**4. Physiopathology**

**Diseases Associated With Iris Neovascularization**

Sturge-Weber disease with choroidal hemangioma

Pseudoexfoliation of the lens capsule

Reticulum cell sarcoma of ciliary body

**3. Prevalence and incidence**

\*Most frequently associated with iris neovascularization

**Table 2.** Diseases Associated With Iris Neovascularization

Neovascular glaucoma\* Uveitis

Coats' disease Eales' disease

Retinal detachment surgery Vitrectomy

Laser coreoplasty Cataract extraction

Diabetes mellitus\* Norrie's disease Sickle cell disease Neurofibromatosis Lupus erythematosus Marfan's syndrome

Retinoblastoma\* Melanoma of the choroid Melanoma of the iris Metastatic carcinoma

Overall incidence and prevalence of NVG has not been accurately reported, a retrospective study has shown a prevalence rate of 3.9%. The most common conditions associated with NVG are central retinal vein occlusion (CRVO), proliferative diabetic retinopathy (PDR),

Central retinal vein occlusion\* Central retinal artery occlusion Branch retinal vein occlusion Carotid occlusive disease

Takayasu's disease Giant cell arteritis

Cartotid artery ligation Carotid-cavernous fistula Leber ciliary aneurysms Retinopathy of prematurity

Endophthalmitis Vogt-Koyanagi syndrome Retinal detachment Persistent hyperplastic vitreous

Sympathetic ophthalmia Surgery and radiation therapy

Vascular disorders

336 Glaucoma - Basic and Clinical Aspects

Ocular diseases

Radiation Trauma Systemic diseases

Neoplastic diseases

Salus first observed abnormal vessels in the iris in 1928, calling the condition rubeosis iridis. Neovascularization of the iris (INV) is often followed by NVG, with its associated blindness and pain. (Laatikainen, 1979). The most common conditions that develop NVG as a compli‐ cation of the disease are Diabetic Retinopathy (DR) and Central Retinal Vein Occlusion (CRVO), both having retinal hypoxia and ischemia as main contributory factor. (Al-Shamsi HN, Dueker DK, et, al. 2009)

Retinal hypoxia-ischemia increases the production of multiple factors: Vascular endothelial grow factor, nitric oxide, inflammatory cytokines, free radicals and accumulation of intracel‐ lular glutamate. (Charanjit Kaur et, al. 2008). The mechanism for reaching the critical level of retinal hypoxia-ischemia is different between DR and CRVO, because the first may need years to reach the level of VEGF that can develop INV and NVG, but CRVO could reach that level in only a few weeks.

#### **4.1. Physiopathology of central retinal vein occlusion**

Green made the most relevant histopathology study, in our opinion, in 1981. This study showed the natural history and characteristic evolution of thrombi in CRVO. First there is adherence of the thrombus to an area of the vein wall without its endothelium.

Inflammatory cell infiltration becomes prominent as a secondary factor. In early thrombosis, neutrophils may be seen clinging to the wall of the vein. After several weeks, a variable de‐ gree of lymphocyte infiltration was present in almost half of their cases. The infiltrate was seen in three places: around the vein (periphlebitis), in the wall of the vein (phlebitis) and/or in the occluded area. Endothelial-cell proliferation is an integral part of the process of organ‐ ization and recanalization of the thrombus, and it occurs after several days.

In some of the eyes with an interval of a year or more between CRVO and the histologic study, a thick-walled vein with a single channel was present. They believe that these cases represent an old thrombus that now has a single or a main channel of recanalization. (Green, et al.1981)

Rubeosis iridis and NVG had a high prevalence in Green's study, reaching 82.8%. Other au‐ thors had previously described the high incidence of rubeosis iridis in CRVO, associated with clinical risk factors such as visual acuity less than 6/60 (20/200), more than 10 cottonwool spots and/or severe retinal oedema seen by ophthalmoscopy. Some fluorescein angiog‐ raphy findings were also described, such as: severe capillary occlusion, prolonged arteriovenous transit time (over 20 seconds), posterior pole or peripheral severe large or small diameter vessel leakage. (Stephen H. Sinclair, Evangelos S. Gragoudas,1979). All these fea‐ tures are signs of hypoxia-ischemia and enhance the production of multiple vascular growth factors, the most important being vascular endothelial growth factor (VEGF).

In the retina, VEGF-A is produced by retinal pigment epithelium (RPE), endothelial cells, peri‐ cytes, astrocytes, Muller cells, amacrine, and ganglion cells. (Will Whitmire, Mohammed MH

Neovascular Glaucoma http://dx.doi.org/0.5772/53115 339

There is a high level of VEGF in the anterior chamber of patients with ischemic CRVO and PDR. A close temporal correlation between aqueous VEGF levels and the degree of iris neovasculari‐ zation has been demonstrated. (Sohan Singh Hayreh. 2007. Ciro Costagliola, Ugo Cipollone, et,

VEGF enhances the development of new abnormal vessels in the iris (INV) and the associated growth of fibrovascular tissue causes the formation of anterior synechiae and angle closure, which mechanically blocks aqueous humour outflow through the trabecular meshwork and in‐

A histopathological staging of eyes with neovascular glaucoma, according to the formation and extension of fibrovascular tissue in the anterior chamber angle and on the iris surface, has divid‐ ed the condition into four stages. (Table 3, Figure 1)(Nomura T, Furukawa H, et, al. 1976).

2 Fibrovascular tissue extends from the trabecular meshwork into the anterior chamber: peripheral

4 A single layer of endothelial cells develops on the surface of the fibrovascular membrane overlying

**Figure 1.** Fibrovascular tissue spreads on the anterior surface of the iris. The tissue pulls the posterior epithelial pig‐ ment of the iris over the pupil, causing ectropion uveae. Photography from Pathology Service, Asociación Para Evitar la

anterior synechiae develop because of shrinkage of the fibrovascular tissue within the angle.

creases intraocular pressure. (Ciro Costagliola, Ugo Cipollone, et, al. 2008)

1 Fibrovascular tissue occurs in the trabecular meshwork. Angle is open.

**Table 3.** Histopathological staging of neovascular glaucoma. (Nomura T, Furukawa H, et, al. 1976).

3 Fibrovascular tissue spreads on the anterior surface of the iris.

Al-Gayyar, et, al. 2011).

**Stage Characteristics**

Ceguera en México.

the iris.

al. 2008)

#### **4.2. Physiopathology of diabetic retinopathy**

DR is widely regarded as a microvascular complication of diabetes. Clinically, DR can be classified into non-proliferative DR (NPDR) and proliferative DR (PDR) (Cheung et al., 2010. Remya Robinson, Veluchamy A. Et, al. 2012). In contrast to CRVO, the establishment of hy‐ poxia-ischemia is slow. The transition between subsequent events caused by retinal hypo‐ xia-ischemia in DR is reflected in the clinical classification. The most important factor that causes almost all vascular complications in diabetes mellitus is chronic hyperglycemia, al‐ though chronic hypoxia-reperfusion events may play an important role (Shiba et al. 2011).

The pathogenesis of the development of DR is complex and the exact mechanisms by which hyperglycemia initiates the vascular or neuronal alterations in DR have not been completely determined (Curtis et al., 2009; Villarroel et al., 2010; Remya Robinson, Veluchamy A. Et, al. 2012). Chronic hyperglycemia thickens the endothelial basement membrane of the capilla‐ ries and produces endothelial damage. Damaged endothelium can't be replaced properly because of perycite disfunction. Pericytes provide vascular stability and control endothelial proliferation, they are essential for the maturation of the developing vasculature.(Hans-Pe‐ ter Hammes et, al. 2002).

Cellular damage could be caused by several mechanisms such as increased flux through the pol‐ yol pathway, production of advanced glycation end-products, increased oxidative stress and activation of the protein kinase C pathway, but many of these potential mechanisms remain as hypotheses. Chronic inflammatory response and the expression of vasoactive factors and cyto‐ kines may also play an important role in the pathogenesis of DR. (Remya Robinson, Veluchamy A. Et, al. 2012) In both CRVO and DR a hypoxic-ischemic retinal environment enhances the pro‐ duction of vascular proliferation factors, such as VEGF, in a dose-dependent manner, and the re‐ sultant rubeosis iridis is related to the degree of retinopathy, especially in proliferative diabetic retinopathy. (Francesco Bandello, Rosario Brancato, et, al. 1994)

#### **4.3. Vascular Endothelial Growth Factor (VEGF)**

One of the most important molecules involved in the pathogenesis of NVG is VEGF. This molecule is an endothelial cell specific angiogenic and vasopermeable factor (Lloyd Paul Aiello, Robert L Avery, et, al. 1994) and a molecule of convergence of various physiopatho‐ logical mechanisms in both diseases.

VEGF incorporates five ligands (A, B, C, D & Placenta Growth Factor) that bind to three re‐ ceptor tyrosine kinases (VEGFR-1 to 3). The founding member and the most characterized member is VEGF-A, for its angiogenic and permeability effects. VEGF-A binds to VEGFR-1 and 2, which may explain the properties of each regarding vascular permeability, angiogen‐ esis, and survival. (Will Whitmire, Mohammed MH Al-Gayyar, et, al. 2011).

In the retina, VEGF-A is produced by retinal pigment epithelium (RPE), endothelial cells, peri‐ cytes, astrocytes, Muller cells, amacrine, and ganglion cells. (Will Whitmire, Mohammed MH Al-Gayyar, et, al. 2011).

raphy findings were also described, such as: severe capillary occlusion, prolonged arteriovenous transit time (over 20 seconds), posterior pole or peripheral severe large or small diameter vessel leakage. (Stephen H. Sinclair, Evangelos S. Gragoudas,1979). All these fea‐ tures are signs of hypoxia-ischemia and enhance the production of multiple vascular growth

DR is widely regarded as a microvascular complication of diabetes. Clinically, DR can be classified into non-proliferative DR (NPDR) and proliferative DR (PDR) (Cheung et al., 2010. Remya Robinson, Veluchamy A. Et, al. 2012). In contrast to CRVO, the establishment of hy‐ poxia-ischemia is slow. The transition between subsequent events caused by retinal hypo‐ xia-ischemia in DR is reflected in the clinical classification. The most important factor that causes almost all vascular complications in diabetes mellitus is chronic hyperglycemia, al‐ though chronic hypoxia-reperfusion events may play an important role (Shiba et al. 2011). The pathogenesis of the development of DR is complex and the exact mechanisms by which hyperglycemia initiates the vascular or neuronal alterations in DR have not been completely determined (Curtis et al., 2009; Villarroel et al., 2010; Remya Robinson, Veluchamy A. Et, al. 2012). Chronic hyperglycemia thickens the endothelial basement membrane of the capilla‐ ries and produces endothelial damage. Damaged endothelium can't be replaced properly because of perycite disfunction. Pericytes provide vascular stability and control endothelial proliferation, they are essential for the maturation of the developing vasculature.(Hans-Pe‐

Cellular damage could be caused by several mechanisms such as increased flux through the pol‐ yol pathway, production of advanced glycation end-products, increased oxidative stress and activation of the protein kinase C pathway, but many of these potential mechanisms remain as hypotheses. Chronic inflammatory response and the expression of vasoactive factors and cyto‐ kines may also play an important role in the pathogenesis of DR. (Remya Robinson, Veluchamy A. Et, al. 2012) In both CRVO and DR a hypoxic-ischemic retinal environment enhances the pro‐ duction of vascular proliferation factors, such as VEGF, in a dose-dependent manner, and the re‐ sultant rubeosis iridis is related to the degree of retinopathy, especially in proliferative diabetic

One of the most important molecules involved in the pathogenesis of NVG is VEGF. This molecule is an endothelial cell specific angiogenic and vasopermeable factor (Lloyd Paul Aiello, Robert L Avery, et, al. 1994) and a molecule of convergence of various physiopatho‐

VEGF incorporates five ligands (A, B, C, D & Placenta Growth Factor) that bind to three re‐ ceptor tyrosine kinases (VEGFR-1 to 3). The founding member and the most characterized member is VEGF-A, for its angiogenic and permeability effects. VEGF-A binds to VEGFR-1 and 2, which may explain the properties of each regarding vascular permeability, angiogen‐

esis, and survival. (Will Whitmire, Mohammed MH Al-Gayyar, et, al. 2011).

retinopathy. (Francesco Bandello, Rosario Brancato, et, al. 1994)

**4.3. Vascular Endothelial Growth Factor (VEGF)**

logical mechanisms in both diseases.

factors, the most important being vascular endothelial growth factor (VEGF).

**4.2. Physiopathology of diabetic retinopathy**

ter Hammes et, al. 2002).

338 Glaucoma - Basic and Clinical Aspects

There is a high level of VEGF in the anterior chamber of patients with ischemic CRVO and PDR. A close temporal correlation between aqueous VEGF levels and the degree of iris neovasculari‐ zation has been demonstrated. (Sohan Singh Hayreh. 2007. Ciro Costagliola, Ugo Cipollone, et, al. 2008)

VEGF enhances the development of new abnormal vessels in the iris (INV) and the associated growth of fibrovascular tissue causes the formation of anterior synechiae and angle closure, which mechanically blocks aqueous humour outflow through the trabecular meshwork and in‐ creases intraocular pressure. (Ciro Costagliola, Ugo Cipollone, et, al. 2008)

A histopathological staging of eyes with neovascular glaucoma, according to the formation and extension of fibrovascular tissue in the anterior chamber angle and on the iris surface, has divid‐ ed the condition into four stages. (Table 3, Figure 1)(Nomura T, Furukawa H, et, al. 1976).


**Table 3.** Histopathological staging of neovascular glaucoma. (Nomura T, Furukawa H, et, al. 1976).

**Figure 1.** Fibrovascular tissue spreads on the anterior surface of the iris. The tissue pulls the posterior epithelial pig‐ ment of the iris over the pupil, causing ectropion uveae. Photography from Pathology Service, Asociación Para Evitar la Ceguera en México.

#### **4.4. Physiopathology of optic nerve damage**

VEGF, the main protein in the pathogenesis of NVG, plays a nonvascular and neuropro‐ tective role in adult normal retinas. VEGF-A neutralization can cause neuroretinal cell apoptosis and loss of retinal function without affecting the normal vasculature of the reti‐ na. Treatment with VEGF-B protects retinal ganglion cells (RGC) in various models of neurotoxicity. This neuroprotective effect of VEGF-B was attributed to inhibition of proapoptotic proteins like p53 and caspases. The detrimental effects in environments with ex‐ cessive VEGF-A, as happens in PDR, might be explained by excessive levels of peroxynitrite that can inhibit the VEGF-mediated survival signal via tyrosine nitration and subsequent inhibition of key survival proteins in retinal cells. (Will Whitmire, Mo‐ hammed MH Al-Gayyar, et, al. 2011).

**5.3. Fluorescein iris angiogram classification**

guera en México.

Asociación Para Evitar la Ceguera en México.

findings, diabetic iridopathy was divided in 4 grades (Table 4).

Fluorescein iris angiogram could help differentiate normal iris vessels from INV. The vascu‐ lar abnormalities revealed by fluorescein angiography of the iris are: dilated leaking vessels around the pupil, irregular or slow filling of the radial arteries, superficial arborizing neo‐ vascularization, usually starting in the angle; and dilatation and leakage of the radial ves‐ sels, particularly the arteries. (Leila Laatikainen, 1979). On the basis of angiographic

Neovascular Glaucoma http://dx.doi.org/0.5772/53115 341

**Figure 2.** Early rubeosis at the pupillary margin. Photography from the Glaucoma Service, Asociación Para Evitar la Ce‐

**Figure 3.** Late rubeosis with mid-peripheral neovascularization of the iris. Photography from the Glaucoma Service,

Ischemia of the optic nerve head is the main reason of optic nerve damage in NVG. As the IOP rises the perfusion pressure decreases, worsening the ischemic condition of the optic nerve and retinal ganglion cells. (Ciro Costagliola, Ugo Cipollone, et, al. 2008).
