Multiple Sclerosis

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Multiple Sclerosis(MS) Presented by MANCHALU SRINIVAS 11408024 B.Tech Genetic Engineering VII Semester

Transcript of Multiple Sclerosis

Page 1: Multiple Sclerosis

Multiple Sclerosis(MS)Presented by

MANCHALU SRINIVAS11408024

B.Tech Genetic EngineeringVII Semester

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Also called as

MS

Disseminated Scleorosis

Encephalomyelitis Disseminata

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The name…..

Sclerosis means scars/plaques/lensions.

Presence of many scars in white matter of brain & spinal card of Myelin sheath.

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Biology of MSAttacks on Central Nervous System(CNS).

Brain and Spinal cord are targeted.

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Formation of plaques on Myelin sheath leads to damage of tissue.

Leads to loss of nerve impulse.

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BASICALLY IT IS A AUTOIMMUNE DISEASE

Autoimmune diseases arise from an overactive immune

response of the body against substances and tissues normally

present in the body. In other words, the body actually attacks its

own cells. The immune system mistakes some part of the body as

a pathogen and attacks it.

This may be restricted to certain organs (e.g. in autoimmune

thyroiditis) or involve a particular tissue in different places The

treatment of autoimmune diseases is typical with

immunosuppression—medication which decreases the immune

response.

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History

Dr. Jean Martin Charcot(1825 - 1893)

Decsribed scientifically, Documented first in 1868 and noticed & named as presence of many scars in CNS.

Dr. Freud

Treated first patient “Nanny” his former, who was suffering with MS.

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Dr. V.B. Dolgopol in 1938

Described a case of optic neuritis, caused by severe demyelination and attributed it to Devic's Syndrone. This syndrone was considered to be a subclass of Multiple Sclerosis during this time period.

Merck Manual - 16'th Edition - 1992 States: "Plaques or islands of demyelination along with destruction of both oligodendroglia and perivascular inflammation are disseminated through the CNS, primarily in the white matter, with a predilection for the lateral and posterior column (esp. in the cervical and dorsal regions), the optic nerves and periventricular areas.

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Famous people triggered by MS

Chrissy Amphlett - American lead singer.Nicky Broyd - BBC Radio Journalist. Luca Coscione - Italian Politician. Betty Cuthbert - Olympic Gold Medallist, Sprinting from Austrailia.Christian Johann Heinrich Heine - German poet (1797-1856) diagnosed with MS.

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MS involved in movies

GURU (film in 2007) by Mani Ratnam Character “Meenu” by Vidya Balan

Duet for One- A Play About Multiple Sclerosis

about a woman who has to give up her career as a violinist because of multiple sclerosis. The play is a series of scenes of the woman and her therapist as she struggles to remake herself after multiple sclerosis.

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PrevalenceMostly affected age 20-40.Rarely before 12 and after 55.Mostly women's are affected than men and ration is 2:1.Approximately one third of a million Americans.And every week some 200 people are diagnosed with the disease. More than one person an hour. Across the world, about 2.5 million people have the disease.

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In INDIA…

• Multiple Sclerosis in India is known to be different from West .

• MS in India has Optico-spinal phenotype (as generally reported in Asian population). Which means that the attacks are mostly confined to optic nerve and spinal cord.

• In India alone, there are 40,000 to 50,000 people who are affected with Multiple Sclerosis.

• Neurologists state that the cases reported are much more than what used to be a decade ago. More cases have been observed in North-west India.

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Causes of MS

Genetics

Environmental Factors

Infections

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GENETICS Researchers believe that multiple sclerosis may in part be inherited (genetics contribute to the increased risk of MS seen in family members).

But a number of genetic variations have been shown to increase the risk of developing the disease.

There are specific genes linked with MS.

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CONTD…..

Differences in the human leukocyte antigen (HLA) system—a group of genes in chromosome 6 serves as the major histocompatibility complex (MHC) in humans—increase the probability of suffering MS.

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CONTD……

The most consistent finding is the association between multiple sclerosis and alleles of the MHC are as DR15 and DQ6. Other loci have shown a protective effect, such as HLA-C554 and HLA-DRB1 11.The risk of acquiring MS is higher in relatives of a person with the disease than in the general population, especially in the case of siblings, parents, and children.

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Family Studies

Monozygotic (identical) twinsDizygotic (non-identical) twinsChild of parent with MSSibling of person with MS

25 – 30%3 – 4.5%

1.9%0.9%

Up to 19% of patients have an affected relative.

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A study published in the New England Journal of Medicine in August 2007 found a new genetic risk factor for multiple sclerosis (MS).

The study shows that people who have certain variations or mutations of two different genes (IL7RA and IL2RA) are more likely to have MS than people without these mutations.

IZ7RA and IL2RA are proteins that guide the actions of one type of immune cell (T cell). As genes control how proteins are made in the body, changes in protein type represent a difference in genetics.

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The MS-related protein may contribute to MS by guiding those immune cells to attack the nervous system, which leads to demyelination and lesions on the brain and spinal cord. 

Interestingly, IL2R mutations have been associated with type 1 diabetes and Graves’ disease, also autoimmune disorders.

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ENVIRONMENTAL FACTORS

Sunlight

MS is more common in people who live farther from the equator, although many exceptions exist. 

Decreased sunlight exposure has been linked with a higher risk of MS. 

Decreased vitamin D production and intake has been the main biological mechanism used to explain the higher risk among those less exposed to sun.

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Stress 

may also be a risk factor although evidence is weak. Smoking has also been shown to be an independent risk factor for developing MS.

Association with occupational exposures and toxins—mainly solvents—has been evaluated, but no clear conclusions have been reached.

Vaccinations were also considered as causal factors for the disease; however, most studies show no association between MS and vaccines.

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Several other possible risk factors, such as diet and hormone intake, have been investigated.

Low levels of uric acid have been found in MS patients as compared to normal individuals.

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INFECTIONSMany microbes have been proposed as potential infectious triggers of MS, but none have been substantiated.

Different hypotheses have elaborated on the mechanism by which this may occur.

 Hygiene hypothesis 

Exposure to several infectious agents early in life is protective against MS, the disease being a response to a later encounter with such agents. 

 Prevalence hypothesis  The disease is due to a pathogen more common in regions of high MS prevalence. This pathogen is very common, causing in most individuals an asymptomatic persistent infection.

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CONTD…. Evidence for viruses as a cause includes the presence of oligoclonal bands in the brain and cerebrospinal fluid of most patients, the association of several viruses with human demyelination encephalomyelitis, and induction of demyelination in animals through viral infection.

Human herpes viruses are a candidate group of viruses linked to MS. Individuals who have never been infected by the Epstein-Barr virus have a reduced risk of having the disease, and those infected as young adults have a greater risk than those who had it at a younger age.

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Multiple Sclerosis Clinical Subtypes

Lublin FD et al. Neurology. 1996;46:907-911.

Relapsing-remitting

Primary-progressive

DisabilityTime

Time

Disability

Secondary-progressive

Progressive-relapsing

Time

Time

Disability

Disability

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Symptoms

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DAIGNOSTICSLumbar Puncture

Also called a spinal tap.

This test requires that a small amount of cerebrospinal

fluid(CSF) be taken from your spinal column via a needle that is

inserted between your vertebrae.

The doctor will send the fluid for evaluation, looking for the

presence of oligoclonal bands (an increased number of certain

antibodies) an indicator of increased immune activity in the spinal

fluid.

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Diagnostic Criteria

There are two basic rules for diagnosing

MS:The person must have had at least

two relapses (an episode where symptoms were

present). These episodes must have been

separated by at least one month.

There must be more than one lesion on the brain or

spinal cord.

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Negative: You don’t have MS. It is possible for

the doctor to give this diagnosis only when

another definite diagnosis is made that can

account for your symptoms.

Possible: This means that you may have

symptoms that look like MS, but your tests are

normal. No other diagnosis which accounts for

the symptoms has been confirmed.

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Probable: Many people fall into this category when they are

first seen by a neurologist. You may have symptoms that look

like MS and have had two separate episodes separated by at

least a month, but normal findings on an MRI. You could also

have an MRI that showed only one lesion in your brain or spine.

In this case, your doctor will probably recommend repeating the

MRI after a certain period of time (for instance, 3 months) to see

if any other lesions appear.

Definite:  You have had at least two attacks, separated in time,

plus at least two areas of demyelination

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Magnetic Resonance Imaging (MRI) Scan

MRIs use magnetic waves to produce images of the brain and

spinal cord.

If MS is suspected, a special contrast material (gadolinium)

injection is usually at the time of the scan, as it reacts to

areas of inflammation and will "light up" when a lesion is

active.

This indicates that demyelination is occurring.

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Neurologic Exam

The doctor will be testing for the following:

◦Functioning of the cranial nerves (these control

the senses, as well as how you talk and

swallow)

◦Coordination

◦Strength

◦Reflexes

◦Sensation

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TREATMENTS The primary aims of therapy are returning function

after an attack, preventing new attacks, and

preventing disability. As with any medical treatment,

medications used in the management of MS may have

several adverse effects, and many possible therapies

are still under investigation. At the same time

different alternative treatments are pursued by many

patients, despite the paucity of supporting,

comparable, replicated scientific study.

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CONTD……

Clinically isolated syndrome

The earliest clinical presentation of relapsing-remitting MS (RRMS) is the

clinically isolated syndrome (CIS), that is, a single attack of a single symptom.

During a CIS, there is a subacute attack suggestive of demyelination but the

patient does not fulfill the criteria for diagnosis of multiple sclerosis. 

Several studies have shown that treatment with interferons during an initial

attack can decrease the chance that a patient will develop clinical definite MS.

These results support the use of interferon after a first clinical demyelinating

event and indicate that there may be modest beneficial effects of immediate

treatment compared with delayed initiation of treatment.

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Glatiramer acetate

Is a random polymer (average molecular mass 6.4 kD) composed of four amino

acids that are found in myelin basic protein. The mechanism of action for glatiramer

is unknown, although several have been proposed. Administration of glatiramer

shifts the population of T cells from pro-inflammatory Th1 cells to regulatory Th2

cells that suppress the inflammatory response. Given its resemblance to myelin

basic protein, glatiramer may also act as a sort of decoy, diverting an autoimmune

response against myelin.

The mechanism(s) by which glatiramer acetate exerts its effects in patients with

Multiple Sclerosis (MS) is (are) not fully elucidatedStudies in animals and in vitro

systems suggest that upon its administration, glatiramer acetate-specific suppressor

T-cells are induced and activated in the periphery.

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Natalizumab

 Is a humanized monoclonal antibody against the cellular adhesion molecule α4-

integrin. Natalizumab is used in the treatment of multiple sclerosis and Crohn's

disease.

It is co-marketed by Biogen Idec and Élan as Tysabri, and was previously

named Antegren. Natalizumab is administered by intravenous infusion every 28

days.

Natalizumab appears to reduce the transmission of immune cells into the central

nervous system by interfering with the α4β1-integrin receptor molecules on the

surfaces of cells. The effect appears to occur on endothelial cells expressing

the VCAM-1 gene, and in parenchymal cells expressing the osteopontin gene. In

animals used to model MS and test therapies, repeated administration of

natalizumab reduced migration of leukocytes into the brain's parenchyma, and also

reduced lesioning, though it is uncertain if this is clinically significant for humans.

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Interferon beta-1a

Is a drug in the interferon family used to treat multiple sclerosis (MS).

It is produced by mammalian cells, while Interferon beta-1b is

produced in modified E. coli. Interferons have been shown to produce

about a 18–38% reduction in the rate of MS relapses, and to slow the

progression of disability in MS patients.

There is currently no cure for MS, though starting a course of

interferons early may slow its progress.

Interferon beta-1a is sold under the trade names Avonex (Biogen Idec)

and Rebif (Merck Serono); CinnoVex (CinnaGen) is biosimilar.

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Vitamin D  

A vitamin D deficiency has been shown to cause a multiple sclerosis, which

is interesting, because many people with MS have also been found to be

low in vitamin D. 

MS is less common in areas with lots of sunlight exposure, in both

geographic areas at higher altitudes and areas closer proximity to the

equator.  Sunlight exposure is a major source of vitamin D. 

MS is also less common in areas where fish is commonly eaten.  Fish oils

are another major natural source of vitamin D.  There seems to be some

very suggestive evidence that vitamin D may well play a role in MS. 

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NeuroVax (Vaccine) 

This vaccine has been developed to teach one part of the immune system

(specifically, FOXP3+ regulatory T-cells) to control or down regulate the part of

the immune system that attacks myelin in people with MS (pathogenic T-cells).

Pathogenic T-cells are a subset of white blood cells, which in the case of MS,

attack myelin in the brain, spinal cord and optic nerves, causing inflammation

and eventual demyelination.

FOXP3+ regulatory T-cells (or Treg cells) control pathogenic T-cells in healthy

individuals, giving them the signal of when to stop attacking foreign invaders.

People with MS have been shown to have lower levels of these FOXP3+

regulatory T-cells than healthy individuals. NeuroVax is designed to restore the

level of FOXP3+ regulatory T-cells to the same level as in healthy individuals.

NeuroVax is injected intramuscularly every four weeks indefinitely.

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Ongoing Research for MS Therapy

Richard Burt of Northwestern University Feinberg School of Medicine in

Chicago and his colleagues had previously tried using stem cells to

reverse this process in patients with advanced stages of the disease,

with little success.

They removed stem cells from the patients' bone marrow, and then

used chemicals to destroy all existing immune cells in the body, before

re-injecting the stem cells. These then developed into naïve immune

cells that do not see myelin as alien, and hence do not attack it.

Three years later, 17 of the patients had improved by at least one point

on a standard disability scale, while none of the patients had

deteriorated.

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LIST OF ORGANIZATIONSMultiple Sclerosis Society of India (MSSI),

New Delhi, Mumbai, Bangalore,Pune, Chennai, Hyderabad.

Multiple Sclerosis International Federation, US.

European Multiple Sclerosis Platform.

Multiple Sclerosis Association of America.

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WORLD MS DAY

The third World MS day took place on the 25th May 2011 and was a great success with activities taking place in more than 70 countries around the World.

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References www.ncbi.nlm.nih.gov

www.medicinenet.com

www.ninds.nih.gov

Harris VK, Sadiq SA (2009). "Disease biomarkers in multiple sclerosis: potential

for use in therapeutic decision making". Mol Diagn Ther 13 (4): 225–

44. doi:10.2165/11313470-000000000-00000.PMID 19712003.

Galetta, S; et al. (2008-04-18). "Natalizumab Increases the Proportion of

Patients Free of Clinical or MRI Disease Activity in Relapsing Multiple

Sclerosis".unpublished/unpresented conference poster. Retrieved 2008-03-11.;

industry publication -"New TYSABRI Data to Be Presented at the European

Committee for Treatment and Research in Multiple Sclerosis". Élan. 2007-10-

11. Archived from the original on 2007-10-29. Retrieved 2008-03-09.

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