Taylor Slotte Pathology Disease Report Spring 2014 Multiple Sclerosis

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1 Taylor Slotte Pathology Disease Report Spring 2014 Multiple Sclerosis Abstract Multiple sclerosis (MS) is a chronic autoimmune disorder that attacks the body s central nervous system. It affects the brain, spinal cord, as well as the optic nerves. According to the Multiple Sclerosis Association of America, 2.5 million people worldwide are diagnosed with MS, and among those, 400,000 individuals have been diagnosed in the United States alone. This neurological condition is a result of the demyelination of the fatty myelin sheath which surrounds the nerve fibers of the CNS. This demyelination leads to a buildup of scar tissue called sclerosis, which gives the disease its name. When any part of the myelin sheath is destroyed, nerve impulses traveling to and from the brain and spinal cord are disrupted. This disruption can produce an array of symptoms that are highly unpredictable. There are four different types of MS, each with variable symptoms. Symptoms of the disease include tingling in the limbs, tremors, trouble speaking, dizziness, fatigue, bladder and bowel dysfunction, vertigo, sexual dysfunction, depression, and even cognitive impairment. Some less common symptoms can include swallowing dysfunction, headache, hearing loss, as well as respiratory problems. Symptoms of MS can often cause patients to have a limited dexterity. This can often make it hard for them to hold a toothbrush, floss, and go about their daily oral hygiene routines. Dental professionals need to modify their oral health education to best fit their patients with MS. There are several strategies for the diagnosis of MS, all requiring clinical tests and evidence based research. In order for an official diagnosis, a person must also have evidence of damage in two separate areas of the central nervous system at least one month apart. There is currently no cure for MS, but there are a variety of treatments available. Ten medications have been approved by the Food and Drug Administration to help with the symptoms of MS. These disease-modifying drugs have been shown to slow the progression of MS is certain people. They work by altering the immune system which in turn will reduce the frequency and severity of their MS attacks. It is critical for patients who are newly diagnosed with MS to start treatment as soon as possible. MS and its associated symptoms and treatments can have a major impact on a patient s oral health. The medications can cause significant oral health changes in patients with MS, such as xerostomia (dry mouth), gingival hyperplasia, mucositis, candidiasis, and angular cheilitis. Preventative care is the key to maintaining oral health, which will in turn affect the overall health of the individual. {1}

2 Introduction Multiple sclerosis (MS) is a chronic autoimmune disorder that attacks the body s central nervous system. It affects the brain, spinal cord, as well as the optic nerves. This neurological condition is a result of the demyelination of the fatty myelin sheath which surrounds the nerve fibers of the CNS. This demyelination leads to a buildup of scar tissue called sclerosis, which gives the disease its name. This damage caused to the myelin sheath hinders the nerve impulses that are traveling to and from the brain and spinal cord 1. This disruption can produce an array of symptoms that are highly unpredictable. MS primarily occurs in women, and is most often found in people ranging from the ages of 15 years old, to 50 years old. It is the leading cause of disability in young adults, and one of the most common immune-mediated inflammatory diseases of the CNS. Both the environment and genetics are contributions to the development of MS, but the main cause is still unknown 2. Etiology and Pathology Multiple sclerosis is believed to be an autoimmune disorder that showed clinical symptoms as far back as 150 years ago. This neurological disorder can be influenced by genetics, environment, and even climate. While the exact pathogenesis is unknown, it is believed that the body s immune system attacks its own tissues and cells. In the case of multiple sclerosis, the immune system attacks and penetrates the blood brain barrier, enters the central nervous system, and recognizes certain surface proteins such as the myelin based protein (MBP) and the proteolipid protein(plp) on the outer surfaces of cells. Once the immune system recognizes these proteins and sees them as foreign, it signals an attack to demyelinate the fatty myelin sheath. Figure I shows the sheath which surrounds the nerve fibers, also called axons, of the CNS. Without the myelin sheath Figure 1: Damaged Nerve Fiber surrounding the axons, it has limited protection against the body s defense system. As the immune system strips off the myelin sheath, the body tries to repair itself. Myelin forming cells called oligodendrocytes will go in and try to create more myelin, but will instead cause a buildup of excess scar tissue also known as gliotic plaque or sclerosis. This plaque will build up and thicken, resulting in reduced neural conduction of action potentials along the axon of the neuron. Once the conduction of action potentials decreases significantly, neuromuscular and neurocognitive impairment can occur. The inflammatory attack not only demyelinates the axons, but it attacks the oligodendrocytes, as well as the axons themselves after demyelination. Research is ongoing to determine the link between MS and the abnormal immune response 2. There are a few theories on why the body s immune system attacks the myelin sheaths on the neurons, but further research has to be done. One theory is that MS is triggered in susceptible individuals by a viral or bacterial infection that contains an antigen which mimics the MS selfantigen on the myelin sheath of the neuron. A white blood cell called a macrophage then engulfs the pathogen and displays the self-mimicking antigen fragment derived from the pathogen on its surface. When a circulating T-cell recognizes this, it will bind to it and begin primary activation {2}

3 and replication. These new T-cells that are made will travel around the body and attack any cells that have the self-mimicking antigen. Within the CNS, cytokines will be released by the T-cells which in turn will thin the blood-brain barrier allowing T-cells, B-cells, and macrophages in. Macrophages will complete the process of axon demyelination and in doing so will release a substance called necrosis factor alpha which is believed to kill the myelin producing cells called oligodendrocytes. With no myelin producing cells present, the damage is irreversible. There are four main types of MS depending on the course it takes. These four types include relapsing-remitting (RRMS), primary-progressive (PPMS), secondary-progressive (SPMS), and progressive-relapsing (PRMS) 3, as shown in figure The first type is called relapsing-remitting MS (RRMS), and 80-85% of people with MS are initially diagnosed with this type. Most people with this type of MS experience symptoms flare-ups. These flare-ups are also known as exacerbations, relapses, and or attacks. One can experience new symptoms, or have an increase in their existing symptoms. Symptoms can last for a short period of time like a week to a month, and then remit anywhere from a month to many years. In this period of remission, the disease does not progress any further. 2. The second type is called primary-progressive MS (PPMS), and this affects approximately 10% of the total people initially diagnosed. Primary-progressive is characterized by a slow and steady worsening in their symptoms neurologically. There are no relapses nor periods of remission, and only minor improvements can be seen with this type of MS. 3. The third type is called secondary-progressive MS (SPMS), and this course follows relapsing-remitting MS. It is a continuation of this type, and is the more advanced or further progressed type. It worsens over time, and has little amounts of flare-ups, remissions, or exacerbations of the symptoms. There are now treatments available to try and halt the disease progressing to this stage, but prior to treatments being available, 50% of people with RRMS progressed to this disease course within 10 years. 4. The fourth type is called progressive-relapsing MS (PRMS), and it affects the least amount of people with MS at approximately 5%. It initially begins with steady attacks on neurological function, and continues to progress at a slow rate with little to no relapses. This course of disease has no remissions, therefore it continues to worsen gradually throughout their life 3. Figure 2- Types of MS {3}

4 There are two less common types of MS called benign, and fulminate. Benign MS occurs in about 10% of people with MS. This is a less severe type with rare attacks, and most are only slightly disabled after being diagnosed for over 15 years. There is a chance for further progression of the disease later on, so it is greatly advised that people with this disease course start drug therapy as soon as possible. Fulminate MS is characterized by a rapid progression of the disease, with extreme relapses within 5 years of being diagnosed. There is a significant decrease in neurological function, and in most cases death occurs shortly after disease onset 3. Epidemiology According to the Multiple Sclerosis Association of America, 2.5 million people worldwide are diagnosed with MS. Among those, 400,000 individuals have been diagnosed in the United States. Annually, it is estimated that 10,000 new cases of MS will be diagnosed. The peak age of onset is between the ages of 15 and 50, although individuals of any age may be diagnosed. Women are three times more likely than men to develop relapsing forms MS, while the genders are more equally divided with the primary-progressive form. The average risk of developing MS is 1:1,000, and can increase if a family member has the disease already. Even though MS is not contagious or hereditary, susceptibility is increased if a family member already has the disease. Geographically, it is believed that people who live in more temperate climates, and who live far from the equator have a higher risk of developing MS. Individuals who live in very hot areas, or very cold areas are less likely to develop MS. This is especially true for people living in North America, Europe, and Southern Australia, because they live beyond the 40-degree mark north or south of the equator. Asia has a very low incidence of MS, while northern Europeans and Caucasians have a higher incidence than those of African heritage. MS risk is said to be determined by different interactions among race, ethnicity, sex, genotype, and environmental factors. More studies need to be done to confirm the risk of MS among different ethnic populations. It can also depend on healthcare availability, as well as income levels. Other risk factors linked to MS include cigarette smoking, vitamin D deficiency, and parasites. Women who smoke cigarettes are 1.6 times more likely to develop MS than women who are non-smokers. Smokers diagnosed with MS also have a more rapid progression of their disease than non-smokers with MS do. Vitamin D appears to reduce the risk of developing MS, although the reason is unknown. Parasitic infections can diminish the responses of the immune system, making people with these infections less likely to develop MS. As conditions in third world countries become healthier, there are less parasites and the number of individuals being diagnosed with MS has increased 4. Clinical Presentation There are many different signs and symptoms that are associated with MS. These signs and symptoms depend on many factors such as the location of the affected nerve fibers, the size of the sclerotic lesions, and the amount of plaque accumulation. Lesions located on or around the eye can affect vision. One could have partial or complete loss of vision in one eye, as well as pain, and blurring. If the lesions are on or around the brain and spinal cord, problems could arise with balance, movement, and coordination. Some other symptoms include numbness or weakness in the limbs, tingling, tremors, trouble speaking, dizziness, and the most common, {4}

5 fatigue. Some individuals can experience bladder and bowel dysfunction, vertigo, sexual dysfunction, depression, and also cognitive impairment. Some less common symptoms can include swallowing dysfunction, headache, hearing loss, as well as respiratory problems. In severe cases, an electric shock can radiate down the spine in a rare occurrence called Lhermitte s phenomenon. This phenomenon can be caused by flexion of the neck 3. A common temperature sensitivity can occur in people with MS. As the body temperature increases, the symptoms of MS can worsen. Some individuals can experience periods of relapse, and or remission of their symptoms, and some people won t have any symptoms for up to 20 years after the initial diagnosis. Since some people with MS can have little to no symptoms, it may be hard for a dental professional to realize their patient may have MS, unless they were told so. There are certain clinical manifestations that affect the oro-facial region which may be evident. Three clinical manifestations commonly seen in patients with MS include, trigeminal neuralgia, sensory neuropathy of the trigeminal nerve (paresthesia), and facial palsy Trigeminal neuralgia is a nerve disorder characterized by pain such as an electric shock. This pain can be triggered by toothbrushing, mastication, or even the touching of the cheek. The pain is short-lived, however it often happens multiple times per day. It may be hard for dental professional to distinguish this pain from other types of facial pain that is dental related. 2. Sensory neuropathy of the trigeminal nerve (paresthesia) is characterized by numbness of the chin and lower lip, and is not always associated with pain. The differential diagnosis of this condition is that the paresthesia is provoked by local trauma, neoplasms of the central nervous system, or cerebrovascular conditions. 3. Facial paralysis often happens in the latter stages of MS. Facial paralysis caused by MS is often confused with facial paralysis due to Bell s Palsy, despite that diagnostic tools available to distinguish the two. On average, 25% of individuals with MS experience facial paralysis. When the primary symptoms mentioned above are not treated, secondary and tertiary symptoms can result; this is called a cascade effect. When an individual with MS presents with symptoms of a loss of coordination, he/she may fall and break his/her arm resulting in a psychological feeling of grief. The broken arm would be the secondary symptom, and the grief caused by the broken arm would be tertiary. Each individual with MS has different signs and symptoms, and these commonly change on a day to day basis. Since there is no cure for MS, treatment is focused on the signs and symptoms of each individual 5. Diagnosis Since every patient s symptoms can be different, diagnosing a patient with MS can be extremely challenging. In order to diagnose someone with MS, all other causes of neurological symptoms must be excluded. Symptoms alone cannot be definitive evidence that a person has MS. There is a specific criteria for diagnosing MS in people. First, the physician must find evidence of damage in at least two separate areas of the central nervous system. This means that there must be two areas of damage in either the brain, spinal cord, and/or optic nerves. Another criteria is that damage must have occurred at least twice in those two different areas. And finally, {5}

6 all other possible diagnoses must be ruled out as mentioned above. The physician must also take note of the patient s medical history. He/she needs to know if there is a family history of MS, any specific environmental exposures, places traveled, birthplace, as well as a history of prior illnesses. Some cognitive and behavioral tests will also be given in order to evaluate strength, coordination, balance, reflexes, vision, sense of taste and smell, as well as any language impediments 3. There are a few additional tests that are used in modern medicine today to also help in the diagnoses of MS. These tests include, optical coherence tomography (OCT), magnetic resonance imaging (MRI), cerebrospinal fluid analysis (CSF), and visual evoked potentials (EP). 1. Optical coherence tomography (OCT) is a relatively new test that is painless and noninvasive. This test helps researchers view retinal structures at the back of the eye. The retinal nerve does not have a myelin sheath, therefor OCT provides critical information about the health of the nerve after an episode of optic neuritis. Optic neuritis is a condition where the optic nerve is targeted during MS disease activity. One thing that researchers have noticed is that the retinal nerve is different in people with MS, making it a good diagnostic tool for people suspected of having MS. 2. Magnetic resonance imaging (MRI) is another non-invasive way of imaging water content in tissues such as the brain, and spinal cord. It is the preferred method of testing for diagnosing MS. An MRI helps identify MS in many ways. First, the myelin sheath covering nerve cell fibers is very fatty, and fatty materials repel water. When the fatty myelin sheath has been stripped away, the area will hold more water; hence being visible by an MRI. 3. Cerebrospinal fluid analysis (CSF) is a test to determine the components of a person s cerebrospinal fluid. This fluid is retrieved using a long needle inserted into a person s spine when laying on their side. The CSF of a patient with MS will contain specific proteins called oligoclonal bands, certain proteins that breakdown myelin, and will also have elevated levels of IgG antibodies. While this test is very useful, it is very painful and is only present in 90% of patients with MS. This test alone is not enough to make an official diagnosis, it must be used in conjunction with other tests. 4. Visual evoked potentials (EP) is a test that measures electrical activity in the brain. Once demyelination occurs and a slowing of electrical conduction is present, this test can detect it. Evoked potential testing requires that wires are placed on a person s scalp, and is extremely harmless and painless. There are three types of EP testing, yet only this type is used. It requires a patient sit before a screen while alternating checkerboard patterns are displayed 3. Treatment The goal for the treatment of MS is to ease symptoms and improve one s quality of life. There is currently no cure for MS, so the treatment mainly consists of medications that help ease the attacks, and possibly slow the disease. Disease-modifying drugs have been shown to slow the progression of MS is certain people. They work by altering the immune system which in turn will reduce the frequency and severity of MS attacks. It is critical for patients who are newly diagnosed with MS to start treatment as soon as possible. Studies show that the most damage occurs within one year of diagnosis. Before choosing a specific medication, there are many {6}

7 factors that should be considered. These factors include lifestyles, priorities, possible side effects, benefits, methods of medication delivery, cost, and any personal concerns. Some disease-modifying drugs include Aubagio, Avonex, Betaseron, Copaxone, Gilenya, Novantrone, Rebif, Tecfidera, and Tysabri Aubagio is an oral compound that inhibits specific functions of some immune cells. It does this by inhibiting an enzyme required by lymphocytes for immune function. It is mainly used for people with relapsing forms of MS. One warning for this drug is liver toxicity from the long-term use of this drug. Possible side effects of this drug include alopecia, nausea and diarrhea, and influenza. 2. Avonex is a medication administered by an injection. It is an interferon beta-1a drug that mimics the interferon beta found in Figure 3- Disease-modifying drugs proteins in the body. It has been proven to reduce MS attacks, slow for treatment of MS disease progression, and reduce the number and size of lesions in the brain. This medication is also for the treatment of people with relapsing forms of MS. 3. Betaseron is an interferon beta-1b drug given intravenously. It is produced by a biotechnological process from a naturally occurring protein interferon. This medication has been shown to decrease the effects of MS exacerbations as well as lengthen the time between exacerbations. This drug is also made for patients with the relapsing forms of MS. 4. Copaxone aka glatiramer acetate is a synthetic protein that stimulates the production of the basic protein found in myelin. This protein helps insulate the nerve fibers in the brain and spinal cord by blocking myelin-harming T-cells. This drug reduces the amount of relapses, as well as blocks the majority of new forming lesions. This drug is also injected subcutaneously. 5. Gilenya is an oral medication taken in capsule form. This is a relatively new medication that is called a sphingosine 1-phosphate receptor modulator. The mechanism of action of this drug is the retention of certain lymphocytes in the lymph nodes, therefore preventing them from causing damage in the central nervous system. 6. Novantrone is an injectable medication in a subtype called an antineoplastic. Prior to being used for MS, is was used to treat certain forms of cancer. It reduces the effects of B and T cells, as well as macrophages. It has been shown to delay disease progression, and reduce the number of relapses and new lesions. 7. Rebif is an interferon beta-1b drug given intravenously. It is produced by a biotechnological process from a naturally occurring protein interferon and has been shown to prolong the time to the first relapse, lower the number of active lesions, and delay the progression of the disease. 8. Tecfidera is an oral medication in capsule form. It is a dimethyl fumarate formulation that was created by people with MS. It has been used prior to treat flare-ups of psoriasis, and the mechanism of action is currently unknown. A common side effect of tecfidera is flushing, which can create a sensation of heat or itching. 9. Tysabri is a laboratory-produced monoclonal antibody given by IV infusion. This medication slows the movement of immune cells from the blood to the CNS. It has been proven to slow disease progression, and reduce number of exacerbations. {7}

8 Since most of these drugs are experimental maintenance drugs and have recently been approved for use, though not much information is available regarding long term safety or side effects. Non-medicinal treatments regarding MS include cognitive specialists, rehabilitation centers, speech pathologists, as well as the use of assisted devices like canes, walkers, and in some cases wheelchairs. Other alternative therapies include, diet, exercise, acupuncture, massage therapy, yoga, aromatherapy, marijuana, and in some cases herbal remedies. It is best for individuals to keep an open mind and try a variety of treatments in order to see what works best for them 6. Implications for Dental Hygiene Care For people with MS, normal oral hygiene routines such as brushing and flossing can be extremely difficult. The wide array of symptoms can make it very hard for someone with MS to maintain their oral health, and seek out dental hygiene treatments when needed. It is important that dental professionals recognize and support the needs of their patients with MS. Often, the nerve damage done in their bodies can cause paralysis, trouble with speech, swallowing, hearing, focusing, and memory. They could have numbness of their extremities, depression, anxiety, spasms, and even facial pain. Trigeminal neuralgia is an early symptom of MS, which is a stabbing pain in the facial region. It is important to distinguish the difference between normal dental pain and trigeminal neuralgia. When patients with no history of MS state they have a shooting or stabbing pain in their face, it is critical to refer the patient to their MD for a neurologic assessment 7. It is important to create a relaxing and stress free environment, as stress and anxiety can exacerbate the normal symptoms of MS. It is best to schedule shorter appointments, and early in the day. This is best for patients with MS because they are not as fatigued early in the morning. It is also best to only schedule them an appointment when they are in remission, and not experiencing flare-ups. Symptoms of MS can often cause the patient to have a limited dexterity. This can make it hard for them to hold a toothbrush, floss, and go about their oral hygiene routines. Dental hygienists need to modify their oral health education to best fit their patients with MS. Recommending such things as electric toothbrushes and floss holders can make their job a lot easier, and give them the motivation they need to go about their oral hygiene routines more regularly 8. Medications taken by people with MS may also have a significant effect on their oral health. Certain medications may cause xerostomia (dry mouth), which can increase their risk for developing caries. It may be necessary to recommend xylitol containing products, or saliva replacements such as Biotene to regulate and increase their saliva flow. Medications can also cause gingival hyperplasia, mucositis, candidiasis, and angular cheilitis. They may also counteract with certain medications given during the dental appointment. These include medications like anesthesia, or nonsteroidal anti-inflammatory drugs 5. It is also believed that certain cases of periodontal disease may be linked to the pathogenesis of certain central nervous system disorders like MS. Infections caused by periodontal disease may worsen the immune response in the body, making conditions like MS worse. Maintaining good oral health is critical for patients with MS 9. If their oral health becomes compromised, their overall general health can be greatly impacted. {8}

9 Conclusion Multiple sclerosis is an unpredictable and degenerative disorder of the central nervous system. It has an array of symptoms that can be very challenging for any person to manage. There are various treatments for MS, although there is no known cure. The goals of treatment are to improve the quality of life by managing symptoms and removing triggers that may exacerbate them. Each individual with MS is different, and needs of each can vary. Healthcare professionals need to be aware and knowledgeable about all the effects of MS, in order to provide the best care possible to their patients. There are various support groups in efforts to raise awareness and support for all individuals. Oral health needs to be a major priority in all patients with disabilities, as it could greatly affect the overall general health of their bodies. {9}

10 References 1. About MS [Internet]. National Multiple Sclerosis Society [cited 2014 May 10]. Available from: 2. Burkart, N. DeLong L. General and oral pathology for the dental hygienist. Third edition. Baltimore: Lippincott Williams & Wilkins; p Diagnosis of MS. [Internet] Teva Canada Innovation. 2001[cited 2014 Apr 6]. Available from: 4. Krementsov D, Teuscher C. Environmental factors acting during development to influence MS risk: insights from animal studies. MS J [Internet]. November 2013 [cited 2014 May 2]; 19(13): Available from: Academic Search Premier 5. Diseases and Conditions of Multiple Sclerosis [Internet] [cited 2014 April 10]. Available from: 6. Negahban H, Rezaie S, Goharpey S. Massage therapy and exercise therapy in patients with multiple sclerosis: a randomized controlled pilot study. [Internet]. December 2013 [cited 2014 Apr 1]; 27(12): Available from: Academic Search Premier 7. Campbell P, Reich M. The oral implications of MS [Internet]. Santa Ana (CA); Belmont publication; 2010 Jan [cited 2014 Apr 6]. Available from: 8. Elemek E, Almas K. Multiple Sclerosis and Oral Health. NY State Dent J [Internet]. April 2013[cited 2014 Apr 1]; 79(3): Available from: Dentistry & Oral Sciences Source. 9. Baird, Wendy. When did you last see you re your dentist? - The oral health of people with MS [Internet]. Letchworth (Eng): Department of Epidemiology and Public Health, University of Leicester; 2004 [cited 2014 Apr 7]. Available from: Images obtained from: {10}

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