NV - Neuromuscular Disorders II: Myasthenia Gravis - Week 2

Question 1

Recap: what test detects proptosis? What test measures it? What does scleral show indicate and what is checking for lid lag on down gaze helpful for?

Answer 1

Birds eye - detection
Side view - measurement
Scleral show can indicate proptosis
Lid lag on downgaze is helpful for diagnosis

Question 2

How can you tell whether ocular misalignment is comitant or incomitant? What List a cause for both of these.

Answer 2

Comitant - decompensated congenital deviation
Incomitant - CN4 palsy or acquired

Question 3

List three acquired causes of incomitant ocular misalignment.

Answer 3

Paretic
Mechanical (TED)
Neuromuscular

Question 4

What kind of disorder is myasthenia gravis?

Answer 4

Autoimmune disorder

Question 5

Antibodies against what is produced in myasthenia gravis? Describe what this causes and how this affects receptor binding, number, and activation.

Answer 5

Nicotinic acetylcholine receptors (nAchR)
Local membrane internalisation increases
-internalised nAchR does not bind as readily
Receptor numbers decrease and activation decreases

Question 6

What are two expressions of myasthenia gravis (3)?

Answer 6

Systemic
Ocular
Both

Question 7

What percentage of myasthenia gravis patients have only ocular problems? What is this known as? What Percentage of myasthenia gravis patients with only ocular problems develop systemic problems and within what timeframe?

Answer 7

40% of all MG patients have only ocular problems - ocular MG
60-80% of ocular myasthenics develop systemic problems within 2 years of diagnosis

Question 8

What organ does systemic myasthenia gravis particularly affect?

Answer 8

Lungs

Question 9

What antibody type is produced with myasthenia gravis? What does it do and what happens over time?

Answer 9

IgG
Blocks nAChR, they break down with time
-results in decreased number of functional receptors

Question 10

What additional component co-localises with antibodies in myasthenia gravis and what is the consequence of this (3)? What does this mean for repeated use of the neuromuscular junction?

Answer 10

Complement (C9) co-localises with the IgG
-affects local membranes carrying nAChR
-nAChRs internalise
-this speeds the breakdown of nAChRs
-results in loss of functional nAChRs with use

Question 11

List the two mechanisms that result in dysfunction of cholinergic receptors in myasthenia gravis and note which one results in fatigability. Describe why.

Answer 11

Antibody IgG mediated
-directed against receptors
Complement C9 mediated
-membrane internalisation
-results in fatigability

Question 12

Below what percentage of active nAChRs do symptoms of myasthenia gravis begin to manifest?

Answer 12

Below 35%

Question 13

Note two associations of myasthenia gravis. Note the percentage for each.

Answer 13

Thymus dysfunction - 70% of MG patients have thymus hyperplasia
Thyroid dysfunction - 5% in MG

Question 14

What percentage of thyroid dysfunction patients develop myasthenia gravis (male and female)?

Answer 14

Male - 9%
Female - 20%

Question 15

What three ocular signs would you expect to see with myasthenia gravis? Note the most common expression.

Answer 15

Ptosis - most common
Vertical diplopia
Fatigue on repeated effort (10-20 times)

Question 16

Does fatigue from myasthenia gravis improve or worsen with cooling? Explain why (2).

Answer 16

Improves
-cooling acts to stabilise the membrane
-stops internalisation

Question 17

List four systemic expressions that may be seen in myasthenia gravis (organs).

Answer 17

Face
Tongue
Lungs
With time - ANS (bowels, heart etc)

Question 18

List two compounds that are used to test for myasthenia gravis. Note what each of these are and how they work.

Answer 18

Compounds that increase muscle action with injection:
Neostigmine
-an ACh agonist - slow release of ACh
Tensilon
-an AChE inhibitor - binds to AChE, increasing [ACh] in the synapse

Question 19

List three ways that fatigability can be exposed with myasthenia gravis.

Answer 19

Cogan’s lid twitch (2)
-exaggerated ptosis after repeated/sustained upgaze
-a 2 minute sustained downgaze gives lid twitch on returning to primary gaze
Sleep/ice bag
-sleep/cold improves response
-icepack over muscle for 2-5 minutes

Question 20

Based on one of the tests for exposing fatigability in myasthenia gravis, when would you expect lid function to be its worst?

Answer 20

Afternoon - muscle function improves with sleep

Question 21

What is the typical age of onset for myasthenia gravis? Is older worse in females or males?

Answer 21

30-80
Older is milder in females, worse in males

Question 22

Why is asymmetric ptosis seen in myasthenia gravis? What percentage of patients will have this?

Answer 22

Levator palpebrae superioris involvement (85%)

Question 23

Involvement of what muscles in myasthenia gravis will gibe nystagmus/diplopia? What percentage of patients will have this?

Answer 23

EOM involvement in 5-10% gives nystagmus/diplopia

Question 24

Is the orbicularis commonly or rarely involved in myasthenia gravis? How are the brows normally used by MG patients?

Answer 24

It is rarely involved <5%
The brow is often used by MG patients to keep lids open (only when there is no orbicularis involvement)

Question 25

What is a myasthenic crisis and is it an emergency?

Answer 25

Respiratory failure resulting in tachycardia Urgent action needed as it has death potential

Question 26

Describe what herring's law means for ptotic eyelid and contralateral eyelid function. Describe in what two ways this effect can be eliminated and what it reveals.

Answer 26

Levator stimulation in the ptotic eye increases causing grater activation of the contralateral eyelid Covering the ptotic eye or manually raising the eyelid eliminates overstimulation, allowing the contralateral eyelid to express its true lid position

Question 27

What should you do if ptosis is found in the absence of miosis? What id you have a positive result on this?

Answer 27

Check herrings law -if positive, reconsider MG diagnosis

Question 28

What happens to sympathetic receptors on muscles with peripheral denervation? What about central denervation? What consequence does this have on lid and pupil dilator's sensitivity to adrenergic agonists? Note which alpha receptor type these two are.

Answer 28

Peripheral denervation - causes upregulation of sympathetic receptors on muscles Central innervation does not Lid (alpha 2) and pupil dilator (alpha 1) are both supersensitive to adrenergic agonists with peripheral denervation

Question 29

What kind of response would you expect if you use adrenergic drops OU on a case of peripheral Horners and after how long? Name two drugs that can be used and note which of the two alpha receptors they target.

Answer 29

Asymmetric response 10-30 minutes after instilling -apraclonidine 0.5/1% (alpha 2 > 1) -phenylephrine 2.5% (alpha 1 > 2)

Question 30

What should you do if you see pain free Horners syndrome? Is it more likely to be benign or malignant?

Answer 30

Check adrenergic suprasensitivity - indicates peripheral horners -most likely benign

Question 31

What history is indicative of myasthenia gravis?

Answer 31

Fatigue worse in the afternoon or repeated use

Question 32

If you confirm myasthenia gravis with lid twitch/ice, what should you do and for what (2)?

Answer 32

Refer to GP for DDX -CT scan, blood test for antibody assay/thyroid dysfunction -tensilon/neostigmine test

Question 33

What is the management for myasthenia gravis (4)?

Answer 33

Ptosis crutch (hold eyelid up or surgery) Medications Surgery (thymectomy) Plasmapheresis

Question 34

What does plasmapheresis do?

Answer 34

Decreases ACh antibody load

Question 35

List 4 medications available for myasthenia gravis.

Answer 35

Mestinon Steroids (prednisolone) Cyclosporine Azathioprine

Question 36

What is lambert-eaton myasthenic syndrome an abnormality of? Is it common or rare? Is it similar to MG? Is it more severe or mild?

Answer 36

Ca+ (VGCC) regulation abnormality reduces ACh release at the synaptic cleft Is rare Similar but more severe than myasthenia gravis

Question 37

How does botulinum toxin work? Include what it targets specifically.

Answer 37

Stops ACh release into the synaptic cleft by degrading SNAP needed for vesicle fusion Causes major paralysis of muscular activity Its effects mimic myasthenia gravis but more severe (and both ocular/systemic)

Question 38

What does myotonic dystrophy lead to?

Answer 38

Myotonia -inability to relax muscle contraction

Question 39

What age is myotonic dystrophy expressed? When is death expected?

Answer 39

20s to 30s -death by 50s

Question 40

What is myotonic dystrophy associated with and why? What two other things does it this cause?

Answer 40

Associated with endocrine dysfunction -due to epithelial dystrophy -baldness and testicular dysfunction - male infertility

Question 41

List four ocular changes with myotonic dystrophy.

Answer 41

Cataracts (young males) Pigment epithelial dystrophy Retinal changes Ciliary body - reduced IOP

Question 42

What is the cause of myotonic dystrophy?

Answer 42

Repeated sequences at chromosome 19

Question 43

Which of the mitocondrial complex proteins can electron leakage occur (3)? List in order of likelihood. What can these electrons bind to and what does it result in the formation of?

Answer 43

C1 >> C3 > C4 Can bind with O2, to give a superoxide, very potent free radical

Question 44

List three ways mitochondrial dysfunction can be expressed. Describe where electron loss occurs in each if applicable (2).

Answer 44

Abnormality in mtDNA Energy deficiency (RPE) and myopathy (C1, ealry complex loss) Oxidative stress and neuropathy (C4, later complex loss)

Question 45

What is lebers optic neuropathy due to? What kind of complex loss is seen? What does it lead to?

Answer 45

Point mutations in mtDNA -late complex loss leads to advanced neural apoptosis

Question 46

What happens to the disc with lebers optic neuropathy?

Answer 46

Normal disc undergoes optic neuroapthy with age (teens to forties)

Question 47

What kind of vision loss would you expect with lebers optic neuropathy?

Answer 47

Profound vision loss (6/24 to NLP)

Question 48

What family history would you expect of lebers optic neuropathy?

Answer 48

Positive maternal side

Question 49

What are mitochondrial myopathies characterised by on histology?

Answer 49

Ragged red fibles

Question 50

What appearance do RPE disorders have? Why does mitochondrial dysfunction often result in them?

Answer 50

Salt/pepper appearance -RPE is high energy tissue

Question 51

What is the onset for chronic progressive external ophthamoplegia?

Answer 51

Childhood up to 30s

Question 52

Is the levator palpebrae superioris involved in chronic progressive external ophthamoplegia? Do you see ptosis? List three other ocular signs.

Answer 52

Ptosis with no LBS involvement Ophthalmoplegia Pigmentary retinopathy (salt/pepper) Retained lid crease

Question 53

Describe kearns-sayre syndrome (6).

Answer 53

As with chronic progressive external ophthamoplegia with the addition of: Heart block Mental retardation Hearing loss Endocrine disorder Cerebellar ataxia

Question 54

What is the onset of mitochondrial encephalomyopathy lactic acidosis stroke (MELAS)? Before what age?

Answer 54

Onset in childhood - before 15

Question 55

What kind of vision loss would you expect in MELAS (2)? List four other symptoms.

Answer 55

Vision loss as in chronic progressive external ophthamoplegia with the addition of hemianopia Other symptoms are: Hemiparesis Headaches Convulsions Short stature due to stroke-like episodes