Multiple sclerosis 2024.pdf

Multiple sclerosis Dr. Dalia Nawwar Introduction Multiple Sclerosis What is multiple sclerosis? Definition A disease of the central nervous system (brain and spinal cord) characterized by inflammation and multifocal scarring of the protective myelin sheath of nerves, which damages...

Multiple sclerosis Dr. Dalia Nawwar Introduction Multiple Sclerosis What is multiple sclerosis? Definition A disease of the central nervous system (brain and spinal cord) characterized by inflammation and multifocal scarring of the protective myelin sheath of nerves, which damages and destroys the sheath and the underlying nerve, disrupting neural transmission.  What Is a Myelin Sheath? Myelin is an insulating layer, or sheath that forms around nerves, including those in the brain and spinal cord. It is made up of protein and fatty substances. This myelin sheath allows electrical impulses to transmit quickly and efficiently along the nerve cells. If myelin is damaged, these impulses slow down.  What Is a Myelin Sheath? Myelin sheath is produced by different types of glia cells. The two types of glia cells that produce myelin are: Schwann cells are located within the peripheral nervous system (PNS). oligodendrocytes are located within the central nervous system (CNS). What Is a Myelin Sheath?  What Is a Myelin Sheath? There are breaks of between 0.2 and 2 mm. in the myelin sheath, these are called nodes of Ranvier. Action potentials (nerve impulses) traveling down the axon “jump” from node to node. This speeds up the transmission (salutatory conduction). Likewise, in unmyelinated axons, the electrical signal will not be sped up by the nodes of Ranvier, meaning the signals will travel through each part of the cell, which slows down the speed of the signal’s conduction.  MS Risk factors People of any age can be affected by multiple sclerosis, but the disease is more commonly diagnosed among people aged 20 to 40 years. Gender  Multiple sclerosis clinical features Multiple sclerosis signs and symptoms may differ greatly from person to person and over the course of the disease depending on the location of affected nerve fibers. Common symptoms include:  Clinically isolated syndrome (CIS) ????? ❑The 1st demyelinating neurological event before the diagnosis of MS has been made. ❑ Is used to describe the 1st clinical presentation for which the criterion of dissemination in time has not been met to diagnose MS. ❑CIS can present as a single symptom, such as optic neuritis, or multiple symptoms depending on the number and location of CNS lesions. Recognizing a relapse of MS if the person: Develops new symptoms or has worsening of existing symptoms That last for more than 24 hours in the absence of infection or any other cause after a stable period of at least 1 month. Types of multiple sclerosis Types of multiple sclerosis Vision Sensation Movements Balance Diagnosis of multiple sclerosis Bladder dysfunction Recording the electrical signals produced by the nervous system in response to stimuli (visual stimuli or electrical stimuli). Electrodes measure how quickly the information travels down your nerve pathways. Diagnosis of multiple sclerosis ✓full blood count ✓inflammatory markers for example ESR, C-reactive protein ✓liver, renal and thyroid Function tests ✓Calcium, ✓glucose ✓vitamin B12 ✓HIV serology. FYI  Definition of MS What Is a Myelin Sheath? MS Risk factors MS clinical features Types of MS Diagnosis of MS Pathophysiology Basics of immunology  Immunity Adaptive Innate (Acquired) Tumor cells Virus infected cells Tumor cells Virus infected cells Main T cells Types A B Main T cells Types  T helper (Th) cells Th1 cells Secrete cytokines which help activation of macrophages…… making macrophages more capable of killing any bacteria inside them. Cytotoxic T cell activation Th2 cells Secrete certain cytokines which help in B cell activation…… plasma cells…… produce antibodies to deal with those extra cellular pathogenes. Naïve T cell Effector T cell Naive T cells continually reticulate between the blood and the lymph system. lymphocytes recognize a certain antigen undergo a series of changes …… ready to start working against the antigen The changes which occur are: Differentiation Activation Proliferation They change into Become lymphoblast Rapid multiplication Effector cells Molecular Mechanisms of T Cell Activation by Dendritic cells (DCs): There are three stages during T cells activation by DCs 1- Antigen presenting 2- Antigen recognition of T cells 3- two signals formation.  Activation of T cells The professional antigen presenting cells (APCs): These are the only cells capable of activating naïve T cells. They are concentrated in peripheral lymphoid tissues, such as lymph nodes, where they trap antigen and present it to the recirculating T cells: Dendritic cells Macrophages B cells most important and most efficient APCs  1- Antigen presenting Antigen is degraded by DCs to a suitable length. These antigenic peptides bind to specific grooves in the MHC class II molecules. At the local draining lymph node, DC present complexes of processed peptides together with MHC class II to naïve CD4+ T cells which bind to this combination with their TCR and initiate signaling. The peptide binding to MHC class I is subsequently presented to CD8+ T cells  2- Antigen recognition of T cells T cell receptor (TCR) on T cells not only identify peptide-MHC complexes derived from host cells infected by pathogens, but also recognize similar structures derived from healthy host cells, so called autoantigens. MHC I and II molecules present protein fragments to CD8+ and CD4+ T cells, respectively.  3- two signals formation. Two Signals Are Necessary for Activation of Naïve T Cells Signal-1 is equivalent to the binding of TCR to peptide-MHC complex. Signal2 requires the interaction of co-stimulatory molecules at the interface between DCs and T cells (B7/CD28)  MHC I molecules are found on all nucleated cells. MHC II molecules are only found on the surface of APCs  B Cell Activation B cells become activated by antigen via the B cell receptor (BCR) Protein antigens become internalized, digested and presented to T cells as peptides via MHCII. Cognate B cell / T cell interaction provides co-stimulation to B cells via CD40, which becomes activated on B cells via CD40 ligand (CD40L) expressed on T cells. T cells also provide cytokines to B cells that support their survival (IL-4), differentiation into plasma cells (IL-21). B Cell Activation Major cytokines produced by Th1 or Th2 TGF-B  NKC T cytotoxic cells MHC restriction  Immune Tolerance Tolerance is the prevention of an immune response against a particular antigen. For instance, the immune system is generally tolerant of self-antigens, so it does not usually attack the body's own cells, tissues, and organs. However, when tolerance is lost, disorders like autoimmune disease or food allergy may occur.  Central and peripheral tolerance of B or T cells. Central tolerance of T cells, which makes the repertoire of T cells in the periphery non-responsive to self-antigens, is clonal deletion in the thymus (or negative selection). In B-cell repertoire, central tolerance (in the bone marrow) is made by clonal deletion of developing B cells that can recognize self-antigens associated with cell membranes or solid surfaces.  Peripheral tolerance In fact, by chance some “forbidden” auto-reactive clones may escape negative selection and come out to the periphery. Peripheral tolerance describes the mechanisms that prevent auto-reactive lymphocytes from initiating potentially harmful immune responses against the body's own antigens, or food through anergy, deletion, or development of induced Tregs. Auto-reactive clones can become accidentally activated by antigen during infection and thus damage the host organism. Breakdown in the immune network which may occur as a result of: (polyclonal activation of lymphocytes): certain agents (e.g. viruses or bacteria) are capable of non-specifically stimulating many clones of lymphocytes, incloding self- reactive clone.  Antigens Protein antigens are normally processed by macrophages and other antigen-presenting cells (APC) into peptide fragments, which are expressed on the surface of these cells in association with MHC class II molecules. Only those T-cells with receptors (TCR), which recognize the antigen together with the MHC molecule, are activated.  Superantigen Superantigens are not processed in this way but can bind to MHC class II molecules on many APC surfaces directly. Superantigens simultaneously bind to MHC class II molecules on the APCs and to the variable region of the TCR. This leads to the stimulation of many T-cells and an excessive production of interleukin-2 and other inflammatory cytokines. imunopathogenesis  How do auto-reactive T cells become activated Molecular mimicry Superantigens Peptide fragments of these microorganisms activate autoreactive T lymphocytes specific to myelin basic protein (MBP), the most represented protein of the myelinic envelope. via two mechanisms: molecular mimicry, and damaging functional anergy in the inflammatory environment. Immunopathogenesis of M.S Immunopathogenesis of M.S B cells can contribute to the pathogenesis of MS in various ways, e.g., 1- as antigen presenting cells that co-stimulate autoreactive T cells, 2- as a source of autoantibodies to different components of myelin, axon and neurons, which contributes to demyelination and axonal damage.  The current concept of the pathogenesis of MS involves the Immunopathogenesis of M.S activation of potentially autoreactive CD4+ T lymphocytes as an initial and key event in its pathogenesis. Activated autoreactive T lymphocytes express on their surface adhesive molecules that enable them to bind to the endothelium-brain barrier. At the same time, activated T lymphocytes produce matrix metalloproteinase enzymes that allow the creation of openings in endothelium-brain barrier, thereby disrupting its semi- permeability and consequently enabling activation of activated T lymphocytes in the cerebral parenchyma. Immunopathogenesis of M.S When such lymphocytes within the CNS meet the myelin basic protein presented by the microglia in the role of the antigen presenting cells of the CNS, the autoreactive T lymphocytes are reactivated and initiate the secretion of pro-inflammatory cytokines that contribute to further deterioration of the semi-permeability of endothelium- brain barrier and determine the formation of inflammatory lesions. Immunopathogenesis of M.S In the demyelinating plaque, apart from demyelinization, axonal damage and oligodendrocyte destruction also occur through numerous processes involving free radicals, myelin phagocytosis natural-killer cell (NKC) mediated cytotoxicity direct complement depletion  These inflammatory events in MS relapse on average last from Immunopathogenesis of M.S several days to two weeks. Residual cells and oligodendrocyte precursors that are still present in the adult CNS are afterwards activated and remyelination of the unmyelinated axons begins, although the thickness of the newly formed myelin sheath can never be fully restored, causing the remyelinized fibers to have slower conductivity of the nerve pulse compared to intact fibers. Additionally, restored myelin sheath also differs in composition because it contains certain isoforms of MBP considered to be functionally insufficient and vulnerable to inflammation. Immunopathogenesis of M.S Peripheral activation Migration of autoreactive T cells Central reactivation Myeline damage Remyelination Axonal loss Schematic diagram of possible pathogenesis of multiple sclerosis. Lymphocytes activated in the periphery by a particular event will bypass the blood-brain barrier. Initially, they bind with the cell adhesion molecules present on the capillary endothelium and gain access into the brain. Once inside, the reactive cells activate the immune cell traffic (T-and B-cells) and mediate the devastating cascade. Cytotoxic T-cells release perforins and granzymes, and activated B-cells produce antibodies against the myelin sheath, thus mediating the demyelination process. What are the treatment goals of MS? Delay disease progression. Limit disability over time. by reducing the inflammatory component of the disease.  Treatment of Acute Episode: Corticosteroids Maintenance therapy (Disease Modifying therapy ; DMT) Symptomatic Treatment.  Treatment of Acute Episode: Corticosteroids Goal of Therapy for Acute MS Exacerbation Shorten duration of relapse and accelerate recovery The most common treatment regimen is a three or five- days course of I.V (methylprednisolone) or oral (prednisone) corticosteroids. Corticosteroids are not believed to have any long-term benefit on the disease.  Treatment of Acute Episode: Corticosteroids At molecular level methylprednisolone (MP) diffuses due to its lipophilic nature across cellular membranes. It mediates genomic effects through binding to the cytosolic glucocorticoid receptor (cGCR). The cGCR/ methylprednisolone (MP) complex subsequently translocates to the nucleus, where it binds specific DNA-binding sites termed glucocorticoid response elements. ✓Gene expression of the anti-inflammatory cytokines IL-10 and TGF-b can be induced. ✓Likewise, the expression of a number of pro-inflammatory cytokine genes, such as IFN-c and TNF-a can be inhibited.  Treatment of Acute Episode: Corticosteroids MP also mediates rapid non-genomic effects leading to the activation of several signal transduction cascades that have suppressive effects on immune cells. There are two main effects relevant to MS immunopathogenesis. First, there is a redistribution of circulating T cells with a transient decrease in the numbers of CD4+ lymphocytes, facilitation of apoptosis of activated immune cells and inhibition of T cell activation. Second, there is a reduction of the adhesion and transmigrating capacity of peripheral blood mononuclear cells into the CNS by down-regulating the expression of adhesion molecules on the surface of both T cells and endothelial cells Maintenance therapy (Disease Modifying therapy ; DMT) The main goal of current disease modifying therapy (DMT) is to quiet the disease by reducing inflammation, myelin injury and relapses. A meta-analysis of various DMTs demonstrated that all studied DMTs reduced relapse rate within 2 years. ▪NO agents are approved for primary progressive MS. ▪HOWEVER the available disease modifying therapies may be effective in patients with progressive disease who have relapses 1- Interferon β1a & b “Parenteral”Intramuscular or subcutaneous injection  Interferon β1a & b “Parenteral”Intramuscular or subcutaneous injection Interferon beta is a cytokine with several functions, which include downregulation of antigen presentation, thereby: suppressing T cell activity, induction of IL10, which skews the differentiation of CD4+ T cells toward a Th2 phenotype, blockade of T cell migration by decreasing adhesion molecules and matrix metalloproteinase. Clinical trials assessing interferon therapy have shown to: 1- Delay the onset of clinically definite MS in patients with CIS 2- Reduce the severity and frequency of attacks.  The main side effects of interferon therapy are ▪ injection site reactions ▪ post-injection flu-like symptoms. Helpful tips to reduce flulike Helpful tips to reduce these symptoms !!!! reactions include ✓Administering the injections at night ✓ Injecting the drug in areas with more to sleep through the time of peak SC fat (abdomen or buttocks). symptoms. ✓Rotating injection sites. ✓Taking ibuprofen or acetaminophen ✓ Icing the site before and after before and every 4 to 6 hours as injection. needed after the injection. ✓ Warm medication to room temperature before administration. ✓Begin with ¼-1/2 dose for two weeks then full dose ✓ If severe, use hydrocortisone 1% cream on the site.  2- Glatiramer Acetate(GA) SC It is a mixture of four amino acid polymers that bind to myelin- specific autoantibodies due to antigenic similarity to myelin basic protein to reduce autoreactivity and promote a predominant Th2 phenotype. GA is indicated for the treatment of relapsing forms of MS, included CIS, RRMS and active SPMS Common adverse events include injection-site reactions, flushing, chest tightness, dyspnea, palpitations.  3- Sphingosine-1-Phosphate (S1P) Receptor Modulators Fingolimod,(first oral DMT) siponimod, ozanimod, ponesimod S1P is a phospholipid with five subtypes present in lymphoid tissue. In the lymph nodes, S1P binding to S1P receptors is important for lymphocyte trafficking. Fingolimod initially activates lymphocyte S1P1 via high-affinity receptor binding, yet subsequently induces S1P1 down- regulation that prevents lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the CNS.  Sphingosine-1-Phosphate (S1P) Receptor Modulators Fingolimod,(first oral DMT) siponimod, ozanimod, ponesimod Fingolimod requires a 6-h first dose observation due to the risk for bradycardia as this risk is highest at 4–5 h. Macular edema is swelling or thickening of the eye's macula, the part of your eye responsible for detailed, central vision. Increase risk of infection If fingolimod is stopped abruptly without effective transition to a new medication, rebound relapses occurs.  4-Fumarates Dimethyl fumarate was first approved for MS in 2013. The mechanism of action is ❖ shifting cytokine production from interferon gamma and TNFa to IL4 and IL5. A phase 3 placebo-controlled trial demonstrated a 44% relative reduction in annualized relapse rate with twice daily dimethyl fumarate. The main side effects reported in this class of medications include gastrointestinal (GI) problems and flushing ❑Slow dose titration. ❑Administration with food. ❑(antihistamines).  5-Monoclonal antibodies: Natalizumab “IV infusion”, ocrelizumab, ofatumumab and alemtuzumab. Natalizumab is a monthly infusion DMT that was FDA approved in 2004. Natalizumab is a monoclonal antibody against the alpha chain in a4b1 integrin, also known as very late-activation antigen-4 (VLA-4), and the therapeutic mechanism of action is through inhibiting leukocyte infiltration across the endothelium into the brain. Phase 3 clinical trials showed that natalizumab reduced clinical relapses at 1 year by 68 % and had better efficacy in combination with interferon beta-1a compared to interferon alone.  Natalizumab is linked to Progressive multifocal leukoencephalopathy (PML) which is related to John Cunningham (JC) virus reactivation as a consequence of impaired leukocyte migration and decreased T-cell mediated responses in the brain. ▪ Progressive multifocal leukoencephalopathy (PML) ✓ A very rare, but serious, adverse effect ✓ It is caused by JC polyomavirus (JCV) reactivation. ✓ It is characterized by progressive damage or inflammation of the white matter of the brain in multiple areas ✓Symptoms of PML: include neurobehavioral, motor, language, and cognitive changes; seizures; vision changes and tremor. Therefore, its use is reserved for patients with severe, active MS, or who do not respond to or can't tolerate other treatments.  6- Cladribine Oral Cytotoxic effects on T and B cells by impairing DNA synthesis. Cladribine, has a similar chemical structure to purine — one of the building blocks of DNA — and gets incorporated into the genetic material of these immune cells. This interferes with DNA repair and replication and leads to immune cell death, reducing the damaging immune responses in those with MS. The most common side effects headache upper respiratory tract infection  Symptomatic Treatment Besides immunomodulation and immunosuppression, the specific treatment of symptoms is an essential component of the overall management of multiple sclerosis (MS). Symptomatic treatment is aimed at the elimination or reduction of symptoms impairing the functional abilities and quality of life of the affected patients.  Symptomatic Treatment Dalfampridine, an oral potassium channel blocker. Dalfampridine was shown in clinical trials to improve walking speeds in patients with MS vs placebo, and it acts by enhancing conduction in damaged nerves. It is FDA approved for this use Common side effects: urinary tract infections, insomnia, dizziness, headache, nausea. 1- Interferon β1a & b 2- Glatiramer Acetate 3- Fingolimod 4-Fumarates 5-Natalizumab 6- Cladribine  1 2 3 4 5 6 THANK YOU