fluid flows between the second and the third one. a remarkable finding in ms is that some follicle-like aggregates appear in the meninges (composed by b-cells mostly infected with ebv). these aggregates grow during the disease process and is mostly found in secondary progressive patients. inflammation in the meninges has been found to be associated to gray mater (cortical) demyelination. besides subpial demyelination suggest either a problem in the csf or in the pia mater that should protect the cortex whatever the underlying condition for ms is, some damage is triggered by a csf unknown soluble factor, which is produced in meningeal areas and diffuses into the cortical parenchyma. it destroys myelin either directly or indirectly through microglia activation. the infiltration into meninges, which has been referred to as tertiary lymphoid tissues (tlts), prepares the infiltration into the cns parenchyma causing demyelination in subpial and cortical areas. animal models suggest that infiltrating th17 cells remodel the meningeal stromal (non-immune) cells and initiate the formation of tlts during eae. the remodeled stromal cells retain and promote the production of th17 and the accumulation of b cells. the collaboration between ltb on th17 cells and ltbr (lymphotoxin beta receptor) on meningeal radio-resistant cells is very crucial for the induction and progression of ms. meningeal tertiary lymphoid-like structures follicle-like aggregates in the meninges are formed only in secondary progressive ms. and correlate with the degree of subpial cortical demyelination and brain atrophy, suggesting that they might contribute to cortical pathology in spms these ectopic lymphoid follicles are composed mainly of ebv infected b-cells. peripheral nervous system involvement though ms is defined as a cns condition, some reports link problems in the peripheral nervous system with the presence of ms plaques in the cns currently, a new disease entity, combined central and peripheral demyelination has been defined as the simultaneous demyelination of the periferal and central nervous systems. lesion structure and evolution layers of a lesion ms lesions mainly consist in demyelination and scarring in the fatty myelin sheaths around the axons of the brain and spinal cord. lesions evolve from the normal appearing white matter. in mtr-mri, the apparent diffusion coefficient (adcav) is a measure of water molecule motion. it can be seen that before the bbb breakdown, this coefficient increases until, at some point, the blood-brain barrier breaks down and immune cells enter the brain producing the lesion. according with the most recent (2009) research, an active lesion is composed of different layers: nawm border with the lesion: these areas contained activated microglia, antibodies binding to astrocytes, axons, oligodendrocytes and dendritic cells along blood vessels. no t or b cells are present. lesion external layer: number of oligodendrocyte cell bodies decreases. remaining oligodendrocytes are sometimes swollen or dying. myelin sheaths are still intact but swollen. small increase in microglia and t cells. active layer: phagocytic demyelinating areas: there is myelin debris taken up by local microglia and phagocytes entering from the bloodstream. more t cells in these areas, and in the space adjacent to blood vessels. recently demyelinated tissue: tissues were full of myelin-containing phagocytes. signs of early remyelination together with small numbers of oligodendrocytes. large numbers of t cells, b cells, and other immune cells concentrated around blood vessels. inactive layer: again activated microglia and dendritic cells were also found around blood vessels. some lesions named "slowly eroding lesions" or "slowly expanding" feature myelin phagocytosis at the lesion edge and evolve expanding across the white matter. lesions under mri most ms lesions are isointense to white matter (they appear bright) on t1-weighted mri, but some are "hypointense" (lower intensity). these are called "black holes" (bh). they appear specially in the supratentorial region of the brain. when bh's appear, around half of them revert in a month. this is considered a sign of remyelination. when they remain, this is regarded as a sign of permanent demyelination and axonal loss. this has been shown on post-mortem autopsies. small lesions are invisible under mri. therefore, clinically assisted diagnostic criteria are still required for a more accurate ms diagnosis than mri alone. the lesion evolution under mri has been reported to begin as a pattern of central hyperintensity. this was seen in the majority of new lesions, both on proton density and contrast-enhanced t1-weighted images. when gadolinium is used, the lesion expansion can be classified as nodular or ringlike whatever the demyelination process is, currently it is possible to detect lesions before demyelination, and they show clusters of activated microglia and leukocyte infiltration, together with oligodendrocytes abnormalities. some research groups consider some areas of the nawm with clusters of microglial nodules as "preactive ms lesions". but their relevance is disputed. lesion evolution can be followed via mri damage before bbb disruption special mri methods main magnetic resonance imaging the classic mri methods are named t1-relaxation and t2-relaxation. they create the images based in the "relaxation time", i.e., the time it takes for a molecule to realign its magnetic with its environment after an electromagnetic pulse has taken it out of the equilibrium. a third type of mri is based in the water diffusivity. it is called "diffusion mri" or "diffusion tensor mri". and the images produced are normally named diffusion tensor images (dti). a modification of the image post-processing is to account for the water density in each area. these are called "diffusion weighted images" (dwi) or difussion tensor mri, dt-mri. the diffusion measures the water response and the tensor structure takes account of the orientation of the tissue fibers. it is important because nawm and nagm show abnormal dt-mri a fourth important mri technique is the magnetization transfer technique, mt-mri. it measures differences in the magnetization transfer ration (mtr). the idea is that the nucleus of any atom that has a net nuclear spin and that is bonded to a hydrogen atom could potentially be imaged via "heteronuclear magnetization transfer mri". this would image the high-gyromagnetic-ratio hydrogen nucleus instead of the low-gyromagnetic-ratio nucleus that is bonded to the hydrogen atom. in principle, hetereonuclear magnetization transfer mri could be used to detect the presence or absence of specific chemical bonds. nawm and diffusely abnormal areas (dawm) appear under mt-mri. finally, the fifth more important mri technique is the proton magnetic resonance spectroscopy. based in the different response to the electromagnetic pulses that different substances present, an mrs scanner is able to identify chemical substances in the brain. this is important because n‐acetylaspartate is a marker of axonal damage that can be now identified in-vivo. lesions under the special mri methods normally two different kind of lesions appear on a normal