Multiple sclerosis (MS) can be pathologically defined as the presence of distributed glial scars (scleroses) in the central nervous system that must show dissemination in time (DIT) and in space (DIS) to be considered MS lesions.

The scars that give the name to the condition are produced by the astrocyte cells attempting to heal old lesions. These glial scars are the remnants of previous demyelinating inflammatory lesions (encephalomyelitis disseminata) which are produced by the one or more unknown underlying processes that are characteristic of MS.

Apart from the disseminated lesions that define the condition, the CNS white matter normally shows other kinds of damage. At least five characteristics are present in CNS tissues of MS patients: Inflammation beyond classical white matter lesions (NAWM, normal-appearing white matter and NAGM, normal-appearing gray matter), intrathecal Ig production with oligoclonal bands, an environment fostering immune cell persistence, Follicle-like aggregates in the meninges (B-cells mostly infected with EBV) and a disruption of the blood–brain barrier even outside of active lesions.

Confluent subpial cortical lesions are the most specific finding for MS, being exclusively present in MS patients. Though this feature can only be detected during an autopsy there are some subrogate markers under study Damage in MS consists also in areas with hidden damage (normal appearing white and gray matters) and two kinds of cortical lesions: Neuronal loss and cortical demyelinating lesions. The neural loss is the result of neural degeneration from lesions located in the white matter areas and the cortical demyelinating lesions are related to meningeal inflammation.

The scars in the white matter are known to appear from confluence of smaller ones

Currently the term "multiple sclerosis" is ambiguous and refers not only to the presence of the scars, but also to the unknown underlying condition that produces these scars. Besides clinical diagnosis uses also the term "multiple sclerosis" for speaking about the related clinical courses. Therefore, when referring to the presence of the scars is better to use the equivalent term astrocytic fibrillary gliosis.

Lesions consistent with MS

A combination of histologic and/or immunohistochemical stains can be used to visualize post-mortem MS characteristic lesions and to diagnose post-mortem "inflammatory demyelinating lesions consistent with MS":

hematoxylin and eosin stain (demonstrates tissue and cell morphology) myelin stains (Luxol fast blue/periodic acid-Schiff, Luxol fast blue/hematoxylin/eosin, or immunohistochemistry for myelin proteins) macrophage-specific markers (immunohistochemistry for KiM1P or CD68) stains for axons (Bielschowsky silver impregnation or immunohistochemistry for neurofilament protein) stains for astrocytes (hematoxylin and eosin or immunohistochemistry for glial fibrillary acidic protein) and stains for the different lymphocyte subtypes (immunohistochemistry for CD3, CD4, CD8, CD20, and/or CD138)

These markers are specific for the different processes that drive the formation of plaques: inflammation, myelin breakdown, astrogliosis, oligodendrocyte injury, neurodegeneration, axonal loss and remyelination. MS lesions evolve differently during early versus chronic disease phases, and within each phase, different kind of activity appears.

The classification system for the lesions was updated in 2017. This system classifies MS lesions as active, mixed active/inactive, or inactive lesions based on the presence and distribution of macrophages/microglia. They locate the slowly expanding lesions inside the mixed subtype and provide a description of the different lesion types and required staining techniques.

To consider some lesions as a case of MS, even under autopsy, they must be disseminated in time and space. Dissemination in time can be shown by the stage of the lesion evolution. If only a lesion is present it could be a case of solitary sclerosis.

MS is usually defined as the presence of disseminated lesions in space and time with no other explanation for them. Therefore, given the unspecificity of the lesions, several MS pathological underlying conditions have been found, which are now considered separate diseases. There are at least three kind of lesions that were historically considered inside the MS spectrum and now are considered as separate entities: Anti-AQP4 disease Anti-MOG disease Anti-Neurofascin disease

Demyelination process

Lesions in MS are heterogeneous and there are four different patterns in which they start, probably due to different underlying pathogenesis. Nevertheless, it seems than the last stage of damage is similar for all of them. Traditionally it was thought that MS lesions were produced by CD4+ T-cells but after the discovery of anti-MOG and anti-NF demyelinating diseases, it has been noticed that most CD4+ cases are anti-MOG in reality, and now CD8+ cases are considered the real MS cases.

In some cases (pattern II), a special subset of lymphocytes, called T helper cells or "CD4+ T-cells" play a key role in the development of the lesion in a way similar to the CD4+ attacks that appear in anti-MOG associated encephalomyelitis.

In the standard cases, the trigger and the underlying condition of MS is a soluble factor produced by CD8+ T-cells (or maybe B-cells). Also B Cells have been implicated in the pathogenesis of MS, and some theoretical models link the presence of EBV-infected B-cells to the development of MS.

The first stage of a MS lesion is thought to be the development of an area called "normal appearing white matter" (NAWM). In this area activated microglia appears, as shown by positron emission tomography. MS lesions appear in these areas as pre-active lesions without autoimmune infiltrates at this stage They show microglia activation and degeneration of the neuron axons without T-cell infiltration. Both problems appear together though it is not known which one is first.

T-cells attack is followed by leaks in the blood–brain barrier where T-cells infiltrate causing the known demyelination.

HERVs and microglia

Human endogenous retroviruses (HERVs) have been reported in MS for several years. In fact, one of the families, Human Endogenous Retrovirus-W was first discovered while studying MS patients.

Recent research as of 2019 point to one of the HERV-W viruses (pHEV-W), and specifically one of the proteins of the viral capside that has been found to "activate microglia" in vitro. Activated microglia in turn produces demyelination. Some interactions between the Epstein-Barr virus and the HERVs could be the trigger of the MS microglia reactions.

Last stage damage

Regardless of which kind of trigger initiates the damage, the axons themselves and the oligodendrocytes. are finally damaged by the T-cell attacks.Cause of nerve fiber damage in multiple sclerosis identified Often, the brain is able to compensate for some of this damage, due to an ability called neuroplasticity. MS symptoms develop as the cumulative result of multiple lesions in the brain and spinal cord. This is why symptoms can vary greatly between different individuals, depending on where their lesions occur.

Repair processes, called remyelination, also play an important role in MS. Remyelination is one of the reasons why, especially in early phases of the disease, symptoms tend to decrease or disappear temporarily. Nevertheless, nerve damage and irreversible loss of neurons occur early in MS.

The oligodendrocytes that originally formed a myelin sheath cannot completely rebuild a destroyed myelin sheath. However, the central nervous system can recruit oligodendrocyte stem cells capable of proliferation and migration and differentiation into mature myelinating oligodendrocytes. The newly formed myelin sheaths are thinner and often not as effective as the original ones. Repeated attacks lead to successively fewer effective remyelinations, until a scar-like plaque is built up around the damaged axons. These scars are the so-called "scleroses" that define the condition. They are named glial scars because they are produced by glial cells, mainly astrocytes, and their presence prevents remyelination. Therefore, there is research ongoing to prevent their formation.

Under laboratory conditions, stem cells are quite capable of proliferating and differentiating into remyelinating oligodendrocytes; it is therefore suspected that inflammatory conditions or axonal damage somehow inhibit stem cell proliferation and differentiation in affected areas

Specific areas of damage

The unknown underlying condition produces inflammation, demyelination and atrophy in several areas. Some of the body tissues mentioned, like the retina, do not have myelin. In those cases, only inflammation and atrophy appears.

Brain lesions distribution Main: Lesional demyelinations of the CNS

Multiple sclerosis is considered a disease of the white matter because normally lesions appear in this area, but it is also possible to find some of them in the grey matter.

Using high field MRI system, with several variants several areas show lesions, and can be spacially classified in infratentorial, callosal, juxtacortical, periventricular, and other white matter areas. Other authors simplify this in three regions: intracortical, mixed gray-white matter, and juxtacortical. Others classify them as hippocampal, cortical, and WM lesions, and finally, others give seven areas: intracortical, mixed white matter-gray matter, juxtacortical, deep gray matter, periventricular white matter, deep white matter, and infratentorial lesions. The distribution of the lesions could be linked to the clinical evolution

Post-mortem autopsy reveal that gray matter demyelination occurs in the motor cortex, cingulate gyrus, cerebellum, thalamus and spinal cord. Cortical lesions have been observed specially in people with SPMS but they also appear in RRMS and clinically isolated syndrome. They are more frequent in men than in women and they can partly explain cognitive deficits.

Regarding two parameters of the cortical lesions (CLs), fractional anisotropy (FA) is lower and mean diffusivity (MD) is higher in patients than in controls. The differences are larger in SPMS (secondary progressive multiple sclerosis) than in RRMS (relapsing-remitting multiple sclerosis) and most of them remain unchanged for short follow-up periods. They do not spread into the subcortical white matter and never show gadolinium enhancement. Over a one-year period, CLs can increase their number and size in a relevant proportion of MS patients, without spreading into the subcortical white matter or showing inflammatory features similar to those of white matter lesions.

Due to the distribution of the lesions, since 1916 they are also known as Dawson's fingers.Dawson fingers, at Radiopedia They appear around the brain blood vessels.

Spinal cord damage

Cervical spinal cord has been found to be affected by MS even without attacks, and damage correlates with disability. In RRMS, cervical spinal cord activity is enhanced, to compensate for the damage of other tissues. It has been shown that Fractional anisotropy of cervical spinal cord is lower than normal, showing that there is damage hidden from normal MRI.

Progressive tissue loss and injury occur in the cervical cord of MS patients. These two components of cord damage are not interrelated, suggesting that a multiparametric MRI approach is needed to get estimates of such a damage. MS cord pathology is independent of brain changes, develops at different rates according to disease phenotype, and is associated to medium-term disability accrual.