Multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

(MS) can be pathologically defined as the presence of distributed

glial scar Glial scar formation (gliosis) is a reactive cellular process involving astrogliosis that occurs after injury to the central nervous system. As with scarring in other organs and tissues, the glial scar is the body's mechanism to protect and begin ...

s ( scleroses) in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

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 of 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 Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

beyond classical white matter lesions (NAWM, NAGM),

intrathecal Intrathecal administration is a route of administration for drugs via an injection into the spinal canal, or into the subarachnoid space so that it reaches the cerebrospinal fluid (CSF) and is useful in spinal anesthesia, chemotherapy, or pain man ...

Ig production with

oligoclonal bands Oligoclonal bands (OCBs) are bands of immunoglobulins that are seen when a patient's blood serum, or cerebrospinal fluid (CSF) is analyzed. They are used in the diagnosis of various neurological and blood diseases, especially in multiple sclerosis. ...

, an environment fostering immune cell persistence, Follicle-like aggregates in the

meninges In anatomy, the meninges (, ''singular:'' meninx ( or ), ) are the three membranes that envelop the brain and spinal cord. In mammals, the meninges are the dura mater, the arachnoid mater, and the pia mater. Cerebrospinal fluid is located in th ...

(B-cells mostly infected with EBV) and a disruption of the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...

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 In anatomy, the meninges (, ''singular:'' meninx ( or ), ) are the three membranes that envelop the brain and spinal cord. In mammals, the meninges are the dura mater, the arachnoid mater, and the pia mater. Cerebrospinal fluid is located in th ...

inflammation. The scars in the white matter are known to appear from confluence of smaller ones Currently the term "multiple sclerosis" is

ambiguous Ambiguity is the type of meaning (linguistics), meaning in which a phrase, statement or resolution is not explicitly defined, making several interpretations wikt:plausible#Adjective, plausible. A common aspect of ambiguity is uncertainty. It ...

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 Haematoxylin or hematoxylin (), also called natural black 1 or C.I. 75290, is a compound extracted from heartwood of the logwood tree (''Haematoxylum campechianum'') with a chemical formula of . This naturally derived dye has been used as a h ...

and

eosin Eosin is the name of several fluorescent acidic compounds which bind to and form salts with basic, or eosinophilic, compounds like proteins containing amino acid residues such as arginine and lysine, and stains them dark red or pink as a resul ...

stain (demonstrates tissue and cell morphology) *

myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...

stains (

Luxol fast blue Luxol fast blue stain, abbreviated LFB stain or simply LFB, is a commonly used stain to observe myelin under light microscopy, created by Heinrich Klüver and Elizabeth Barrera in 1953. LFB is commonly used to detect demyelination in the central ne ...

/periodic acid-Schiff, Luxol fast blue/hematoxylin/eosin, or immunohistochemistry for myelin proteins) * macrophage-specific markers (immunohistochemistry for KiM1P or

CD68 CD68 ( Cluster of Differentiation 68) is a protein highly expressed by cells in the monocyte lineage (e.g., monocytic phagocytes, osteoclasts), by circulating macrophages, and by tissue macrophages (e.g., Kupffer cells, microglia). Structure a ...

) * stains for

axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...

s ( Bielschowsky silver impregnation or immunohistochemistry for

neurofilament protein Neurofilaments (NF) are classed as type IV intermediate filaments found in the cytoplasm of neurons. They are protein polymers measuring 10 nm in diameter and many micrometers in length. Together with microtubules (~25 nm) and mi ...

) * stains for

astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...

s (hematoxylin and eosin or immunohistochemistry for

glial fibrillary acidic protein Glial fibrillary acidic protein (GFAP) is a protein that is encoded by the ''GFAP'' gene in humans. It is a type III intermediate filament (IF) protein that is expressed by numerous cell types of the central nervous system (CNS), including astroc ...

) and * stains for the different

lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...

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-AQP4 diseases, are a group of diseases characterized by auto-antibodies against aquaporin 4. After the discovery of anti-AQP4 autoantibody in neuromyelitis optica, it was found that it was also present in some patients with other clinically ...

* 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

s, called

T helper cell The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...

s 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 MOG antibody disease (MOGAD) or MOG antibody-associated encephalomyelitis (MOG-EM) is an inflammatory demyelinating disease of the central nervous system. Serum anti-myelin oligodendrocyte glycoprotein antibodies are present in up to half of patie ...

. 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 Cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

s 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 Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...

appears, as shown by

positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in Metabolism, metabolic processes, and in other physiological activities including bl ...

. MS lesions appear in these areas as pre-active lesions without autoimmune infiltrates at this stage They show

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 Human Endogenous Retrovirus-W (HERV-W) is the coding for a protein that would normally be part of the envelope of one family of Human Endogenous Retro-Viruses, or HERVs. HERV-W encoding sequences makes up about 1% of the human genome and are pa ...

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

" 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. Supporting this study, a

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ca ...

against the viral capside ( Temelimab) has shown good results in trials in phase IIb.

Last stage damage

Regardless of which kind of trigger initiates the damage, the

s themselves and the oligodendrocytes. are finally damaged by the T-cell attacks.Cause of nerve fiber damage in multiple sclerosis identified
/ref> Often, the brain is able to compensate for some of this damage, due to an ability called

neuroplasticity Neuroplasticity, also known as neural plasticity, or brain plasticity, is the ability of Neural circuit, neural networks in the brain to change through growth and reorganization. It is when the brain is rewired to function in some way that diffe ...

. MS symptoms develop as the cumulative result of multiple

lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals. Types There is no designated classifi ...

s in the brain and

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...

. 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

oligodendrocyte Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...

s that originally formed a

myelin sheath Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...

cannot completely rebuild a destroyed myelin sheath. However, the central nervous system can recruit oligodendrocyte

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...

s 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

s because they are produced by

glial cells Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form mye ...

, 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 The motor cortex is the region of the cerebral cortex believed to be involved in the planning, control, and execution of voluntary movements. The motor cortex is an area of the frontal lobe located in the posterior precentral gyrus immediately a ...

cingulate gyrus The cingulate cortex is a part of the brain situated in the medial aspect of the cerebral cortex. The cingulate cortex includes the entire cingulate gyrus, which lies immediately above the corpus callosum, and the continuation of this in the ci ...

cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...

thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...

and

. 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 Fractional anisotropy (FA) is a scalar value between zero and one that describes the degree of anisotropy of a diffusion process. A value of zero means that diffusion is isotropic, i.e. it is unrestricted (or equally restricted) in all directions. A ...

(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. 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 Fractional anisotropy (FA) is a scalar value between zero and one that describes the degree of anisotropy of a diffusion process. A value of zero means that diffusion is isotropic, i.e. it is unrestricted (or equally restricted) in all directions. A ...

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. Spinal cord presents grey matter lesions, that can be confirmed post-mortem and by high field MR imaging. Spinal cord grey matter lesions may be detected on MRI more readily than GM lesions in the brain, making the cord a promising site to study the grey matter demyelination. Myelin Water Fraction (MWF) shows lesions under MRI Several CSF markers reveal intrathecal inflammation in progressive MS (SPMS and PPMS)

Cerebellum and Thalamus

Cerebellar

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

appears mainly in PPMS and it is related to the pathological changes in the cerebellum. Some special cells present only in the cerebellum,

Purkinje cell Purkinje cells, or Purkinje neurons, are a class of GABAergic inhibitory neurons located in the cerebellum. They are named after their discoverer, Czech people, Czech anatomist Jan Evangelista Purkyně, who characterized the cells in 1839. Stru ...

s, have been reported to be part of this problems. Increasing of neurofilament phosphorylation has been reported Cerebellum is specially affected in progressive variants. Grey matter damage in the cerebellum is linked to inflammation in the subarachnoid space Though most of the cerebellum damage occurs in late stages, it can be seen that there are abnormalities since early disease stages mostly of the "Normal Appearing" kind Thalamus degeneration in MS presents several features, such as trans-neuronal or

Wallerian degeneration Wallerian degeneration is an active process of degeneration that results when a nerve fiber is cut or crushed and the part of the axon distal to the injury (i.e. farther from the neuron's cell body) degenerates. A related process of dying back o ...

Cortex

Around 26% of MS lesions appear inside or adjacent to the cortex. It seems that in RRMS patients, both deep and cortical GM atrophy are associated with pathology in connected 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 spine A dendritic spine (or spine) is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical si ...

s 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 In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual system, visual information from the retina to the brain. In humans, the optic nerve i ...

originate as outgrowths of the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

during embryonic development, so they are considered part of the

(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

. MS patients show axonal loss in the

retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...

and

, which can be measured by

Optical coherence tomography Optical coherence tomography (OCT) is an imaging technique that uses low-coherence light to capture micrometer-resolution, two- and three-dimensional images from within optical scattering media (e.g., biological tissue). It is used for medical ...

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 Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...

was demonstrated on retinal ganglion cells in six of seven multiple sclerosis cases but not in controls. Two eye problems,

Uveitis Uveitis () is inflammation of the uvea, the pigmented layer of the eye between the inner retina and the outer fibrous layer composed of the sclera and cornea. The uvea consists of the middle layer of pigmented vascular structures of the eye and ...

and retinal

phlebitis Phlebitis (or Venitis) is inflammation of a vein, usually in the legs. It most commonly occurs in superficial veins. Phlebitis often occurs in conjunction with thrombosis and is then called thrombophlebitis or superficial thrombophlebitis. Unlike ...

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 In neuroanatomy, the optic radiation (also known as the geniculocalcarine tract, the geniculostriate pathway, and posterior thalamic radiation) are axons from the neurons in the lateral geniculate nucleus to the primary visual cortex. The optic ...

(OR), which is a set of axons that lead to the

visual cortex The visual cortex of the brain is the area of the cerebral cortex that processes visual information. It is located in the occipital lobe. Sensory input originating from the eyes travels through the lateral geniculate nucleus in the thalamus and ...

, 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 Wallerian degeneration is an active process of degeneration that results when a nerve fiber is cut or crushed and the part of the axon distal to the injury (i.e. farther from the neuron's cell body) degenerates. A related process of dying back o ...

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 Pia mater ( or ),Entry "pia mater"
in
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 Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy or magnetic resonance spectroscopy (MRS), is a spectroscopic technique to observe local magnetic fields around atomic nuclei. The sample is placed in a magnetic fiel ...

. Axonal degeneration at CNS can be estimated by

N-acetylaspartate ''N''-Acetylaspartic acid, or ''N''-acetylaspartate (NAA), is a derivative of aspartic acid with a formula of C6H9NO5 and a molecular weight of 175.139. NAA is the second-most-concentrated molecule in the brain after the amino acid glutamate. ...

creatine Creatine ( or ) is an organic compound with the nominal formula (H2N)(HN)CN(CH3)CH2CO2H. It exists in various modifications (tautomers) in solution. Creatine is found in vertebrates where it facilitates recycling of adenosine triphosphate ( ...

(NAA/Cr) ratio, both measured by with proton magnetic resonance spectroscopy.

The meninges in multiple sclerosis

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 In neuroanatomy, dura mater is a thick membrane made of dense irregular connective tissue that surrounds the brain and spinal cord. It is the outermost of the three layers of membrane called the meninges that protect the central nervous system. ...

, the

arachnoid mater The arachnoid mater (or simply arachnoid) is one of the three meninges, the protective membranes that cover the brain and spinal cord. It is so named because of its resemblance to a spider web. The arachnoid mater is a derivative of the neural c ...

and the

pia mater Pia mater ( or ),Entry "pia mater"
in
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...

flows between the second and the third one. A remarkable finding in MS is that some Follicle-like aggregates appear in the

(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

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 The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphatic or lymphoid o ...

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 Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired autoimmune disease of the peripheral nervous system characterized by progressive weakness and impaired sensory function in the legs and arms. The disorder is sometimes called ...

has been defined as the simultaneous demyelination of the periferal and central nervous systems.

Lesion structure and evolution

MS lesions mainly consist in

demyelination A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction ability causes deficiency i ...

and scarring in the fatty

sheaths around the

s 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

, antibodies binding to

astrocytes Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...

, axons,

oligodendrocytes Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the p ...

and

dendritic cells Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...

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 Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...

demyelinating areas: There is myelin debris taken up by local microglia and

phagocytes Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek ', "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek '' ...

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 Medical diagnosis (abbreviated Dx, Dx, or Ds) is the process of determining which disease or condition explains a person's symptoms and signs. It is most often referred to as diagnosis with the medical context being implicit. The information req ...

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 Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...

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 MRI: T2-hypertense lesions and T1-hypointense. The first one are demyelinating lesions and appear brighter than the surroundings in T2-MRI. The T1-hypointense are areas less dense than the surrounding NAW, and appear black on T1-MRI. They are mainly axonal degeneration areas. Because their black appearance they are sometimes known as black holes. They seem to appear as a sequel after a strong demyelinating lesion. BBB disruption is normally shown using

gadolinium Gadolinium is a chemical element with the symbol Gd and atomic number 64. Gadolinium is a silvery-white metal when oxidation is removed. It is only slightly malleable and is a ductile rare-earth element. Gadolinium reacts with atmospheric oxygen ...

. It is a contrast that cannot cross the BBB except when it is dysfunctional. Therefore, in active lesions with BBB implication the contrast enters the brain and appears in the MRI. Before BBB disruption, some brain tissues which present normal aspect under T1 and T2 MRI (Normal appearing

white matter White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distribution ...

, NAWM and normal appearing

grey matter Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil (dendrites and unmyelinated axons), glial cells (astrocytes and oligodendrocytes), synapses, and capillaries. Grey matter is distingui ...

, NAGM), can show several abnormalities under special MRI technologies:

Magnetization transfer Magnetization transfer (MT), in NMR and MRI, refers to the transfer of nuclear spin polarization and/or spin coherence from one population of nuclei to another population of nuclei, and to techniques that make use of these phenomena. There is some ...

multi-echo T(2) relaxation. Subjects with Long-T(2) lesions had a significantly longer disease duration than subjects without this lesion subtype. It has been found that grey matter injury correlates with disability and that there is high oxidative stress in lesions, even in the old ones. Diffusion tensor MRI or Magnetic Transfer MRI are two options to enhance MRI-hidden abnormalities discovery. This is currently an active field of research with no definitive results, but it seems that these two technologies are complementary. Other methods of MRI allow us to get a better insight of the lesions structure. Recently MP-RAGE MRI has shown better results than PSIR and DIR for gray matter lesions.

Susceptibility weighted imaging Susceptibility weighted imaging (SWI), originally called BOLD venographic imaging, is an MRI sequence that is exquisitely sensitive to venous blood, hemorrhage and iron storage. SWI uses a fully flow compensated, long echo, gradient recalled echo ( ...

(SWI-MRI) has shown iron (

hemosiderin Hemosiderin image of a kidney viewed under a microscope. The brown areas represent hemosiderin Hemosiderin or haemosiderin is an iron-storage complex that is composed of partially digested ferritin and lysosomes. The breakdown of heme gives rise ...

) deposition in lesions, and helps to detect otherwise invisible lesions. Abnormalities in the gray matter (Diffusion tensor MRI alterations) of the brain parenchyma are present early in the course of multiple sclerosis

Normal appearing brain tissues

Using several texture analysis technologies, it is possible to classify white matter areas into three categories: normal, normal-appearing and lesions. Currently, it is possible to detect lesions before they present demyelination, and they are called pre-active lesions. A fourth area called DAWM (diffusely abnormal white matter) has been proposed and can help to differentiate PPMS and SPMS. Abundant extracellular myelin in the meninges of patients with multiple sclerosis has been found Brain tissues with MRI-hidden problems are usually named Normal Appearing. Exploring the normal-appearing

corpus callosum The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental mam ...

has been found a possible primary

hypoperfusion Perfusion is the passage of fluid through the circulatory system or lymphatic system to an organ or a tissue, usually referring to the delivery of blood to a capillary bed in tissue. Perfusion is measured as the rate at which blood is deliver ...

, according with other findings in this same direction. Also iron (in

deposits and as well as in ferritin-like structures inside the macrophage) accumulation has been reported Several findings in these areas have been shown. Post-mortem studies over NAWM and NAGM areas (Normal appearing White and Gray Matters) show several biochemical alterations, like increased protein

carbonylation Carbonylation refers to reactions that introduce carbon monoxide into organic and inorganic substrates. Carbon monoxide is abundantly available and conveniently reactive, so it is widely used as a reactant in industrial chemistry. The term carbon ...

and high levels of

Glial fibrillary acidic protein Glial fibrillary acidic protein (GFAP) is a protein that is encoded by the ''GFAP'' gene in humans. It is a type III intermediate filament (IF) protein that is expressed by numerous cell types of the central nervous system (CNS), including astroc ...

(GFAP), which in NAGM areas comes together with higher than normal concentration of protein

carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...

s, suggesting reduced levels of antioxidants and the presence of small lesions. The amount of interneuronal

Parvalbumin Parvalbumin (PV) is a calcium-binding protein with low molecular weight (typically 9-11 kDa). In humans, it is encoded by the ''PVALB'' gene. It is not a member of the albumin family; it is named for its size (''parv-'', from Latin ''parvus'' smal ...

is lower than normal in brain's motor cortex areas, and oxidative injury of oligodendrocytes and neurons could be associated with active demyelination and axonal injury. NAWM in MS has been reported to be similar to NAWM in

leukoaraiosis Leukoaraiosis is a particular abnormal change in appearance of white matter near the lateral ventricles. It is often seen in aged individuals, but sometimes in young adults. On MRI, leukoaraiosis changes appear as white matter hyperintensities ( ...

, though NAWM damage in MS is inflammatory and special microscopic techniques like CARS microscopy show that the CNS of MS patients may be globally altered, and both lesions and NAWM are just manifestations of another underlying problem. The NAWM is specially abnormal close to the ventricles, which may indicate a pathogenic mechanism mediated via the CSF or ependyma.

Non-lesional White Matter

Most of the brain in MS is unaffected. Though obviously normal white matter appears normal under MRI, so does the NAWM white matter described in the next section. To establish a difference, normal white matter is named Non-lesional white matter (NLWM) This normal white matter is reported to be around 56% of the total WM of the patients.

Normal appearing White Matter

The white matter with hidden but MRI-visible damage is known as "Normal-appearing white matter" (NAWM) and is where lesions appear. The NAWM is considered a non-visible kind of lesion, produces disability and it is responsive to

natalizumab Natalizumab, sold under the brand name Tysabri among others, is a medication used to treat multiple sclerosis and Crohn's disease. It is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin. It is given by intravenou ...

The pathology of the NAWM differs from areas near the lesions or near the cortex. Close to WM lesions, axonal pathology and microglial activation may explain subtle MRI changes. Distant from lesions, microglial activation associated with proximity to cortical lesions might underlie MRI abnormalities. The NAWM precedes the lesions. It has been shown that the apparent diffusion coefficient (ADC) precedes the development of new plaques. Later increases during BBB breakdown (gadolinium enhancement) and finally decays after the enhancement. BBB disruption takes place on NAWM areas. This can be read in different ways. Maybe some hidden changes in White Matter structure trigger the BBB disruption, or maybe the same process that creates the NAWM areas disrupts the BBB after some time. Pre-active lesions are lesions in an early stage of development. They resolve sometimes without further damage, and not always develop into demyelinating lesions. They present clusters of activated microglia in otherwise normal-appearing white matter.

Oligodendrocyte Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...

abnormalities appear to be crucially involved. The earliest change reported in the lesions examined is widespread oligodendrocyte apoptosis in which T cells, macrophages, activated microglia, reactive astrocytes, and neurons appear normal. This observation points to some change in the local environment (NAWM) to which oligodendrocytes are especially susceptible and which triggers a form of apoptosis. Water diffusivity is higher in all NAWM regions, deep gray matter regions, and some cortical gray matter region of MS patients than normal controls.

Citrullination Citrullination or deimination is the conversion of the amino acid arginine in a protein into the amino acid citrulline. Citrulline is not one of the 20 standard amino acids encoded by DNA in the genetic code. Instead, it is the result of a post-tr ...

appears in SPMS. It seems that a defect of

sphingolipid Sphingolipids are a class of lipids containing a backbone of sphingoid bases, a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sphinx because ...

metabolism modifies the properties of normal appearing white matter. Related to these, peptidylarginine deiminase 2 is increased in patients with MS, and is related to arginine de-imination. NAWM shows a decreased

perfusion Perfusion is the passage of fluid through the circulatory system or lymphatic system to an organ or a tissue, usually referring to the delivery of blood to a capillary bed in tissue. Perfusion is measured as the rate at which blood is deliver ...

which does not appear to be secondary to axonal loss. The reduced perfusion of the NAWM in MS might be caused by a widespread

dysfunction, possibly related to a deficiency in astrocytic beta(2)-adrenergic receptors and a reduced formation of

cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...

, resulting in a reduced uptake of K(+) at the

nodes of Ranvier In neuroscience and anatomy, nodes of Ranvier ( ), also known as myelin-sheath gaps, occur along a myelinated axon where the axolemma is exposed to the extracellular space. Nodes of Ranvier are uninsulated and highly enriched in ion channels, al ...

and a reduced release of K(+) in the perivascular spaces. This would be consistent again with cases of

Chronic cerebrospinal venous insufficiency Chronic cerebrospinal venous insufficiency (CCSVI or CCVI) is a term invented by Italian researcher Paolo Zamboni in 2008 to describe compromised flow of blood in the veins draining the central nervous system. Zamboni hypothesized that it migh ...

. White matter lesions appear in NAWM areas, and their behavior can be predicted by MRI parameters as MTR (magnetization transfer ratio). This MTR parameter is related to axonal density. It also seems that myelin basic protein (MBP) from multiple sclerosis (MS) patients contains lower levels of phosphorylation at Thr97 than normal individuals. NAWM is the place where lesions appear and the process seems to be made by microglia, in absence of leukocyte infiltration, astrogliosis or demyelination. At the final stage of the process, these microglia develop into active demyelinating MS lesion In PPMS there is evidence that NAWM is affected by the same pathological processes that characterize WM lesions, namely inflammation, demyelination, axonal injury, macrophage infiltration and gliosis. Some evidence suggests that WM changes predict subsequent GM abnormalities, rather than the opposite. Anomalies in NAWM rather than lesions have a greater impact on later GM damage.

Gray matter damage. Normal Appearing Gray Matter

Gray matter tissue damage dominates the pathological process as MS progresses, and underlies neurological disability. Imaging correlates of gray matter atrophy indicate that mechanisms differ in RRMS and SPMS. Epstein-Barr virus could be involved, but is not likely. Involvement of the deep gray matter (DGM), suggested by magnetic resonance imaging, is confirmed, and most DGM lesions involve both GM and white matter. Inflammation in DGM lesions is intermediate between the destructive inflammation of white matter lesions and the minimal inflammation of cortical lesions. Iron depositions appear in deep gray matter by magnetic field correlation MRI Differently from NAWM, NAGM areas are not related to the development of lesions

Diffusely abnormal white matter

Other active area of study is the Diffusely abnormal white matter (DAWM). It seems to be a reduction of myelin phospholipids that correlates with a reduction of the myelin water fraction. The DAWM consisted of extensive axonal loss, decreased myelin density, and chronic fibrillary gliosis, all of which were substantially abnormal compared with normal-appearing WM and significantly different from focal WM lesion pathology. Changes in the vasculature take place not only in focal lesions but also in DAWM as detected by postmortem MRI

Dirty appearing white matter

Dirty-appearing white matter (referred to as DAWM like the former case) is defined as a region with ill-defined borders of intermediate signal intensity between that of normal-appearing white matter (NAWM) and that of plaque on T2-weighted and proton density imaging. It is probably created by loss of myelin phospholipids, detected by the short T2 component, and axonal reduction.

Microglial nodules

Originally proposed as a biomarker, the presence of these nodules has a possible pathogenetic significance. Though their role in the lesion evolution is still unclear, their presence in normal-appearing white matter have been suggested to be an early stage of lesion formation

Heterogeneity of the disease

Multiple sclerosis has been reported to be heterogeneous in its behavior, in its underlying mechanisms, in its response to medication and remarkably, also respect the response to the specific potassium channel autoantibody

Kir4.1 ATP-sensitive inward rectifier potassium channel 10 is a protein that in humans is encoded by the ''KCNJ10'' gene. Function This gene encodes a member of the inward rectifier-type potassium channel family, Kir4.1, characterized by having a gre ...

. For some authors, what we call MS in reality is a heterogeneous group of diseases Some independent reports take also PPMS apart Some others point a connection between some MS cases and

peripheral neuropathies Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...

Some reports propose the existence of molecular biomarkers that determine the clinical course of the disease, but the relationship to the pathological types has still not been established as of 2016.

Demyelination patterns

Four different damage patterns have been identified in patients' brain tissues. The original report suggests that there may be several types of MS with different immune causes, and that MS may be a family of several diseases. Though originally was required a biopsy to classify the lesions of a patient, since 2012 it is possible to classify them by a blood test looking for antibodies against seven lipids, three of which are cholesterol derivatives. It is believed that they may correlate with differences in disease type and prognosis, and perhaps with different responses to treatment. In any case, understanding lesion patterns can provide information about differences in disease between individuals and enable doctors to make more accurate treatment decisions Patterns I and II show the classical pathological features of MS lesions with microglia and macrophages, while patterns III and IV are considered atypical and could be separated from the MS spectrum at some point. The four identified patterns are: ; Pattern I : The scar presents

T-cells A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...

and

macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

around blood vessels, with preservation of

s, but no signs of

complement system The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and at ...

activation. ; Pattern II : The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, as before, but also signs of

activation can be found. This pattern has been considered similar to damage seen in NMO, though AQP4 damage does not appear in pattern II MS lesions Nevertheless, pattern II has been reported to respond to

plasmapheresis Plasmapheresis (from the Greek πλάσμα, ''plasma'', something molded, and ἀφαίρεσις ''aphairesis'', taking away) is the removal, treatment, and return or exchange of blood plasma or components thereof from and to the blood circulati ...

, which points to something pathogenic into the blood serum. :The

infiltration in these cases convert this pattern into a candidate for research into autoimmune connections like anti-

, anti- Anoctamin-2 or anti-MOG mediated MS About the last possibility, research has found antiMOG antibodies in some pattern-II MS patients. :Sometimes autoimmunity against the human CNS has been triggered by accident or medical mistake. The reactions have been diverse according to the sources of the disease but pathological confirmed MS (damage fulfills all pathological criteria of MS) is among them, and it shows pattern II :Pattern II pathogenic T cells clonally expanded were found in the CN, specifically, CD4+ Th2 cells (secreting IL-4, L-5, and IL-13) have recently been described in pattern II MS, and their clones have been isolated as living cells The functional characterization shows that T cells releasing Th2 cytokines and helping B cells dominate the T-cell infiltrate in pattern II brain lesions. ; Pattern III : The scars are diffuse with inflammation, distal oligodendrogliopathy and

l activation. There is also loss of

myelin-associated glycoprotein Myelin-associated glycoprotein (MAG, Siglec-4) is a type 1 transmembrane protein glycoprotein localized in periaxonal Schwann cell and oligodendrocyte membranes, where it plays a role in glial-axonal interactions. MAG is a member of the SIGLEC f ...

(MAG). The scars do not surround the blood vessels, and in fact, a rim of preserved myelin appears around the vessels. There is evidence of partial remyelinization and oligodendrocyte apoptosis. For some researchers this pattern is an early stage of the evolution of the others. For others, it represents ischaemia-like injury with a remarkable availability of a specific biomarker in CSF :Some authors have stated that distal oligodendrogliopathy could come from a metabolic process. ; Pattern IV : The scar presents sharp borders and

degeneration, with a rim of normal appearing

. There is a lack of oligodendrocytes in the center of the scar. There is no complement activation or MAG loss. These differences are noticeable only in early lesions and the heterogeneity was controversial during some time because some research groups thought that these four patterns could be consequence of the age of the lesions. Nevertheless, after some debate among research groups, the four patterns model is accepted and the exceptional case found by Prineas has been classified as NMO For some investigation teams this means that MS is a heterogeneous disease. The latter hypothesis is further corroborated by a recent study that demonstrated significant differences in routine cerebrospinal fluid findings between patients with pattern I lesions and patients with non-pattern I lesions, including a lack of CSF-restricted oligoclonal bands, in most pattern II and III patients. Finally, some patients previously diagnosed with pattern II MS were later found to have in fact MOG-IgG-related encephalomyelitis, suggesting that both the current clinicoradiological diagnostic criteria for MS and the histopathological criteria for MS may be insufficiently specific. Currently antibodies to

lipids Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...

and

peptides Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...

in sera, detected by

microarrays A microarray is a multiplex lab-on-a-chip. Its purpose is to simultaneously detect the expression of thousands of genes from a sample (e.g. from a tissue). It is a two-dimensional array on a solid substrate—usually a glass slide or silicon t ...

, can be used as markers of the pathological subtype given by brain biopsy. Other developments in this area is the finding that some lesions present

mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...

defects that could distinguish types of lesions.

MRI Phenotypes

Several studies trying to stablish a relationship between the pathological findings and MRI findings have been performed. For example, pulsed magnetization transfer imaging, diffusion Tensor

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...

, and VCAM-1 enhanced MRI have been reported to show the pathological differences of these patterns. Together with MRI,

allows to see the

biochemical Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology an ...

composition of the lesions, which shows at least two different patterns Currently as of 2014, the MRI studies have led to the proposal of four MRI phenotypes, though both the classification and the relationship with the pathology remains controversial.

Other proposed correlations

Several correlations have been studied trying to establish a pathological classification: *With clinical courses: No definitive relationship between these patterns and the clinical subtypes has been established by now, but some relations have been established. All the cases with PPMS (primary progressive) had pattern IV (oligodendrocyte degeneration) in the original study and nobody with RRMS was found with this pattern.

Balo concentric sclerosis Baló's concentric sclerosis is a disease in which the white matter of the brain appears damaged in concentric layers, leaving the axis cylinder intact. It was described by József Mátyás Baló who initially named it "leuko-encephalitis periaxial ...

lesions have been classified as pattern III (distal oligodendrogliopathy).

Neuromyelitis optica Neuromyelitis optica spectrum disorders (NMOSD), including neuromyelitis optica (NMO), are autoimmune diseases characterized by acute inflammation of the optic nerve (optic neuritis, ON) and the spinal cord (myelitis). Episodes of ON and myelitis ...

was associated with pattern II (complement mediated demyelination), though they show a perivascular distribution, at difference from MS pattern II lesions. *With Optic Coherence Tomography: OCT of the retinal layer yields different results for PPMS and RRMS *With CSF findings: Teams in Oxford and Germany, found correlation with CSF and progression in November 2001, and hypotheses have been made suggesting correlation between CSF findings and pathophysiological patterns. In particular, B-cell to monocyte ratio looks promising. The anti-MOG antibody has been investigated and finally led to the description of a new disease,

AntiMOG associated encephalomyelitis MOG antibody disease (MOGAD) or MOG antibody-associated encephalomyelitis (MOG-EM) is an inflammatory demyelinating disease of the central nervous system. Serum anti-myelin oligodendrocyte glycoprotein antibodies are present in up to half of patie ...

. High levels of

anti-nuclear antibodies Antinuclear antibodies (ANAs, also known as antinuclear factor or ANF) are autoantibodies that bind to contents of the cell nucleus. In normal individuals, the immune system produces antibodies to foreign proteins (antigens) but not to human prot ...

are found normally in patients with MS. Recently, it has been shown that the CSF from PPMS patients can transport the disease. Some cases could belong to the

anti-neurofascin demyelinating diseases Anti-neurofascin demyelinating diseases (anti-NF diseases) refers to health conditions engendered by auto-antibodies against neurofascins, which can produce both central and peripheral demyelination. Some cases of combined central and peripheral ...

category. *Cortical lesions: Not all MS patients develop cortical lesions. Only around 40% of patients do. When they appear, they correlate to meningeal inflammation. *With responses to therapy: It is known that 30% of MS patients are non-responsive to Beta interferon. The heterogeneous response to therapy can support the idea of heterogeneous

aetiology Etiology (pronounced ; alternatively: aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek (''aitiología'') "giving a reason for" (, ''aitía'', "cause"); and ('' -logía''). More completely, e ...

. It has also been shown that IFN receptors and

interleukin Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...

s in blood serum predicts response to IFN therapy, specially IL-17, and interleukins IL12/IL10 ratio has been proposed as marker of clinical course. Besides: ** Pattern II lesions patients are responsive to

, while others are not. ** The subtype associated with macrophage activation, T cell infiltration and expression of inflammatory mediator molecules may be most likely responsive to immunomodulation with interferon-beta or glatiramer acetate. **People non-responsive to interferons are the most responsive to Copaxon

** In general, people non-responsive to a treatment is more responsive to other, and changing therapy can be effective. ** There are genetic differences between responders and not responders. Though the article points to heterogeneous metabolic reactions to interferons instead of disease heterogeneity, it has been shown that most genetic differences are not related to interferon behavior *With response to NMO-IgG:: NMO-IgG is the immunoglobulin that attacks Aquaporin-4 in

Devic's disease Neuromyelitis optica spectrum disorders (NMOSD), including neuromyelitis optica (NMO), are autoimmune diseases characterized by acute inflammation of the optic nerve (optic neuritis, ON) and the spinal cord (myelitis). Episodes of ON and myelitis ...

. Multiple sclerosis patients do not have it in blood, but it has been shown that 13% of tested patients reacted with the epitope AQPaa252-275. It is not known if these antibodies define distinct MS subsets, or are simply markers of astrocytic damage *With lesion structure: Cavitary lesions appear only in a subset of patients with a worse clinical course than normal *Response to intravenous immunoglobin: The response to IVIG is strongly dependent from the genetic profile of each person in a predictive way *Comorbidity with diabetes: Diabetes mellitus type 1 (T1D) is produced by special leukocyte antigen haplotypes, which seem to be involved also in some cases of MS

Progressive MS

Primary progressive MS

It is currently discussed whether Primary Progressive MS (PPMS) is a different pathological entity or a different degree of the same pathology. No agreement has been established but there are some pathological features that are specific to PPMS. For example, meningeal inflammation is different respect standard cases of Recurrent-Recidivant MS (RRMS) and sodium accumulation is higher. Diffusely Abnormal White Matter (DAWM) is different than in RRMS/SPMS patients and it has been shown that CSF from PPMS patients can transport the disease From a pathological point of view, PPMS characteristics are slow expansion of pre-existing white matter lesions, massive cortical demyelination, and extensive diffuse injury of the normal appearing white matter. As in relapsing MS also in progressive MS active tissue injury is invariably associated with inflammation, but inflammation seems to be trapped behind a closed blood brain barrier A specially remarkable difference between PPMS and SPMS are some follicle-like B-cells structures in the meninges of SPMS patients, that have never been reported in PPMS patients. These follicles appear to be related to cortical demyelination in SPMS. No disease modifying drug is approved for PPMS. Currently Natalizumab is being studied

Secondary progressive MS

Secondary progressive MS shows follicle-like B-cells structures (a.k.a. Ectopic Follicle-Like Structures, EFS's, or Tertiary Lynphoid Tissues, TLT's) in the meninges that appear associated with underlying subpial cortical damage. These follicles do not appear in Primary Progressive (PPMS) nor in Remitant-Relapsing MS (RRMS).

Pathology of early MS and silent MS

McDonald criteria The McDonald criteria are diagnostic criteria for multiple sclerosis (MS). These criteria are named after neurologist W. Ian McDonald who directed an international panel in association with the National Multiple Sclerosis Society (NMSS) of America ...

rely in detecting the lesions disseminated in time and space that define MS by clinical observations. Therefore, normally they do not allow to establish a diagnosis for definite MS before two clinical attacks have appeared. This means that for clinical definite cases, MS condition has been present for a long time, difficulting the study of the initial stages. To study the initial stages of MS, some additional paraclinical tests must be used to prove the presence and dissemination of the lesions. Sometimes patients with their first isolated attack (Clinically Isolated syndrome, or CIS) but before the confirming second attack (Preclinical MS) can be accepted to study the initial MS pathology but there is a study suggesting that any MS case begins as a silent pathology that can remain unnoticed even for five years. Therefore, even the CIS can appear too late in MS evolution. Cases of MS before the CIS are sometimes found during other neurological inspections and are referred to as subclinical MS., or sometimes Clinically silent MS. The previous reference states that clinically silent MS plaques were located in the periventricular areas. This reference also reports an estimate of the prevalence of silent MS as high as about 25%. Oligodendrocytes evolution is similar to normal MS clinical courses Sometimes patients that undergo an MRI examination for an unrelated cause can show lesions in their brains. These cases of isolated MRI findings have been recently baptised as RIS (Radiologically Isolated Syndrome) and are the most common inspections in which suggestions of silent MS have appeared. In respect to the pathology of the RIS cases, we can point out that they show cortical lesions, mainly in patients with oligoclonal bands. Macroscopic damage is similar to RRMS cases but milder. Cervical cord lesions are an important predictor of progression and the quotient N-acetylaspartate to creatine suggest axonal damage

References

External links

The lesion project page
MedPix Image Database {{DEFAULTSORT:Pathophysiology Of Multiple Sclerosis Multiple sclerosis