EBM Journal Reading

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EBM Journal Reading
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Epidemiology

• Corneal neovascularization (CNV) is a sight
  threatening condition affecting millions of
  people
• Blinding CNV is a sequela of various conditions
• Chlamydial infection
• (estimated to blind 6 million people,
  15 of world blindness)
• Onchocerciasis infections
• (?????, estimated to have blinded
  270,000 people)
• Herpetic infections
• (affect 500,000 people in the United
  States)
• Contact lens wear

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Epidemiology

• The reported prevalence of CNV is 4.14
• of the general ophthalmic eye service in the
  United States
• Angiogenesis is a common histopathological
  feature of corneal diseases leading to corneal
  transplantation

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Risk Factors for Neovascularization

• The normal cornea is an avascular structure
• Avascularity is necessary for corneal
  transparency and immune privilege
• At resting basal conditions, a high level of
  antiangiogenic and low level of angiogenic
  molecules maintain homeostasis
• Additionally, there are a number of defense
  mechanisms that protect against angiogenesis

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Risk Factors for Neovascularization

• Critically, soluble VEGF receptor-1 (sFlt-1)
  inhibits the angiogenic effects of VEGF by
  inactivates Flt (a VEGF receptor)
• Fas ligand (FasL) induces apoptosis to invading
  inflammatory cells and endothelial cells
• Thrombospondin-1 activating CD-36 which
  downregulates VEGF secretion
• The hemeoxygenase system has also been shown to
  be an intrinsic cytoprotective and
  anti-inflammatory system in the cornea

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Risk Factors for Neovascularization

• The presence of new corneal vessels indicates an
  imbalance between angiogenic and antiangiogenic
  factors
• an upregulation of angiogenic factors,
  accompanied by a downregulation of antiangiogenic
  factors
• CNV may be a physiological healing response to an
  allergic, infectious, immunologic, anoxic,
  traumatic, or degenerative stimulus, but an
  inappropriate local tissue reaction results in
  pathological CNV

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Pathogenesis

• CNV involves the sprouting of new vessels from
  capillaries and venules of the pericorneal
  (limbal) plexus
• Patterns of CNV include
• Superficial vascularization
• -extend only beneath the epithelium
• Vascular pannus
• -vessel and collagen growth onto the
  peripheral cornea
• -mainly associated with ocular surface
  disorders
• Stromal vascularization
• -extend between the Bowman and Descemet
  layers

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Pathogenesis

• CNV can be broadly divided up into
• a latent prevascular phase
• an active neovascularization (NV) phase
• finally a vessel maturation and regression phase

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Pathogenesis

• Klintworth(1991) describes,
• a latent period between corneal injury and
  angiogenesis onset, characterized by pericorneal
  vessel dilation, increased vessel permeability,
  leukocyte and platelet migration
• an endothelial cell activation phase follows
• cell retraction and decreased endothelial cell
  junctions
• degradation of the endothelial lamina,
  simultaneous endothelial cell migration into the
  surrounding extracellular matrix, and replication
• degradation of the extracellular matrix that
  allow endothelial cells to invade and form
  vessels
• vascular sprouting, vessel lumen formation, and
  anastomosis
• formation of a supporting basal lamina around new
  vessels

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Pathogenesis

• Macrophages and pericytes play a prominent role
• Matured vessels become angiogenic factor
  independent
• However, vessels that are not supported by
  pericytes beyond this stage undergo apoptosis
• The window period between the vascular
  endothelial network creation and pericyte
  recruitment is a potential target for
  angioregressive therapies

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Pathogenesis

• The major difference between health and disease
  NV is
• controlled and regulated v.s. unregulated
• Pathological blood vessels are immature and lack
  structural integrity their increased vascular
  permeability causes chronic corneal edema, lipid
  exudation, inflammation, and scarring
• Moreover, CNV can worsen the prognosis of
  subsequent penetrating keratoplasty

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Impact on Corneal Transplantation

• Corneal vascularization of the recipient corneal
  bed is an established risk factor for corneal
  graft rejection and failure
• the most clinically evident cause of earlier
  rejection
• CNV after penetrating keratoplasty can adversely
  affect graft longevity
• Vail et al reported that
• deep vascularization increased the risk of graft
  failure
• superficial vascularization affect postoperative
  visual acuity (VA)

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Impact on Corneal Transplantation

• The Collaborative Corneal Transplantation Study
• high risk was defined as a cornea with 2 or more
  quadrants of vascularization
• the incidence of rejection increases with both
  the number of quadrants vascularized and with the
  total number of vessels crossing the proposed
  graft/donor junction
• graft rejection in a previously grafted eye
  relates more to the number of blood vessels in
  the cornea than to the number of previous grafts

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Impact on Corneal Transplantation

• Corneal avascularity suppresses the immune reflex
• Corneal lymphangiogenesis enables the exit of
  antigenic material and antigen presenting cells
  to the regional lymph nodes
• Corneal blood vessels provide a route of entry
  for the immune effector cells (CD4 T lymphocytes
  and memory T lymphocytes)
• Corneal lymphangiogenesis seems related to the
  degree of CNV
• The neovascular response leads to a loss of
  immune privilege

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TREATMENTS FOR CNV

• Treatment of CNV can be challenging and
  problematic
• Many medical and surgical options are available
  for the management of CNV
• Antiangiogenic therapy
• aims to stop neoangiogenesis and is most
  effective if applied early
• Regressive therapy
• aims to induce regression of formed immature
  or old vessels
• This article will review treatments of historical
  interest, followed by medical and surgical
  treatments

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Treatments of Historical Interest

• A number of techniques are mentioned in the
  literature
• Invasive technique removal of pannus,
  surgical/diathermic peritomy, mechanical scar
  tissue barrier, heat cauterization, cryotherapy,
  and lamellar grafts
• Noninvasive technique ionizing rays
• In an article written in 1964, Lavergne and
  Colmant mention a number of techniques including
• Surgical removal of pannus, surgical/diathermic
  peritomy, and heat cauterization
• However, in 1968, Ey et al noted that the
  practical details and comparative value of these
  techniques were lacking in the literature

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Treatments of Historical Interest

• A mechanical scar tissue barrier was
  advocated on the basis that the wound surrounding
  the penetrating keratoplasty acts as a partial
  barrier of NV
• The clinical application of the technique was
  limited because the vessels showed extreme
  facility in growing around or below the area of
  scarring
• Heat cauterization has been mentioned in the
  literature, but the practical details remain
  uncertain
• After cauterization of the NV, a complete
  peritomy and resuturing of the conjunctiva
  approximately 4 mm posterior to the limbus,
  leaving a bare area of sclera, has been described

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Treatments of Historical Interest

• Cryotherapy has been described as causing rupture
  of small capillaries
• subsequent recanalization
• grafthost interface hemorrhage
• deep ulceration and perforation

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Treatments of Historical Interest

• Beta irradiation has been used to manage CNV
  using radium D and strontium-90 (Sr-90)
• The biological effect of ionizing radiation
• temporary inhibition of metabolic activity
• complete and permanent cellular disintegration

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Treatments of Historical Interest

• The complication of beta irradiation
• corneal erosions
• corneal ulceration and corneal telangiectasia
• late lipid infiltration
• intensification of the corneal arcus
• nonprogressive corneal thinning
• iris atrophy and cataract
• The availability of steroids and the side effects
  associated with beta radiation greatly reduced
  its use

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Medical Treatments

• Steroids
• Topical steroids are the mainstay for the
  suppression of actively proliferating corneal
  vessels
• The antiangiogenic effect was first reported in
  1950
• Subsequently, a number of studies have
  investigated the inhibition of CNV by
  corticosteroids, including
• -Cortisone
  -Dexamethasone
• -Hydrocortisone
  -Methylprednisolone
• -Prednisolone
  -Medroxyprogesterone
• -Triamcinolone -Ticabesone
  propionate

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Medical Treatments

• However, not all studies have noted the
  suppression of CNV with steroids
• Klintworth(1991), in his review of the use of
  steroids in angiogenesis suppression, points out
  that steroids are most effective when they are
  applied before, or immediately after the corneal
  injury

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Medical Treatments

• Despite the widespread use of dexamethasone and
  other steroids, little is known about the
  detailed mechanisms
• The antiangiogenic effect of steroids is thought
  to result from multiple anti-inflammatory
  properties, include
• inhibition of cell chemotaxis
• modulation of proteolytic activities of vascular
  endothelial cells
• inhibition of proinflammatory cytokines (TNFa,
  IL-1, and IL-6) inhibition of plasminogen
  activator (PA) and prostaglandin (PG) synthesis
• inhibition of vascular dilation, stabilization of
  lysosomal membranes, and destruction of
  lymphocytes

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Medical Treatments

• However, steroid provide incomplete suppression
  of CNV
• suppress inflammation associated new vessels
• but not angioregressive
• Side effects
• glaucoma
• cataracts
• superinfection
• herpes simplex recurrence
• Thus, more effective treatments are still sought

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Medical Treatments

• Nonsteroidal Anti-inflammatory Agents
• Although corticosteroids are an effective class
  of drugs for the treatment of ocular
  inflammation, their prolonged use may result in
  severe ocular side effects
• NSAIDs agents that have similar or greater
  efficacy than steroids, but do not share their
  ocular side effects
• NSAIDs target PG synthesis
• PGs (specifically PGE2)
• produced in corneal inflammation and wound
  healing
• proangiogenic

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Medical Treatments

• NSAIDs specifically inhibit the enzyme
  cyclooxygenase (COX) (converts arachidonic acid
  to PGs)
• Normal blood vessels express the COX-1 enzyme
  new angiogenic endothelial cells express a COX-2
  isoform
• The eicosanoids (produced by inducible COX-2)
  stimulate VEGF expression in inflammation-associat
  ed angiogenesis

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Medical Treatments

• Experimentally, NSAIDs reported to inhibit CNV
  include
• -Flurbiprofen -Indomethacin
• -Ketorolac -Diclofenac
• -Nepafenac
• Unfortunately, the clinical effects of NSAIDs
  have proved to be very variable
• Additionally, corneal complications, especially
  ulceration and melting, have been reported
• Therefore, they are not typically used as
  first-line agents to suppress CNV

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Impact on Corneal Transplantation

• Studies using univariate and multivariate
  survival analysis divide the recipient corneas
  into low, medium, and high risk depending on the
  number of quadrants of vascularization
  (avascular, 12 quadrants, and 3 quadrants,
  respectively).

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Treatments of Historical Interest

• Leigh describes a complicated technique of
  keratoplasty
• involving a central lamellar keratoplasty, after
  a peripheral annular lamellar keratoplasty, and
  then after a central (full thickness) PK
• Very few vessels were able to traverse the
  resulting tortuous route to the central cornea
  and were very attenuated if at all present.
• The technique was successful in 2 of 3 patients
  in the remaining patient, the initial central
  lamellar graft remained sufficiently clear to
  obviate the need for further surgery

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Medical Treatments

• The antiangiogenic effect of cortisone has been
  shown to enhance with heparin and cyclodextrins
• The observation that cortisone administered with
  heparin is antiangiogenic led to the discovery of
  a new class of compounds referred to as
  angiostatic steroids.
• The mechanism of the action of angiostatic
  steroids is thought to be related to the
  modulation of collagen metabolism, induction of
  basement membrane dissolution, and promotion of
  PA inhibitor