March 20 - Multiple Sclerosis

Question 1

What is the incidence of multiple sclerosis in Canada?

Answer 1

1:500 to 1:1000 (it is about 3x higher in the Manitoba area)

Question 2

How much money, on average, is invested in one MS patient?

Answer 2

1.6 million/patient

Question 3

What are contributing factors of multiple sclerosis?

Answer 3

Race (caucasians), age (25-38), sex (females are more likely to be diagnosed, males have a poor prognosis), infection (Epstein-Barr, HHV6, chlamydia, pneumoniae, etc.), injury, genetics (it’s not hereditary, but there can be a genetic predisposition), geography, diet/sunshine (make sure patients are supplemented with vitamin D

Question 4

Explain genetics as a contributing factor for MS

Answer 4

In a first degree family relative of patient with MS, absolute risk of MS is: <5% which equates to 20 to 40 times increased risk compared to general population. In monozygotic twins: concordance rate for MS is higher (31%) than in dizygotic twins (5%). As such since not 100% concordance rates in identical twins, this is proof that genetics alone is not solely responsible for this disease. Presence of HLA-DR2 allele increases the risk of MS. MS is not hereditary disease but patient may have a genetic predisposition for the disease

Question 5

What are the theories associated with the development of MS?

Answer 5

Infectious theory (measles, mumps, rubella, EBV, HHV-6)
Molecular mimicry
Autoimmune disease

Question 6

Explain the pathophysiology leading to multiple sclerosis

Answer 6

MS is an autoimmune disorder that is caused by the pathological activation of inflammatory Th1 cells. A foreign antigen enters our blood. An antigen-presenting cell (APC; macrophages, monocytes, dendritic cells) picks it up by binding it to the HLA-DR2. It presents the antigen to a naive T cell and it activates it to an inflammatory Th1 cell.

Question 7

What are mediators of inflammation?

Answer 7

IL-12, IL-2, IL-6, IFN-gamma, TNF-alpha. There are too many of these in MS

Question 8

What are protective mediators (anti-inflammatory)?

Answer 8

Il-4, IL-10, TGF-beta

Question 9

Describe a model of MS immunology

Answer 9

An antigen binds to an APC. There is the production of inflammatory mediators. These mediators make the blood-brain barrier (BBB; area between PNS and CNS) very sticky with adhesion molecules. Th1 cells dock to adhesion molecules. The production of mediators of inflammation continues. A protease on the surface of the BBB is activated. The BBB is usually really tight but the protease causes it the integrity of the BBB to loosen up. Th1 cells pass into the CNS, where they can’t differentiate between the foreign antigen they are supposed to protect against and myeline

Question 10

How do Th1 cell damage the myeline

Answer 10

They create lesions in the myeline sheaths which causes the dissipation of the electrical activity (neurological deficits). As the disease progresses, the lesions get bigger and eventually there is no more myeline around the neuron. The nerve cell dies, causing cognitive deficits

Question 11

What is the median time to requiring cane/crutch?

Answer 11

15 years

Question 12

What is the median time to wheelchair confinement?

Answer 12

25 years

Question 13

What are current opinions regarding treatment effects?

Answer 13

Someone who decides they don’t want treatment will have tremendously worse disabilities. Starting treatment right at the diagnose results in minimal disability

Question 14

What is one clinical diagnostic tool?

Answer 14

Cerebrospinal fluid exam - determine the presence or absence for IgG antibodies against oligodendrocytes (Oligoclonal IgG bands)

Question 15

Describe the clinical course of the disease

Answer 15

Patients will have first clinical attack (loss of vision, numbness, can’t move a limb, etc. - very pronounced). After a few weeks, the patient gets better. Several years later, they have a second clinical attack. For a while the attack will descend below clinical threshold (the patient will not notice any symptoms below threshold). This is called relapsing remitting (RR) MS (80% of patients are RR MS). As the disease progress, the attack doesn’t go back to below threshold. This is called secondary progressive (SP) MS.

Question 16

What is it called when an MS patient only has one attack?

Answer 16

Clinically isolated syndrome (CIS) MS

Question 17

What is primary progression MS?

Answer 17

When the patient has the first attack, it never comes back down to baseline. So the after the first attack, they never recover and it only gets worse. This is the most debilitating form of MS (it’s the rarest - predominantly found in males)

Question 18

What are symptoms of MS?

Answer 18

Fatigue and weakness, bladder control problems, neuropathic pain, cognitive defects, optic neuritis, sexual dysfunction, ataxia, depression

Question 19

Why would a patient experience fatigue and weakness?

Answer 19

Their immune system is always fighting. But also because more energy is lost through the dissipation of electrical impulses (like when you have a gas leak, you could put the peddle to the metal and still only go 40 km/hour)

Question 20

Why would a patient experience bladder and bowel control problems?

Answer 20

The myelination on the nerve that controls either inhibition (results in incontinence) or excitatory (results in bladder retention) nerves are damaged

Question 21

What are the McDonald clinical criteria for RRMS-Definitive diagnosis?

Answer 21

Clinical attack(s) +/- MRI must show dissemination in time and space
2 clinical attacks where each attack lasted greater than 24 hours; dissemination in time (at least 30 days apart)
Does not require an MRI

Question 22

How is a clinically isolated syndrome diagnosed?

Answer 22

1 attack that lasted greater than 24 hours even with a postive or negative MRI that doesn’t fulfill McDonald’s criteria in regard to dissemination in time and/or space. This is not a definitive diagnosis of MS

Question 23

What is required for Manitoba/Alberta IMA drug coverage?

Answer 23

2 attack where each attack lasts greater than 24 hours and is separated in space by at least 30 days with a positive MRI that meets McDonald criteria within the past 2 years

Question 24

What is a reasonable clinical end point in the treatment of MS?

Answer 24

Stop myeline from being attacked. These drugs (interferon-beta 1a and 1b and glatiramer acetate) suppress the production of Th1 cells. So these drugs stop the production of Th1 cells (block the immune system response)

Question 25

What are immunomodulatory (IMA) therapies for RRMS?

Answer 25

Interferon beta 1a 30 ug IM once weekly
Interferon beta 1b 8 M.U. sc EOD
Interferon beta 1a 44 ug sc tiw
Glatiramer acetate 20 mg sc qd
All these IMA agents work in a similar manner to suppress Th1 production (they shift the Th1 balance)