Lecture 11: Multiple Sclerosis Flashcards
What age group has highest onset for MS? Gender discrepancy?
25-35 (median 23.5, mean 30)
M:W 2:1
What is Multiple Sclerosis?
Chronic primary demyelinating disease of CNS
Characterized by EPISODIC neurologic dysfunction
-eventually may result in a progressive course of persistent neurologic deficits
-only shortens lifespan by 1-2 years
What is the epidemiology of MS?
350,000 cases in US -10,000 new cases yearly M:W is 1:2 Affects ages 15-45 (think of basketball player) -high risk in North America/Europe
When a young blood presents with acute motor/sensory symptoms, what should you always suspect?
Multiple Sclerosis
Is there a diagnostic test for MS?
NO
-because other shit can mimic it
What is the etiology of MS?
MULTIFACTORIAL Autoimmuity (allergy to CNS myelin) Infections genetic predisposition Immunogenice triggers like EBV and HHV-6
What are types of immunogenic triggers?
- Viruses like EBV and HHV-6
2. Bacteria (Chlamydia pneumonia, mycoplasma)
HLA-DRB1501 (MHC class II)
The gene that is most associated with MS
What gene is most associated with increased risk in MS?
HLA-DRB1501
-identical twins = 30% risk
1st degree relatives = 4%
What are the typical MS signs and symptoms?
Focal weakness -monoparesis, hemiparesis Focal numbness/paresethesias -tingling, band-like sensation Optic neuritis Speech difficulties -dysarthria, slurring Lhermitte’s -flexion of neck leads to paresthesia Uhthoff’s -symptoms exacerbated by heat Coordination/gait/balance Urinary symptoms; bladder spasticity, frequency Spasticity (UMN signs)
What is Lhermitte’s sign?
An indication of MS
When you flex your neck and induce traction on a demylinated nerve, you get a mild shooting paresthesia
-barber chair phenomenon
What is Uhthoff’s sign?
An indication of MS
Heat fucks with demyelinating nerves so MS patients do better in the cold
What is RRMS?
Relapsing-remitting MS
-85% of patients
-relapses occur over 10-20 years after initial presentation
-less frequent as years pass
In episodes, symptoms get worse, plateaus,
Then goes back to normal
What is SPMS?
Secondary progressive MS
What is PPMS?
Primary progressive MS
No episodes
MS just keeps getting progressively worse
What is PRMS?
Progressive relapsing MS
Symptoms get progressively worse with constant progression
What do 75% of MS patients present with?
Motor and sensory symptoms or optic neuritis
What is the point of MS treatment?
The longer a patient has MS, the less likely it is he/she can walk independently
Treatment is used to prevent loss of walking
Example: Interferon Beta
What are the key steps in MS neuropathogenesis
- CNS entry of activated T cells, monocytes
- neuroinflammation
- axonal degeneration (white matter lesions)
- Brain atrophy (black holes)
Goes from immune reaction to just plain ol’ degeneration
What is one key feature of MS in MRI?
MS lesions do NOT respect vascular boundaries or distributions
What is the purpose of gadolinium lesions?
These show up in MRI and demonstrate INFLAMMATION
What is the most characteristic step in MS pathogenesis?
Immune activation of T cells (CD4 and CD8) as well as B cells in periphery
-mechanisms are poorly defind
What is the significance of molecular mimicry?
An attractive explanation for induction of “auto-immune responses” Non-self antigens include i. EBV, HHV-6 ii. Borrelia iii. Chlamydia Potential self antigens i. myelin basic protein ii. proteolipid protein
What are the inflammatory mechanisms in MS?
Predominantly T-cell-mediated inflammatory disorder Activation and CNS entry of t cells specific for myelin antigens BBB breakdown -gadolinium enhancement of lesions Demyelinations Lesions via T2/FLAIR Axonal injury Brain Atrophy
What is the proposed correlation of MS clinical course, axonal loss and neurologic disability?
There is a certain clinical threshold of axonal loss in which there is irreversible neurologic disability
- CNS can no longer compensate for neuronal loss - prior to threshold, CNS was able to compensate for neuronal loss
What are the classic clinical features of MS?
Waxing and waning “long-tract” signs occurring over weeks – months (motor, sensory, coordination, others)
What is one diagnostic criteria for MS?
Characterized by lesions disseminated in time AND space
What is the McDonald Criteria for MRI?
Important for Clinically Isolated Syndrome (CIS)
Uses MRI to show dissemination in space (DIS) and dissemination in time (DIT)
What are the classic MRI findings of MS?
- T2/FLAIR hyperintense lesions
- Dawson’s fingers AND corpus callosum
- periventricular demylination
- seeing white in T2
- Gadolinium-enhancing lesions
- inflammation
- Confluence of lesions
- T1 black holes
- Brain atrophy
How can DIS be demonstrated?
Lesions in at least 2 of 4 areas
1. Periventricular 2. Juxtacortical 3. Infratentorial 4. Spinal cord
How can DIT be demonstrated?
A new T2 and/or gadolinium-enhancing lesions on follow-up MRI with reference to a baseline scan
OR
Simultaneous presence of asymptomatic gadolinium-enhancing/nonenhancing lesions at any time
If you see 2 or more clinical attacks and 2 or more clinical lesions then
Clinical evidence suffices for MS
If you have fewer than 2 of each, then you still need to prove diagnosis of MS
Aside from MRI, what else is important to diagnose MS?
History and neurologic exam Adjunctive tools like evoked potentials (measuring nerve conduction) Lumbar puncture (oligoclonal bands) Must exclude demyelinating causes or diseases including i. small strokes ii. Lyme iii. Sarcoid iv. B12 deficiency v. HIV
What is the classic syndrome of white matter tract dysfunction?
Internuclear Opthalmoplegia (INO)
What are Dawson’s fingers?
When you see white on T2 on the sides of the ventricles
These represents demyelination perivascularly
90% diagnostic of MS
What is the approach and criteria for diagnosis of MS?
Multiple CNS deficits and lesions of white matter due to PRIMARY demyelination (excluding other knowns)
What are the key characteristics of gadolinium staining?
Indicative of inflammation
Acute plaques take up gadolinium in T1
Frequent in subclinical phase of MS and in silent periods
5-10 times MORE FREQUENT than relapses
Resolve in 4-6 weeks and leaves T2 hyperintense lesion
What are the key characteristics of T1 Hypointense lesions “black holes”?
A subset of T2 lesions becomes T1 HYPOintense lesions
Reflect CHRONIC MS lesions with localized areas of axonal loss and gliosis
-gliotic scar
The number and volume of black holes are associated with neurologic diability
What is the significance of oligoclonal IgG bands?
A type of test that is indicative of MS
-oligoclonal bands that are NOT present in serum but present in CNS are indicative of IG production in CNS
How do we treat MS?
Treat or remove inciting agents or stimulus
-stress, infection
For mild MS
-observe, reassurance, treat symptoms
For moderate/severe MS
-IV steroids, physical therapy, treat symptoms
What is the basic rationale for current disease-modifying therapy for MS?
To slow progression of MS
Do so by targeting T cells and monocytes (inhibiting their activation) and also by preventing CNS entry
What are examples of drugs used in the MS treatment?
Interferons Avonex, Rebif, Betaseron Shit that traps T cells in lymph nodes Gilenya Blocks proliferation of activated B and T cells Aubagio Immunosuppressive and induces anti-oxidant response genes Dimethyl fumarate
