Demyelinating Disorders

Prof. Dr.
Nevine El Nahas

Myelin formation and structure

The myelin sheath is a spiral of modified plasma membrane which envelops the axon. It is formed by the oligodendrocytes in the central nervous system and by the Schwann cells in the peripheral nervous system. Each myelin-producing cell only provides myelin for a segment of a given axon. There are small interruptions in the myelin sheath called the nodes of Ranvier, in which a large number of sodium channels are to be found. Myelin is an electrical insulator, that serves to speed the conduction of nerve impulses. This occurs as conduction which jumps from Ranvier node to Ranvier node, giving rise to a much faster depolarization than in nerve fibers which do not have a myelin sheath. With regard to the molecular structure of myelin, this is formed by a membrane containing asymmetrically organized lipids and proteins. Myelin basic protein (MBP) is an extrinsic protein found on the cytoplasmic surface; it can form dimers and thus becomes the principal stabilizing protein of myelin .

Transmission
Myelin covers each nerve fiber insulating them and helping with the transmission of nerve impulses between the brain and other parts of the body.

Breakdown

The destruction of the myelin sheath leads to impaired communication between nerve cells and neurological symptoms such as abnormal sensations, vision problems , and weakness.

Classification of demyelinating disorders

Isolated demyelinating synd.: Acute disseminated encephalomyelitis Optic neuritis Isolated spinal cord synd. Devics disease

Classification of demyelinating disorders

Multiple sclerosis Central pontine myelinolysis leucodystrophies

Isolated syndromes
ADEM Follows exanthems or infections Headache, drowziness, fits, focal lesions, visual disturbance. Brainstem, optic nerve, spinal cord Peripheral nerves May be first presentation of MS

CSF: polymorphs, lymphocytes, proteins. MRI: multifocal white matter abnormalities may be similar to MS. Serial enhanced MRI can differentiate. Prognosis infuenced by early high dose steroids.

Optic neuritis
Painful eye movement, blurred vision evolve over hours or days. Can be bilateral simultaneous Can be first manifestation of MS (MRI, EP, CSF)

Devics dis. (neuromyelitis optica)

Demyelintion both optic nerves and spinal cord Simultaneous or sequential. CSF ( Abs against aquaporin 4)

Central pontine myelinolysis

Rapid overcorrection of hyponatremia Paralysis, facial and bulbar weakness, disordred eye movement, imbalance, altered consciousness. Ttt.: stabilize serum sodium, good prognosis

Leucodystrophies
Non-inflammatory demyelinating dysmyelinating Defects of genes regulating synthesis and maintenance of myelin progressive Infants and adults Affect vision, behaviour, intellect, cerebellar, Pyramidal, epilepsy, peripheral nerves

Multiple sclerosis

Results of demyelination
Partially demyelinated axons cant transmit fast impulses fatigue. Depolarization traverses the lesion with reduced velocity delayed evoked pot.s Partially remyelinated axons discharge spontaneously Lhermittes symptom, myokymia, flashes of light.

Common sites of demyelination

Optic nerve Around lateral ventricles, Corpus callosum, Cortical-subcortical junction, Brainstem, Cerebellum Cervical cord.

Defining multiple sclerosis

- A chronic demyelinating disease

- Affects the central nervous system . - Most common cause of chronic neurologic

disability in young adults.

- Prevalence of 1 in one thousand

- Characterized by relapses and remissions or a

progressive course.

Defining multiple sclerosis

- Presence within the central nervous system of inflammation, demyelination and scarring by gliosis.

- Current evidence suggest that multiple sclerosis is an autoimmune disease which develops in genetically susceptible individuals living in a predisposing environment .

Genetic Factors
Sex:
Women are more likely to have MS than men by a 2:1 ratio. They also think that this is true because women are in general more likely to have an Auto immune Disease.

Racial Group:

other races to develop MS

Whites are more than twice as likely as

Family History:
In a normal population the chance of someone to exhibit the symptoms of MS is only 0.1%. If your first-degree relative has MS your chance increases to 3%. If a second-degree relative , you only have a 1% chance. If both parents have the disease you have a risk of 20%. Identical twin your risk is 30%.

Environmental Factors
Latitude:
above and below 40 latitude, MS is more common. These are temperate and cooler climates. It is five times more likely in these regions.

SES: It is least common in the lower class and in rural residence. Migration: If you move before the age of 15, your risk is that of the people in
the country you move to. If you move after the age of 15, your risk stays fixed at that of the country you grew up in.

Infection:
They believe MS is a delayed reaction to a viral infection contracted during childhood by a genetically susceptible person. Viral infections may include shingles, chicken pox, measles, or certain herpes.

Demyelinating plaque

* Inflammation

* Demyelination
* Gliosis * Axonal loss

Pathogenesis
- Autoreactive T cells enter though broken BBB by

help of adhesion molecules secrete proinflammatory cytokines activate microglia (antigen presenting cells) binds to CD4 cells (T helper1) cytoxicity (interferon , TNF) to oligodendrocytes,

- or CD4Th1 & CD8 direct injury to oligodendrocyte.

- B cells antibody injury

Pathogenesis
The demyelinating plaque consists of an area of myelin loss, a relative preservation of the axon and the formation of an astrocyte scar. The acute lesion is usually perivenular, formed of an inflammatory infiltrate of T lymphocytes and macrophages that infiltrate the white matter and cause demyelination. There is an alteration of the bloodbrain-barrier at the sites of inflammation. CD4 T lymphocytes activated by autoantigens adhere to the endothelial cell surface in the venules of the central nervous system, migrate into the organ through the altered blood-brain-barrier and act against antigens in the myelin sheath. Antibodies to antigens in the myelin sheath and oligodendrocytes reach the central nervous system through the disruption in the bloodbrain- barrier, leading directly to demyelination through a complement-mediated process .

Pathogenesis (cont.)
-The early symptomatology: axonal demyelination, blocking conduction. -

- Regression of the symptoms: due to * resolution of the inflammation * partial remyelination. - Axonal conduction can recover due to redistribution of the sodium channels along the demyelinated segments. - Progressive loss of neurologic functions: irreversible axonal damage with gliotic scar formation and depletion of the oligodendrocyte reserve.

Clinical patterns
85% of patients present a sudden onset of symptoms. Four clinical patterns : -Relapsing-remitting the patient suffers relapses which may or may not present a complete recovery; however, patient is clinically stable between the relapses. 50% of these patients convert to another pattern, - Secondary progressive within ten years of developing the disease. Gradual progression of the disability, with or without relapses. -Primary progressive the patients present a gradual progression of the disability from the onset of the disease and do not suffer relapses. -Relapsing progressive there is a gradual progression of the disability from the onset of the disease, associated with one or more episodes of relapses

Relapsing Remitting
Exacerbations: flare-up or attack of symptoms such as numbness or tingling of hands and feet that typically last for a few weeks; exacerbations come and go throughout the disease course of MS.

Occur by an area of inflammation in the tracts of the brain and spinal cord after demyelination
Disease does not worsen in periods between the attacks

Secondary Progressive

Begins with relapsing remitting but evolves into progressive disease Can occur over a long stretch of time

Primary Progressive
Gradual but steady progression of disability No obvious relapses and remissions 15% of people with MS Develop disease after 40 years of age

Progressive Relapsing

Least common form Steady progression in disability with acute attacks

There may be no recovery after attacks

Clinical manifestations

Clinical Picture
- 80% of the patients present a relapsing remitting pattern,

- Mental : impaired memory , learning, depression, emotional lability - Relapse is usually associated with unilateral optic neuritis, diplopia due to internuclear ophthalmoplegia, - Sensory symptoms , paresthesia, paroxymal pains, trigeminal neuralgia, Lhermittes sign (paresthesia in the trunk and limbs caused by flexion of the neck), - Limb weakness, progressive tetraparesis, spasticity, clumsiness, ataxic gait, and neurogenic bladder. - Fatigue associated with increased temperature. - Vertigo, tremor, dysphagia dysarthria, sexual dysfunction and are also often observed . - The cortical symptoms (aphasia, apraxia, convulsions, loss of visual fields, early dementia) and extrapyramidal phenomena such as chorea and rigidity can occur, though they are not the most common. -

Prognosis

MRI and evoked potentials

MRI

has improved the diagnostic accuracy of multiple sclerosis

Changes related to the disease are detected in 95% of patients. Acute lesion: Increased vascular permeability, observed as Gadolinium enhancement, appears as a very early sign of the formation of a new lesion and is perhaps a marker of inflammation. MS Plaque: Inflammation, demyelination, axonal loss and gliosis of the multiple sclerosis plaque remains as a hyperintense area in T2 weighted images. The relationship between the number of T2-weighted lesions and the degree of clinical disability is poor.

Evoked potentials detect whether there is any problem of slowing or

blockade of conduction in the auditory, visual or somatosensory pathways. This test uses computerized instruments which record the response of the nervous system to repetitive stimuli .

CSF examination
Increased levels of oligoclonal bands of IgG in 75-90% of patients. Mononuclear pleocytosis with more than five cells per milliliter. In general, the cell count is less than 20 cells per microliter. A pleocytosis of greater than 75 cells per microliter or the finding of polymorphonuclear cells makes a diagnosis of multiple sclerosis unlikely .
There are several formulae which are used to differentiate between IgG of intrathecal synthesis and IgG from the blood which can enter the central nervous system passively through the altered blood-brain-barrier.

Three Categories of Treatment

Treatment of Exacerbations .. Disease modifying ttt

Specific MS symptom treatment

Treatment of relapse
Treatment of exacerbations must be done with glucocorticoids to : Reduce swelling and inflammation in the plaques of demyelination, accelerate recovery. - Intravenous methylprednisolone 0.51gm/day for five days, followed by a short course of oral prednisone .
-

Disease modifying agents

Interferons vs. Glatiramer Acetate

Copaxone is a substitute antigen that mimics myelin basic protein. It inhibits the CNS immune reactions that are responsible for tissue damage.

Given subcutaneously daily injection

Reduces number of attacks and brain lesions seen on MRI patients

No flu-like side effects associated with interferons

Interferons
Discovered in 1957 Significant antiviral agents phenomenon where one infection with one virus interferes with a subsequent infection with another virus

What are they??

A protein substance naturally produced in the body and believed to function to modulate the immune system.

Interferons interact with receptors on non-infected cells to promote the synthesis of antiviral proteins that prevent further infection. They antagonize proinflammatory cytokines.

Beta Interferon

Beta interferon-1a Avonex administered weekly by an intramuscularly injection (2003) Rebif administered subcutaneously three times a week (2002) Beta interferon-1b Betaseron administered subcutaneously every other day (1993)

Common Side Effects

Typical Flu-like symptoms headache, nausea, and fever

muscle aches
Chills Irritation at the injection site

Treatment (disease modifying)

Glatiramer acetate is a synthetic polypeptide that is similar to myelin basic protein; it acts by inducing a suppression of antigenspecific T cells by sharing determinants between this copolymer and the myelin basic protein; it also acts by binding to the major histocompatibility complex molecules on the surface of the antigen presenting cells. The interferons appear to act by reducing the expression of the major histocompatibility complex molecules on the surface of the antigen presenting cells, reducing the proinflammatory cytokines and reducing the expression of the adhesion molecules on

the endothelial cells .

Treatment (disease modifying)

Mitoxantrone acts as a B and T cell immunosuppressor. Other treatment options are available for patients with a relapsing-remitting pattern or with secondary progressive multiple sclerosis, including azathioprine, methotrexate, cyclophosphamide, intravenous immunoglobulins, and methylprednisolone. To date there is no adequate treatment for primary progressive multiple sclerosis .

Disease modifying drugs

Mitoxantrone (Novantron) modulates the immune system
through a variety of mechanisms, including antiproliferative effects on T cells and suppression of humoral immunity.

Natalizumab (Tysabri) is a humanized monoclonal antibody

specifically designed for use in MS. Natalizumab binds to the a4 subunit of a4b1 and a4b7 integrins that are present on most leukocytes, other than neutrophils. Antibody binding blocks the interaction with complementary endothelial molecules known as vascular cell adhesion molecules and thereby inhibits the migration of leukocytes across the blood-brain barrier.

 Early and aggressive treatment can delay or possibly even prevent crippling symptoms of MS

Thank you