MS I Flashcards
Global distribution of MS–risk and lattitude
Increased MS risk as you move away from the equator
Areas most affected by MS
includes: Canada, northern Europe, New Zealand, South Africa
Places far from the equator and having northern European descent
MS prevalence in canada
High in Canada,
esp. in prairies and Atlantic
MS in alberta ___ cases/100 000 people
340 cases/100 000 population
effects ~15 000 people in Alberta
Most affected ages
most patients between the ages of 15-45
can also have pediatric cases or late onset
Pediatric MS makes up ___% of total MS patients
6%
__ % of MS patients are under 18 years old
3-10%
Sex differences in MS
MS, like other autoimmune diseases effect females more
3:1 ratio of females to males
Clinical manifestations of MS
- ocular manifestations
- cerebellar manifestations
- Autonomic manifestations
- Motor manifestations
- sensory manifestations
ocular manifestations examples
Blurred vision, diplopia
cerebellar manifestations examples
Ataxia, vertigo, nystigmus
Autonomic manifestations examples
urinary incontinence, sexual disorders
Motor manifestations examples
Reduced strength and activity
muscle spasms
muscle weakness and loss of strength
Sensory manifestations examples
sensory changes, hypoesthesia, progressive sensory los
MRI imaging in MS
help see issues prior to clinical manifestation
2 stages of MS
relapsing-remitting and secondary progression
Relapsing-remitting
Symptoms will almost completely disappear and then return (altering on/off of symptoms)
- Goes on until recovery from symptoms is incomplete
Secondary progression
Once recovery from symptoms is incomplete and the subject can no longer relapse –> accumulate disability and get gradually worse
Usually 15-17 years into the disease, fewer relapses start 2nd progressive MS
T/F: there is a disconnect between the neurodegenerative and inflammatory aspects of the disease
TRUE
Will get progressively worse but maintain relapsing and remitting until a certain point
Expanded disability status scale (EDSS)
The scale used to measure disability over time
looks at motor, sensory, cerebellar systems and score them –> get score
0 = normal
10 = death
6 on EDSS
assistance required to walk
use of cane
7 on EDSS
restricted to wheelchair
MS
Demyelination causes damage to nerve can have two outcomes:
Transection (not-desired)
Remyelination (and therefore repair)
get a mix of the two
Transection
Disconnection over time
axons cut
Remyelination
mechanism of repair
patch over damage, not perfect (worse than pre-demyelination)
Demyelination causes
axonal injury and loss over time
significant injury –> decreased # of fibres
Brain of MS patient
periventricular lesions
Causes of MS
Genes and environment interact to cause MS
Environmental triggers include
- infections
- smoking
- salt
= things that trigger inflammation - lack of sun exposure (low vit D)
Triggers facilitate disease progression
Genetic contribution to MS risk
HLA complex marker–Markers of immunity
Not genetically transmissible
Genetic contribution is low
MS thought to be
IMMUNE MEDIATED
Although the initiating etiological factors are unknown,
the destruction within the CNS is thought to be
immune-mediated
MS as immune-mediated evidence
- Many inflammatory cell types are localized to lesion sites in the CNS
- The activity of several inflammatory cell types is dysregulated
- Levels of several inflammatory cytokines are increased in the serum, CSF and CNS of patients with MS
EAE
Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune disease of the CNS that causes the CNS myelin to be recognized as an exogenous immunogen and subsequently be attacked by T-cells
Mice EAE
EAE injected into muce –> diseases mediated by myelin basic protein-specific Th1 cells –> can transmit EAE through transfer of injected T-cells into healthy mice
MBP
Myelin basic protein (protein of myelin)
Immunology of EAE
Inject MBP into mice –> MBP-recognizing T-cell (in a pool of naive T-cells) is usually silent but will pick up antigen and present it to lymphocyte –> expansion of MBP-reactive T-cells –> enter CNS –> reactivated in CNS –> CNS pathology attacking myelin
How models of molecular mimicry can cause MS
virus with molecular similarly to MBP –> in a pool of naive T-cells both a virus recognizing cell and the MBP-recognizing cell are activated –> antigen presentation of virus to naive T-cells –> expansion of both virus-speicifc and cross-reactive MBP-specific T cells –> enter CNS where they recognize MBP and initiate inflammatory damage
Naive T cells types
Pro-inflammatory: - TH1 cytokine (IL-2, IL-12, IFN-gamma, TNF-alpha) - TH17 cytokines (IL-17, IL-23) Anti-inflmamatory: - Th2 (IL-4,5,10,13,25; TGF-beta) - Treg (TGF-beta, IL-10, IL35)
Goal of therapeutics on cytokines
pro-inflammatory factors cause auto-immune response so want to increase the anti-inflammatory side
T-cells action in brain
get in brain (trans-migration through BBB) –> activated inflammatory cells in CNS will be re-stimulated –> look for myelin (MBP) –> attack
Perivacular inflammatioon in MS plaques
perivascular infiltrate of the lymphocyte that surrounds the vessel then infiltrates the brain parenchyma causing injury
Transection of Axons: longterm effect
Accumulation of transected axons causes disaease symptoms
goal in treatment: prevent transection
Transection of axons correlated well with disease progression TRUE or FALSE
TRUE
Brain atrophy: HOW
loss of axons –> complete atrophy –> widening of venticles
2 approaches to MS treatment
Disease-modifying treatment
Symptom treatment
Disease-modifying treatment
Long-term treatments to modify disease course, delay
accumulation of disability
No direct impact on symptoms
Symptom treatment
Treatments to settle symptoms
No direct impact on disease
Spasms in MS–why
b/c lesions affect the corticospinal tract
Loss of inhibitory signals = muscle continuously contracted –> spasticity (+ main and functional loss)
Most used drug for spasms
Baclofen
Baclofen
most relevant drug for MS-related spasticity
GABA agonist
Side effects: Sedation, drowsiness, muscle weakness
Benzos
used for spasticity in MS
Facilitate postsynaptic effect of GABA and increase presynaptic inhibition
Side effects: Fatigue, drowsiness, dry mouth, postural hypotension
Drugs for spasticity
Baclofen (GABA agonist)
Tizanidine (Alpha2 agonist)
Dantrolene (reduces Ca2+ release)
Benzos (increases Cl- channel opening, increase GABA)
Gabapentine (Decreses release of gluatmate presynaptic terminal)
For severe spasticity use….
- Intratechal baclofen
- Chemodenervation (Botox injections)
- Delta9-tetrahydrocannabinol (Sativex)
Intrathecal baclofen
Pump baclofen into spinal CSF
continuous
Used in severe spasticity
Botox
Used in severe spasticity to relax muscles
Fatigue–definition
a feeling of physical tiredeness and
lack of energy distinct from sadness or
weakness
Severe fatigue is seen in ___ % of patients
Severe in up to 74 % of pts, the worst symptom of the disease in 50-60 % of pts
Drugs to treat fatigue
Amantadine (MA, Ach and Glut effects on CNS)
Modafinil (CNS stimulant)
Pemoline (CNS stimulant)
4-Aminopyridine (Blocks K+ channels –> longer APs, more NT)
Amantadine
Drug to treat fatigue
Monoaminergic, cholinergic and glutamatergic effects of the CNS
Side effects: Anorexia, nausea,
insomnia, hallucinations, blurred vision, peripheral edema, urinary retention
Main side effect from anti-fatigue drugs
tend to be stimulants, cause lack of sleep
Bladder dysfunction–3 types
Bladder overactivity: urgency, frequency, urge incontinece.
Bladder inefficiency: incomplete emptying, residual, urine.
Detrusor-sphyncter dyssinergia: co-contraction of bladder and urethral sphyncter
Bladder overactivity
urgency, frequency, urge incontinece.
Bladder inefficiency
incomplete emptying, residual, urine.
Detrusor-sphyncter dyssinergia
co-contraction of bladder and urethral sphyncter (can’t let urine down from bladder)
Bladder dysfunction affects ___% of patients
75%
Treatment of Bladder dysfunction: 2 categories to treat
Storage dysfunction (Bladder inefficiency, Bladder overactivity) Voiding dysfunction (Detrusor-sphyncter dyssinergia)
Treating bladder storage dysfunction
• Behavioural therapy • Antimuscarinic agents (oxybutynin, tolterodine, solifenacin) • Desmopressin • Botox • Beta3-adrenoceptor agonists (mirabegron) • Bladder augmentation • Sacral deafferentation/anterior root stimulation
Treating Bladder Voiding dysfunction
- Intermittent catheterization
- Indwelling catheterization
- Alpha-adrenoceptor blockers
Pain 2 types in MS
- Persistent neurogenic pain
- Paroxismal neurogenic pain (trigeminal
neuralgia)
Persistent neurogenic pain
burning dysestesia of the limbs and/or trunk attributed to disruption of the spinothalamic pathway usually within the spinal cord
Paroxysmal neurogenic pain (trigeminal
neuralgia)
episodes of excruciating facial pain.
triggered by light touch to face
shooting pain
Pain affects __ % of patients
40-50%
To induce bladder relaxation
use anticholinergics to blocks Ach cascade
Main drug type for bladder storage dysfunction
Antimuscarinic agents (oxybutynin, tolterodine, solifenacin) act on mAchRs
SC control of pain main NTs
NE and 5HT
Treatment of trigeminal neuralgia: 2 categories
Anti-epileptics (stabilize cell memb)
Surgical interventions
Pharmaceutical treatment of trigeminal neuralgia
- Carbamazepine
- Oxacarbazepine
- Lamotrigine
- Gabapentin
Surgical treatment of trigeminal neuralgia
used when especially bad
• Radiofrequency thermocoagulation
• Glycerol rhizothomy
• Balloon compression
Treatment of persistent neuropathic pain
- Tricyclic antidepressant (amitryptiline, nortriptiline)
- Gabapentin
- pregabalin
- Serotonin or norepinephin reuptake inhibitors (SNRIs–duloxetine, venlafaxine)
- cannabinoids
