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Introduction

Introduction. Myelin Sheath (With Axon Through It). Nucleus. Schwann Cell. Soma. Node of Ranvier. Axon Terminal. Dendrite. What Is Multiple Sclerosis?. Chronic progressive autoimmune disease Immune system attacks the myelin sheath on nerve fibers in the brain and spinal cord (CNS)

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Introduction

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  1. Introduction

  2. Myelin Sheath (With Axon Through It) Nucleus Schwann Cell Soma Node of Ranvier Axon Terminal Dendrite What Is Multiple Sclerosis? • Chronic progressive autoimmune disease • Immune system attacks the myelin sheath on nerve fibers in the brain and spinal cord (CNS) • May lead to focal areas of damage, axon injury, axon transection, neurodegeneration, and subsequent scar or plaque formation Graphic by Quasar Jarosz at en.Wikipedia.org

  3. What the Primary Care Clinician Needs to Know About MS Common presenting symptoms of demyelinating disease For example, what is CIS, optic neuritis, brain stem syndrome, etc How the diagnosis of MS is made Early symptoms that trigger need to refer patient to neurologist How to classify MS How to manage treatment of MS/monitor MS patients (and what to monitor for) How to manage treatment side effects

  4. PIK NW Regional Survey (N = 50)Barriers to Diagnosis and Treatment • Lack of clinician knowledge about MS, its diagnosis, and treatments • Infrequency of MS in primary care populations • Lack of time, especially since patients have other complaints to address • Absence of screening tools • Financial/insurance-related obstacles • Side effects of treatment • Patients’ psychosocial status and lack of support • Poor adherence to treatment

  5. To address the needs identified in the local survey, this activity provides education regarding the following MS topics: Risk factors Pathogenesis Diagnostic criteria Role of imaging Efficacy, safety, and initiation of current therapies Efficacy and safety of emerging therapies Monitoring for response, adherence, and tolerability of therapy Management of MS symptoms Addressing Local Needs

  6. What Factors Contribute to the Risk for MS?

  7. MS Epidemiology Compston A, et al. McAlpine’s Multiple Sclerosis, 4th ed. Churchill Livingston; 2006. HauserSL, et al. Multiple Sclerosis. In: Fauci AS, et al. Harrison’s Principles of Internal Medicine. Available at: http://www.accessmedicine.com/content.aspx?aID=2906448. Accessed on: February 19, 2010.

  8. Multiple SclerosisAn Immunogenetic Disease Environmental Factors Genetic Predisposition Immune Dysregulation MS Graphic courtesy of Suhayl Dhib-Jalbut, MD.

  9. Evidence for Genetic Basis of MS 50 45 40 35 Approximate Probability of Developing MS 30 25% 25 20 15 2% 5% 10 3% 5 1% 0.1% 0.1% 0 Identical Fraternal Parent or First Spouse No Sibling Twin Twin Half- Cousin Family Sibling Member Hauser SL, et al. Multiple Sclerosis. In: Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. Available at: http://www.accessmedicine.com/content.aspx?aID=2906445. Accessed on: February 19, 2010. Willer CJ, et al. Proc Natl Acad Sci U S A. 2003;100:12877-12882.

  10. Evidence for Environmental Basis of MS • No evidence of MS prior to 1822 (~ onset of industrial revolution in Europe) • Change in the gender ratio over time • These changes (eg, gender ratio, increasing incidence) took place over ~ 30 years (1–2 generations)—too fast for a genetics cause • Increased incidence of MS in many regions (especially in women) • When individuals migrate before age 15 from a region of high MS prevalence to one of low prevalence (or vice versa), they seem to adopt a prevalence similar to that of the region to which they moved • When they make the same move after age 15, they seem to retain the risk of the region from which they moved

  11. Multiple Sclerosis What Are the Environmental Factors? • Many environmental factors have been proposed • Two currently popular candidates for involvement in MS pathogenesis are: • Epstein-Barr virus (EBV) infection • Vitamin D deficiency (sunlight exposure) • Cigarette smoking • These are hypotheses—not proven facts! • Either, neither, or both may be correct

  12. Evidence for EBV • Indirect evidence • Late EBV infection is associated with MS • Symptomatic mononucleosis is associated with MS • Direct evidence • 10 out of 12 studies found a significantly higher rate of EBV positivity in MS patients than in controls1-12 • When data from these 12 trials are combined (N = 4155), EBV positivity is found in 99.5% of MS patients vs 94.2% of controls (P <10-23) 1. Sumaya, 1980. 2. Bray, 1983. 3. Larson, 1984. 4. Sumaya, 1985. 5. Shirodaria, 1987. 6. Munch, 1998. 7. Myhr, 1998. 8. Wagner, 2000. 9. Ascherio, 2001. 10. Sundström, 2004. 11. Haahr, 2004. 12. Ponsonby, 2005.

  13. Direct Evidence for Vitamin D • >185,000 women interviewed about their diet: Those in highest quintile of vitamin D consumption had significantly less new-onset MS compared with lowest quintile1 • Study of MS patients and controls from Tasmania found significant negative association between total sun exposure during childhood (especially in those 6–10 years old) and adolescence and the subsequent development of MS2,3 • Evaluation of stored serum samples from 257 MS patients and 514 matched controls (US Military) showed the risk of MS was significantly decreased in those with increased serum vitamin D3 levels4 1. Munger KL, et al. Neurology. 2004;62:60-65. 2. Van der Mei IA, et al. J Neurol. 2007;254:581-590. 3. Van der Mei IA, et al. BJM. 2003;327:316. 4. Munger KL, et al. JAMA. 2006;296:2832-2838.

  14. Cigarette Smoking and MS • Several cohort and case-control studies have suggested that cigarette smoking nearly doubles the risk of MS1-3 • Risk increases with cumulative smoking “dose”2 • Parental smoking also doubles the risk of MS in children who are passively exposed to the smoke4 • Smokeless tobacco has not been found to increase MS risk1,2 • Implies that non-nicotinic components of cigarette smoke are responsible 1. Carlens C, et al. Am J Respir Crit Care Med. 2010;Mar 4:epub ahead of print. 2. Hedström AK, et al. Neurology. 2009;73:696-701. 3. Riise T, et al. Neurology. 2003;61:1122-1124. 4. Mikaeloff Y, et al. Brain. 2007;130(pt 10):2589-2595.

  15. Risk Factors for MSSummary • MS is caused by a complex interaction of genetic and environmental factors • In someone with an affected identical twin, risk of MS is 25%, suggesting that genetics play a role in susceptibility but are not the complete story • Vitamin D insufficiency, EBV infection, and cigarette smoking have shown possible links to MS • This research is thought-provoking, but these factors have not been definitely proven as causes of MS

  16. Pathophysiology of MS

  17. Pathophysiology of MS • Acute Inflammation Relapses • Neuronal Degeneration Disability

  18. Immune Dysregulation in MST Cells • T cells normally recognize specific antigens • CD8+ T cells destroy infected cells • CD4+ T cells release cytokines that mediate inflammatory and anti-inflammatory responses • T cells reactive to myelin are found in MS lesions, blood, and cerebrospinal fluid • CD8+ T cells transect axons, induce oligodendrocyte death, promote vascular permeability1 • There is a cytokine imbalance in MS, favoring secretion of inflammatory (Th1) cytokines • T cells that normally regulate immune function have reduced activity in MS2 1. Dhib-Jalbut S. Neurology. 2007;68:S13-S21. 2. Viglietta V, et al. J Exp Med. 2004;199:971-979.

  19. TH1 TH2 Normal Inflammatory Anti-inflammatory IFN-g, IL-12, TNF IL-4, IL-10, TGFß TH2 MS Anti-inflammatory TH1 IL-4, IL-10,TGFß Inflammatory IFN-g, IL-12, TNF Cytokine Imbalance in MS Graphic courtesy of Suhayl Dhib-Jalbut, MD.

  20. Immune Dysregulation in MSB Cells • In some MS patients, ectopic lymphoid follicles have been found in the meninges1 • Mechanisms of B cells in MS may include: • Antimyelin antibody production • Antigen presentation to autoreactive T cells • Proinflammatory cytokine production 1. Uccelli A, et al. Trends Immunol. 2005;26:254-259.

  21. Immune Dysregulation in MSOther Involved Cells • Natural killer (NK) cells • May play opposing roles as both regulators and inducers of disease relative to cytokine environment and cell:cell contact • NK cell function may be lost during clinical relapse • Monocytes • Secrete IL-6 (promotes B cell growth) and IL-2 (aids differentiation of Th1 cells) • Macrophages • Phagocytic activity may contribute to demyelination • Microglia • Specialized macrophages in the CNS, also may contribute to T cell activation

  22. Neurodegeneration • Loss of axons is the main cause of permanent disability in MS • Axonal damage has been shown to occur in acute inflammatory plaques1 and can lead to brain atrophy • Occurs in white and gray matter • May also produce cognitive impairment • Axonal damage could be the result of • Cumulative inflammatory damage over time • A parallel degenerative process related to loss of trophic support or an independent axonal degeneration2 • Can effective immune therapy early in MS prevent worsening disability? 1. Trapp BD, et al. N Engl J Med. 1998;338:278-285. 2. Trapp BD. Neuroscientist. 1999;5:48-57.

  23. Conclusions • Pathogenesis of MS involves complex interactions between genetic and environmental factors • Multiple genes are involved • Vitamin D deficiency, EBV infection, and cigarette smoking are environmental candidates • MS incidence has increased over the past 30 years due to a change in environmental exposure • MS pathogenesis involves multiple immune cell types (T cells, B cells, NK cells, others) • Along with chronic inflammation, MS pathogenesis involves axonal loss • Neurodegeneration is the major source of disability in MS

  24. Challenges in Diagnosing MS

  25. What Is an MS “Attack”? • Neurologic symptoms lasting ≥24 hours but generally longer • Not explained by other conditions • Do not represent recurrent symptoms in association with increased body temperature or infection (pseudoexacerbations) • To be considered separate attacks, the interval between episodes must be ≥30 days McDonald WI, et al. Ann Neurol. 2001;50:121-127.

  26. Clinical Presentation • MS symptoms vary widely among individual patients • Numbness, tingling, or weakness in the limbs • Usually unilateral or only lower half of body • Tremor, spasticity, incoordination, unsteady gait, imbalance • Vision loss (usually unilateral), pain with eye movement, double vision • Fatigue, dizziness, cognitive impairment, unstable mood • Urinary and bowel incontinence or frequency • Increased body temperature may trigger or worsen symptoms

  27. RRMS PPMS Disability Disability Time Time SPMS RPMS Disability Disability Time Time Four Clinical Subtypes of MS Fauci AS, et al. In: Harrison's Manual of Medicine, 17th ed. McGraw-Hill Medical; 2009. Reprinted with permission from McGraw-Hill.

  28. Disease Course • After initial episode, MS patients typically follow a chronic pattern of acute neurologic symptoms (relapses) followed by periods of stability (remission) • Timing, progression, duration, severity, and specific symptoms are variable and unpredictable • Typically 2 to 3 relapses per year in untreated patients; treated patients have significantly fewer relapses • Some symptoms may be ongoing/chronic; these do not represent relapse • Long-term deficits range from mild to severe

  29. Diagnosis of MS • Clinically definite MS must meet criteria for1 • Dissemination in space • Dissemination in time • A single episode of MS-like symptoms (clinically isolated syndrome [CIS]) will not meet these criteria • But if MS is likely based on MRI, it still should be treated like MS • Delaying treatment may be missing an important window of opportunity to delay the onset of irreversible disability • Requires close monitoring over time to confirm diagnosis 1. Polman CH, et al. Ann Neurol. 2005;58:840-846.

  30. * CIS Natural History of MSClinical and MRI Measures Relapses/Disability MRI Activity MRI T2 Burden of Disease Secondary Progressive MS Axonal Loss Relapsing-Remitting MS Preclinical Disability Time Trapp BD, et al. Neuroscientist. 1999;5:48-57. Reprinted with permission from Sage Publications.

  31. 92% 89% 87% 88% 87% 85% 80% 79% 54% 19% 11% 6% Natural History of CIS (Queen Square) Risk of Conversion Based on LesionCount at Presentation Morrissey S, et al. Brain. 1993;116:135-146. O’Riordan J, et al. Brain. 1998;121:495-503. Brex PA, et al. N Engl J Med. 2002;346:158-164.

  32. Revised McDonald Criteria • At least 3 of the following on MRIa: • ≥1 Gd-enhancing brain or spinal cord lesion or ≥9 T2 hyperintense brain and/or spinal cord lesions of ≥3 mm in size if none of the lesions are Gd-enhancing • ≥1 brain infratentorial lesion or spinal cord lesion ≥3 mm in size • ≥1 juxtacortical lesion ≥3 mm in size • ≥3 periventricular lesions ≥3 mm in size aTo meet criteria for dissemination in space Polman CH, et al. Ann Neurol. 2005;58:840-846.

  33. Revised McDonald Criteria • At least 1 of the followinga • A 2nd clinical episode • A Gd-enhancing lesion detected ≥3 months after onset of initial clinical event • Located at a site different from the one corresponding to the initial event • A new T2 lesion detected any time after a reference scan that was performed at least 30 days after the onset of an initial clinical event • Thus, it is not always necessary to wait for 2 attacks to diagnose MS. A first attack plus changes on MRI may be enough aTo meet criteria for dissemination in time Polman CH, et al. Ann Neurol. 2005;58:840-846.

  34. Typical MRI Lesions in MS Gd-enhancing Corpus Callosum A and B: Courtesy of Tracy M. DeAngelis, MD.

  35. Typical MRI Lesions in MS Infratentorial Juxtacortical C and D: Courtesy of Daniel Pelletier, MD.

  36. Typical MRI Lesions in MS Periventricular Spinal Cord E: Courtesy of Daniel Pelletier, MD.F: Courtesy of Tracy M. DeAngelis, MD.

  37. CMSC MRI Protocol 2009 • Obtain brain MRI at baseline, with contrast • Obtain spinal cord MRI if symptoms pertaining to spinal cord lesions or no evidence of disease activity in brain • Repeat scan if: • Unexpected clinical worsening • Need to re-evaluate diagnosis • Starting or modifying treatment • Consider serial MRI every 1-2 years to evaluate subclinical activity Consortium of Multiple Sclerosis Centers. http://www.mscare.org/cmsc/images/pdf/mriprotocol2009.pdf

  38. Performing Serial MRIs for Follow-up • A standardized protocol using consistent technology and protocols is essential to serial MRI interpretation • Same magnet strength and slice thickness • Same sequence acquisition • Same patient positioning • Same plane • Section selection should match prior MRIs as closely as possible • Radiologists should follow the updated CMSC protocol1 for standardizing MRIs in clinical MS applications 1. Consortium of Multiple Sclerosis Centers. http://www.mscare.org/cmsc/images/pdf/mriprotocol2009.pdf

  39. MRI Correlates Poorly With Clinical Outcomes • T2 lesion volume at a single point in time correlates weakly with clinical disability and is a measure of past attack frequency1 • Change in lesion volume over time may be a better correlate2 • T1-weighted black holes are a better but still imperfect correlate of disability3 • Brain atrophy is a measure of neurodegeneration that may predict disability4 1. Bar-Zohar D, et al. Mult Scler. 2008;14:719-727. 2. Brex PA, et al. N Engl J Med. 2002;346:158-164. 3. Truyen L, et al. Neurology. 1996;47:1469-1476. 4. Miller DH, et al. Brain. 2002;125:1676-1695.

  40. Why MRI Correlates Poorly with MS Disability • MRI cannot determine extent/nature of tissue damage • Location of lesion influences its clinical manifestation • MRI cannot distinguish between demyelinated and remyelinated lesions • MRI cannot detect gray matter lesions or diffuse damage in normal-appearing white matter • Plasticity of CNS may lead to compensatory use of alternative neural circuit to circumvent damaged areas

  41. Emerging MRI Technologies • Measures of CNS atrophy • Magnetization transfer imaging • Proton magnetic resonance spectroscopy • Diffusion tensor imaging • Susceptibility weighted imaging

  42. Other Diagnostic Tools for MSCSF Analysis • Positive if oligoclonal IgG bands present but absent from corresponding serum sample or IgG index is elevated • Sensitive but not specific: other causes of CNS inflammation can yield similar findings • Lymphocytic pleocytosis is rarely >50/mm3 • Protein levels rarely exceed 100 mg/dL • Elevated myelin basic protein is not pathognomonic for MS

  43. Other Diagnostic Tools for MSVisual Evoked Potentials (VEPs) • Provides evidence of a lesion associated with visual pathways • Positive if shows delayed but well-preserved wave forms • Abnormal VEP is not specific for MS • Can help establish dissemination in space

  44. EDSS1 Bedridden Death Restricted to wheelchair Need for walking assistance Some limitation in walking ability 10.0 9.5 Minimal disability 9.0 Normal neurologic exam 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 Time to EDSS score of 4.0 strongly influenced by relapses in the first 5 years and time to CDMS.2 3.0 2.5 2.0 1.5 1.0 0 1. Kurtzke JF. Neurology. 1983;33:1444-1452. 2. Confavreux C, et al. Brain. 2003;126:770-782.

  45. Residual Disability Sustained After a Relapsea aIn 224 placebo patients from the NMSS task force on clinical outcome assessment. Lublin FD, et al. Neurology. 2003;61:1528-1532.

  46. Neuromyelitis Optica (NMO) • Syndrome of aggressive inflammatory demyelination afflicting the optic nerves and spinal cord1, often associated with severe disability • Associated with infections and collagen vascular diseases1 • Idiopathic form is considered a variant of MS • Modern case series indicate that NMO is characterized by1 • Recurrent attacks of optic neuritis and acute transverse myelitis • Multisegmental spinal cord lesion >3 vertebral segments • Initial brain MRI that is often (but not always) normal • The NMO-IgG antibody recognizes aquaporin-4 (AQP4),2 a water channel expressed on astrocytes • Anti-AQP4 antibody is 73% sensitive and 91% specific for NMO3 • Blood testing is available at Mayo Medical Laboratories4 1. Cree B. Curr Neurol Neurosci Rep. 2008;8:427-433. 2. Lennon VA, et al. J Exp Med. 2005;202:473-477. 3. Lennon V, et al. Lancet. 2004;364:2106-2112. 4. Mayo Medical Laboratories. http://www.mayomedicallaboratories.com/test-catalog/Overview/83185.

  47. Distinguishing NMO from MS NMO MS Courtesy of Bruce A.C. Cree, MD, PhD, MCR Courtesy of Tracy M. DeAngelis, MD

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