Lectures 4 and 5 Multiple Sclerosis and Inflammation PDF

Lectures 4 and 5 Multiple Sclerosis and Inflammation Useful Link: http://www.myvmc.com/diseases/multiple-sclerosis-ms/ Overview  What is Multiple Sclerosis (MS)?  Clinical Subtypes Disease Progression  Diagnosing MS  Environmental/ Risk factors  Brain Pathology Neuroinflammatio...

Lectures 4 and 5 Multiple Sclerosis and Inflammation Useful Link: http://www.myvmc.com/diseases/multiple-sclerosis-ms/ Overview  What is Multiple Sclerosis (MS)?  Clinical Subtypes Disease Progression  Diagnosing MS  Environmental/ Risk factors  Brain Pathology Neuroinflammation Useful Link: https://www.wingd.ca/a-journey-through-multiple-sclerosis/  Quick Facts about MS  Canadians have one of the highest rates of MS in the world (~ 100,000)  MS is the most common neurological disease affecting young adults in Canada (aged 15 to 40)  Women are more than three times as likely to develop MS as men  MS can cause loss of balance, impaired speech, extreme fatigue, double vision and paralysis Symptoms  Abnormal Sensations: ”Pins and needles" sensation  Bladder Problems  Difficulty Walking: MS can cause muscle weakness or spasms  Dizziness  Fatigue: Weak muscles, slowed thinking, or sleepiness  Muscle Spasms: Mild stiffness or strong, painful muscle spasms MS Symptoms  Vision problems such as blurred vision, double vision or paralysis of eye muscles  Muscle stiffness and lack of balance and co- ordination There is loss of dexterity and fine movement  Fatigue http://www.news-medical.net/health/Multiple-Sclerosis-(MS).aspx What is Multiple Sclerosis (MS)?  Disease characterized by damage to myelin Myelin sheath (oligodendrocytes) and in some cases the axons are destroyed Relapses and remissions are common Brain imaging reveals discrete lesions Proposed causes include: bacterial or viral infection, pesticides, CNS immune response https://en.wikipedia.org/wiki/Multiple_sclerosis http://www.optum.com.br/content/optum/en/thought-leadership/ms-spending-cost-drivers.html http://blogs.biomedcentral.com/on-medicine/2016/04/26/multiple-sclerosis-clinical-trials-fighting-cure/ http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis/ http://multiple-sclerosis-research.blogspot.com/2013_07_01_archive.html Diagnosing MS  By definition, a diagnosis of MS must include evidence of disease activity separated in time and space http://www.consultantlive.com/nervous-system-diseases/advanced-mri-may-speed-diagnosis-multiple-sclerosis  MRI in a Patient with RRMS MRI scans obtained at a) baseline, b) 1 year, c) 2 years, d) 3 years. Disease progression can clearly be seen in the form of new and enlarging focal lesions over time (white spots) http://www.nature.com/nrneurol/journal/v11/n10/fig_tab/nrneurol.2015.157_F1.html Diagnosis of MS  When diagnosing MS, doctors are looking for evidence of lesions in the central nervous system  The location of the lesion can be determined by the symptoms on physical examination  Sometimes lesions occur but do not cause symptoms use MRI and evoked potential testing to determine their location Diagnosis of MS  Gadolinium enhancement is used to detect a compromised BBB or lesions with active inflammation  Once axonal loss occurs, dark zones (black holes) may appear within the plaques http://multiple-sclerosis-research.blogspot.com/2015/01/education-whats-mri.html http://multiple-sclerosis-research.blogspot.com/2015/01/education-whats-mri.html http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61620-7/fulltext?version=printerFriendly Spinal Tap  A spinal tap is used to rule out other diseases and also help confirm the MS diagnosis  The CSF typically shows an increase in oligoclonal banding and elevation of myelin basic proteins http://www.diagnosisms.com/2012/08/04/lumbar-puncture/ Spinal Tap  The term oligoclonal bands refers to the presence of two or more protein bands of a specific immunoglobin (IgG) in CSF that have similar intensity than in the concurrent serum sample  This pattern of banding is seen in patients with MS http://www.slideshare.net/GauravShelgaonkar/csf-examination-53071410  Visual-Evoked Potentials  Stimulus evokes pulses down the optic nerve, into the primary visual cortex of the occipital lobe  A delay of approximately 100 msec occurs by the time the visual evoked potential (VEP) is elicited in the visual cortex http://www.mindmods.com/resources/Study-Biomaghistmech.html  Visual-Evoked Potentials  Conduction latency longer in MS  VEP’s are useful in detecting potential diagnosis of Multiple Sclerosis but conduction can also be affected by many other conditions such as a tumor completely unrelated to MS http://www.msunites.com/blog/2015/07/12/evoked-potentials-testing/ Causes of MS https://www.ucsf.edu/news/2011/08/10431/major-genetic-study-multiple-sclerosis-reveals-dna-hot-spots-disease  Inflammatory Causes of MS  MS is considered an autoimmune disease because of the presence of T cells that recognize oligodendrocyte myelin-specific antigens  T cells cross the blood– brain barrier and secrete pro-inflammatory cytokines http://www.hendess.net/ms_e.htm  Immunity and Inflammation Autoimmune MS Hypothesis  Immune cells from blood vessels enter the brain, spinal cord, or optic nerves and cause areas of inflammation, demyelination, and nerve damage http://www.mult-sclerosis.org/news/Apr2003/FullTextNewImmunopathologicInsightsintoMS.html Blood Brain Barrier  When a MS relapse or exacerbation occurs, the blood-brain barrier has been weakened, allowing the peripheral immune system to invade the central nervous system http://slideplayer.com/slide/3866064/  The Dark Side of Microglia  Inflammatory microglia display the M1-like phenotype (left) and stimulate astrocyte activation, neuronal damage, T-cell activation (re-stimulation) and disruption of the BBB -> neuroinflammation and subsequent neuronal loss http://www.nature.com/nrneurol/journal/v11/n1/full/nrneurol.2014.207.html?message-global=remove Environmental Causes of MS https://www.ucsf.edu/news/2011/08/10431/major-genetic-study-multiple-sclerosis-reveals-dna-hot-spots-disease Environmental Factors  The risk for MS is much greater in people who live above 40°latitude in the Northern hemisphere, determined by the location of residence up to about age 15 Migration from high-risk to low-risk areas before adolescence reduces risk, whereas migration from low- risk to high-risk areas increases the risk This may be related to a deficiency in Vitamin D Geographic Distribution of MS http://www.21stcentech.com/multiple-sclerosis-research-identifies-role-problem-cells-potential-treatments/  The Vitamin D Hypothesis  Vitamin D is formed in the body from the action of sunlight on the skin  Vitamin D has immunomodulatory effects in the brain Lessens the inflammatory impact of neurodegenerative and neuroimmune diseases, http://journal.frontiersin.org/article/10.3389/fphys.2014.00244/full typified by MS Other Potential Risk Factors  Infections with measles, human herpes virus-6, Epstein-Barr (E-B) virus, and Chlamydia pneumoniae may increase risk for MS  About 90% of MS patients have also had E-B infections, such as mononucleosis http://www.mult-sclerosis.org/news/Apr2003/FullTextNewImmunopathologicInsightsintoMS.html Epstein-Barr Virus (EBV)  MS is thought to be mediated by T cells attacking myelin sheath  EBV-specific T cells (1) or antibodies (2) could falsely recognize and attack CNS auto-antigens, a process called molecular mimicry http://www.hhmi.org/news/epstein-barr-virus-might-kick-start-multiple-sclerosis Immune Responses and MS  In acute MS lesions, demyelination of axons, activation of microglia, and infiltration of immune (T) cells into the CNS are key features  The infiltrates mostly consist of T cells and macrophages  An array of inflammatory agents are expressed in acute MS lesions Immune Responses Contributing to MS Propagation T-Immune cells activated in the periphery, (Step 1) and adhere (Step 2) to endothelial cells of BBB Immune cell invasion into the CNS where T-cells impact CNS elements (Step 6) such as microglia http://www.medscape.com/viewarticle/572284_3  Immune Responses Contributing to MS Propagation  T cells enter the brain and initiate inflammation (recognize self-antigens expressed in the CNS)  Activated Th1 lead to M1 microglia and are believed to be responsible for the demyelination by production of cytotoxic factors, inflammatory cytokines and reactive oxygen species Destroy cells (oligodendrocytes) that myelinate axons  M1-like phenotype: inflammatory factors: neuronal injury  M2-like phenotype: neurotrophic factors: neuroprotection http://www.intechopen.com/books/cell-interaction/cells-molecules-and-mechanisms-involved-in-the-neuro-immune-interaction Inflammation Chronic inflammation in MS can be thought of as an inflammatory process with a disordered resolution phase. Still do not know why inflammation in MS does not resolve in all cases