GLAUCOMA : OLD VIEWS

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GLAUCOMA OLD VIEWS

• Glaucoma was widely known as the disease related
  to the rise in intraocular pressure (IOP) gt 21 mm
  Hg.

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GLAUCOMATHE SNEAK THIEF OF SIGHT

• Second leading cause of blindness worldwide
• Around 50 of patients do not know that they have
  the disease, because of which it is called The
  Silent Blinder or The Sneak Thief of Sight
• Glaucoma are of 2 types
• Open Angle Glaucoma (OAG)
• Angle Closure Glaucoma (ACG)
• Lancet, November 1999, 354 (80) 1803-1810

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GLAUCOMA EMERGING NEW CONCEPTS
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GLAUCOMA NEW VIEWS

• Glaucoma is an optic neuropathy with
  characteristic structural damage to the optic
  nerve, associated with progressive retinal
  ganglion cell death, loss of nerve fibres and
  visual field loss
• American Academy of Ophthalmology

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GLAUCOMAWhere new concepts are vital

• Glaucoma is widely known as a disease related to
  the intraocular pressure
• IOP control is not only mainstay of glaucoma
  therapy, but something beyond ...

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GLAUCOMA PATHOPHYSIOLOGY
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GLAUCOMA PATHOPHYSIOLOGY

• So, what is Glaucoma according to the new
  theories?

• Definition
• Progressive optic neuropathy characterized by
  specific morphological changes (optic disc
  cupping) resulting in acquired loss of retinal
  ganglion cells (RGCs) and RGC axons.

• The RGCs die by apoptosis (programmed cell death)
  
• RGC death leads to peripheral visual field loss

Glaucoma
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GLAUCOMA OPTIC NERVE DAMAGE

• Elevated IOP
• Mechanical back pressure
• On the junction of optic nerve/retina
• Reduce the blood supply to the optic nerve
• Loss of blood supply (lt in pOBF)
• Ischaemia
• RGC cell loss

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GANGLION CELL DEATH IN GLAUCOMA

•  
• Elevated intraocular pressure causes decreased
  perfusion, reduced retrograde transmission of
  brain derived growth factor thus primary injury
  to RGCs, which inturn causes elevated vitreal
  glutamate and further axonal injury. Ganglion
  cell die by the process of apoptosis.
•  

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APOPTOSIS

•  
• Apoptosis in RGC is activated by either loss of
  neurotrophic support or over exposure to
  excitotoxins like glutamate.

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GLAUCOMA OPTIC NEUROPATHY
Intact nerve
Injury
Site of injury
Primary neuronal loss
Secondary
degeneration
Site of injury
Secondary loss
Survey of Ophthalmol,Jan-Feb 1998,V.42 (4)
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GLAUCOMA OPTIC NEUROPATHY

• Axons of optic nerve die
• Visible optic nerve head, assumes a cupped
  appearance
• Peripheral vision declines as axons are lost
• Central vision affected due to severe axonal loss
• Finally, leads to blindness

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SHRINKING OF VISUAL FIELD.
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OPTIC NEUROPATHY
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OPTIC NEUROPATHY

• What is optic neuropathy?
• Optic neuropathy means death of the neurons of
  the retina.

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NEUROPROTECTION DEFINITION

• Neuroprotection refers to any intervention,
  either external to the optic nerve or internally
  that will lead to an intracellular change in the
  balance between survival and death signals in
  favour of survival.

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STRATEGIES FOR NEUROPROTECTION

•  Various neuroprotective strategies may be useful
  for preventing retinal ganglion cell death
  includes
•  
• Delivery of brain derived neurotrophic factor
  (BDNF) to RGC
• Pharmacological-antagonists that inhibit
  excitotoxicity by activation of NMDA receptor
  with drug like Memantin.
• Ca-channel blocking agents
• Antioxidant and free radical scavengers
•  

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STRATEGIES FOR NEUROPROTECTION

• Alpha 2 adrenergic agonist
• Ginkgo biloba extract
• Nitric oxide synthetase inhibitor
• Gene therapy of gene delivery by corneal
  inoculation, scleral or choroidal implant or
  daily topical drug
• Boosting of protective autoimmunity

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CRITERIA FOR EVALUATION OF NEUROPROTECTIVE
COMPOUNDS

• Compound should have a specific target in the
  retina
• Should have a profile of neuroprotective activity
• Drug should reach to target issue in
  pharmacological concentrations sufficient to
  activate its target.
• Evidence of neuroprotective activity in animal
  model
• Should demonstrate neuroprotective activity in
  controlled clinical trial
•  

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BRIMONIDINEIN NEUROPROTECTION
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BRIMONIDINE THE NEUROPROTECTIVE a2 AGONIST

• IOP lowering is the main aim of any anti-glaucoma
  agent.
• But, there is something beyond this IOP
  reduction. Neuroprotection.

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BRIMONIDINETHE NEUROPROTECTIVE AGENT
Intact nerve
Injury
Site of injury
Primary neuronal loss
(about 60)
BRIMONIDINE
Secondary degeneration
Site of injury
Primary and secondary loss
(about 90)
Survey of Ophthalmol,Jan-Feb 1998,V.42 (4)
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NEUROPROTECTION COMPARISON WITH VEHICLE
A
B

• More labeled cells in the brimonidine treated (A)
  retina than in the vehicle treated one (B).

IOVS, No. 2001, 42 (12), 2849-2855.
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BRIMONIDINE THE NEUROPROTECTIVE AGENT
RGC survival (Ratio)
Time of injection of brimonidine before nerve
injury (hrs)

• Brimonidine brought about a higher rate of RGC
  survival

Survey of Ophthalmol.,May 2001,45,
Suppl.3,S290-S294.
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BRIMONIDINE THE NEUROPROTECTIVE AGENT (contd.)
Percent RGC lost
Drug

• Brimonidine and not timolol showed significant
  neuroprotective effects.

Survey of Ophthalmol.,May 2001,45,
Suppl.3,S290-S294.
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BRIMONIDINE NEUROPROTECTION

• What is pulsatile ocular blood flow?
• It is the blood supply to the retina and optic
  nerve head thereby providing oxygen and
  nutrients.
• Alpha 2 adrenoceptors mediate vasoconstriction.
• Brimonidine brings about vasodilation of the
  endothelial cells of the blood vessel.
• Therefore, flow of blood to the retinal layers
  increases.

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BRIMONIDINE EFFECT ON pOBF
Change
Time (h)

• One drop of brimonidine increased the pOBF value
  from 15.7to 26.1 with a peak of 29.9 after 8
  hours.
• An increase in pOBF was seen since day 1 of
  treatment which was consistent throughout.

Clinical Therapeutics,2001,23(9),1519-1528
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BRIMONIDINE VISUAL FIELD

• Aim To evaluate the efficacy of topical
  brimonidine in visual
• field preservation and / or improvement
  in eyes
• undergoing controlled glaucoma
• No. of Patients 70 eyes of patients were checked
  for
• improvements in visual field following 2-4
  months of
• brimonidine treatment
• Conclusion Brimonidine may prevent visual field
  loss in
• patients with glaucoma. It is possible
  that the
• neuroprotective qualities of brimonidine
  may contribute to
• visual field preservation in glaucomatous
  eyes.

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BRIMONIDINE NEUROPROTECTION

• REMEMBER
• RGC survival increased
• Brimonidine and not timolol
• exhibit neuroprotective effects
• Brimonidine increases pOBF
• Brimonidine increases the
• visual field