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Neuro 4100: Basic and Clinical Foundations of Neurological Disease > 10/28: Treatment of Retinal Disorders > Flashcards

10/28: Treatment of Retinal Disorders Flashcards

1
Q

Why don’t I see?

Can neuroscience help?

A

Colleen M. Cebulla, MD, PhD

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2
Q

The Eye is an extension of the Brain.

A

The retina is part of the brain.

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3
Q

Pupil

A

The hole in the center of the eye that lets light through to the retina.

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4
Q

Choroid

A

supplies blood to the outer retina.

Contains blood vessels.

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5
Q

Techniques to diagnose visual

disorders: mostly noninvasive

A
  • Pupil exam
  • Fundus photos
  • Optical coherence tomography
  • Fluorescein angiography
  • Visual Field testing
  • Electrophysiology (assess signaling)
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6
Q

OCT-noninvasive imaging

based on coherence of light

A
  • OCT: light as ultrasound : sound
  • Noninvasive
  • Micron resolution
  • 3 -D
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7
Q

Categories of Visual Loss

A
  • Anterior Segment (Cornea, cataract)
  • Glaucoma*
  • Retina*
  • Neuro-ophthalmology*
  • Oculoplastics* (eyelid & orbital disease)

*Important for Neuroscientists

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8
Q

Keratoprosthesis:

A

Artificial Cornea

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9
Q

the most common cause of irreversible blindness worldwide

A

Glaucoma

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10
Q

What cells are damaged in Glaucoma?

A

ganglion cells

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11
Q

Glaucoma:

What happens…

A

Aqueous Fluid enters the
front the eye.
In certain people, the fluid drains (out through the angle)
too slowly out of the eye causing the fluid to build up and the pressure to increase.

Glaucoma can occur in low pressure individual, not just high pressure ones, as previously thought.

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12
Q

Glaucoma Diagnosis:

A Historical Perspective

A

Pre 1980’s
• Intraocular pressure (IOP) > 21 =
glaucoma

1980’s to mid 1990’s
• IOP > 21 + visual field (VF) loss =
glaucoma

Mid 1990’s to present
• Glaucomatous optic disc damage = glaucoma

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13
Q

IOP

A

Intraocular pressure

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14
Q

Definition of Glaucoma

A

• A group of disease in which results in optic neuropathy characterized by “cupping” optic nerve rim loss

• Optic nerve damage which
correlate with visual field loss

• How can we study this?

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15
Q

Optic Nerve Cup-to-Disc Ratio

A

….OCT Retina NFL

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16
Q

Pathophysiology

A
  • Intraocular Pressure related connective tissue stress and strain
  • Blood flow deficiency/nutrient diffusion/ischemia of the laminar and prelaminar tissue
  • Auto-immune and inflammatory mechanism
  • Genetic Predisposition
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17
Q

Types of Glaucoma:

Primary vs Secondary

A

• Primary is used when no
identifiable cause for the
glaucoma can be identified.
Starts with the eye.. internal causes.

• Secondary is used when an
abnormality can be found.
Like blood vessels invading the wrong areas of the eye.

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18
Q

There are many different types of glaucoma.

A

They can be divided into 5 groups, depending on whether someonre is born with the disease, whether they are open or closed angle, and primary or secondary:

  • Primary OAG
  • Secondary OAG
  • Primary ACG
  • Secondary ACG
  • Congenital Glaucoma
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19
Q

Measuring Intraocular Pressure

A

lowering interocular pressure is one of the ways glaucoma is treated.

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20
Q

Medication

A

Some people use eye drops to ease glaucoma

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21
Q

Surgical Procedures

A
  • Laser Surgery
  • Filtering Surgery
  • Cyclodestructive Surgery
  • Drainage Device Surgery
22
Q

Glaucoma

A

“Caveman” procedures

Huge need for new animal models and treatments
• Neuroprotection!!

23
Q

Retinal Problems

A

Many retinal problems are blood vessel problems!
• Hypoxia
• Oxidative stress

24
Q

Dry Macular Degeneration

A

Drusen

25
Q

Wet Macular Degeneration

A

Abnormal blood vessel development under the retina that causes leaking of blood in the eye and scar tissue.

The worst form of macular degeneration.

Treated by applying anti-VEGF medication.

Remember that the brain cells hate blood, and the retina is part of the brain.

26
Q

Macular Degeneration

A

Caused by Abnormalities in the retinal epithelium.

Causes loss of photoreceptors and vision loss over time.

27
Q

Diabetic Macular Edema

A

Capillary dropout is a big problem in diabetes

28
Q

Central Retinal Artery

Occlusion

A

……

29
Q

Central Retinal Vein Occlusion

A

……

30
Q

Retinal Detachment:

A

results in Retinal hypoxia

§ Prevalent cause of visual loss
§ 28,000 cases per year
§ 1/300 lifetime risk
§ Incidence increases with pseudophakia, aphakia, myopia, and trauma

31
Q

Causes of Vision Loss After Retinal Detachment:

A

• Photoreceptor cell
loss/dysfunction

•“Re-wiring” of the retina

• Formation of scar tissue
(proliferative vitreoretinopathy)

32
Q 
Scarring: 
Proliferative Vitreoretinopathy (PVR)
A
  • Scar tissue forms around the retina after RD
  • Leading cause of failure of retinal detachment repair
  • Severe visual loss
33
Q

Retinal Degenerations:

Retinitis Pigmentosa

A
  • Loss of photoreceptors (first rods, then cones)
  • Progressive
  • Night blindness
  • Tunnel vision
  • Severe vision loss
34
Q

hypoxia

A

reduction of oxygen supply to a tissue below physiological levels despite adequate perfusion of the tissue by blood.

Insufficient levels of oxygen in blood or tissue.

35
Q

Retinitis Pigmentosa genetics

A

One of the most common inherited retinal degenerations

Can be autosomal dominant, autosomal recessive, or X-linked inheritance

36
Q

Electroretinogram

A

…..

There’s a loss of transmission in Retinal Pigmentosa.

37
Q

Novel strategies to treat retinal

degenerations

A
  • Neuroprotective growth factors
  • Artificial Vision
  • Stem Cells
  • Gene therapy
38
Q

CNTF

A

Neuroprotective Growth Factor

CNTF Trials for retinal degeneration

Cell Capsules full of CNTF suetered into the eye to release CNTF gradually over time did well at protecting cones from dying.
Didn’t improve anything, just slowed down degeneration.

39
Q

CNTF:

What it does….

A
  • Reduced loss of photoreceptor density
  • Improved retinal thickness
  • Not significant for visual acuity/function
  • Reversible decrease in sensitivity in high dose early Retinitis Pigmentosa group
  • Under evaluation for other retinal diseases
40
Q

Artificial Vision?

A
  1. Camera Glasses:
    Captures image and wirelessly transmits data to implant
  2. Microchip placed on the surface of the retina.
    Retinal implant and processor stimulates retina.
  3. Electrical Signals are sent from the retina via the visual pathway (galnglion cells —> optic nerve, etc.) to vision processing centers in the brain.

Not great vision,
Can see high contrast objects.

41
Q

Eye Transplant?

A
  • How to reattach 1-2 million axons?

* Analogous to spinal cord injury problems

42
Q

Stem cells for retinal degenerations

A
  • Lack structure
  • Would they “know where to go?”
  • Would they integrate with the right cells and function properly within tissues and systems?
43
Q

Press Release: 10/2014

A

Subretinal injection human embryonic stem cell-derived RPE

No immune suppression

Out of the 18 study participants
•10/18 “significantly 
better” vision 
• 1/18 worse 
• 7/18 stable

Expanding to multiple centers

Watching for cancers…

44
Q

Leber’s Congenital Amaurosis

A
  • Leber’s Congenital Amaurosis (LCA) was first described in 1869 by Theodore Leber.
  • Type of RP
  • Affects 1 in 80,000 individuals
  • Autosomal recessive
  • Severe vision loss at birth or in the first months of life
45
Q

Genetics of LCA

A

• Over 12 known genes cause various forms of LCA (LCA1 – LCA12).
Additional genes exist.

• LCA genes encode proteins which are crucial for
photoreceptor function and/or survival.

• Some proteins associated with LCA are expressed in photoreceptors; others in RPE cells

46
Q

RPE

A

retinal pigment epithelium

47
Q

Mutations in RPE65

A

Inherited mutations in the RPE65 gene (LCA2)
•Absent or dysfunctional protein

Target for gene therapy:
•Goal: delivery RPE65 gene into RPE cells
•Express normal RPE65 protein
•Restore functional Vitamin A metabolism and photoreceptor function

48
Q

Animal Models for LCA2

RPE65

A
  • RPE65 knockout mice
  • Briard dog which has inherited mutations in RPE65.
  • Both these animal models have severe loss in vision but retain some of their photoreceptor cells
49
Q

Results of the Canine Gene Therapy

A

RPE65 protein expressed in RPE cells

Restoration in vision in this eye

Durable response with a single injection
• recovery of vision> 8 years

Good safety profile

50
Q

Gene Therpy Clinical Trials For Leber’s Congenital Amaurosis (LCA2)

A

3 human Phase I clinical trials started in 2008 –
(London, Philadelphia)

Initial studies on 9 young adults (19–26 yrs old) with LCA2 have been reported.

All had significant visual loss, but some remaining photoreceptors.

51
Q

Early Results from the Phase I Trials

A

In essentially all cases, there was significant improvement in retinal function and visual response.

Patients reported 
• General improvement in vision 
• Increased sensitivity to light 
• Ability to get around in dim light 
• Some cases: ability to read several lines in an eye chart.

Importantly, No noticeable toxic effects or immune response

52
Q

More comprehensive and long-term study to fully

evaluate LCA2-RPE65 gene therapy …..

A

Dose of the AAV-RPE65

Site of injection

Single vs multiple injections

Long term effect on visual function

Determine long term safety

Assessment of Rod vs Cone Function

Can visual acuity be improved?

Evaluate more patients of different ages

Neuro 4100: Basic and Clinical Foundations of Neurological Disease (18 decks)

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