Multiple+Sclerosis+II

= = =OVERVIEW:= [] Multiple Sclerosis (MS) is a progressive demyelinating disease of the Central Nervous System (CNS) and stands as the most common neurological disorder diagnosed in young adults and women are twice as likely to develop MS then men (9). Approximately 400,000 people in the United States have MS and 2.5 million people worldwide suffer from this chronic disease (9). Although the official cause of MS is unknown, the most widely accepted theory of causation is that of an autoimmune response in which the body mistakenly attacks its own myelin and nerve tissue in the CNS. This damage causes problems with communication of the nerve signals. This interference among the nerve signals results in neurological symptoms characterized by MS. There are many different symptoms of MS and no two patients experience the exact same symptoms. Types of MS symptoms depend on where the damage has occurred. When MS lesions occur in the brain or spinal cord, the patient usually experiences problems with movement (motor symptoms) and/or sensation (sensory symptoms). This allows for a wide variation of symptoms of MS because attacks can occur all over the CNS in multiple places. Symptoms of MS occur when the brain and spinal cord nerves no longer communicate properly with other parts of the body. Demyelination of nerve pathways that bring signals to the muscles causes problems with movement, while demyelination of nerve pathways that carry input to the brain causes disturbances in sensation. MS is not a fatal disease. Most people that develop MS can live a normal life with an average lifespan.

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=**FUNCTIONAL ANATOMY:**= [] Neurons are the nerve cells found in the nervous system. These cells communicate with one another to process information in form of electrical impulses. Components of the neuron include: dendrites (input), axon (conduction to output), and the cell body (integration). Myelin is a fatty material made up of lipids and lipoproteins that acts as an insulating sheath that surrounds the axons and nerve fibers. Gaps along the axon that are not covered with myelin are known as the Nodes of Ranvier. Myelin insulation increases the rate of signal transmission, helping to speed up neural impulses. It is our axon’s electrical insulator. Thicker myelination gives rise to faster conduction. Damage to this myelin results in impaired function of neural impulses. Messages sent by the damaged nerve are sent more slowly and less efficiently. It is this demyelination that causes the symptoms of MS []

=**PATHOPHYSIOLOGY:**= MS affects movement, sensation, and bodily functions and yet the exact cause of the disease remains unknown. Like stated above, it is thought that MS is brought about by abnormalities within the immune system which causes demyelination of axons in the CNS. Demyelination is the process of destroying the fatty material myelin (explained above) that insulates the nerves. Patches of scar tissue known as plaques form over the damaged area. These plaques or lesions further disrupts nerve communication.

In MS, immune cells known as T-cells (lymphocytes and macrophages) are activated and penetrate the blood-brain barrier (BBB). The BBB is the layer of cells and tissues that lines the blood vessels that creates a selectively permeable barrier between the blood and the CNS. The T-cell’s ability to cross this barrier has had researchers stumped for years because immune cells stay in the blood stream outside the CNS. In MS, an unknown trigger activates helper T-cells and enables the T-cells to adhere to the BBB and then cross its normally prohibiting barrier into the CNS (3). Once inside the BBB, antigen specific receptors on the surface of T-cells recognize CNS myelin as an antigen (13). So, the T-cells attack the myelin that surrounds the axons and produces inflammation.

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This inflammation and damage to myelin causes the CNS to lose some of its ability to send signals throughout the body thus causing the symptoms of MS. Increased inflammation and damage to the myelin can result in total loss of nerve fibers. The CNS does have the ability to repair itself, however, after many inflammatory attacks, repair becomes less successful and astrocytes can form scars in the area of myelin damage, creating plaques or lesions. Plaques or scarring (hence the name “sclerosis” which means “scars”) are the result of our body’s patch-work done on the damaged myelin sheath as a result of healing. When the insulating myelin around nerve fibers are damaged, the nerve conduction from the brain to spinal cord is disrupted or blocked. When nerve signals are disrupted or blocked, signals are not carried out. When signals are not carried out, messages are not received or are disrupted which causes a person to experience some sort of neurological problems and symptoms appear.

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=CLASSIFICATIONS OF MS:=

By clinical definition there are four main types of MS. Because each person with MS has different symptoms, the exact course a person’s MS will take cannot be accurately predicted even by the best physicians. For this reason, there can be slightly different definitions of the classifications of MS. The progression of an individual’s MS cannot be predicted. Still, the main stages of MS are as follows: Relapses refer to the attacks or exacerbations that occur in this stage. Remitting is the recovery period. In this stage, attacks are followed by a remission period where the symptoms usually improve without any further progression of neurological dysfunction. Some attacks can lead to permanent damage, but usually in the early stages of the disease the remission stage is almost complete. This pattern repeats itself as recurrent attacks occur. RRMS is the most common course of MS. 85% of patients (usually young adults) with MS are initially diagnosed with RRMS (10).
 * Relapsing-remitting MS (RRMS)**: (attacks à recovery à stability)

Secondary-progressing MS (SPMR) SPMS follows relapsing-remitting MS and becomes progressive, but not at a consistent rate, possibly with an occasional relapse and small remission. Basically, it is a more intensified RRMS with more attacks and less recovery.

Primary-progressive MS (PPMS): (no attacks, just progression) PPMS is usually diagnosed in older individual’s in their 40s – 50s and is characterized by an initial slow progression of the disease from the beginning. Again, progression depends on the individual and their symptoms. Serious disability can occur in a few months,.Usually however, progression is slow. Common symptoms tend to be numbness and stiffness in legs that slowly works up the body. Eventual speech difficulty is common. PPMS effects 20% of people diagnosed with MS (10).

Progressive-relapsing MS (PRMS): (progression and attacks from beginning. Progresses even without attacks) PRMS is the least common type of MS, effecting only 5% of people diagnosed with MS (10). Patients must deal with a steady disease progression as well as attacks or exacerbations. PRMS progresses without recovery from an attack. []

=PATHWAYS:=

Like stated before, MS affects movement, sensation, and bodily functions. The pathways involved with Multiple Sclerosis depend on the location of the lesion. Lesions caused by MS can occur anywhere in the CNS. Which means they can appear in the brain, spinal cord, and even the optic nerve. This means that MS does not have one specific pathway in which it effects, but multiple. Lesions in the spinal cord can affect the descending pathway known as the corticospinal tract. The corticospinal tract is known to be the primary pathway that carries the motor commands of voluntary movement (5). Lesions found anywhere throughout this tract will most likely cause some sort of motor problem. Damage to neurons of the corticospinal tract effects motor control in different ways, depending on the location of damage. Lesions within the lateral corticospinal tract can cause a period of flaccid paralysis (11). This period of paralysis can be used as an example of exacerbation of multiple sclerosis. Other symptoms that occur from lesions in this pathway are spasticity, limb weakness, ataxia, or other gait disturbances, even bladder dysfunction, sexual dysfunction, and dysesthesias. Explained in a case report summary from the University of Rochester Medical Center, most acute symptoms in MS are caused by spinal lesions rather than brain lesions (4).

The corticospinal tract begins in the precentral gyrus AKA the primary motor cortex. The primary motor cortex has neurons that make connections to local circuits in the spinal cord. Upper motor neurons start in the cortex of the brain and end in the medulla or the spinal cord. Damage to upper motor neurons can result in spasticity and exaggerated reflexes (7). The axons of the upper motor neurons in the primary motor cortex descend through the internal capsule. The axons continue through the anterior portion of the medulla. In the medulla the majority of fibers decussate (which is just a fancy word for: crossing over to the opposite side of the body). The fibers that decussate, innervate the limbs while the fibers that do not decussate head to innervate the axial muscles. The crossing fibers (limb fibers) enter the lateral funiculus of the spinal cord where they form the lateral corticospinal tract (LCST). The majority of fibers that project from the motor cortex to the spinal cord are contained in the lateral corticospinal tract. The rest of fibers that project to the axial muscles have axons that do not cross at the medulla and travel within the anterior corticospinal tract in the spinal cord.

Although it is the primary motor pathway, the corticospinal pathway is not the only pathway effected by MS. Like stated before, the symptoms of MS depend on where in the CNS the lesions are located. Many other pathways are involved in MS. We can see through their functions that lesions located in any of these pathways cause symptoms of MS. Other descending pathways involved with MS include:

Function: facilitates extension of limbs Pathway : reticular nuclei (pons) --> ipsilateral medulla and spinal cord --> ipsilateral ventral horn --> (synapse on interneurons excite gamma, extensors)
 * Medial reticulospinal tract **:

function: contraction of flexor muscles of limbs pathway: reticular formation (medulla) --> crosses in medulla --> contralateral interneurons that excite alpha and gamma motor neurons (flexors)
 * Lateral reticulospinal tract **


 * Lateral and medial vestibulospinal tract ** : balance maintenance, posture, head movement

function: flexor of limb muscles pathway: red nucleus (midbrain) **-->** crossing in ventral midbrain --> lateral brainstem --> lateral spinal cord --> anterior horn of cervical spinal cord
 * Rubrospinal tract: **

function: reflexive head movements pathway: superior colliculus --> MLF --> tectospinal tract --> anterior funiculus
 * Tectospinal tract **

Sensory dysfunction if also a large contributor to symptoms of MS. Another pathway effected by MS is that of the somatosensory pathways. The somatosensory system is a 3-neuron system that relays sensations detected in the periphery and conveys them via pathways through the spinal cord, brainstem, and thalamic relay nuclei to the sensory cortex in the parietal lobe (2). This "3-neuron system" can be summarized: First-order neurons begin at the dorsal root ganglia and conducts impulses from the skin to the spinal cord or brain stem, Second-order neurons begin at the dorsal horn and transmit impulses to the thalamus or cerebellum, theThird-order neurons begin from the thalamus and conduct impulses to the somatosensory cortex of the cerebrum. The somatosensory system processes many types of sensory information including discriminative touch, pain and temperature, as well as proprioception (1). These different types of sensory information have different receptors, follow different pathways, cross at different levels, and end on different targets. Discriminative touch: crosses in the medulla, pain system: crosses in the spinal cord, and proprioceptive goes to the cerebellum WITHOUT crossing. If lesions occur in these pathways, the sensory pathways in the spinal cord are blocked, and can result in numbness, paresthesis (tingling), and other strange sensations.

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=**SYMPTOMS, DIAGNOSIS, TREATMENT****:**=

SYMPTOMS:
As stated before, lesions associated with MS can be found anywhere in the CNS which creates a long list of possible symptoms. Symptoms fluctuate among patients and can be mild for one patient but extreme for another.
 * fatigue
 * weakness
 * tingling and numbness
 * dizziness
 * muscle stiffness/spasticity
 * balance trouble
 * pain
 * bowel/bladder problems
 * sexual dysfunction
 * depression
 * memory problems
 * shortened attention span
 * language problems ability to control emotions
 * difficulty swallowing

DIAGNOSIS:
Diagnosis of Multiple Sclerosis is initially made by the physician taking a history of symptoms and conducting a good neurological exam. Neurological exams test parts of the nervous system such as reflexes, muscle strength, muscle tone, coordination and balance, sensations of pain, heat, touch and vibration. Neurological tests also include asking questions to test thinking, judgment, and memory (McDonald). Abnormalities such as lesions/inflammation can be found by MRI scanning. Lumbar puncture or spinal tap and evoked potential tests are also used to diagnose MS.

TREATMENT:
There is no straight up cure for multiple sclerosis. However, there are many treatments that aid in relieving the symptoms and ailments of MS. Early treatment of MS does seem to delay disability. Treatment aims to help control the symptoms of MS as well as aim to slow the progression of the disability and help modify the number and intensity of attacks (MS Foundation).These products include:

Interferon treatments are normally aimed at patients with relapsing-remitting MS. Interferons are proteins produced naturally by the body. Within the body interferons act as defense against viruses as well as bacterial and parasitic infections (britannica). Interferons enhance T-cell activity. Interferon beta have a primary function of inducing resistance in cells. Although “It is not completely clear how interferon beta medicines work in people with MS” (webmd) this form of treatment works by preventing inflammation and demyelination in the CNS. Do not confuse interferon-beta with interferon-gamma. Interferon –gamma is a protein produced by the immune system that actually makes MS worse. Interferon medications are used to treat Relapsing-remitting MS and seem to decrease lesions picked up on MRIs.
 * INTERFERON TREATMENT:**

Amino acids structured similar to myelin. Aims to suppress immune system’s attack on myelin. Decreases frequency and severity of attacks but less effective on decreasing MRI lesions
 * AMINO ACID TREATMENT (copaxone)**

Blocks white blood cell receptors that allow them to cross BBB in order to keep white blood cells out and decrease inflammation. Decreases lesions seen on MRI, slows progression of disability, 70% reduction in relapses
 * ANTIBODY TREATMENT (****Tysabri)**

Nontoxic chemotherapy agent that suppresses Tcell and Bcell activity. This medication is conducted for a limited time period (Intravenous injection once every three months for two years)
 * CHEMOTHERAPY TREATMENT** (mitoxantrone)

(prednisone, prednisolone, methylprednisolone, betamethasone, dexamethasone) Shortens acute exacerbations and lessens inflammation in MS lesions
 * CORTICOSTERIOD TREATMENT**

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=CONCLUSION:=

Multiple Sclerosis is a demyelinating, autoimmune disease of the CNS. MS presents itself with many different symptoms and progresses in many different ways and at different speeds. Although there is still no cure for MS, progress is being made with treatments aimed at alleviating the symptoms of this disease.

= = =GLOSSARY:= Autoimmune: body attacks itself Myelin: fatty insulating sheath that covers axons Blood-Brain barrier: layer of cells that separates blood and CNS T-cells: immune cells that penetrate BBB and attack myelin sheath Lesions: scar tissue result of damage to myelin Relapse: attack/exacerbation Remission: recovery period Interferon: protein produced in body. Defense against invaders

=QUIZ=


 * True/False:**

1.) Most people with MS suffer from Progressive-relapsing MS 2.) Multiple Sclerosis is most commonly diagnosed in women 3.) People with MS should not exercise 4.) Multiple Sclerosis usually affects young adults between the ages of 20-30 years = =
 * Multiple Choice:**

5.) What type of disease is multiple sclerosis a.) Viral disease b.) Blood disease c.) Infectious disease d.) Autoimmune disease

6.) What is myelin: a.) Fatty coating around the nerves b.) Nerve insulator c.) lipids and lipoproteins d.) all the above

7.) Symptoms of Multiple Sclerosis may be caused by: a.) damage to axons b.) damage to myelin c.) both a and b d.) none of the above

8.) How does Multiple Sclerosis usually progress? a.) Attacks and remissions b.) Slow decline of function with no remission c.) No progression d.) All the above

9.) List and summarize the four clinical types of multiple sclerosis
 * Short answer:**

10.) Why are symptoms of multiple sclerosis different for each person

11.) Most treatment for multiple sclerosis includes injection of interferons. What are interferons and how do these injections alleviate exacerbations/progression of the disease?

=QUIZ ANSWERS:= 1:F 2:T 3:F 4:T

5: D 6:D 7:C 8:D

9. Relapsing-remitting MS (RRMS): attacks, recovery from attacks Secondary-progressing MS (SPMR) : more intensified RRMS with more attacks and less recovery Primary-progressive MS (PPMS): no attacks, just progression Progressive-relapsing MS (PRMS): progression and attacks from beginning. Progresses even without attacks

10. Symptoms depend where damage has occurred and where lesion is located. Severity of symptom depends on how much damage has been done to myelin and if fibers themselves have been damaged

11. Interferons are proteins produced naturally by the body. Within the body interferons act as defense against unwanted invaders. Interferons enhance T-cell activity. Interferon beta have a primary function of inducing resistance in cells.

=SUGGESTED READING := = = =Nutritional component of MS= Farinotti, M., McDowell N, and Simi S. "Result Filters." //National Center for Biotechnology Information//. U.S. National Library of Medicine, n.d. Web. 15 Dec. 2013. []
 * Diet and MS:**

Blaylock, Russell L., MD. "The Connection Between MS And Aspartame." //The Connection Between MS And Aspartame//. N.p., n.d. Web. 15 Dec. 2013. []
 * Connection between MS and Aspertame?**

Aziz H. Poonawalla, Ping Hou, Flavia A. Nelson, Jerry S. Wolinsky, Ponnada A. Narayana. (2008) Cervical Spinal Cord Lesions in Multiple Sclerosis: T1-weighted Inversion-Recovery MR Imaging with Phase-Sensitive Reconstruction. Radiology 246:1, 258-264 Online publication date: 1-Jan-2008. []

Burks JS, Johnson KP. Multiple Sclerosis: Diagnosis, Medical Managementand Rehabilitation. 1st ed. New York, NY: Demos Medical Publishing; 2000. : [|http://yester.ispub.com/journal/the-internet-journal-of-neurology/volume-10-number-2/pathogenesis-and-treatment-of-multiple-sclerosis-ms.html#e-65]

Gray E, Thomas TL, Betmouni S, Scolding N, Love S. Elevated Matrix Metalloproteinase-9 and Degradation of Perineuronal Nets in Cerebrocortical Multiple Sclerosis Plaques. Brain Pathol 2008;18(1):86-95. []

Olek, Michael J., DO. "Epidemiology and Clinical Features of Multiple Sclerosis in Adults." Epidemiology and Clinical Features of Multiple Sclerosis in Adults. N.p., n.d. Web. 15 Dec. 2013. []

Pithadia, A., S. Jain, and A. Navale. "Pathogenesis and Treatment of Multiple Sclerosis (MS)." - ISPUB. Department of Pharmacology, Parul Institute of Pharmacy Gujarat India, n.d. Web. 17 Dec. 2013. [|http://web.ebscohost.com/ehost/detail?sid=35e65dc4-aee3-4d96-b4b6-74f2b5ac5a17%40sessionmgr115&vid=1&hid=121&bdata=JkF1dGhUeXBlPWlwJnNpdGU9ZWhvc3QtbGl2ZSZzY29wZT1zaXRl#db=aph&AN=36114647]

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