THERAPEUTICS IN MULTIPLE SCLEROSIS Flashcards
PEDIATRIC
MS
*6 % of MS in total
*3 to 10% of MS
patients onset </= age
18
*treated similarly to
adult MS with therapies
THE EXACT CAUSE FOR MS
IS UNKNOWN
MS is an Overactive Immune
Disease
* Breakdown of myelin &
inadequate myelin repair
* Degeneration/progression
* T cell and B cell mediated
If you grow up farther from the equator in Australia, that you have a higher chance of developing MS compared to if you’re on the side of the continent that’s close to the equator.
When you smoke, you have an increased chance of developing MS in the future. And not only that, but if you continue to smoke when you have MS, it actually worsens the progression of your MS over time. So stopping smoking is a big lifestyle strategy
childhood obesity has also been associated with the development of MS. And all of this culminates in this idea of this overactive immune system problem. Where there’s a breakdown in the myelin. The myelin recovers and repairs, but it doesn’t recover that well.
DEFINITION OF MS
“separate events in space and time”
1. chronic inflammation in brain, spinal
cord, optic nerves
* Breakdown of myelin around nerves
= demyelination
2. Slow degeneration = axonal loss
* Autoimmune: T cells, B cells
* Peripheral activation, central
inflammation cascade
* Subcortical & Cortical
Multiple Sclerosis = “Many Scars”
Axonal loss: thought to be partly disconnected from the inflammation that occurs in somewhat independent, although related. So this is where we get a peripheral activation of our T-cells and B-cells. And then our leukocytes cross the blood-brain barrier and set off a series of central inflammation cascade that builds upon itself and then keeps going with that inflammatory attack on the myelin and the axonal loss over time.
CURRENT MS IMMUNOPATHOPHYSIOLOGY
“Broken Wire”
- T cell
- B cells are relatively
passive - T cell
- B cell Independent
roles (cytokines)
‘De’-
Myelination
–>
“Fixed Wire”
=
‘Re’-
Myelination
it was really an imbalance between the pro-inflammatory T type one helper T cells. And then that’s what caused the MS and that we had B-cells, but they were relatively passive in the process. T cells pass BBB and attack myelin
uccess of the anti CD20 therapies acting on B-cells - revised whole approach, B-cells are actually quite atcive
SYMPTOMS OF MULTIPLE
SCLEROSIS
*Sensory (20-55%)
*Weakness (30%)
*Bladder and Bowel (75%)
*Coordination
*Impaired vision (15%)
SYMPTOMS OF MULTIPLE
SCLEROSIS
* Depression (50%)
* Cognition (65%)
* Fatigue (85%)
* Heat intolerance
* Balance/gait
* Sexual Dysfunction
(<90%)
* Pain (70%)
* Paroxysmal
MULTIPLE SCLEROSIS SYMPTOMS
Relapse = > 24 hours
(Days/Weeks/Months)
= a clinical event of MS inflammation
Chronic, progressive (years)
= degeneration of MS
you can either get a relapse or an attack. As I said before, this is a clinical event of inflammation where there’s a breakdown in myelin and a certain spot. By definition, these have to last at least 24 h to really start. So they come on over days to weeks to months, reach a plateau and then get better either right back to normal or not quite back to normal depending on how well the scar repairs.
the second way that you have having MS symptoms is where they complained a more chronic progressive symptoms and that’s associated with the degeneration and the gradual axonal loss. just can’t walk as well as they could a year before or two years before.
HISTORICAL CLINICAL SUBTYPES OF MS
Relapsing–remitting (40 to
50%)
Secondary progressive (30
to 40%)
Primary progressive (10
to 15%)
Progressive relapsing
(<5%)
Relapse-remitting: people generally have attacks or relapses. And then they’re fairly stable in-between. So they’ll go along, they’ll have a relapse. Remember those are symptoms that last days to weeks and then get better. And then they recover, go along again. as they get older, tend to lose their relapses over a lifetime is like their inflammatory component of their MS kinda burns out, usually for in their 50s and 60s.
secondary progressive : they’re no longer having a tax or relapses, but they kinda just transition into that gradual progression over time, We only have one disease modifying therapy that’s been approved for secondary progressive
primary progressive: These are usually a bit older. They’re usually men, starts off in their 50s. And when you ask them, but they have no relapses, They just noticed this slow gradual progression, such as they found that they started dragging their leg a couple of years ago and it’s getting a bit worse over time
progressive relapsing: getting multiple relapses. They’re not really recovering from their relapses and then they’re progressing as well over time.
PRE-MS STATES
- MS Prodrome – various symptoms with increased
physician encounters and increased prescription drug use: haven’t had any focal neurologic symptoms like numbness or weakness or other things that we usually use to make the diagnosis. - Radiologic Isolated Syndrome – no history of MS, but
MRI looks like MS: they’ve had no symptoms of MS in their lives. They just live their lives and feel well. And then they have an MRI for another reason, like maybe a headache or something
- 50% have a clinical event of MS within 10 years - Clinically Isolated Syndrome = 1st spell of demyelination
- they’ve had a first clinical event of inflammation and demyelination. But they don’t fit the multiple, right? Because they haven’t had multiple spells affecting different parts of the brain and the spinal cord. This is just their first single event.
a. With abnormal MRI – 75% 2nd clinical spell in 20 years
b. With ”normal” MRI – 20-30% 2nd clinical spell in 15 years.
MS PRODROME
risk factors
prodrome symptoms
risk facotrs: genetic factors, environmental exposures
prodrome: fatigue, pain, headache, low mood, anxiety, bladder issues, infections
NATURAL HISTORY OF MS
With time:
* ↓ inflammation (response to treatment)
* ↓ number of relapses
* ↑ axonal damage
* ↑ disability
* ↑ progression
Clinically Isolated Clinical Picture
Syndrome
MRI = yellow; Progression = blue; Red = brain volume; dotted line is clinical
threshold
Therapeutic Window
Immune Therap
What it’s showing here with the blue is that we do see more spots on the MRI of inflammation over time. So the MRI is usually about five to ten times more active than clinical relapses or events.
green line that this is this first clinical relapse that brings them to attention. That we’re now realizing that if we’re going to prevent them from getting to secondary progressive, it’s best to treat them earlier in the course of the disease as soon to that first attack as possible.
. We use the MRI more and more to monitor the efficacy of our disease-modifying therapies and how well our drugs are working to try to suppress inflammation. And we do monitoring MRIs annually or if they’ve been stable for awhile biannually.
Clinical course of
Multiple Sclerosis
MS COURSE IS VARIABLE & THE
EXPERIENCE OF MS IS UNIQUE
FOR EACH PERSON WITH MS
MILDER COURSE OF MS IN THE
LAST DECADE1
Changes in diagnostic criteria2
* Changes in MS epidemiology
* Impact of early, appropriate Disease Modifying
Therapies (DMT)
* Improved general health in populations
* Treatment of comorbidities (eg: hypertension,
smoking, lipids, depression/anxiety
LATER START OF DISEASE MODIFYING THERAPIES
AFTER ONSET INCREASES LONG-TERM DISABILITY
Purple = later DMT start
Dotted = early DMT start
42% increased
hazard of
walking with a
cane
. They noticed that those people that started really early on with their disease modifying therapies, We’re pretty stable regarding their disability over time.
if you’ve started disease-modifying therapies early, you start to split off and remain stable compared to those people who started at later. If they start at two years later after their diagnosis, they had a 42% increased chance of walking with a cane
APPROACHES TO TREATING MS
- Relapse
- Disease modifying therapies
- Symptomatic
- Lifestyle
There are currently three approaches to MS treatment 4 Approaches to MS Treatment
Relapse Treatment: Steroids (IV or oral) to quicken recovery - No proven impact on disease activity
DiseaseModifying Treatments: Long-term treatments to
modify disease course, delay
accumulation of disability
No direct impact on symptoms
- people don’t actually feel any better when they’re on disease-modifying therapies, usually because you’re just trying to prevent future attacks and sometimes they can actually feel crummy on them
Symptom
Treatments: Treatments to settle symptoms
No direct impact on disease
activity
- Eg. Cramps in legs from spasticity
Lifestyle/Comorbidity
Treatments: Lifestyle Strategies outside of medications &
Treatment of Comorbidities
May directly impact disease activity, and
settle symptoms
MULTIPLE SCLEROSIS RELAPSE
TREATMENT OF RELAPSE
- Relapses (> 24 hours)
= a clinical spell of
inflammation/demyelination
Relapses or new or old neurologic symptoms, numbness and tingling, weakness, troubles with balanced loss of vision in one eye, comes on over days to weeks to months, reaches a plateau and then gets better as the myelin repairs itself in completely, usually left with a little bit of disability afterwards can last anywhere from days to months.
- Screen for UTI and infection (“pseudorelapse”)
- Stop inflammation (steroids only shorten relapse)
- Rest
- IV methylprednisolone 1 g daily x 3 to 5 days
- PO Prednisone 650 mg bid x 3 days
- Counsel: Coping strategies, work, physio, children
- Symptom management
- Try to prevent more inflammation
(Immunomodulatory Therapies)
