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Module 2 > MS > Flashcards

MS Flashcards

1
Q

What are the main deficits in cognitive impairment?

A

Memory
Speed of information processing
Attention
Executive function

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2
Q

What are the multi factors in aetiology?

A

Genetics
Viruses
Environmental
Hormones

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3
Q

How have hormones seemed to influence MS?

A

Disease activity decreases during pregnancy and increases in the first 3 months post partum.

MS twice as likely as men to have MS.

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4
Q

How do plaques form and what are they indicative of?

A

Demyelination after inflammation.

They are the pathological substrate of acute relapses.

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5
Q

What are some relapse symptoms?

A

Optic neuritis (monocular vision loss)
Spinal cord lesion (weakness, spasticity)
Brainstem lesion (diplopia, dysarthria)
Cerebellar lesion
Cerebral lesion (seizures, psychiatric disturbances)
Severe fatigue

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6
Q

Describe relapsing remitting MS.

A

Relapsing remitting:
Common symptoms: Optic neuritis, sensory disturbances
Initially a LOT of inflammation.
Demyelination occurs early, alongside relapses. There is permanent axonal loss.

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7
Q

What are the Mcdonald criteria for diagnosis?

A

Dissemination in time and space. MRI evidence provides this.

Space: More than 1 T2 lesion in at least 2 of 4 typical locations (periventricular, subcortical, Infratentorial, spinal cord)

Time: New T2 lesion and/or galinium (GAD) enhancing lesions on follow up MRI.

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8
Q

What does CSF analysis show?

A

Increased immunoglobulin production
Mostly normal proteins
Oligoclonal bands in CSF only.

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9
Q

Give 2 differential diagnoses that are CNS specific.

A

Acute disseminated encephalomyelitis (ADEM).
Motor deficit, ON bilateral, encephalopathy, seizure. Initially a large affected area. A monophasic disease (patient back to normal after 6 months).

Neuromyelitis optica
Sever CNS demyelinating syndrome characterised by optic neuritis and acute myelitis. Acute monophasic or relapsing. Cord lesion is longer along spinal cord, whereas MS lesions are distinct.

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10
Q

What are some good and bad prognostic indicators?

A 
Good:
Young onset
Female
Optic neuritis or only sensory symptoms at onset
Low frequency of attacks
Bad:
Male
>40 years onset
Pyramidal tract involvement. 
Prominent cerebellar involvement
Frequent early attacks
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11
Q

What are some pathological signs and their clinical correlates?

A

Inflammatory foci without demyelination: Acute relapses
Primary demyelination: Acute and chronic
Grey matter demyelination: Progressive
Axonal loss: Progressive
Grey matter neuronal and axonal loss: Progressive motor, sensory and cognitive fatigue.
Diffuse white matter changes
Diffuse grey matter changes

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12
Q

What are some other pathological features seen?

A

Demyelination on the underside of the pons

Extensive lesions follow lateral ventricles

Atrophy in severe cases

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13
Q

Where are CD4+ and CD8 T cells and B cells commonly found?

A

Perivascular space

Meningeal space

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14
Q

Why are macrophages significant?

A

Contain myelin debris which they have engulfed. Determine the lesion edge. Wave of demyelination.

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15
Q

What are some inflammatory mechanisms seen?

A

Release of free radicals by immune cells and microglia
Glutamate release by microglia- excitotoxicity.
Hypoxia like events
Mitochondrial dysfunction
TNF,lymphotoxin, IL1B, interferon-y

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16
Q

What are 4 mechanisms of demyelination?

FGCA: Fat girls are clapped

A

Free radical release
Glutamate
Antimyelin antibodies
Cytotoxic cytokine

17
Q

What cells are seen in meningeal inflammation?

A

CD20 B cells

Follicular dendritic cells- normally only in lymphoid tissues.

18
Q

What cells are there in a tertiary lymphoid follicle?

A 
Plasma cells
CD8+ , CD4+ T cells
Dendritic cell
Follicular helper T cell
Macrophage
Follicular dendritic cell
19
Q

What mediators are released by the follicle

A 
Antibodies
IFN-y
Type I IFNs
TNF
MMPs
Cytokines
Chemokines
Granzymes
Perforin
20
Q

How is CNS remyelination induced?

A

NG2 expressing glial progenitors are ubiquitously distributed throughout the mammalian adult CNS. NG2 OPCs respond to demyelination and increase in cell number/

21
Q

What is the EAE model of MS?

A

Experimental autoimmune encephalomyeletis.

Immunisation of animals with myelin antigens:
MOG35-55 : Monophasic
MOG37-46: CD8+ T cells
Human MOG: B cells
PLP/MPB peptides: RRMS

Very good model for autoimmunity, not so good for MS:
Short- No remyelination
No relapses
Mainly spinal cord white matter

22
Q

What is TMEV model?

A

Theiler’s murine encephalomyelitis virus.

Epstein Barr virus
Coronavirus
Rabies
PicoRNA virus.

This is the chronic progressive type of MS. It infects neurons and is inflammatory myelinating disease.

Infection-> Nuerodegeneration-> Inflammation-> Demyelinatoin->Axonal/neuronal loss

23
Q

Discuss the cuprizone toxic model.

A

This is a copper chelator. Causes mitochondrial/metabolic problems, causing premature oligodendrocyte cell death and demyelination.

Activation of glial cells-> inflammation.

Remyelination after cuprizone removal. Therefore good for demyelination/remyelination, and can study mitochondrial dysfunctions.

24
Q

Discuss the Lysolecithin toxic model.

A

Direct injection into spinal cord, activates phospholipase A2. Direct toxicity to myelin sheath.

Rapid demyelination, no axon damage.

Can observe remyelination and possible role of leukocyte infiltration in repair.

25
Q

In EAE, how does some different pathology correlate with disease severity?

A

OX-42 cell density correlates significantly with disease severity in progressive EAE.
Demyelination correlates significantly with disease severity.
Axon loss correlates significantly.

26
Q

What are different possible induction mechanisms of immune activation?

A 
Induction of immunosuppression
Activation of NKT cells
Induction of Th1 responses
increased self-peptide presentation
Bystander activation
Cross reactivity with self peptides
27
Q

How does EBV contribute to MS?

A

Infects B cells nad uses their differnetiation progtram to establish a persistent, usually, asymptomatic latent infection in humans.

Escape T cell control, interact with antigen presenting cells, produce cytokines and recruit proinflammatory lymphocytes.

28
Q

What are some symptoms and how can some of these be treated?

A

Spasticity- Baclofen, stretching, physio
Sphincter disurbance
Pain- Paroxysmal (Gabapentin) or chronicdysaesthetic (amitriptyline)
Fatigue- Energy savings, Modafinil, planning day, make patient active, physio therapy.
Depression
Tremor
Sexual dysfunction

29
Q

What are the primary and secondary outcomes of RR MS?

A 
Primary: 
Annualised relapse rate, proportion of relapse free patients
Number/volume of T2/GAD+ MRI lesions
Time to next relapse
Time to disability progression
30
Q

What are 2 immunomodulatory treatments and which one is more effective?

A

IFN-B: Type I interferon, has antiviral and antiproliferative effects as well as immunomodulatory.

Fingolimod: INterferes with T cell trafficking, no effect on T cell activation, proliferation or cytokine production or B cell antibody production.
Internalisation of S1P1 recpetor-> Reduce T cell response to chemotactic cues, preventing exit from lymphoid organs.

FINGOLIMOD more effective.

31
Q

What are 3 other immunomodulatory treatments and their MOA?

A

Dimethyl fumarate: Anti oxidant properties by activating Nrf2. Blocks cytokine production through unknown mechanisms.

Natalizumab: Binds to lymphocytes, prevents their adhesion to VCAM receptors expressed on endothelial cells, therefore inhibiting lymphocyte migration through BBB, preventing lesion formation. Natalizumab prevents disease activity in patients with RRMS.

Alemtuzumab: Targets CD52 on B & T lymphocytes. Depletes their levels. This mediates inflammatory processes.

32
Q

What would be the ideal outcomes of treating MS?

A 
Prevention
Freedom of clinical disease activity
Cessation of biological disease activity
Reversal of disability
Reasonable mode of action
No ongoing therapy

Module 2 (7 decks)

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