Muscle Disorders Of The Eye - Week 4 Flashcards
List the neural causes of Extraocular Muscle (EM) disorders (3)
- abnormal control: brain/mid-brain centres
- bad neural connections: cranial nerve & pathways
- problems at neuromuscular junction
List the muscular/mechanical causes of extraocular muscle disorder (3)
- muscle insertion (tropia/phoria)
- orbital congestion/swelling: leads to restriction of eye movement
- muscle capacity: limited due to energy or trauma related limitations (the muscles fatigue and can’t move eyes)
List EOM types and examples
Inflammatory orbital congestion
- Graves’ disease
Muscular disease
- NMJ: innervational problems (NMG, neuromuscular junction)
- myasthenia graves
- myotonic dystrophy
Inherited mitochondrial disorders
- neuropathy: leber’s
- myopathy: CPEO, MELAS
Muscle capacity
Is Graves’ disease the same as thyroid eye disease (TED)
No. People can have graves without having TED and vice versa
Graves can express TED, but not always the case
Explain Graves’ disease: What type of disorder is it? (more specifically than just saying EOM disorder). What does it result in biochemically?
Autoimmune endocrine disorder
Involves overactive thyroid gland, leading to increased thyroid hormone production
- hyperthyroidism, increased blood t3, t4 levels, reduced blood tsh
Where is the primary insult in Graves’ disease? (I.e the primary affected area)
Thyroid
Where is the primary insult (affected area) for Thyroid eye disease (TED)? What is thyroid function like? (In TED alone, assume no graves)
Primary insult is ‘Ocular’
Thyroid function unaffected/normal (euthyroid)
What is the cause of Thyroid eye disease (TED)?
Aberrant immune response (same as Graves)
What links TED with graves?
The fact that TED is secondary to hyperthyroidism, a component of graves
What process involved in TED (thyroid eye disease) might suggest early or preclinical Graves’ disease?
Low grade inflammation
What does the thyroid gland control? [3]
- uses of energy
- proteins production
- how sensitive the body is to other hormones
List the methods of hormonal control:
Endocrine: distance control via blood borne hormones
Paracrine: local control of neighbouring cells via ionotropic receptors
Autocrine: self control via a 2nd messenger
Describe endocrine feedback: locations and actions
- hypothalamus: senses low t3, t4 levels in blood. Releases TRH
- Ant. pituitary gland: TRH stimulates secretory cells to release TSH
- TSH released into blood stream
- Thyroid gland: TSH stimulates prod. of TGB, which becomes t3, t4
- t3/t4 released into blood
- t3 feeds back to pituitary and hypothalamus
TRH ==> TSH ==> TGB ==> t3/t4 ==> t3 feeds back
Name an EOM disorder that has inflammatory orbital congestion
Graves Disease
Name 3 EOM ‘muscular’ disorders
- disorder of NMJ innervation
- myasthenia gravis
- myotonic dystrophy
Define neuropathy
disease or dysfunction of one or more peripheral nerves, typically causing numbness or weakness
Define myopathy
A disease of muscle tissue
Name a neuropathic inherited mitochondrial disorder
Leber’s syndrome
Name 2 myopathic inherited mitochondrial disorders
CPEO - Chronic progressive external ophthalmoplegia
MELAS - Mitochondrial encephalomyopathy, lactic-acidosis and stroke
What can inaccurate muscle insertion (mechanical EM disorder) result in?
When one of the extra-ocular muscles inserts into a slightly different/inaccurate position on an eye, this can cause:
- misalignment of the eyes (phoria or tropia)
What happens to the thyroid in Graves Disease?
Hyperthyroidism - too much thyroid hormone produced
What is Thyrotoxicosis
Excess thyroid hormone in body (such that it becomes toxic to your body)
Is Thyroid Eye Disease (TED) associated with hyperthyroidism when it’s the primary insult, or is it only when TED is secondary to Grave’s Disease
Can be either. Though is more often when secondary to Grave’s Disease
What 3 glands work together to control how hard the thyroid gland works? What type of control is this?
Hypothalamus, Pituitary Gland, and Pineal Gland.
- this is endocrine control
Where is the pituitary gland situated?
Just underneath the optic chiasm
How can pituitary gland problems lead to visual field loss?
If you have pituitary gland swelling (e.g. pituitary tumour/adenoma), this will press on the optic chiasm, and can injure it.
Type of visual field loss depends on what side of the pituitary gland is swelling (front or back)
How is cAMP important for thyroid hormone production?
It produces a pre-cursor to thyroglobulin
How does TSH stimulate the production of TGB (thyroglobulin)?
TSH acts on TSH receptor which converts ATP to cAMP, which produces a precursor to TGB, which then turs into TGB
What processes or systems in the body are controlled by thyroid hormones?
- Heart rate
- glucose/oxygen turn over (therefore ATP production)
- Body temperature + caloric intake (calories)
- Na/K-ATPase synthesis
- Protein synthesis
- lipid turn over (lipolysis)
- bone turn over
What effect does increased thyroid hormone (T3, T4) have on lipolysis?
Increases lipolysis
What effect does increased thyroid hormone have on bone turnover?
Increases bone turn over
How is thyroid hormone production altered in Grave’s Disease?
TS antibodies (TSAb) mimic the action of TSH to activate the TSH receptor. However, these antibodies are NOT subject to negative feedback, so you get this over-production of thyroid hormones
What 2 Hypotheses could explain altered thyroid hormone production in Grave’s Disease?
- Genetic tendency for Grave’s. i.e. lack of T-cell suppression, or
- prior exposure to a bacteria with homologically similar receptors to TSH-receptors, resulting in the production of similar antibodies
As Grave’s Disease develops, what happens to the production of t-cells? How do they respond?
Over-production of Helper T-cells (CD4+) that are self-reactive.
- this produces an anitbody-mediated autoimmune response
Is Grave’s a systemic or local disease?
Systemic Disease
How often is the eye effected in Grave’s Disease? (the proportion)
25-50% of cases
What eye related manifestations occur in Grave’s Disease?
Lid retraction, lid lag, and proptosis (eye looks like it’s popping out)
Also: EOM involvement or optic nerve dysfunction
Can the TSAb antibody in grave’s disease target anything other than the TSH receptors? If so, where? And what does this lead to?
These antibodies can target the orbital fat and muscles in the eye. They go to the back of the eye and recruit white blood cells. [local response]
- This leads to TED
Explain how an inflammatory response at the back of the eye proceeds.
- T-cell infiltration produces inflammatory cytokines
- Excessive ECM production
- Proliferation of adipocytes produce fat
- Tissue and muscle swelling
At what age and form does grave’s disease manifest in women?
Ages 20-40. Mild form
At what age and form does grave’s disease manifest in men?
Ages 50-60. Severe form
What proportion of grave’s disease patients are male vs female?
Male: 35%
Female: 65%
- more frequent in females
How does smoking affect the risk of Grave’s Disease?
Doubles the risk
List 4 possible systemic symptoms of Grave’s Disease [note: there are many more]
- anxiety, irritability, insomnia, irregular heart beat, frequent bowel movements
What changes to your skin might occur in Grave’s Disease?
local swellings of feet, lower legs (altered colour, itch)
What might be the consequences of EOM swelling?
- eye gets pushed forward: proptosis
- diplopia
- squashing of optic nerve (therefor damage)
How might EOM swelling impact IOP levels?
Increase IOP, which can then add to nerve damage
What major histopathological changes can TED result in?
- increased fat content of orbit (upper)
- swelling of EOMs (upper)
- Increased fibrosis and GAG synthesis in connective tissue of orbit
- presence of inflammatory cells in EOM (mainly CD4+ and CD8+)
What techniques can you use for the early diagnosis of TED?
- MRI
- OCT
What proportion of TED patients have hyperthyroid vs normal (euthyroid)?
80% hyperthyroid
20% euthyroid
What type of clinical signs can develop in TED?
- orbital congestion: local rigidity gives proptosis
- chemosis: swelling fluid retention
- inflammation: redness
Describe what happens in orbital congestion
Blood flows into the orbit, but at high pressure, the veins will get crushed and so the blood can’t flow out and gets trapped – so the tissue swells and looks really red
What gene mutations have been implicated int he development of TED?
Cytokien genes: assoc. with imbalance of pro-inflammatory cytokine production
HLA gene: assoc. with autoreactivity
CTLA-4 gene: disturbance in T-cell suppression
Note: these genes are genes that are related to increased chance of having inflammation [that’s really the take-home message]
What type of EOM disorder is Myaesthenia Gravis?
Muscular, auto-immune.
How does Myaesthenia Gravis affect muscles?
Leads to weakness of skeletal muscles
Describe the autoimmune reactivity in Myaesthenia Gravis?
antibodies form against nicotinic acetylcholine receptors
Where can systemic manifestations for Myaesthenia Gravis occur?
In the lungs
What percentage of ocular myaesthenics develop systemic problems in less than 2 years?
60-80%
List 3 clinical symptoms of myaesthenia gravis
- lid ptosis
- diplopia (often vertical)
- fatigue on repeated effort (e.g. more ptosis after blinking many times in a row)
When do myaesthenia gravis patients experience the LEAST amount of lid ptosis?
In the morning, when the muscles are less fatigued
What is IgG and what does it do?
IgG is an agonist for the acetylcholine receptor (nAChR). It blocks receptor activation by ACh.
Where does IgG bind?
At the neuromuscular junction (NMJ)
What type of people get myaesthenia gravis?
young women and old men
Where/How does myaesthenia gravis express?
in EM, arms, legs, breathing, swallowing
Define Myasthenic Crisis
Complete loss of breathing capacity (px requires artificial ventilation)
What percentage of myaesthenia gravis cases have thyroid/thymus dysfunction? Can this be resolved?
5-15%. Px can have thymectomy (remove thyroid gland), which leads to resolution in some people
What clinical tests can we use to test for myesthenia gravis?
Tensilon/edrophonium chloride testing
or
Single Fibre Electromyography (SFEMG)
How does Tensilon/edrophonium chloride testing work?
- inject a short acting acetyl-cholinesterase inhibitor that prolongs the action of ACh in NMJ, meaning there is now more ACh to compete with the IgG
- should transiently improve muscle strength
- Observe if this improved ptosis
What effect might an ice-pack have on lid ptosis?
Improves it
What would SFEMG (single fibre electromyography) find for patients with myaesthenia gravis?
Abnormal muscle fibre jitter in 95-99% of cases
What type of mendelian inheritance is Myotonic dystrophy? What age onset?
Autosomal dominant. Occurs due to repeated sequence of 3’ nucleotides. 20s-30s yr old
What does myotonic dystrophy lead to?
Myotonia, inability to relax muscle
How is myotonic dystrophy expressed?
as a multi-system disorder. Expressed in several forms (DM1-DM4)
What are the ocular manifestations of myotonic dystrophy, and in what form are they most prominent in?
Most prominent in DM1.
- ptosis and fatigue
- cataracts
- pigment epithelium dystrophy
- retinal degeneration
- ciliary body dysfunction
