Multiple Sclerosis Flashcards
What is Multiple Sclerosis?
- An immune-mediated [inflammatory] disorder involving destruction of the myeline sheath that surrounds neuronal axons - leaves scar
What is the ‘Charcot Triad’?
- Nystagmus
- Intention Tremor
- Telegraphic Speech
What are the symptoms of Mulitple Sclerosis?
- Common: Visual problems, Numbness tingling, fatigue, motor weakness, difficutly walking, dizziness, vertigo,…
- Less Common: tremor, seizures, speech and swallowing issues, headache…
What are some of the enivornmental risk factors of MS?
- Age, geography, decreased Vit D, smoking, genetic factors…
What is important to understand about viral infections and how they relate to MS?
- Infections may INCREASE the risk of MS by activating autoreactive immune cells - increasing the immune response
- Increase IgG, Antibody titers, childhood infections
How is Epstein-Barr Virus involved in developing MS?
- activation of autoreactive T- and B-cells [Molecular Mimicary]
- HLA phenotype with anti-EBNA antibodies
What are the different clinical forms of MS?
- Relapsing-Remitting MS: RRMS
- Secondary Progessive MS: SPMS
- Primary Progressive MS: PPMS
- Clinically Isloated Syndrome: CIS
What is the Clinically Isolated Syndrome [CIS]?
- It is the first initial inflammatory response
- Resulting in demyelination
- Most likely will become MS
What is Relapsing-Remitting MS [RRMS]?
-The MOST COMMON
- Has a flair up of symptoms which crosses the clinical threshold then remission occurs, repeating the process
- RRMS to SPMS
What is Secondary Progressive Remission [SPMS]?
- Have very little Relapsing-Remitting phase BUT becomes very increasing disability
- Slow neurological decline
- Less inflammation
What is Primary Progessive Remission [PPMS]?
- Just a constant increasing of disability; very closly related to SPMS
- Occurs later in the disease
What is involved in the progressive phases?
- Cytodegeneration [loss of myelin, axons, oligodendrocytes]
Describe the Autoimmune phase of MS?
-
Describe the Degenerative phase of MS?
-
Briefly describe the Autoimmune response in MS?
- Neuron leaks out ANTIGENS that pass through the BBB to DENDRITIC CELLS activating T-CELLs
- The T-Cells use A4-INTEGRIN to pass through the BBB
- CD8+ T-Cells attack OLIGODENDROCYTES while CD+ T-Cells bind to MIRCOGLIAL CELLS releasing CYOTKINES
How do macrophages harm the myelin sheath?
- They get recruited to the lesion and release harmful cytotoxic agents that harm the lesion [Reactive oxygen and nitrogen; glutamate]
- Phagocytosis
What happens to action potentials in zones of demyelination?
- In demyelinated zones, the action potential becomes slower and will become nothing
What is the normal process of an action potentail?
- The action potential will travel quickly down the insulated axon [because of the myelin]
- Node of Ranvier: demyelinated segment - has Na channels that reactive the action potential
What is the process of which we can remyelinate the demyelinated sections?
- Oligodendrocytes form the myelin sheath on the axon
- White matter inflammation will cause the break down of the myelin sheath [oligodendrocytes]
- Remyelination occurs with the recruitment of OPC; increasing the Oligodendrocytes production
- Astrogliosis causes the increase in astrocytes = scars
Briefly explain remyelination simply?
- White Matter Inflammation/Breakdown
- OPC recuitment
- Astrocytes formation [Scars]
- New Myelin is thinner and weaker
How does remyelination fail within MS?
- Ongoing inflammation and the demyelination of the axon/neurons
What are some example therapies for MS?
Targeting Immune System
- T cell Binding/Penetration of BBB [a4-Intrgrin antibodies; IFN-b][
- T cell/APC interaction [APLs - copaxone; statins]
- Cytokines [IL-23 antibodies; osteopontin]
Example why gadolinium [Gd] in MS?
- Visualization tool that will penetrate the brain where the BBB is compromised
What is Guillain-Barre Syndrome?
- Autoimmune attack on the peripheral nerves by circulating antibodies, causing demyelination
- Very slow recovery and death is caused by respiratory issues
What are the 3 categories of treatment in MS?
- Acute attacks, Disease-Modifying Treatment, Symptomatic
What are the drugs used to treat Acute Attacks?
- Corticosteroids [Methyprednisolone, Prednisone, ACTH
- Act by up-regulating anti-inflammatory genes and down-regulating pro-inflammtory genes = DECREASE INFLAMMATION
What are the Disease modifying drugs in MS?
- First Line: Interferon B1a, Interferon B1b, Glatiramer Acetate, Fingolimod
- Second Line: Natalizumab, Mitoxantrone
- New Drugs: Teriflunomide Dimethyl Fumarate, Cladribine
What is the function of the Interferons?
- MOA: inhibit lymphocytes in periphery [T Cells; Dendritic Cells] and inhibits BBB penetration [decrease in matrix matalloproteinase]
- delays the CIS
- Decrease Antibodies
What is the function of Glatiamer Acetate?
- MOA: Synthetic polypeptide that mimics antigenic properties of myelin; modulates antigen-presenting cells = inhibiting lymphoctyes periphery [T Cells; Dendritic Cells]
- Delays the CIS
- Could be use in Pregnancy
- Lipoatrophy
What is the function of Fingolimod?
- MOA: Sphingosine-1-Phosphate agonist; stimulates olgiodendrocyte survival in CNS; inhibits lymphocytes out of lymphoid organs in periphery
- Approved for RRMS
- SE: cardiotoxicity, fatal encephalitis, PROGESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY [PML]
What is the function of Natalizumab?
- MOA: a monoclonal antibody that acts on a4-integrin making VLA-4 which stops B- and T-Cells from crossing into BBB
- SE: PML
- Increases neutralizing antibodies
What is the function of Mitoxantrone?
- MOA: Reduces lymphocyte number by causing DNA breaks and delaying DNA repair via inhibiting topoisomerase II in the periphery [Cytotoxic Effect]
- First Cytotoxic Drug for SPMS
- Need a - Pregnancy test
What is the function of Terifluomide?
- MOA: Cytotoxic Agent that inhibits dihydroorotate dehydrogenase that inhibits proliferation of peripheral lymphocytes [B- and T-Cells]
- SE: Hepatotoxicity and Teratogenicity
What is the function of Dimethyl Fumarate?
- MOA: Metabolizes esterases that will activate NrF2-mediated antioxidant responses and anti-inflammatory pathways and promote remyelination in CNS; suppress T-Cells/Dendritics Cells in the Periphery
- SE: PML
What is the function of the new “imods”?
[Siponimod, Ozanimod, Ponesimod]
- MOA: Sphingosine-1-Phosphate Agonist; Stimulates oligodendrocyte survival in the CNS; inhibits lympocyte movement out of lymphoid organs peripherally
- For RRMS and SPMS
- SE: PML?
- Ozanimod: AVOID with MAO-I
- Siponimod: need 2C9 genotyping
What is the function of Cladribine?
- Phosphorylated to the triphosphate form of 2-chloro-dATP; 2-chloro-dATP damages DNA causing cell death and decrease in lymphocyte depletion
- cytotoxic agent
What is the function of Ocrelizumab [Rituximab] in MS?
- Monoclonal antibody that targets CD20 [marker for mature B-Cells] so that immune functions are unperturbed
- Decreases progression in PPMS and relapse rate in RRMS
What is the function of Firategrast in MS?
- MOA: Small molecule that targets a4-Integrin, limiting the movement of B- and T-Cells into the CNS
What is the function of Amiloride in MS?
- MOA: Small molecule that targets the ASIC-1, which is responsible for neurotoxic levels of Ca2+ in the CNS; Blocking this could increase neuroprotective effects
What is the function of Laquinimod in MS?
- MOA: produces immunomodulatory effects and may up-regulate brain derived neurotrophic factors in the CNS; increasing to Neuroprotective effects
What is the diagnostic for Multiple sclerosis?
- NO single feature
- Dissemination in Time & Dissemination in Space
What is Dissemination in Time in Multiple Sclerosis?
- The time between new lesions; damage that happens more than once
What is Dissemination in Space in Multiple Sclerosis?
- Multiple lesions in 2 of 4 CNS regions; damage that is in more than one place
What are the different types of Multiple Sclerosis?
- Clinically Isolated Syndrome [CIS], Relapsing Remitting MS [RRMS], Secondary Progessive MS [SPMS], Primary Progressive MS [PPMS], Progressive Relapsing MS [PRMS]
What is Clinically Isolated Syndrome [CIS] in Multiple Sclerosis?
- The firest demyelinating event that occurs; inflammation that crosses the threshold
What is Relapsing Remitting Multiple Sclerosis [RRMS]?
- RRMS: Relapses and partial to complete remissions of the inflammation during the disease; slowly progressing over time
- Most Common
What is Secondary Progressive Multiple Sclerosis [SPMS]?
- SPMS: Usually starts out as RRMS with less relapses/remissions overtime to where there is none and its constant disabilty
What is Primary Progressive Multiple Sclerosis [PPMS]?
- PPMS: Start out with the slow progression over time BUT there are NO relapses/remissions that occur ever
What is Progressive Relapsing Multiple Sclerosis [PRMS]?
- PRMS: Starts out as PPMS [slow progression with constant disability] but laters has relapses with NO remission
What is the EDSS in multiple sclerosis?
- The Expanded Disability Status Scale: Measures the degree of disability
What are the different ranks of the EDSS
- 0: Normal
- 1: NO disability
- 2: Minimal disability
- 3: Moderate disability
- 4: Severe disability
- 5: disability affects daily activities [cane]
- 6: assistance to walk & work [walker]
- 7: Restricted to [Wheelchair]
- 8: Restricted to [Bed or wheelchair]
- 9: Bedridden
- 10: Death
What are some of the goals of treatment for Multiple Sclerosis?
- Start Early [Hopefully stall the deneurogeneration], Acute Treatment [treat relapses better and promote complete remission], Disease Modifying Drugs [Start at CIS]
What is the treatment for the acute attacks in Multiple Sclerosis?
- High dose Corticosteroids is the 1st line
- Methylprednisolone 500-1000mg IV daily
- OUTPATIENT: Prednisone 1250mg every other day x 5 doses
What are some of the markers that show treatment failure in Multiple Sclerosis?
- No decrease in Relapse rate [hard to determine]
- Acquiring Disabilities [EDSS INCREASE]
- MRI Activity [more and more lesions forming]
What are the oral medications that are used in treating Multiple Sclerosis?
- Dimethyl Fumurate, Fingolimd, Ozanimod, Ponesimod, Siponimod, Terfluonimide
What are the injectable medications that are used in treating Multiple Sclerosis?
- Interferon b1a, Peginterferon b1a, Interferon b1b, Glatiramer Acetate
What are the infusion medications that are used in treating Multiple Sclerosis?
- Alemtuzumab, Natalizumab, Ocrelizumab
What is Progressive Multifocal Leukowncephalopathy [PML]?
- Rare, reactivition of JCV; causing the cells that produce myelin to break down, looking similar to MS relapse
- Patients MUST be tested for JCV
What type of vaccines can and/or should be given to a patients that has multiple sclerosis?
- Inactivated vaccines given 6 WEEKS before any drug therapy
- Live, attenuated are not recommended [could still get the disease]
- Varicella for those who haven’t have chicken pox with MS
What are the important things to note about using Dimethyl Fumarate in Multiple Sclerosis?
- Capsule SHOULD NOT be opened
- Monitor for Hepatotoxicity and increase risk of infections
- PML
What isimportant to know about the Sphingosine-1-Phosphate Receptor modulators in Multiple Sclerosis?
- Fingolimod, Ozanimod, Ponesimod, Siponimod
- CONTRAINDICATED: arrhythmias; any CV issue in the last 6 months
- Monitor: Bradycardia, Infections, Macular edema
- Ozanimod: AVOID with MAO inhibitor
What is important to know about Glatiramer Acetate in Multiple Sclerosis?
- Injection site reactions: Flushing, Sweating, Dyspnea, Chest Pain, Anxitey, Itching
- Rotate injection sites: DECREASE Lipoatrophy
- Maybe used in pregnancy
What is important to know about Interferons in Multiple Sclerosis?
- 1st line treatment
- Can develop flu like symptoms - pretreat with acetaminophen or an NSAIDS
- Depression, Suicidal Thinking
What is important to note about taking teriflunomide during pregnancy in Multiple Sclerosis?
- CONTRAINDICATED
- Takes 2 years to fully eliminate; take cholestyramine or activated charcoal for 2 week elmination
What is important to note about taking mitoxatrone during pregnancy in Multiple Sclerosis?
- Contraceptive and negative test required
