The Eye Flashcards

1
Q

What is neurotrophic keratitis?

A

Caused by damage to trigeminal nerve which results in damage in tear ducts, therefore decrease vitamins and Gf into the cornea causing corneal epithelial breakdown and ulceration

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2
Q

How is aqueous humor produced?

A

Active secretion and ultrafiltration by ciliary epithelium (part of ciliary bodies) which suspend lens

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3
Q

What happens during posterior vitreous detachment

A

Not harmful in itself until it pulls the retina, but it causes floaters in vision

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4
Q

What are the visual photoreceptor cells of the retina?

A

Cones- used in brighter light to see colour

Rods - extremely sensitive, used at low light levels and do not mediate colour vision (located further away from fovea)

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5
Q

What is the Walds visual cycle?

A

In the dark, cGMP levels are high and keep cGMP-gated sodium channels open allowing a steady inward current, called the dark current. This dark current keeps the cell depolarised at about -40 mV, leading to glutamate release which inhibits excitation of neurons

Light closes cGMP-gated sodium channels, reducing the influx of both Na+ and Ca2+ ions. Stopping the influx of Na+ ions effectively switches off the dark current. Reducing this dark current causes the photoreceptor to hyperpolarise, which reduces glutamate release which thus reduces the inhibition of retinal nerves, leading to excitation of these nerves. This reduced Ca2+ influx during phototransduction enables deactivation and recovery from phototransduction

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6
Q

What is RPE?

A

Retinal pigment epithelium (RPE) is the pigmented cell layer just outside the neuro-sensory retina that nourishes retinal visual cells and had multiple functions: here are a few:

  1. lAbsorption of scattered light to improve the quality of the optical system
  2. epithelial transport: RPE supply nutrients to photoreceptors, control ion homeostasis and eliminate water and metabolites
  3. Phagocytosis of photoreceptor outer segment (POS) membranes: POS are exposed to constant photo-oxidative stress, and they go through constant destruction by it. They are constantly renew, by shedding the ends and then RPE phagocytose and digest these segments.
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7
Q

What is the optic nerve?

A

The optic nerve, also known as CN II, is a paired nerve that transmits visual information from the retina to the brain

The optic nerve transmits all visual information including brightness perception, colour perception and contrast (visual acuity).
The eye’s blind spot is a result of the absence of photoreceptors in the area of the retina where the optic nerve leaves the eye.

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8
Q

What are 3 examples of optic nerve damage?

A
  • Glaucoma (Transport problem)
  • Leber hereditary optic neuropathy (mitochondrial DNA)
  • dominant optic atrophy (Genetic disorder)
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9
Q

What is Glaucoma?

major risk factors

Key findings on examination?

A

Glaucoma is a group of eye diseases which result in damage to the optic nerve and vision loss.

  • The most common type open-angle glaucoma develops slowly over time and there is no pain. Peripheral vision may begin to decrease followed by central vision resulting in blindness if not treated.
  • closed-angle glaucoma can present gradually or suddenly. The sudden presentation may involve severe eye pain, blurred vision, mid-dilated pupil, redness of the eye, and nausea. Vision loss from glaucoma, once it has occurred, is permanent.

The major risk factor for most glaucomas and the focus of treatment is increased intra-ocular pressure, problems with axoplasmic flow. Intra-ocular pressure is a function of production of liquid aqueous humour by the ciliary processes of the eye, and its drainage through the trabecular meshwork.

Key finding:
Cotton wool spots are an abnormal finding on funduscopic exam of the retina of the eye. They appear as fluffy white patches on the retina. They are caused by damage to nerve fibers and are a result of accumulations of axoplasmic material within the nerve fiber layer.

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10
Q

Describe the mitochondrial placement of the optic nerve head

A

Cytochrome C stain for mitochondria indicates the mt is located at the top before it passes through the lamina cribrosa - The nerve fibers forming the optic nerve exit the eye posteriorly through a hole in the sclera that is occupied by a mesh-like structure called the lamina cribrosa where myelination is prevalent on optic nerve after the lamina cribrosa

2 possible explanations for mt placement:
1. axonal constriction by lamina beams
2 mitochondria ‘held’ in place according to physiological need as lots of Na+ channels present without myelination

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11
Q

What is Leber’s hereditary optic neuropathy (LHON)?

Who does it affect more?

How do patients present?

A

is a mitochondrially inherited (transmitted from mother to offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision

Affects Male> female by 5x

Presentation: caecocentral scotoma, acute disc swelling and pupils usually spared in early vision but it is a central vision problem

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12
Q

What is the clinical presentation of LHON?

A

Clinically, there is an acute onset of visual loss, first in one eye, and then a few weeks to months later in the other. Onset is usually young adulthood, but age range at onset from 7-75 is reported.

This typically evolves to very severe optic atrophy and a permanent decrease of visual acuity.

Examination reveals decreased visual acuity, loss of color vision and a cecocentral scotoma, vascular tortuosity, telangiectatic vessels around optic disc, swelling of the retinal nerve fibre layer on visual field examination.

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13
Q

Describe the genetics of LHON

A
  • It is a primary mitochondrial DNA disorder
  • Three mtDNA point mutations account for ~90% of cases
  • 11778G>A is the most common mutation, others are 14484T>C and 3460G>A
  • primary LHON mutations tend to be specific to retinal ganglion cells (RGC)
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14
Q

How are RGC affected in LHON?

What causes its destruction?

A

RGC are preferentially affected in LHON

Experimental evidence reveals impaired glutamate transport and increased reactive oxygen species (ROS) causing apoptosis of retinal ganglion cells.

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15
Q

Describe the mitochondrial respiratory chain

A

Mitochondrial DNA makes 13 proteins where 4 out of 5 complexes have subunits are encoded by mitochondrial genome.

The electron transport chain: transfer electrons from electron donors to electron acceptors via redox (both reduction and oxidation occurring simultaneously) reactions, and couples this electron transfer with the transfer of protons (H+ ions) across a membrane. This creates an electrochemical proton gradient that drives the synthesis of adenosine triphosphate (ATP)

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16
Q

How does LHOn mutation affect the e- transport chain (ETC)?

A

All 3 primary LHON mutations affect complex 1 subunits

  • impair ATP production
  • Oxidative phosphorylation converts oxygen and simple sugars to energy. Mutation causes increase reactive oxygen species (ROS)
17
Q

Describe the pathophysiology of LHON

What are the 3 factors that contribute to this?

A

Primary mtDNA mutation causes mt dysfunction which leads to retinal ganglion cell dysfunction, optic nerve degeneration and therefore visual failure.

The following factors affect mt DNA dysfunction:

  1. Mitochondrial factors
    - Heteroplasmy (above threshold)
    - Mt haplogroup J
  2. Genetic factors
    - Visual loss susceptibility: X linked (e.g. Xp21.1) but may not all be the same place
  3. Environmental factors
    - Heavy smoking was strongly associated with increase risk of visual loss in LHON carriers
    - Oestrogen have the potential to ameliorate mitochondrial dysfunction in LHON
18
Q

How do we manage LHON?

A
  1. Supportive measures: genetic counselling, low visual aids, occupational rehabilitation
  2. Disease modifying strategies: e.g there is an increase O2- species in complex 1 dysfunction therefore use Idebenone as a possible neuroprotective agent - scavenge for reactive O2 species
  3. ?gene therapy
19
Q

What is Dominant Optic Atrophy (DOA)?

A

It’s s an autosomally inherited disease that affects the optic nerves, causing reduced visual acuity and blindness beginning in childhood. This condition is due to mitochondrial dysfunction mediating the death of optic nerve fibers.
Retinal ganglion cells (RGCs) are preferentially affected in DOA

20
Q

Describe the genetics of DOA

A

It is the most common inherited optic neuropathy. - where 60% of cases harbour pathogenic OPA1 mutations. OPA1 has distinct roles in the fusion of mitochondrial inner membranes during mitochondrial fusion events, and in regulation of cell death.

In DOA patients, 10% of muscle fibres were COX negative i.e. blue counterstain. The mosaic pattern in muscle is highly suggestive mitochondrial disease.

21
Q

Describe the pathogenesis of OPA1 protein mutation

A
  1. The OPA1 gene a nuclear-encoded mitochondrial protein codes for a dynamin-related GTPase protein targeted to the mitochondrial inner membrane.
    It is involved in modeling cristae structures - where infolding in mt is held together by OPA1. - Without OPA1, cristae falls apart
  2. Fission and fusion in mt is also regulated by OPA1. Mitochondria in normal cells have a lot of budding and fusion
    Biochemical and mitochondrial morphological studies on cells from patients affected by autosomal dominant optic atrophy have shown a severe defect in the shape (with a very remarkable fragmentation of the mitochondrial tubules in small spheres) and distribution of mitochondria, occurring independently from a bioenergetic defect (respiratory chain function, ATP synthesis, and reactive oxygen species production) or apoptosis, indicating that the mitochondrial fusion defect is the primary pathogenetic mechanism
22
Q

What investigation can we use to diagnose mitochondrial dysfunction?

A

Muscle biopsy to look for histochemical markers of mt biochemical dysfunction

23
Q

Explain the principles of COX-SDH histochemistry

A

There are 5 complexes involved in oxidative phosphorylation.

Complex IV is also known as cytochrome C oxidase (COX) and we are also able to stain muscle sections for COX activity - (Brown) stain and the intensity correlates to the level of ATP production.

Complex II is the only complex of oxidative phosphorylation that isn’t encoded by mitochondrial DNA and therefore can be counterstained with succinate dehydrogenase (Blue)

Mitochondrial respiratory change activity:
normal = Brown
abnormal = Blue = COX negative

24
Q

What is Charcot Marie Tooth disease?

A

Charcot–Marie–Tooth disease (CMT) is one of the hereditary motor and sensory neuropathies, a group of varied inherited disorders of the peripheral nervous system characterised by axonal degeneration and/or demyelination
Various mode of inheritance: AD, AR, Xl

25
Q

Describe the genetics of CMT

A
  1. CMT type 2A - AD and the most common form with classic signs of optic neuropathy
    - Causes by MFN-2 (nuclear genome) which is involved in mitochondrial fusion
    - It is a GTPase protein in the mitochondrial outer membrane
  2. A small group of CMT-2A patients instead have the KIF1B (nuclear) mutation - KIF1B protein is part of kinase 3 family that transports cargo along actin /myosin within axons and cells in general. It interacts with mitochondria and regulates their movement within the cell
26
Q

What is the relationship between MFN2 and OPA1?

A

MFN2 mediated outer membrane fusion

OPA1 then coordinated inner membrane fusion