MS and Spasticity

Question 1

Multiple Sclerosis refers to (two)

Answer 1

• multiple neurologic symptoms that accrue over time
• characteristic plaques or sclerosed areas that are seen in numerous areas of the brain and spinal cord

Question 1

are men or women more commonly affected?

Answer 1

women

Question 2

MS primary risk factors

Answer 2

geography, age, environmental influences (smoking or vit D deficiency) and genetics

Question 3

Why is cigarette smoking a risk factor?

Answer 3

the lung is a critical site for the activation of pathogenic T lymphocytes responsible for autoimmune demyelination

Question 4

Genetic association

Answer 4

HLA DRB11501 and Interleukin-2alpha/7alpha

Question 5

etiology

Microbrial theory

Answer 5

• a direct attack on myelin/oligodendrocytes
• may stimulate autoimmune response causing demyelination
• increased IgG synthesis in CNS as well as antibody titers to certain viruses
• gut microbes may alter microglia functioning resulting in increased activity of astrocytes

Question 6

What viruses could cause MS?

Answer 6

HCV, herpes, human endogenous retrovirus, Epstein-barr

Question 7

etiology

autoimmune theory

Answer 7

attack against myelin and oligodendrocytes, myelin basic proteins may serve as an autoantigen

Question 8

Which cell is the key initiator

Answer 8

TH1 (t helper cells) are activated in the periphery by interacting with antigen presenting cells and then cross the blood brain barrier and attack myelin

Question 9

what breaks down the blood brain barrier for t-cells to pass through?

Answer 9

MMP: matrix metalloproteins

Question 10

Th17 cells

Answer 10

potentially activated inside the blood brain barrier and move from ventricles through choroid plexus

Question 11

Th2 or Treg

Answer 11

usually supresses T cell activation, but in MIS it is impaired or there are less

Question 12

what cytokines are involved in the inflammatory response?

Answer 12

VEGF-B, TNF-alpha, INF-gamma, IL-2

Question 13

what are the modulators (good guys) of the immune response?

Answer 13

TGF-beta, TGF-alpha, and IL-10 can down-regulate immune response

Question 14

B cell involvement

Answer 14

traffic into CNS and activate pro-inflammatory T cells to promote secretion of pro-inflammatory cytokines
also involved in autoantibody production against myelin

Question 15

What is the pathologic hallmark of MS?

Answer 15

stripping of the myelin sheath around CNS neurons

Question 16

disruption of nerve impulse transmission leads to

Answer 16

neurologic symptoms
- increased refractory periods delaying impulse conduction
- hyperpolarization due to altered potassium channels

Question 17

neurodegeneration

Answer 17

cumulative axonal and neuronal loss is the most important contributor to irreversible neurologic disability and progressive symptoms

Question 18

Relapsing Remitting MS

Answer 18

clear relapses with either full recovery or will partial recovery and lasting disability.* between attacks there is no progression or worsening of disease*
most common

Question 19

Primary Progressive MS

Answer 19

steady progression or worsening from onset with only occasional plateus or minor recovery

Question 20

Secondary Progressive MS

Answer 20

begins with clear-cut relapses and recovery but becomes steadily progressive over time with continued worsening between attacks

Question 21

Progressive-Relapsing MS

Answer 21

steadily progressive from onset but also has clear acute attacks
rare

Question 22

Spasticity

Answer 22

stiff or rigid muscles - unusual tightness or increased muscle tone due to upper motor neuron deficit/dysfunction

Question 23

Upper motor neuron and Inhibitory interneurons neurotransmitters?

Answer 23

Upper: Glutamate
Inhibitory: GABA

Question 24

Upper Motor Neuron Deficit

Answer 24

normally after a muscle stretch/contraction, the upper motor neuron will release glutamate which activates the inhibitory interneuron to release GABA and cause relaxation at muscle - when deficient: glutamate not released so prolonged muscle contraction and spasticity

Question 25

When are glucocorticoids used? (methylprednisone, prednisone, dexamethasone)

Answer 25

used to manage either first attack or acute exacerbations (antiinflammatory) they can reduce severity and duration of attacks

Question 26

Interferon-beta1a

Answer 26

Avonex, Plegridy (pegylated form)

Question 27

Interferon-beta1b

Answer 27

Betaseron

Question 28

Interferon-beta MOA

Answer 28

1. augmenting suppressor cell function and reducing **IFN-gamma**(pro-inflammatory) secretion by activated lymphocytes 2. macrophage activating effect 3. downregulate expression of IFN-gamma-induced MHC gene producted on antigen presenting glial cells

Question 29

Glatiramer acetate (Copaxone) MOA

Answer 29

- may mimic antigenic properties of myelin basic proteins and therefore inhibit binding of the actual MBP - induces Th2 anti-inflammatory lymphocytes to reduce inflammation, demyelination, and axonal damage - neuroprotective effects by inducing brain-derived neurotrophic factor

Question 30

Mitoxantrone (Novantrone) MOA

Answer 30

DNA reactive agent: intercalates into DNA, causing crosslinks and strand breaks resulting in cytocidal effects - suppresses proliferation of macrophages, t cells, b cells but seems to enhance t-cell suppressor functions

Question 31

Sphingosine-1-Phosphate Receptor Modulators

Answer 31

Ponsimod (Ponvory), Fingolimod (Gilenya), Ozanimod (Zeposia) and Siponimod

Question 32

Sphingosine MOA

Answer 32

immunosuppressants via **sequestration** of circulating lymphocytes and macrophages into secondary lymphoid organs which block their ability to merge from lymph nodes and reduce their infiltration into CNS/inflammation

Question 33

Teriflunomide (Aubagio) MOA

Answer 33

active metabolite of leflunomide (immunosuppressant) **inhibits dihydroorotate dehydrogenase (an enzyme required for pyrimidine synthesis) to prevent proliferation of peripheral T & B cells**

Question 34

Natalizumab (Tysabri) MOA

Answer 34

Partially humanized monoclonal antibody directed at the cell surface adhesion molecule alpha4beta-integrin, it attaches and blocks its interaction with VCAM-1 on BBB endothelial cells **prevents entry of activated lymphocytes in the CNS**

Question 35

Fumerate derivatives and MOA

Answer 35

dimethyl fumarate (tecfidera), diroximel fumerate (vumerity), and monomethyl fumerate (bafiertam) **activates nuclear factor Nrf2 pathyway and independent pathways to be anti-inflammatory and cytoprotective** - been linked with progressive multifocal leukoencephalopahty risk

Question 36

Alemtuzumab-Lemtrada MOA

Answer 36

humanized monoclonal antibody against CD52, a glycosylphosphatidyllinosital anchored protein expressed in high levels on T and B lymphocytes - causes depletion of CD52 positve cells

Question 37

Ofatumumab (Kesimpta), Rituximab and Ocrelizumab MOA

Answer 37

monoclonal antibody targeting CD20-positive B cells - binds to cell surface of CD20 protein preventing B cell from causing myelin and axonal damage

Question 38

Cladribine (Mavenclad) MOA

Answer 38

Purine nucleoside analogue (antimetabolite) **a prodrug which is activated by phosphorylation and converted into the active moiety Cd-ATP. Incorporates into DNA to result in breakage of DNA strand and shut down of synthesis/repair**

Question 39

Agents used for Spasticity

Answer 39

Benzos, Tiagabine, Gabapentin, Pregabalin, Baclofen, Tizanidine, Dantrolene Sodium, Botox, Delfampridine

Question 40

Baclofen MOA

Answer 40

GABA B receptor agonist **causes closure of presynaptic Ca2+ channels and increases postsynaptic K+ conductance** enhances spinal inhibitory interneurons and decreases activity of alpha motor neurons

Question 41

Tizanidine (Zanaflex) MOA

Answer 41

significant alpha2-adrenergic agonist reducing spasticity at doses that cause few CV effects **increases inhibitory action of spinal interneurons acting both pre and post synaptically**

Question 42

Dantrolene Sodium (Dantrium) MOA

Answer 42

works locally at the muscle to impair Ca2+ release from SR by binding to the ryanodine receptor RyR1 to block opening of the channel - minimal effects on cardiac and smooth muscle RyR2

Question 43

Botox MOA

Answer 43

produces chemodenervation and prevents release of Ach by interfering with vesicle fusion by proteolytically cleaving SNAP-25

Question 44

Dalfampridine (Ampyra) MOA

Answer 44

long acting broad spectrum **K+ channel blocker**