Vascular Endothelial Growth Factor in Stage V ROP
Condition: Retinopathy of Prematurity
MeSH terms: Retinal Diseases; Retinopathy of Prematurity; Premature Birth
Study type: Interventional
Phase: Phase 4

Summary: 
      Vascular Endothelial Growth Factor (VEGF) is a dimeric glycoprotein, naturally expressed in
      epithelial and tumor cells (1). Normal Retinal vascularization has two phases: In the first
      fase, cells of mesenquimatous origin form the first superficial plexus (14-21 weeks of
      gestation). In the second phase, denominated "angiogenesis phase", the superficial and deep
      capillary plexus are formed (15,20). The Retinopathy of Prematurity (ROP) was described for
      the first time in 1942 (4), at the present moment it is a public health problem in the
      developing countries. The International Classification of ROP classifies it in 5 stages,
      dividing it in 3 anatomical zones. It is a public health problem that continuous without
      having an effective prophylaxis. The early diagnosis and treatment in thresholds stages have
      changed the prognosis of this disease (11,12).
    

Detailed description: 
      Vascular Endothelial Growth Factor (VEGF) is a dimeric glycoprotein, naturally expressed in
      epithelial and tumor cells (1). In conditions of hypoxia it is secreted by the pericytes, the
      Retina Pigmented epithelium (RPE)and glial cells, including a the Müller cells (1,2,4,5)
      favoring the formation of new abnormal vessels (1). Its activity is mediated by two high
      affinity receptors: the receptor VEGF 1 (FLT-1) and VEGF 2 (FLT-2) (1,9). The FLT-1 promotes
      cellular proliferation whereas FLT-2 the migration and cell- extracellular matrix interaction
      (9). The VEGF is essential as much for the normal retinal vascularization as for pathological
      (5,14).

      Normal Retinal vascularization has two phases: In the first fase, cells of mesenquimatous
      origin form the first superficial plexus (14-21 weeks of gestation). In the second phase,
      denominated "angiogenesis phase", the superficial and deep capillary plexus are formed
      (15,20). The second phase is highly dependent of VEGF induced by hypoxia (15,20). In the
      normal retina the growth occurs from the optical nerve to the periphery (17).

      The scientific progress in the neonatal intensive care units in the last years has allowed
      the survival of a larger number of premature newborns(15).

      The Retinopathy of Prematurity (ROP)(ROP) was described for the first time in 1942 (4), at
      the present moment it is a public health problem in the developing countries. Of each 100.000
      blind child in Latin America, 24.000 are due to ROP (240/1000 blind child) (17). It is the
      main cause of blindness in premature new born (1,4,5). It is of multifactorial etiology (17)
      but it has been related to a short gestational age (smaller to 32 weeks of gestation) (4), to
      low birth weight (less of 1500gr) or very low birth weight (less 1250gr)(1,4,5,17,18,20), to
      the administration of high oxygen concentration immediately after birth (1,3,18), low levels
      of the Insulin-like growth factor(IGF-I) and excessive production of VEGF (3,17).

      All this, combined with large periods of hyperoxia-hypoxia, Produces that the normal
      vascularization of the retina stops. This also produces vascular-occlusive changes,
      arteriovenous anastomoses in the edge of the vascularized with the none-vascularized retina
      (18), begins the formation of abnormal vessels towards the vitreous, finally lead to retina
      detachment in the most severe cases (2,3,4,5).

      The International Classification of ROP classifies it in 5 stages, dividing it in 3
      anatomical zones. A threshold stage is considered when we have the presence of stage 3, in
      zone 1 or 2 in 5 continuous hour uses or 8 discontinuous with plus disease (15,16,17). The
      pre-threshold stage is divided in two types: type 1 is any stage of the disease in zone 1
      with plus disease, stage 3, without plus disease in zone 1 or stage 2 or 3 with plus in zone
      2. Type 2 is stage 1 or 2 without plus disease in zone 1 or stage 3 without plus disease in
      zone 2 (17,19). The threshold stage happens approximately in 5% of the patients with very low
      weight to the birth, of which the 10-15% develop blindness (6,8)

      It is a public health problem that continuous without having an effective prophylaxis (5),
      nevertheless the use of constant oxygen concentrations, avoiding the periods of
      hyperoxia-hypoxia, has demonstrated to produce a decrease of the presentation of advanced
      stages of the disease and the necessity of ophthalmological surgery (5). The early diagnosis
      and treatment in thresholds stages have changed the prognosis of this disease (11,12). The
      use of the laser as treatment in the threshold and prethreshold stages is successful in the
      91-95% of the cases(10), the ablative effect on the neurons, probably diminishes the VEGF
      production (15). The use of the vitrectomy in the early cases of retinal detachment also has
      good results (13).

      For the determination and the quantification of VEGF several laboratory techniques have been
      used, as they are the Westernblot (1), the flow cytometry (7), CBA (7). Nevertheless, the
      Enzyme-linked immunoabsorbent assay (ELISA) remains the gold standard for the measurement of
      interleukins, growth factors and other cytokines in corporal fluids, including the vitreous,
      aqueous and subretinal fluid (1,5,7).

      It has been demonstrated in humans that there are high vitreous concentrations of VEGF in
      eyes with active neovascularization (6,14). In the same way, the animal models of ROP report
      high levels of VEGF (2,21). The levels of this growth factor are altered in both stages, with
      a more marked increase during the first stage (2). Some clinical studies in patients with ROP
      in stage 4 and 5 have reported an increase of up to 90 times greater of the concentration of
      VEGF in the subretinal liquid in comparison with the found in patients with retinal
      detachment of any other cause (1). Finally, when it has been possible to examine retinas
      immediately after the treatment (due to death of the patient) have been found a low
      expression of mRNA of VEGF in the treated cells (6).
    

Intervention name(s): Open-Sky Vitrectomy
Intervention type(s): Procedure
Intervention description(s): Open-Sky vitrectomy with removal of the Tunica vasculosa lentis and retinal reattachment
Other intervention name(s): Vitrectomy
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Retinopathy of Prematurity.; ROP.; Vascular Endothelial Growth Factor.; VEGF.; Vitreous.; Subretinal Fluid.; ELISA.