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Neurology > Multiple Sclerosis > Flashcards

Multiple Sclerosis Flashcards

1
Q

What are some etiology factors of MS?

A
  • MS susceptibility genes (HLA class II genes)
  • Late onset/severe childhood infections (e.g., EBV)
  • Viral infections may also be trigger for new exacerbations
  • Increased vitamin D may be protective
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2
Q

What is the pathophysiology of MS?

A
  • Auto-reactive T lymphocytes are activated, cross into the CNS, and attack myelin
  • Damage to both myelin and underlying axon
  • Damage to grey and white matter caused by inflammation involving activation of T cells
  • T cells differentiate into T helper cells that induce pro-inflammatory response in which cytokines further activate B cells and macrophage
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3
Q

What are some primary clinical presentations of MS?

A
  • Optic neuritis
  • Gait problems
  • Paresthesia
  • Pain
  • Spasticity
  • Weakness
  • Speech difficulty
  • Bowel/bladder dysfunction
  • Sexual dysfunction
  • Tremor
  • Cognitive changes
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4
Q

What are some secondary clinical presentations of MS?

A
  • Recurrent UTI
  • Urinary calculi
  • Decubiti
  • Muscle contractures
  • Resp infections
  • Poor nutrition
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5
Q

What are some tertiary clinical presentations of MS?

A
  • Financial problems
  • Personal/social problems
  • Vocational problems
  • Emotional problems
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6
Q

Relapsing-remitting MS (RRMS)

A
  • Clearly defined relapses with full recovery or with residual deficit following recovery
  • 85%
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7
Q

Secondary progressive MS (SPMS)

A
  • Disease progression with or without occasional relapses, minor remissions and plateau
  • 50% will progress to this form
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8
Q

Primary progressive MS (PPMS)

A
  • Progressive from onset with occasional plateau and temporary improvements
  • 10%
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9
Q

Progressive relapsing MS (PRMS)

A
  • Progressive from onset with acute relapses, with or without full recovery, and continuous progression between relapses
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10
Q

What are some favorable prognostic factors of MS?

A
  • < 40 years
  • Female
  • Optic neuritis or sensory sx
  • Low attack frequency in early disease
  • Relapsing/remitting course of dz
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11
Q

What are some unfavorable prognostic factors of MS?

A
  • > 40 years
  • Male
  • Motor or cerebellar sx
  • High attack frequency in early dz
  • Progressive course of dz
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12
Q

What is the McDonald Criteria for MS indicative for a positive sign with no additional data needed?

A

> = 2 attacks (relapses) and objective clinical evidence >= 2 lesions

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13
Q

What do you look for is CSF evaluation for MS?

A
  • CNS synthesis of IgG is increased, whereas serum IgG are normal
  • Oligoclonal bands are present in electrophoretic studies
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14
Q

What are the 3 broad categories of the treatment of MS?

A
  • Tx of acute attacks
  • Disease-modifying therapies
  • Symptomatic therapy
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15
Q

What is the treatment of acute exacerbations of MS?

A
  • Mild with no functional decline may not require tx
  • IV high dose corticosteroids (DOC methylprednisone) x 3-5 days
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16
Q

What is the disease-modifying treatment?

A
  • The primary MOA for all DMTs is thought to be diminishing neuroinflammation
  • All DMTs modulate the immune system through mechanisms that include sequestration of lymphocytes
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17
Q

What are some oral DMTs?

A
  • Teriflunomide
  • Dimethyl fumerate
  • Monomethyl fumarate
  • Diroxemil fumarate
  • Fingolimod
  • Siponimod
  • Ozanimod
  • Cladribine
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18
Q

Teriflunomide

Broad, general MOA

A

Pyrmidine synthesis inhibitor, anti-proliferative and anti-inflammatory
* first line

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19
Q

Dimethyl fumarate

More broad MOA

A

Fumaric acid derivative, anti-inflammatory and cytoprotective properties
* First line
* Biosimilar available

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20
Q

Fingolimod, Siponimod, Ozanimod

A

Sphingosine 1-phosphate receptor modulator
* First line

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21
Q

Cladribine

A

Purine nucleoside analog, cytotoxic to B- and T-cells
* Second line, due to adverse effects

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22
Q

What are some injectable DMTs?

A
  • Interferon, beta-1a
  • Interferon, beta-2a
  • Peginferon beta-1a
  • Glatiramer
  • Ofatumumab
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23
Q

Interfernon, beta-1a; Interferon, beta-2a; Peginferon, beta-1a

A

Changes cytokine balance, favors anti-inflammatory cytokines
* First line

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24
Q

Glatiramer acetate MOA

A

Induces and activates T-cell suppressor cells specific for myelin antigen
* First line

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25
Q

Ofatumumab

A

Anti-CD20, B-cell depletion
* First line(?) FDA approved recently

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26
Q

What are some infusion DMTs?

A
  • Alemtuzumab
  • Mitoxantrone
  • Natalizumab
  • Ocriluzumab
  • Rituximab (off-label)
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27
Q

Alemtuzumab

A

Anti-CD52, T-cell and B-cell depletion
* Second line due to adverse effects

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28
Q

Mitoxantrone

A

Topoisomerase II inhibitor; inhibits DNA and RNA synthesis; broad immunosuppression
* Third line reserved for rapidly-advancing disease due to adverse effects
* Biosimilar available

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29
Q

Natalizumab

Very broad general MOA

A

Selective adhesion-molecule inhibitor; blocks T cell migration into CNS
* First line

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30
Q

Ocrlizumab, Rituximab

A

Anti-CD20, B-cell depletion
* First line off-label use
* Ocrevus is the only FDA approved drug for PPMS

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31
Q

What are some common side effects of interferon-beta?

A
  • Injection site redness and swelling
  • Flu-like symptoms (fever, chills, myalgias) - 24 hours after inj
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32
Q

What are some less common side effects of interferon-beta?

A
  • SOB
  • Tachycardia
  • Depression
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33
Q

What are some counseling points of interferon-beta?

A
  • CONTRAINDICATED in patients who have severe depression
  • Counsel women to use appropriate contraception
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34
Q

Glatiramer acetate

A
  • 20 mg SQ daily
  • ADE: 10% transient chest tightness, flushing, and dyspnea, if no hx CAD (self-limiting and benign)
  • Store in refrigerator, room temp for up to 1 week
  • Pregnancy category B
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35
Q

What is the MOA of natalizumab (Tysabri)?

Very specific MOA

A

Attaches to VLA-1 and blocks the interaction with CNS endothelium vascular cell adhesion (VCAM)-1. Thus, activated lymphocytes are denied entry past the BBB

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36
Q

What is natalizumab?

A

Partially humanized monoclonal antibody against alpha4 integrins

37
Q

What is the counseling point for natalizumab?

A

Black box warning: Increases the risk of Progressive multifocal leukoencephalopathy (PML)
* was put off the market for awhile bc of this
* A potentially lethal CNS viral infection caused by infection with the John Cunningham polyomavirus (JCV)

38
Q

What is the place of therapy of natalizumab?

A
  • Monotheray for RRMS to reduce the exacerbations and reduce deficits
  • In patients who have not responded adequately to, or who cannot tolerate the other DMDs
39
Q

What are the common AEs of natalizumab?

A
  • Infusion reaction
  • HA
  • Fatigue
  • UTI
  • Depression
  • Joint pain
  • Abdominal pain
40
Q

What are some monitoring parameters of natalizumab?

A

JCV antibody monitoring every 3-6 months

41
Q

What is Fingolimod (Gilenya)?

A
  • First ORAL DMD for use in relapsing MS
  • A sphingosine analogue that modulates sphingosine-1-phosphate receptor
  • Alters lymphocyte migration
42
Q

What are some common side effects of Fingolimod?

A
  • HA
  • Diarrhea
  • Back pain
  • Elevated liver enzymes
  • Cough
43
Q

What are some less common but serious AEs for Fingolimod?

A
  • Bradyarrhythmias
  • AV block
  • Macular edema
  • Diminished respiratory function and tumor development
44
Q

What are some counseling points of Fingolimod?

A
  • CONTRAINDICATION to recent hx of MI, stroke, TIA, heart failure, second or third degree heart block, QTc > 500 ms, use of class 1a or III antiarrhythmics (amio or sotalol)
  • Avoid live attenuated vaccines
  • Eye exams should be repeated 3-4 months after tx started
45
Q

Before starting Fingolimod, patients should have the following?

A
  • CBC, LFTs
  • ECG
  • Ophthalmologic exams
  • Varicella serology and zoster vaccination if antibody negative
  • Pregnancy cat C: inform woman of potential fetal outcomes
46
Q

What is Teriflunomide?

A

Second ORAL agent for relapsing MS

47
Q

What is the MOA of Teriflunomide?

Specific

A
  • Is an active metabolite of leflunomide
  • Reduces B and T cell proliferation by reversibly inhibiting the mitochondrial enzyme dihydro-orotate dehydrogenase
48
Q

What are some counseling points for Teriflunomide?

A
  • Hepatoxicity
  • Risk of teratogenicity (Pregnancy cat X)
49
Q

What are some monitoring parameters of Teriflunomide?

A
  • Check LFTs, before start of med, q month for 6 months
  • Check CBC before start of med, monitor for infection
  • Monitor renal function, electrolytes (K+) and blood pressure
50
Q

What are some drug interactions of Teriflunomide?

A
  • Drugs metabolized by CYP2C8 (repaglinide, pioglitazone)
    • Teriflunomide increases their exposure
  • Drugs metabolized by CYP1A2 (fluoxetine, tizanidine)
    • Teriflunomide decreases their exposure
  • Warfarin – unknown mechanism
    • Teriflunomide may decrease INR
51
Q

What is the MOA of Dimethyl fumarate?

More specific MOA

A

DMF has been shown to activate the Nuclear factor-like 2 (Nrf2) pathway which is involved in cellular response

52
Q

What are the monitoring parameters of Dimethyl fumarate?

A
  • Baseline CBC with lymphocyte count at baseline, 6 months later, then every 6-12 months
  • May cause lymphophenia, interrupt therapy if lymphocyte count is less than 0.5x10^9 cells/L for more than 6 months
  • Consider holding therapy in patients with serious infections
53
Q

What is Alemtuzumab?

A

Humanized monoclonal antibody directed at CD52 on the surface of lymphocytes and monocytes, resulting in rapid and marked lymphopenia

54
Q

What is the place of therapy of Alemtuzumab?

A

Due to safety profile the FDA recommends this be reserved for patients with inadequate response to two or more MS therapies (at least second line)

55
Q

What is the counseling points of Alemtuzumab?

A

Black box warnings:
* Causes serious and sometimes fatal autoimmune conditions such as immune thrombocytopenia
* Causes serious and life-threatening infusion reactions
* May cause increased risk of malignancies including thyroid cancer, melonoma, and lymphoproliferative disorders

56
Q

What is the place of therapy of Ocrelizumab?

A

First treatment approved for RMS and PPMS

57
Q

What is Ocrelizumab?

A

Humanized monoclonal antibody designed to target CD20-positive B cells

58
Q

What do you premedicate before giving Ocrelizumab infusion?

A

Methylprednisone and antihistamine

59
Q

What are some AEs of Ocrelizumab?

A
  • Infusion reactions and infections (upper and lower respiratory tract infections, skin infections)
60
Q

What is required before giving Ocrelizumab?

A

Hepatitis B virus screening required before first dose

61
Q

What is the place of therapy of Siponimod?

A

Approved for RRMS and active SPMS

62
Q

What are some counseling points of Siponimod?

A
  • CONTRAINDICATED for patients with CYP2C9 3/3 genotype
  • CONTRAINDICATED in recent MI, unstable angina, advanced HF, AV block
  • Should not be started after alemtuzumab
63
Q

What are some monitoring parameters of Siponimod?

A
  • Liver function and BP during treatment
  • First dose monitored for bradycardia and arrhythmias
64
Q

What are some dose-dependent AE of Siponimod?

A
  • Decreased lymphocyte counts
  • Infections
  • Macular edema
  • Bradyarrhythmia
  • Liver toxicity
65
Q

What is the place of therapy of Cladribine?

A
  • Approved for RRMS and SPMS
  • Reserved for patients who do not tolerate or have inadequate response to other drugs for MS
66
Q

What are the monitoring parameters of Cladribine?

A
  • Lymphocyte counts should monitored before, during, and after treatment
67
Q

What is the treatment course of Cladribine?

A

Each treatment course is divided into two treatment cycles of 4-5 days separated by 4 weeks

68
Q

What are some counseling points of Cladribine?

A
  • CONTRAINDICATED in pregnancy, breastfeeding, and for women and men of reproductive potential (unless effective contraception for 6 months after last dose)
  • CONTRAINDICATED in patients with malignancy or active chronic infections
69
Q

Diroximel fumarate (Vumerity)

A
  • Rapidly converts to mono-methyl fumarate, the same active metabolite as dimethyl fumarate
  • Lower rates of GI ADEs
  • Should NOT be taken concurrently with dimethyl fumarate
70
Q

What is the place of therapy of Ofatumumab?

A

Approved for RRMS and active SPMS

71
Q

What do you give before Ofatumumab?

A
  • Hepatitis B virus (HBV)
  • Quantitative serum immunoglobulins screening is required
72
Q

What is the dosing of Ofatumumab?

A

20 mg SQ at weeks 0,1, and 2
* Subsequent dosing: 20 mg administered monthly starting at week 4

73
Q

What are some counseling points of Ofatumumab?

A
  • CONTRAINDICATED: in active HBV infections
  • Advise females to use an effective form of contraception during treatment and for 6 months after stopping Kesimpta
  • Live, or live-attenuated vaccines are not recommended during treatment
74
Q

What is the place of therapy of Mitoxantrone?

A

SPMS and PRMS or worsening RRMS

75
Q

What is the monitoring of Mitoxantrone?

A

EF (req before each dose), sx of CHF

76
Q

What are some counseling points of Mitoxantrone?

A
  • May impart blue-green color to urine, bluish color to sclera
  • Should NOT be used with natalizumab due to increased risk of PML
77
Q

Stem Cell Transplantation

A

Goal of autologous hematopoietic stem cell transplantation (HSCT) is eliminating and replacing the patient’s pathogenic immune system to achieve long-term remission of MS

78
Q

What is the MOA of Ergocalciferol (D2) and cholecalciferol (D3)?

A

Increasing vitamin D levels may decrease severity of MS symptoms

79
Q

What is the place of therapy of * Ergocalciferol (D2) or Cholecalciferol (D3)?

A

Consider obtaining vitamin D level and/or providing supplementation to every patient with MS

80
Q

Dalfampridine (Ampyra)

A

CNS potassium channel blocker indicated to improve walking in patients with MS

81
Q

What is the administration of Dalfampridine?

A
  • Tablets should only be taken whole
  • Do not divide, crush, chew, or dissolve
82
Q

What are some contraindications of Dalfampridine?

A
  • History of seizures
  • Moderate or seizures renal impairment (CrCl <= 50 mL/min)
83
Q

What are some drug interaction of Dalfampridine?

A

W/ metformin

84
Q

What is the DOC of spasticity?

A
  • Baclofen
85
Q

Baclofen

A

GABA analog
* Must NOT be discontinued abruptly

86
Q

Tizanidine

A
  • 2nd line for spasticity
  • Short acting, centrally acting alpha-adrenergic agonist, increases presynaptic inhibition of motor neurons
87
Q

What is the AEs of Tizanidine?

A
  • Sedation
  • Dizziness
  • Dry mouth
  • Hypotension
  • RARE but SEVERE hepatoxicity
88
Q

What is the treatment options of MS Fatigue?

A
  • Amantadine 100 mg BID
  • Modafinil 100-400 mg daily

Neurology (21 decks)

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