Unlocking the Mysteries of Multiple Sclerosis

1. Unlocking the Mysteries of Multiple Sclerosis A.K. Jaffer, M.D., FAAN Hemet, California May 28th, 2011

2. Agenda Who gets MS What is MS How is MS diagnosed What to expect over time with MS Managing MS symptoms

3. Who Gets MS? 200 people per day are diagnosed 2.5 million worldwide Not infectious Not directly inherited 400,000 in the US ALONE! More people in the US are being diagnosed with MS than before, however it is not clear why this is the case (better diagnosis, better medical care, more people with the disease?)More people in the US are being diagnosed with MS than before, however it is not clear why this is the case (better diagnosis, better medical care, more people with the disease?)

4. Disease Risk Factors in MS Gender Significantly more common in women 2-3 times more MS cases in women Genetics Age Geography

5. Disease Risk Factors in MS Gender Genetics Not directly inherited General risk in population: 1/750 Risk if close relative has MS: 1/40 Risk if identical twin has MS: � Genes identified as important Age Geography MHC, IL2R, and IL7R have now been identified as important in MS, although this does not provide strong evidence that MS is solely an autoimmune disease.MHC, IL2R, and IL7R have now been identified as important in MS, although this does not provide strong evidence that MS is solely an autoimmune disease.

6. Disease Risk Factors in MS Gender Genetics Age Most diagnosed between age 20-50 People diagnosed when over age 50 are often found to have a �progressive� course of MS Geography Less MS in populations living near the equator Sunlight Vitamin D

7. Immunology Studies Tell Us What About MS? Autoimmune disease Abnormal immune response Response directed against myelin What triggers the response is unknown Studies have identified: Which immune cells are mounting the attack Some of the factors that cause them to attack Some of the reasons attacking cells are attracted to the myelin

8. Why �Multiple Sclerosis�? �Scar� in Latin is �sclerosis� 19th century physicians Autopsy studies of MS patients Brains and spinal cords of patients with MS contained many areas where the nervous tissue was hard to the touch and appeared scarred.

9. �Scar� vs. �Plaque� Anatomists Scar Macroscopic inspection of tissue Pathologists Plaques Macroscopic evaluation by MRI Microscopic observation Contain many cell types: Inflammatory cells, astroglial cells, increased water (edema), and destroyed myelin fragments

10. Where does MS occur? Within the Central Nervous System Often abbreviated �CNS� Includes: Brain Spinal Cord Optic Nerve

11. Brain Facts Average number of neurons in the brain = 100 billion Number of neurons in octopus brain = 300 million Number of neurons in honey bee brain = 950,000 Average number of neurons in the brain = 100 billion Number of neurons in octopus brain = 300 million (from How Animals See, S. Sinclair, 1985) Number of neurons in honey bee brain = 950,000 (from Menzel, R. and Giurfa, M., Cognitive architecture of a mini-brain: the honeybee, Trd. Cog. Sci., 5:62-71, 2001.) Number of neurons in Aplysia nervous system = 18,000-20,000 Number of neurons in each segmental ganglia in the leech = 350Volume of the brain of a locust = 6mm3 (from The Neurobiology of the Insect Brain, Burrows, M., 1996) Average number of neurons in the brain = 100 billion Number of neurons in octopus brain = 300 million (from How Animals See, S. Sinclair, 1985) Number of neurons in honey bee brain = 950,000 (from Menzel, R. and Giurfa, M., Cognitive architecture of a mini-brain: the honeybee, Trd. Cog. Sci., 5:62-71, 2001.) Number of neurons in Aplysia nervous system = 18,000-20,000 Number of neurons in each segmental ganglia in the leech = 350Volume of the brain of a locust = 6mm3 (from The Neurobiology of the Insect Brain, Burrows, M., 1996)

12. Nerve Structure 22 April 2008 image retrieved from: simple.wikipedia.org/wiki/Nerve Nerves control the body�s functions including the vital organs, sensation, and movement. The nervous system receives information and initiates an appropriate response. It is affected by internal and external factors (i.e. stimulus).Nerves follow tracts and cross over junctions called Synapses. Simplified, it is a complex communicative process between nerves conducted by chemical and/or electrical changes. 22 April 2008 image retrieved from: simple.wikipedia.org/wiki/Nerve Nerves control the body�s functions including the vital organs, sensation, and movement. The nervous system receives information and initiates an appropriate response. It is affected by internal and external factors (i.e. stimulus).

13. Myelin is Like Insulation 22 April 2008 image retrieved from: http://www.upmc.com/healthmanagement/managingyourhealth/healthreference/diseases/?chunkiid=22566, and http://www.made-in-china.com/showroom/senhall/product-detailAMCEbaYVVmht/China-Silicone-Rubber-Insulated-Wire-VDE-HO5S-K-.html 22 April 2008 image retrieved from: http://www.upmc.com/healthmanagement/managingyourhealth/healthreference/diseases/?chunkiid=22566, and http://www.made-in-china.com/showroom/senhall/product-detailAMCEbaYVVmht/China-Silicone-Rubber-Insulated-Wire-VDE-HO5S-K-.html

14. 22 April 2008 image retrieved from: services.epnet.com/getimage.aspx?imageiid=3036 and/or www.aultman.org/hgcontent.asp?chunkiid=11662 22 April 2008 image retrieved from: services.epnet.com/getimage.aspx?imageiid=3036 and/or www.aultman.org/hgcontent.asp?chunkiid=11662

15. Nerve Transmission Primary afferent neurons come in different diameters and can be divided into different groups based on their size. Here, in order of decreasing size, are the different nerve fiber groups: A-alpha, A-beta, A-delta, and C-nerve fibers. A-alpha, A-beta, and A-delta nerve fibers are insulated with myelin. C-nerve fibers are unmyelinated. The thickness of the nerve fiber is correlated to the speed with which information travels in it. 22 April 2008 From: faculty.washington.edu/chudler/cv.html Primary afferent neurons come in different diameters and can be divided into different groups based on their size. Here, in order of decreasing size, are the different nerve fiber groups: A-alpha, A-beta, A-delta, and C-nerve fibers. A-alpha, A-beta, and A-delta nerve fibers are insulated with myelin. C-nerve fibers are unmyelinated. The thickness of the nerve fiber is correlated to the speed with which information travels in it. 22 April 2008 From: faculty.washington.edu/chudler/cv.html

16. How is MS Diagnosed? No single test for diagnosis Diagnosis can be missed, delayed, or even incorrect Remains a clinical diagnosis MRI technology has improved diagnosis

17. Diagnostic Criteria for MS Medical history May provide enough information for physician to make diagnosis MRI New lesions versus old lesions Diagnosis cannot be made solely by MRI Visual Evoked Potential (VEP) Test response time to stimulation In many instances, the person�s medical history and neurologic exam provide enough evidence to meet the diagnostic criteria. Other tests are used to confirm the diagnosis or provide additional evidence if it�s necessary.�� MRI MRI is the best imaging technology for detecting the presence of MS plaques or scarring (also called lesions) in different parts of the CNS. It can also differentiate old lesions from those that are new or active. The diagnosis of MS cannot be made solely on the basis of MRI because there are other diseases that cause lesions in the CNS that look like those caused by MS. And even people without any disease�particularly the elderly�can have spots on the brain that are similar to those seen in MS. Although MRI is a very useful diagnostic tool, a normal MRI of the brain does not rule out the possibility of MS. About 5% of people who are confirmed to have MS do not initially�have brain lesions on MRI. However, the longer a person goes without brain or spinal cord lesions on MRI, the more important it becomes to look for other possible diagnoses. Visual evoked potential (VEP) Evoked potential (EP) tests are recordings of the nervous system's electrical response to the stimulation of specific sensory pathways (e.g., visual, auditory, general sensory). Because damage to myelin (demyelination) results in a slowing of response time, EPs can sometimes provide evidence of scarring along nerve pathways that does not show up during the neurologic exam. Visual evoked potentials are considered the most useful for confirming the MS diagnosis.In many instances, the person�s medical history and neurologic exam provide enough evidence to meet the diagnostic criteria. Other tests are used to confirm the diagnosis or provide additional evidence if it�s necessary.�� MRI MRI is the best imaging technology for detecting the presence of MS plaques or scarring (also called lesions) in different parts of the CNS. It can also differentiate old lesions from those that are new or active. The diagnosis of MS cannot be made solely on the basis of MRI because there are other diseases that cause lesions in the CNS that look like those caused by MS. And even people without any disease�particularly the elderly�can have spots on the brain that are similar to those seen in MS. Although MRI is a very useful diagnostic tool, a normal MRI of the brain does not rule out the possibility of MS. About 5% of people who are confirmed to have MS do not initially�have brain lesions on MRI. However, the longer a person goes without brain or spinal cord lesions on MRI, the more important it becomes to look for other possible diagnoses. Visual evoked potential (VEP) Evoked potential (EP) tests are recordings of the nervous system's electrical response to the stimulation of specific sensory pathways (e.g., visual, auditory, general sensory). Because damage to myelin (demyelination) results in a slowing of response time, EPs can sometimes provide evidence of scarring along nerve pathways that does not show up during the neurologic exam. Visual evoked potentials are considered the most useful for confirming the MS diagnosis.

18. Diagnostic Criteria for MS CSF Fluid Analysis Spinal tap Oligoclonal Banding (OGB) patterns Blood Tests Rule out other conditions OCT (coming soon) Evaluates retinal nerve for damage Quick and non-invasive Cerebrospinal fluid analysis Analysis of the cerebrospinal fluid, which is sampled by a spinal tap, detects the levels of certain immune system proteins and the presence of oligoclonal bands. These bands, which indicate an immune response within the CNS, are found in the spinal fluid of about 90-95% of people with MS. But because they are present in other diseases as well, oligoclonal bands cannot be relied on as positive proof of MS. Blood tests While there is no definitive blood test for MS, blood tests can rule out other conditions�including Lyme disease, a group of diseases known as collagen-vascular diseases, certain rare hereditary disorders, and AIDS�that cause symptoms similar to those of MS.Cerebrospinal fluid analysis Analysis of the cerebrospinal fluid, which is sampled by a spinal tap, detects the levels of certain immune system proteins and the presence of oligoclonal bands. These bands, which indicate an immune response within the CNS, are found in the spinal fluid of about 90-95% of people with MS. But because they are present in other diseases as well, oligoclonal bands cannot be relied on as positive proof of MS. Blood tests While there is no definitive blood test for MS, blood tests can rule out other conditions�including Lyme disease, a group of diseases known as collagen-vascular diseases, certain rare hereditary disorders, and AIDS�that cause symptoms similar to those of MS.

19. Forms of Multiple Sclerosis Relapsing-Remitting MSPeople with this type of MS experience clearly defined attacks of worsening neurologic function. These attacks�which are called relapses, flare-ups, or exacerbations �are followed by partial or complete recovery periods (remissions), during which no disease progression occurs. Approximately 85% of people are initially diagnosed with relapsing-remitting MS. Primary-Progressive MS This disease course is characterized by slowly worsening neurologic function from the beginning�with no distinct relapses or remissions. The rate of progression may vary over time, with occasional plateaus and temporary minor improvements. Approximately 10% of people are diagnosed with primary-progressive MS. Secondary-Progressive MS Following an initial period of relapsing-remitting MS, many people develop a secondary-progressive disease course in which the disease worsens more steadily, with or without occasional flare-ups, minor recoveries (remissions), or plateaus. Before the disease-modifying medications became available, approximately 50% of people with relapsing-remitting MS developed this form of the disease within 10 years. Long-term data are not yet available to determine if treatment significantly delays this transition. Progressive-Relapsing MS In this relatively rare course of MS (5%), people experience steadily worsening disease from the beginning, but with clear attacks of worsening neurologic function along the way. They may or may not experience some recovery following these relapses, but the disease continues to progress without remissions. Relapsing-Remitting MSPeople with this type of MS experience clearly defined attacks of worsening neurologic function. These attacks�which are called relapses, flare-ups, or exacerbations �are followed by partial or complete recovery periods (remissions), during which no disease progression occurs. Approximately 85% of people are initially diagnosed with relapsing-remitting MS. Primary-Progressive MS This disease course is characterized by slowly worsening neurologic function from the beginning�with no distinct relapses or remissions. The rate of progression may vary over time, with occasional plateaus and temporary minor improvements. Approximately 10% of people are diagnosed with primary-progressive MS. Secondary-Progressive MS Following an initial period of relapsing-remitting MS, many people develop a secondary-progressive disease course in which the disease worsens more steadily, with or without occasional flare-ups, minor recoveries (remissions), or plateaus. Before the disease-modifying medications became available, approximately 50% of people with relapsing-remitting MS developed this form of the disease within 10 years. Long-term data are not yet available to determine if treatment significantly delays this transition. Progressive-Relapsing MS In this relatively rare course of MS (5%), people experience steadily worsening disease from the beginning, but with clear attacks of worsening neurologic function along the way. They may or may not experience some recovery following these relapses, but the disease continues to progress without remissions.

20. What Are Symptoms of MS? Fatigue Walking & Balance Issues Bowel Dysfunction Dizziness and Vertigo Pain Emotional Changes Numbness Bladder Dysfunction Vision Problems Sexual Dysfunction Cognitive Problems Depression Spasticity

21. MS Symptoms are Variable and Unpredictable. . . Your Symptoms Will Not Be The Same As Another PatientSymptoms Will FluctuateSome Patients Will Only Experience A Few Symptoms, While Others Have Many No two people have exactly the same symptoms, and each person�s symptoms can change or fluctuate over time. One person might experience only one or two of the possible symptoms while another person experiences many more. Most of these symptoms can be managed very effectively with medication, rehabilitation, and other management strategies.No two people have exactly the same symptoms, and each person�s symptoms can change or fluctuate over time. One person might experience only one or two of the possible symptoms while another person experiences many more. Most of these symptoms can be managed very effectively with medication, rehabilitation, and other management strategies.

22. How is MS Treated? FDA Approved Disease-Modifying Agents Avonex� (IFN�-1a) Betaseron� (IFN� -1b) Copaxone� (glatiramer acetate) Novantrone� (mitoxantrone) Rebif� (IFN� -1b) Tysabri� (natalizumab) Gelynia � (Fingolamide) - Oral

23. Long-term MS Trials GA Trial1 10 year data (trial to be continued for 15 years) Prospective Only ongoing controlled design Patient visits every 6 months over 10 years IFN�-1a SC Trial3 7-8 year data Post-hoc analysis (retrospective) Controlled trial stopped at 4 years Single patient visit IFN�-1b SC Trial2 16 year data Post-hoc analysis (retrospective) Controlled trial stopped at 5 years Single patient visit IFN�-1a IM Trial4 Controlled trial stopped at 2 years No organized long-term efficacy follow-up conducted

24. Summary of Long-term DataPatients Reaching EDSS 6 While on GA, 89% (24/221) of the mITT cohort were still walking without assistance (had not progressed to EDSS =6) after a mean of 10 years on therapy and a mean of 18 years� disease duration (Table 4 p 316 of Ford et al) vs only 50% of patients at 15 years in the Weinshenker natural history cohort (n=1099) Interferon data are not as rigorous and less patients were walking unassisted at long-term follow-up PRISMS-8 percentage is calculated from patients returning for long-term follow-up (n=382; 110/382 = 29%) Tysabri only has 2-year data and therefore it�s long-term effects cannot be evaluated at this timeWhile on GA, 89% (24/221) of the mITT cohort were still walking without assistance (had not progressed to EDSS =6) after a mean of 10 years on therapy and a mean of 18 years� disease duration (Table 4 p 316 of Ford et al) vs only 50% of patients at 15 years in the Weinshenker natural history cohort (n=1099) Interferon data are not as rigorous and less patients were walking unassisted at long-term follow-up PRISMS-8 percentage is calculated from patients returning for long-term follow-up (n=382; 110/382 = 29%) Tysabri only has 2-year data and therefore it�s long-term effects cannot be evaluated at this time

25. Considerations for MS Treatment Inflammation Demyelination Neurodegeneration Axonal Loss

26. Safety and TolerabilityMost common adverse events*

27. Treating MS Exacerbations Change in symptoms lasting at least 24 hours and be separated from previous exacerbations Last days to several weeks or even months Commonly treated with corticosteroids to reduce inflammation An exacerbation of MS is caused by inflammation in the central nervous system (CNS) that causes damage to the myelin and slows or�blocks the transmission of nerve impulses. To be a true exacerbation, the attack must last at least 24 hours and be separated from a previous exacerbation by at least 30 days. However, most exacerbations last from a few days to several weeks or even months. Exacerbations can be mild or severe enough to interfere with a person�s ability to function at home and at work. Severe�exacerbations are most commonly treated with high-dose�corticosteroids�to reduce the inflammation. An exacerbation of MS is caused by inflammation in the central nervous system (CNS) that causes damage to the myelin and slows or�blocks the transmission of nerve impulses. To be a true exacerbation, the attack must last at least 24 hours and be separated from a previous exacerbation by at least 30 days. However, most exacerbations last from a few days to several weeks or even months. Exacerbations can be mild or severe enough to interfere with a person�s ability to function at home and at work. Severe�exacerbations are most commonly treated with high-dose�corticosteroids�to reduce the inflammation.

28. Steroid Treatment in MS Methylprednisolone (IV) Prednisone (Oral) Prednisolone (IV) Dexamethasone (Oral) Adreno-corticotrophic hormone (ACTH)

29. Managing MS Symptoms Medication Self-care techniques Rehabilitation Physical or occupational therapy Speech/language pathologist Cognitive remediation specialist Assistive devices

30. Image taken from: http://www.sciencedaily.com/gallery/mind_brain/ on 22 April 2008.Image taken from: http://www.sciencedaily.com/gallery/mind_brain/ on 22 April 2008.