CPPS 306 Multiple Sclerosis

What is multiple sclerosis; type of hypersensitivit, onset

• Autoimmune disease of the CNS

• Type 4 hypersensitivity (cell-mediated no antibody-mediated)

• Onset 17-35 year

Explain what happens in multiple sclerosis

1. Normally myelin and oligodendorcytes are isolated form immune cells

2. T cell (immune cell) somehow becomes activated against myelin and destroys it → Type IV hypersensitivity

3. Activated T cells up regulate receptors and release cytokines

4. cytokines cause blood vessles to become leaky

5. B cells and Macrophages are recruited for

• Antibody production and destruction and clearance

6. Results in plaque formations

What cytokines do the acitvated T cells release

• IL-1

• IL-6

• TNF-alpha

• INF gamma

What are the four types of multiple sclerosis

Relapsing-remitting

Primary Progressive

Progressive relapsing

Secondary progressive

What is the most common type of multiple slcerosis

Relapsing remitting

What are the symptoms of multiple sclerosis

• Charcot’s neurologic triad

• Plaques in sensory pathway

• Lhermitte’s sign (electrical sensation that runs down the back into the limbs)

• Plaques in ANS

• Higher order activities (depression + anxiety)

• Uhthoff’s phenomenon

What is charcot’s neurologic triad

Symptom of MS

• Nystagmus (Involuntary rhythmic, and rapid oscillation of eyes)

• Intention tremor

• Unclear speech (dysarthria)

One of the symptoms for MS is plaques in ANS, what does this lead to?

Bowel & bladder symptoms

Sexual dysfunction

What is the uhthoff’s phenomenon

One of the symptoms for MS

• Worsening of symptoms in heat

• Increasing in body temperature can slow or block impulse conduction in demyelinated nerves

What is the aim of acute treatment for Multiple Sclerosis

Stop current inflammatory disease processes

What are the acute treatment drugs used in MS

• Methylprednisolone = immunosuppresive

• Plasma Exchange therapy (PET)

  • Plasma is seperated and discarted (containing autoantibodies

  • Replaced with donor plasma or albumin/saline

What is the goal for disease modifying therapies (DMT) in MS

Decrease risk of relapses with goal of slowing disability progression

Stopping new lesions from happening

What are the disease modifying therapy [DMT] (first line) drugs used in MS

Interferon-B

Glatiramer Acetate

Fingolimod

Compare and contrast interferon-B vs Fingolimod in terms of how much they reduce MS relapses

Intergeron-B = 30% reduction

Fingolimod = 54% reduction

Which of the Disease Modifying therapy drugs crosses the BBB, which doesnt? What does this mean?

Glatiramer Acetate = doesnt cross BBB (works in periphery only)

Fingolimod = crosses BBB (works in PNS and CNS)

What is glatiramer acetate made of

Different sized peptides with 4 amino acids found in myelin basic protein (MBP)

Which of the first line of drugs used for DMT act as a decoy for attacking immune clles

Glatiramer acetate

What drug shifts proinflammatory Th1 T-cells to antiinflammatory Th2 T-cells

Glatiramer acetate

• Reduce inflammatory signalling without entering the CNS

What was the first oral DMT drug approved for MS

Fingolimod

Which DMT drug reduces antigen presentation and T-Cell proliferation

Interferon B

Which DMT drug prevents lymphocytes from entering the CNS for relapse

Fingolimod

What other channels does fingolimod act on, and what does it inihibit

• CB1 antagonist

• Ceramide synthase inhibitor

What are the monoclonal antibody therapy drugs used for DMT

Natalizumab

Alemtuzumab

Ocrelizumab

Daclizumab

How much does Natalizumab reduce MS relapse and what does this drug prevent

68% reduction in MS relapses

• Prevents binding and crossing BBB

Which monoclonal antibody therapy drug tags and destroys lymphocytes?

Alemtuzumab

Which monoclonal antibody therapy drug is immunosuppressive and how

Ocrelizumab

• Kills B cells → decrease antibody production and immune activation

What does daclizumab do

Blocks IL-2 alpha subunit for net reduction in T-cell responses → decreased autoimmune activity in MS

• Well tolerated and manageable

What drug is used to treat difficulty in walking in MS? How does this drug help with MS

Dalfampridine

• Potassium channel antagonist

Thought to increase conduction in absence of myelin

What drugs are used to treat spasticity in MS

Tizanidine

Botulinum toxin

Nabiximols

What is tizanidine?

Drug used for Spasticity

• A2-adrenergic agonist

• Muscle relaxant, may cause hypotension (low BP)

What does botulinum toxin block and what is this drug specific to

Blocks vesicle docking

• specific to ACh containing nerves

What does botilinum toxin cleave and what could the use of this drug lead to

Cleaves SNARE proteins

• Could lead to paralysis