**Ibopamine – A New Alpha-Adrenergic and D1- Dopaminergic Drug**

Italo Giuffré

[163] Chen Y., P. Yang, F. Li, S. Hou, Z. Jiang, Q. Shu,A. Kijlstra. Association analysis of TGFBR3 gene with Vogt-Koyanagi-Harada disease and Behcet's disease in the Chi‐

[164] Horie Y., A. Meguro, M. Ota, N. Kitaichi, Y. Katsuyama, Y. Takemoto, K. Namba, K. Yoshida, Y.W. Song, K.S. Park, E.B. Lee, H. Inoko, N. Mizuki,S. Ohno. Association of TLR4 polymorphisms with Behcet's disease in a Korean population. Rheumatology

[165] Meguro A., M. Ota, Y. Katsuyama, A. Oka, S. Ohno, H. Inoko,N. Mizuki. Association of the toll-like receptor 4 gene polymorphisms with Behcet's disease. Ann Rheum Dis

[166] Li H., Q. Liu, S. Hou, L. Du, Q. Zhou, Y. Zhou, A. Kijlstra, Z. Li,P. Yang. TNFAIP3 gene polymorphisms confer risk for Behcet's disease in a Chinese Han population.

[167] Jung E.S., S.W. Kim, C.M. Moon, D.J. Shin, N.H. Son, E.S. Kim, H.J. Lee, S.P. Hong, T.I. Kim, W.H. Kim,J.H. Cheon. Relationships between genetic polymorphisms of triggering receptor expressed on myeloid cells-1 and inflammatory bowel diseases in

[168] Hou S., Q. Shu, Z. Jiang, Y. Chen, F. Li, F. Chen, A. Kijlstra,P. Yang. Replication study confirms the association between UBAC2 and Behcet's disease in two independent

[169] Karray E.F., I. Ben Dhifallah, K. Ben Abdelghani, I. Ben Ghorbel, M. Khanfir, H. Hou‐ man, K. Hamzaoui,L. Zakraoui. Associations of vitamin D receptor gene polymor‐ phisms FokI and BsmI with susceptibility to rheumatoid arthritis and Behcet's

[170] Nam E.J., S.W. Han, S.U. Kim, J.H. Cho, K.H. Sa, W.K. Lee, J.Y. Park,Y.M. Kang. As‐ sociation of vascular endothelial growth factor gene polymorphisms with behcet dis‐

[171] Du L., P. Yang, S. Hou, X. Lin, H. Zhou, X. Huang, L. Wang,A. Kijlstra. Association of the CTLA-4 gene with Vogt-Koyanagi-Harada syndrome. Clin Immunol 2008;

[172] Hu K., P. Yang, Z. Jiang, S. Hou, L. Du,F. Li. STAT4 polymorphism in a Chinese Han population with Vogt-Koyanagi-Harada syndrome and Behcet's disease. Hum Im‐

[173] Li H., Q. Liu, S. Hou, L. Du, Q. Zhou, Y. Zhou, A. Kijlstra,P. Yang. TNFAIP3 gene polymorphisms in a Chinese Han population with Vogt-Koyanagi-Harada syn‐

Chinese sets of patients and controls. Arthritis Res Ther 2012; 14(2):R70.

nese Han population. Curr Eye Res 2012; 37(4):312-7.

the Korean population. Life Sci 2011; 89(9-10):289-94.

disease in Tunisians. Joint Bone Spine 2012; 79(2):144-8.

ease in a Korean population. Hum Immunol 2005; 66(10):1068-73.

(Oxford) 2009; 48(6):638-42.

470 Ophthalmology - Current Clinical and Research Updates

Hum Genet 2013; 132(3):293-300.

2008; 67(5):725-7.

127(1):43-8.

munol 2010; 71(7):723-6.

drome. PLoS One 2013; 8(3):e59515.

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/58380

### **1. Introduction**

Ibopamine (3,4 di-isobutyrrylester of N-methyldopamine) at 2% concentration, when instilled in the conjunctival sac, stimulates ocular D1-dopaminergic and α-adrenergic receptors [1,2]. It is a pro-drug of epinine (N-methyldopamine) (Figure 1). It has positive inotropic effects: it improves cardiac function and it is effective in the treatment of congestive heart failure. The pharmacological ocular characteristics of ibopamine are as follows:


In the conjunctival sac, ibopamine is fastly hydrolysed to epinine by the esterases of the aqueous humor and ocular tissues. This hydrolysis suggests that epinine is the active compo‐ nent of the molecule. The half-life of ibopamine in the aqueous humor is short (about 2 minutes) and epinine formation precedes the mydriatic effect [3,4] (Figure 1). It has been proved that after the instillation of ibopamine, only epinine can be found in the aqueous humor [3].

When hydrolysed to epinine, ibopamine stimulates the α-adrenergic and D1 dopaminergic receptors. The mydriatic effect of ibopamine is due to the stimulation of the α-adrenergic receptors of the dilating muscle of the pupil. Since ibopamine has no effect on the ciliary muscle, the mydriasis is not accompanied by cycloplegia. Mydriasis can be antagonized and

**2.2. Pathophysiology of IOP**

**•** Physiological studies on IOP;

**•** Treatment of ocular hypotony.

visual field tests in normal individuals [17].

in normal volunteers.

useful in different ways:

2% ibopamine eye drops increases IOP only in patients suffering from POAG. Ibopamine is

Ibopamine – A New Alpha-Adrenergic and D1-Dopaminergic Drug

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473

The instillation of ibopamine increases the IOP only in about 96% of eyes with POAG [8,9,10] (Figures 2, 3). In normal eyes, 2% ibopamine does not significantly affect IOP, with a possible mild hypotensive effect (1-2 mmHg) (Figure 4). The IOP, in POAG patients, increases by a maximum value of 10-11 mmHg within 45 minutes from the instillation and lasts about 180 minutes [7,8,9,10,11,12,13,14]. To observe this effect, 2 drops of 2% ibopamine have been instilled 5 minutes apart, and IOP was measured 45 minutes after the first instillation. The ibopamine provocative test shows a significant correlation with the highest intraocular pressure in the diurnal tension curve in glaucoma patients [15]. Indeed, in glaucoma patients with early visual field defect, the ibopamine provocative test has shown better sensitivity/ specificity than the water drinking test [16]. Ibopamine test does not modify the results of

**Figure 2.** Effect on the intraocular pressure of 2% ibopamine and 10% phenylephrine in glaucomatous patients and

**•** Evaluation of trabecular outflow pathways (pressure-dependent outflow);

**Figure 1.** Dopamine → Epinine → Ibopamine (3,4 dyisobutyrrilester of N-methyldopamine).

reversed by pre-treatment by α-blocking agents (such as thymoxamine and dapiprazole). Some Randomized Clinical Trials (RCTs) show that the D1 dopaminergic activity of the drug increases aqueous humor production and intraocular pressure (IOP) in open-angle glaucoma (POAG) patients [5].

Ibopamine has low toxicity both at systemic and local levels. LD50 is 2056 mg/Kg, 4930 mg/Kg and 1786 mg/Kg in mice, rats and guinea pigs respectively. Ibopamine is well tolerated without any significant change to the haematological and behavioural parameters. 2% ibopamine eye drops show that ibopamine is well tolerated at local level, without systemic side-effects and tachyphylaxis phenomena. One drop of 2% ibopamine contains 1 mg of the compound, while the oral dosage is higher than 400 mg/day. Electrophysiological assessment showed that ibopamine is not retinotoxic at all [6].

### **2. Clinical use**

#### **2.1. Non-cycloplegic mydriatic activity**

In binocular indirect examination of fundus oculi with scleral indentation, fluorescein and indocyanine angiography, and in the laser treatment of retinal lesions, ibopamine can induce a fast, short-lasting (2-3 hours) maximal mydriasis without cycloplegic effects or local a/or systemic side-effects [7]. The mydriatic effect of ibopamine can be prolonged if repeatedly administered (every 30 minutes). Ibopamine-induced mydriasis can be reversed by local application of α-blockers such as thymoxamine and dapiprazole. Ibopamine can substitute phenylephrine in association with tropicamide a/or cyclopentolate to avoid the typical discomfort of cycloplegia mostly in adults [7]. Ibopamine eye drops is effective in inducing pre-operative mydriasis, without effects on the cardiovascular system [7]. In the post-operative period ibopamine can induce a fast and short-lasting mydriasis to induce pupil dilatation.

### **2.2. Pathophysiology of IOP**

2% ibopamine eye drops increases IOP only in patients suffering from POAG. Ibopamine is useful in different ways:


reversed by pre-treatment by α-blocking agents (such as thymoxamine and dapiprazole). Some Randomized Clinical Trials (RCTs) show that the D1 dopaminergic activity of the drug increases aqueous humor production and intraocular pressure (IOP) in open-angle glaucoma

**Figure 1.** Dopamine → Epinine → Ibopamine (3,4 dyisobutyrrilester of N-methyldopamine).

Ibopamine has low toxicity both at systemic and local levels. LD50 is 2056 mg/Kg, 4930 mg/Kg and 1786 mg/Kg in mice, rats and guinea pigs respectively. Ibopamine is well tolerated without any significant change to the haematological and behavioural parameters. 2% ibopamine eye drops show that ibopamine is well tolerated at local level, without systemic side-effects and tachyphylaxis phenomena. One drop of 2% ibopamine contains 1 mg of the compound, while the oral dosage is higher than 400 mg/day. Electrophysiological assessment showed that

In binocular indirect examination of fundus oculi with scleral indentation, fluorescein and indocyanine angiography, and in the laser treatment of retinal lesions, ibopamine can induce a fast, short-lasting (2-3 hours) maximal mydriasis without cycloplegic effects or local a/or systemic side-effects [7]. The mydriatic effect of ibopamine can be prolonged if repeatedly administered (every 30 minutes). Ibopamine-induced mydriasis can be reversed by local application of α-blockers such as thymoxamine and dapiprazole. Ibopamine can substitute phenylephrine in association with tropicamide a/or cyclopentolate to avoid the typical discomfort of cycloplegia mostly in adults [7]. Ibopamine eye drops is effective in inducing pre-operative mydriasis, without effects on the cardiovascular system [7]. In the post-operative period ibopamine can induce a fast and short-lasting mydriasis to induce pupil dilatation.

(POAG) patients [5].

**2. Clinical use**

ibopamine is not retinotoxic at all [6].

472 Ophthalmology - Current Clinical and Research Updates

**2.1. Non-cycloplegic mydriatic activity**

The instillation of ibopamine increases the IOP only in about 96% of eyes with POAG [8,9,10] (Figures 2, 3). In normal eyes, 2% ibopamine does not significantly affect IOP, with a possible mild hypotensive effect (1-2 mmHg) (Figure 4). The IOP, in POAG patients, increases by a maximum value of 10-11 mmHg within 45 minutes from the instillation and lasts about 180 minutes [7,8,9,10,11,12,13,14]. To observe this effect, 2 drops of 2% ibopamine have been instilled 5 minutes apart, and IOP was measured 45 minutes after the first instillation. The ibopamine provocative test shows a significant correlation with the highest intraocular pressure in the diurnal tension curve in glaucoma patients [15]. Indeed, in glaucoma patients with early visual field defect, the ibopamine provocative test has shown better sensitivity/ specificity than the water drinking test [16]. Ibopamine test does not modify the results of visual field tests in normal individuals [17].

**Figure 2.** Effect on the intraocular pressure of 2% ibopamine and 10% phenylephrine in glaucomatous patients and in normal volunteers.

**•** Identification of the responsible receptor (agonist and antagonist);

**•** Evaluation of ibopamine effects when the outflow system was experimentally impaired.

Only the D1 agonist substances, such as fenoldopam, have the same effect as ibopamine on IOP in POAG patients. D1 agonist drugs increase the IOP only in POAG, but never in healthy eyes, stressing the involvement of D1 dopaminergic receptors on the mechanism stimulating

Ibopamine – A New Alpha-Adrenergic and D1-Dopaminergic Drug

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475

The hypertensive effect of ibopamine in POAG is completely counteracted by the pretreatment with a selective antagonist of the D1 receptors such as SCH23390. A clear receptorial antagonism for IOP has been identified. Ocular anti-hypertensive drug, such as β-blockers and α-agonists do not antagonize the hypertensive effects of ibopamine in POAG [14]. The partial antagonism performed by glycerol is due to an osmotic reduction of the vitreous mass.

When there is a marked increase of aqueous humor production, due to the D1 dopaminergic effect of ibopamine, the healthy eye increases its outflow mantaining the homeostasis. Instead, in glaucomatous eyes, the impaired trabecular outflow fails to maintain the hydrodynamic equilibrium and IOP increases. Fluorophotometry proves that the D1 dopaminergic stimula‐ tion, induced by 2% ibopamine, undoubtedly increases the aqueous humor production.

Ibopamine, when instilled, prior to the Laminaria, into the healthy rabbit eyes does not significantly affect the IOP, while in the eyes treated with Laminaria digitata induces ocular

Ibopamine 2% eye drops have a positive pressure effect in 50% of suspected normal-tension glaucoma eyes and may differentiate between eyes with normal trabecular outflow capacity and eyes with increased resistance in the trabecular meshwork that are ready to have pressure

A long-term treatment with corticosteroids can induce ocular hypertension. They increase the IOP by interfering with the aqueous humor outflow system. By administering dexamethasone at two different concentrations (0.1 and 1%) in eyes suffering from allergic conjunctivitis, the

Ibopamine test is useful in detecting an impairment of the outflow system also in patients affected by psudoexfoliative syndrome (PEX) [19]. This test is also positive when PEX syn‐ drome is unilateral. It exerts a significant additive effect on mydriasis of PEX eyes induced

The ibopamine test is positive in 44.33% of offspring of one glaucoma parent without glau‐ comatous damage. It signifies an impaired function of the outflow structures and, therefore, a predisposition to intraocular hypertension and possible glaucoma in some years [21,22].

with 10% phenylephrine-0.5% tropicamide with only minimal increase in IOP [20].

ibopamine test was positive, in a dose-dependent manner, from 33 to 50%.

**•** Evaluation of the change of the aqueous humor dynamics;

the aqueous humor production.

**3. Provocative test in glaucoma**

peaks and deterioration to glaucoma [18].

hypertension.

**Figure 3.** Effect on the pupillary diameter of 2% ibopamine and 10% phenylephrine in glaucomatous patients and in normal volunteers.

**Figure 4.** ibopamine induces a transient ocular hypertensive effect (mean, 8.31±2.14 mmHg) in 96% of eyes of pa‐ tients affected by POAG, whereas in healthy eyes there is a reduction of intraocular pressure (IOP) by 1 to 2 mmHg.

Several studies have been performed to assess the following issues:


Only the D1 agonist substances, such as fenoldopam, have the same effect as ibopamine on IOP in POAG patients. D1 agonist drugs increase the IOP only in POAG, but never in healthy eyes, stressing the involvement of D1 dopaminergic receptors on the mechanism stimulating the aqueous humor production.

The hypertensive effect of ibopamine in POAG is completely counteracted by the pretreatment with a selective antagonist of the D1 receptors such as SCH23390. A clear receptorial antagonism for IOP has been identified. Ocular anti-hypertensive drug, such as β-blockers and α-agonists do not antagonize the hypertensive effects of ibopamine in POAG [14]. The partial antagonism performed by glycerol is due to an osmotic reduction of the vitreous mass.

When there is a marked increase of aqueous humor production, due to the D1 dopaminergic effect of ibopamine, the healthy eye increases its outflow mantaining the homeostasis. Instead, in glaucomatous eyes, the impaired trabecular outflow fails to maintain the hydrodynamic equilibrium and IOP increases. Fluorophotometry proves that the D1 dopaminergic stimula‐ tion, induced by 2% ibopamine, undoubtedly increases the aqueous humor production.

Ibopamine, when instilled, prior to the Laminaria, into the healthy rabbit eyes does not significantly affect the IOP, while in the eyes treated with Laminaria digitata induces ocular hypertension.

### **3. Provocative test in glaucoma**

**Figure 3.** Effect on the pupillary diameter of 2% ibopamine and 10% phenylephrine in glaucomatous patients and in

**Figure 4.** ibopamine induces a transient ocular hypertensive effect (mean, 8.31±2.14 mmHg) in 96% of eyes of pa‐ tients affected by POAG, whereas in healthy eyes there is a reduction of intraocular pressure (IOP) by 1 to 2 mmHg.

Several studies have been performed to assess the following issues:

normal volunteers.

474 Ophthalmology - Current Clinical and Research Updates

Ibopamine 2% eye drops have a positive pressure effect in 50% of suspected normal-tension glaucoma eyes and may differentiate between eyes with normal trabecular outflow capacity and eyes with increased resistance in the trabecular meshwork that are ready to have pressure peaks and deterioration to glaucoma [18].

A long-term treatment with corticosteroids can induce ocular hypertension. They increase the IOP by interfering with the aqueous humor outflow system. By administering dexamethasone at two different concentrations (0.1 and 1%) in eyes suffering from allergic conjunctivitis, the ibopamine test was positive, in a dose-dependent manner, from 33 to 50%.

Ibopamine test is useful in detecting an impairment of the outflow system also in patients affected by psudoexfoliative syndrome (PEX) [19]. This test is also positive when PEX syn‐ drome is unilateral. It exerts a significant additive effect on mydriasis of PEX eyes induced with 10% phenylephrine-0.5% tropicamide with only minimal increase in IOP [20].

The ibopamine test is positive in 44.33% of offspring of one glaucoma parent without glau‐ comatous damage. It signifies an impaired function of the outflow structures and, therefore, a predisposition to intraocular hypertension and possible glaucoma in some years [21,22].

Ocular hypotony is a pathological condition of the IOP when it decreases to values below 6-7 mmHg. IOP values below 4 mmHg usually cause progressive damage to the eye [23]. Ocular hypotony can be caused by a damage to ciliary body from trauma or inflammation. In the treatment of ocular hypotony, ibopamine can be administerd every 3 hours or 3-4 times daily, associated to corticosteroid therapy [24,25].

[6] Giuffre' I., Falsini B., Gari M.A., Balestrazzi E. Pattern-electroretinogram assessment during ibopamine test in ocular hypertension. Eur. J. Ophthalmol. 2013 Jun 24; 23 (6):

Ibopamine – A New Alpha-Adrenergic and D1-Dopaminergic Drug

http://dx.doi.org/10.5772/58380

477

[7] Giuffre' I., Taverniti L., Di Staso S. The effects of 2% ibopamine eye drops on the in‐ traocular pressure and pupil motility of patients with open-angle glaucoma. Eur. J.

[8] Giuffre' I. Ibopamine stimulates α-adrenergic receptors and D1 dopaminergic recep‐

[9] Magacho L., Costa M.L., Dessimoni A., de Avila M.P. Comparison between the 1% and 2% ibopamine provocative test in primary open-angle glaucoma patients: sensi‐ tivity, specificity and tolerability. Arq. Bras Oftalmol. 2006 Sep-Oct; 69 (5): 695-9. [10] Ullrich K., Craig J.E., Landers J. The ibopamine challenge test can be used to differen‐ tiate glaucoma suspects from glaucoma patients. Clin. Experiment. Ophthalmol. 2013

[11] Marchini G., Babighian S., Tosi R. et al. Comparative study of the effects of 2% ibopa‐ mine, 10% phenylephrine, and 1% tropicamide on the anterior segment. Invest. Oph‐

[12] Boles Carenini B., Brogliatti B., Boles Carenini A. et al. Ibopamine: a new drug and its use as provocative test for the diagnosis of glaucoma. New Trends Ophthalmol. 1992;

[13] Nuti A., Ciappetta R., Diadori A., Frezzotti R. Ibopamine provocative test in the diag‐

[14] Virno M., Pecori-Giraldi J., Taverniti L. et al. Indagini sul meccanismo d'azione dell'aumento tensionale di ibopamina nell'iperteso oculare. Boll. Ocul. 1989; 68

[15] Pecori-Giraldi J., De Gregorio F., Carbone F. et al. Curva tonometrica e positivita' al test della ibopamina nella prima diagnosi di glaucoma. Boll. Ocul. 1994; 73 (suppl. 2):

[16] Magacho L., Reis R., Pigini M.A., Avila M.P. 2% ibopamine vs. water-drinking test as a provocative test for glaucoma. Arq. Bras. Oftalmol. 2008 Jul-Aug; 71 (4): 499-503.

[17] Pigini M.A., Avila M.P., Magacho L. Effects of 2% ibopamine eye drops on the results of computerized visual field. Arq. Bras. Oftalmol. 2009 May-Jun; 72 (3): 365-9.

[18] Kniestedt C., Romppainen T., Gloor B.P., Sturmer J. Positive ibopamine provocative test in normal-tension glaucoma suspects. Klin. Monbl. Augenheilkd 2007 Apr; 224

[19] Di Staso S., D'Andrea D., Giuffre' I. et al. Test dell'ibopamina nella sindrome da pseu‐

doesfoliazione. Boll. Ocul. 1994; 73 (suppl. 2): 325-30.

nosis of hydrodynamic disorders. Exp. Eye Res. 1992; 55 (suppl.): S185.

819-22.

Sep. 3.

7: 3.

319-23.

(4): 255-9.

(suppl. 2): 379-84.

Ophthalmol. 2004; 14; 6:508-13.

thalmol. Vis. Sci. 2003; 44: 281-9.

tors in the eye. Curr. Drug Therapy 2007, 2: 1-7.

### **4. Conclusion**

In conclusion, 2% ibopamine eye drops test is a useful pharmacological tool allowing us to study the pathophysiology of hydrodynamic disorders and in evaluating the outflow impair‐ ment. It is useful as a therapeutic drug in ocular hypotony secondary to filtering surgery, vitreo-retinal surgery or long-lasting uveitis. That's why its use is adviced in all the Ophthal‐ mological Department in EU and USA.

### **Author details**

Italo Giuffré\*

Address all correspondence to: italogiuffre@libero.it

Department of Ophthalmology – Medical School – Catholic University of Roma, Italy

### **References**


[6] Giuffre' I., Falsini B., Gari M.A., Balestrazzi E. Pattern-electroretinogram assessment during ibopamine test in ocular hypertension. Eur. J. Ophthalmol. 2013 Jun 24; 23 (6): 819-22.

Ocular hypotony is a pathological condition of the IOP when it decreases to values below 6-7 mmHg. IOP values below 4 mmHg usually cause progressive damage to the eye [23]. Ocular hypotony can be caused by a damage to ciliary body from trauma or inflammation. In the treatment of ocular hypotony, ibopamine can be administerd every 3 hours or 3-4 times daily,

In conclusion, 2% ibopamine eye drops test is a useful pharmacological tool allowing us to study the pathophysiology of hydrodynamic disorders and in evaluating the outflow impair‐ ment. It is useful as a therapeutic drug in ocular hypotony secondary to filtering surgery, vitreo-retinal surgery or long-lasting uveitis. That's why its use is adviced in all the Ophthal‐

Department of Ophthalmology – Medical School – Catholic University of Roma, Italy

[1] Virno M., Taverniti L., Motolese E. et al. Ibopamina: nuovo midriatico non cicloplegi‐

[2] Virno M., Taverniti L., De Gregorio F et al. Increase in aqueous humor production following D1 receptors activation by means of ibopamine. Int. Ophthalmol. 1997; 20:

[3] Soldati L., Gianesello V., Galbiati I. et al. Ocular pharmacokinetics and pharmacody‐ namics in rabbits of ibopamine, a new mydriatic agent. Exp. Eye Res. 1993; 56:

[4] Ugahary L.C., Ganteris E., Veckeneer M. et al. Topical ibopamine in the treatment of chronic ocular hypotony attributable to vitreoretinal surgery, uveitis, or penetrating

[5] De Gregorio F., Pecori-Giraldi J, Pannarale L. et al. Ibopamine in glaucoma diagnos‐ tics: a new pharmacological provocative test. Int. Ophthalmol. 1997; 20: 151-5.

associated to corticosteroid therapy [24,25].

476 Ophthalmology - Current Clinical and Research Updates

mological Department in EU and USA.

Address all correspondence to: italogiuffre@libero.it

co (nota preliminare). Boll. Ocul. 1986; 65: 11-2.

trauma. Am. J. Ophthalmol. 2006; 141: 571-3.

**4. Conclusion**

**Author details**

Italo Giuffré\*

**References**

141-6.

247-54.


[20] Scuderi G.L., Regine F., Perdicchi A. et al. Efficacy of 2% ibopamine on the dilation of patients with pseudoexfoliation syndrome. Eur. J. Ophthalmol. 2010 Jan-Feb; 20 (1): 120-3.

**Chapter 20**

**Clinical Research Progress of Glaucomatocyclitic Crisis**

Glaucomatocyclitic crisis was initially described in detail by Posner and Schlossman in 1948, so it was also called Posner – Schlossman syndrome (PSS). PSS is a special form of anterior uveitis with glaucoma, mainly seen in young adults, characterized by non-granulomatousiri‐ docyclitis with significant elevation of intraocular pressure. In most cases, the disease takes an

This disease is often seen in people aged from 20 to 50, and rarely in people above 60 years old. Five percent or less of PSS cases were reported in people above 60 years old [3]. The disease is rare in Western countries, it was reported that 19 in one million people have suffered from PSS in Finland [4]. As PSS is a kind of disease attacks intermittently, it is difficult to diagnose PSS in intermittent period for the lack of diagnostic signs and investigate the morbidity with epidemiology methods. We used the full text VIP Chinese literature retrieval system and Medeline retrieval system to find PSS reports from 1975 to 2011 in both English and Chinese literature and divided into review, case, experimental study and clinical report four categories, then analyzed the regional distribution of the authors and cases (Chinese reports were divided into the Yangtze river and the other, English reports were divided into Asia and the other).

The report which contained the most number of cases was chosen if there were more than two from a same author statistical results shows that 1262 cases were reported by 33 Chinese clinical reports in which 991 cases were reported by 20 reports from the area near the Yangtze river,

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

He-Zheng Zhou, Wen-Shan Jiang, Han-Guang Jie,

Chang Feng, Wen-Qiang Zhang, Qian Ye, Jian-Guo Wu, Yan-Ping Song and Qin Ding

Additional information is available at the end of the chapter

acute form of recurrent and monocular onset.

http://dx.doi.org/10.5772/58348

**1. Introduction**

**1.1.Definition**

**1.2. Morbidity**


## **Clinical Research Progress of Glaucomatocyclitic Crisis**

He-Zheng Zhou, Wen-Shan Jiang, Han-Guang Jie, Chang Feng, Wen-Qiang Zhang, Qian Ye, Jian-Guo Wu, Yan-Ping Song and Qin Ding

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/58348

### **1. Introduction**

### **1.1.Definition**

[20] Scuderi G.L., Regine F., Perdicchi A. et al. Efficacy of 2% ibopamine on the dilation of patients with pseudoexfoliation syndrome. Eur. J. Ophthalmol. 2010 Jan-Feb; 20 (1):

[21] Pecori-Giraldi J., Damiano A., Gabrielli A. et al. Ocular hypertension induced by ibopamine early discloses glaucoma suspects among relatives of glaucomatous pa‐

[22] Virno M., Sanpaolesi R., Pecori-Giraldi J. et al. Ibopamine: D1-dopaminergic agonist

[23] Pivetti Pezzi P., Da Dalt S., La Cava M. et al. Ibopamine treatment in chronic hypoto‐ ny secondary to long-lasting uveitis. A case report. Eur. J. Ophthalmol. 2000; 10:

[24] Ganteris-Gerritsen E., Ugahary L.C., Jansen J. et al. Six months treatment with ibopa‐ mine in patients with hypotony after vitreoretinal surgery for retinal detachment,

[25] Virno M., De Gregorio F., Pannarale L., Arrico L. Topical ibopamine and corticoste‐ roids in the treatment of post-surgery ocular hypotony. Int. Ophthalmol. 1997;

in the diagnosis of glaucoma. J. Glaucoma 2013; 22: 5-9.

uveitis or penetrating trauma. Retina 2012 Apr; 32 (4): 742-7.

120-3.

332-4.

20:147-50.

tients. Boll. Ocul. 2002; 81: 91.

478 Ophthalmology - Current Clinical and Research Updates

Glaucomatocyclitic crisis was initially described in detail by Posner and Schlossman in 1948, so it was also called Posner – Schlossman syndrome (PSS). PSS is a special form of anterior uveitis with glaucoma, mainly seen in young adults, characterized by non-granulomatousiri‐ docyclitis with significant elevation of intraocular pressure. In most cases, the disease takes an acute form of recurrent and monocular onset.

### **1.2. Morbidity**

This disease is often seen in people aged from 20 to 50, and rarely in people above 60 years old. Five percent or less of PSS cases were reported in people above 60 years old [3]. The disease is rare in Western countries, it was reported that 19 in one million people have suffered from PSS in Finland [4]. As PSS is a kind of disease attacks intermittently, it is difficult to diagnose PSS in intermittent period for the lack of diagnostic signs and investigate the morbidity with epidemiology methods. We used the full text VIP Chinese literature retrieval system and Medeline retrieval system to find PSS reports from 1975 to 2011 in both English and Chinese literature and divided into review, case, experimental study and clinical report four categories, then analyzed the regional distribution of the authors and cases (Chinese reports were divided into the Yangtze river and the other, English reports were divided into Asia and the other).

The report which contained the most number of cases was chosen if there were more than two from a same author statistical results shows that 1262 cases were reported by 33 Chinese clinical reports in which 991 cases were reported by 20 reports from the area near the Yangtze river,

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and 271 cases were reported by 13 reports from the other area. The other 211 cases were reported by 16 English clinical reports in which 144 cases were reported by 7 reports from the Asia area and 67 cases reported by 9 reports from the other area. The results above suggest that there are much more literature and cases related to PSS in the area near the Yangtze river and infer that the prevalence of PSS in that area may be higher.

endothelial halo, clinical difference was not so significant between CMV DNA positive and negative cases as less aqueous humor in sample and weak sensitivity of detection method. In 2008, aqueous analysis for CMV by PCR was performed in 103 eyes of 102 patients with presumed PSS or FHI at the Singapore National Eye Centre. Their records were reviewed for clinical features and human immunodeficiency virus (HIV) status of the CMV-positive patients. The main parameters were age, gender, maximum intraocular pressure, endothelial cell count, endothelial changes, PCR results, and presence of uveitic cataract and/or glaucoma. It was found that there was no clinically detectable differences between CMV-positive and negative presumed PSS eyes. CMV-positive presumed FHI patients are more likely to be male,

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It was reported in South Korean that there was a significant difference of the positive rate of helicobacter pylori serum antibody between cases with PSS (80%) and cases without PSS (56.2%). In another prospective study, 40 cases with PSS and 73 cases without PSS received serologic analysis for the presence of H. pylori infection by an enzyme-linked immunosorbent assay. The positive rate of serum anti-H. pylori IgG was compared between the two groups. It was proved that H. pylori infection occurred significantly more often in PSS patients. This study suggests that exposure to H. pylori infection is associated with PSS in Korea. [10]

**1.** In most cases, the disease always attacks the identical eye repeatedly, binocularly affected cases is not common; PSS results in paroxysmal increase of IOP repeatedly, which reaches as high as 40 to 60 mmHg, and lasts for 1 to 14 days generally, 1 month occasionally, 2

**3.** Eyesight is normal generally, blurred vision when suffers from corneal edema at onset; **4.** Pupil becomes slightly bigger with normal reaction to light, and never adheres to lens; **5.** The KP of PSS appeared in a few days after or before the elevation of IOP with number of 1 to 25, took a form of hoar and suet-shaped and disappeared days to 1 month after the IOP returned normal, distributed mainly in the inferior part of the cornea or concealed in the trabecular meshwork. There were no or at most a few planktonic cells in aqueous while the flare was negative.There is no inflammatory cell in vitreous body (See Figure 1); **6.** The anterior chamber angle is open, no matter IOP is normal or elevated; visual field and fundus of most cases are normal generally, but a reversible expanding of vascular shadow

**7.** Coefficient of outflow facility (C value) descends in episodes and recovers in intermission;

**8.** The forms of onset of PSS could be divided into three kinds: KP, high IOP and intermediate

various stimulation tests for glaucoma are negative in intermission;

type, according to relationship between KP and IOP.

older at diagnosis or have nodular endothelial lesions. [9]

**1.4. Clinical features of typical cases [1, 2, 3, 11, 12, 13]**

may occur during an acute onset.

months rarely; interval of onset is from months to 2 years; **2.** Symptoms are not obvious, just mild discomfort for most cases;

**4.** Helicobacter pylori infection.


**Table 1.** The regional distribution of the authors

#### **1.3. Possible etiology**


The conclusion that PSS was caused by herpes simplex virus (HKS) was reported by Yaina‐ motos in 1995, and was confirmed by many following researches. A recent report showed that antiviral treatment reduced the frequency of the outbreak of the disease. [6-7]

It was reported that aqueous humor of a binocular PSS case was collected after suffering from herpes viral keratitis for five months with anterior chamber paracentesis, then DNA of cytomegalovirus (CMV) and HKS were measured by means of quantitative polymerase chain reaction(PCR), the results showed CMV was positive but HKS was negative. It was speculated that CMV which belongs to herpes virus genera would also lead to PSS. It was considered that PSS is not a separate disease, but a kind of anterior uveitis relating to infections of herpes virus.

A study from Singapore showed that the CMV DNA of aqueous humor was positive for 24 of 104 anterior uveitis cases with monocular high IOP, in which 18 cases were PSS, 5 cases were Fuchs heterochromic iridocyclitis (FHI). [8]Another study showed CMV DNA was positive in 35 of 67 PSS cases (52.2%) and in 15 of 35 FHI cases (41.7%). Although the keratic precipitates (KP) in CMV DNA positive anterior uveitis cases was consider to be accompanied with an endothelial halo, clinical difference was not so significant between CMV DNA positive and negative cases as less aqueous humor in sample and weak sensitivity of detection method. In 2008, aqueous analysis for CMV by PCR was performed in 103 eyes of 102 patients with presumed PSS or FHI at the Singapore National Eye Centre. Their records were reviewed for clinical features and human immunodeficiency virus (HIV) status of the CMV-positive patients. The main parameters were age, gender, maximum intraocular pressure, endothelial cell count, endothelial changes, PCR results, and presence of uveitic cataract and/or glaucoma. It was found that there was no clinically detectable differences between CMV-positive and negative presumed PSS eyes. CMV-positive presumed FHI patients are more likely to be male, older at diagnosis or have nodular endothelial lesions. [9]

**4.** Helicobacter pylori infection.

and 271 cases were reported by 13 reports from the other area. The other 211 cases were reported by 16 English clinical reports in which 144 cases were reported by 7 reports from the Asia area and 67 cases reported by 9 reports from the other area. The results above suggest that there are much more literature and cases related to PSS in the area near the Yangtze river

**research Clinical report Aggregate**

0 11 1 20 32

Other areas 2 11 0 13 26

Aggregate 7 34 3 49 93(total)

**1.** Many factors were considered to be related to the onset of PSS, such as allergy, fatigue, mental fatigue, mental stress, decreased body resistance, infection, hypothalamic disor‐ ders, autonomic dysfunction, abnormal reactions of ciliary vascular and nervous system

**2.** Recent research had confirmed that concentration of prostaglandins (PGs) in the anterior chamber aqueous increased obviously in the PSS cases, especially that of PGE. [5]

The conclusion that PSS was caused by herpes simplex virus (HKS) was reported by Yaina‐ motos in 1995, and was confirmed by many following researches. A recent report showed that

It was reported that aqueous humor of a binocular PSS case was collected after suffering from herpes viral keratitis for five months with anterior chamber paracentesis, then DNA of cytomegalovirus (CMV) and HKS were measured by means of quantitative polymerase chain reaction(PCR), the results showed CMV was positive but HKS was negative. It was speculated that CMV which belongs to herpes virus genera would also lead to PSS. It was considered that PSS is not a separate disease, but a kind of anterior uveitis relating to infections of herpes virus. A study from Singapore showed that the CMV DNA of aqueous humor was positive for 24 of 104 anterior uveitis cases with monocular high IOP, in which 18 cases were PSS, 5 cases were Fuchs heterochromic iridocyclitis (FHI). [8]Another study showed CMV DNA was positive in 35 of 67 PSS cases (52.2%) and in 15 of 35 FHI cases (41.7%). Although the keratic precipitates (KP) in CMV DNA positive anterior uveitis cases was consider to be accompanied with an

Asia 2 0 2 7 11 Other areas 3 12 0 9 24

and infer that the prevalence of PSS in that area may be higher.

Near the Yangtze river basin

480 Ophthalmology - Current Clinical and Research Updates

**Table 1.** The regional distribution of the authors

**types Region Review Case Experimental**

and abnormal development in angle of anterior chamber.[1]

antiviral treatment reduced the frequency of the outbreak of the disease. [6-7]

**Literature**

Chinese

English

**1.3. Possible etiology**

**3.** Infection by herpes virus.

It was reported in South Korean that there was a significant difference of the positive rate of helicobacter pylori serum antibody between cases with PSS (80%) and cases without PSS (56.2%). In another prospective study, 40 cases with PSS and 73 cases without PSS received serologic analysis for the presence of H. pylori infection by an enzyme-linked immunosorbent assay. The positive rate of serum anti-H. pylori IgG was compared between the two groups. It was proved that H. pylori infection occurred significantly more often in PSS patients. This study suggests that exposure to H. pylori infection is associated with PSS in Korea. [10]

### **1.4. Clinical features of typical cases [1, 2, 3, 11, 12, 13]**


**1.6. The outstanding clinical questions and the main points of the chapter**

thus the best opportunity of treatment was lost ; severe damage occurred.

in combination with the research achievements of other authors.

nerve damage in PSS patients; other diseases concomitant with PSS.

relationship between the monocular POAG and binocular PSS?

**2. The main results of our clinical research**

**2.1. Study on the clinical characteristics of the PSS**

PSS patients.

It was considered in the early years that PSS have a favorable prognosis without glaucom‐ atous damage of optic disk and visual field, however, a number of authors have con‐ firmed that part of the PSS cases suffered from glaucomatous damage similar to that in primary glaucoma patients in recent years. A lot of questions remained vague such as monocular or binocular explode, age of onset, the detailed features of its IOP and KP, the incidence and degree and relating factors of glaucomatous damage, especially the clinical approaches via which the damage occurred and disease complicated with PSS. These brought about to two undesirable consequences: on the one hand, PSS patients were misdiagnosed as primary glaucoma and received incorrect treatment even led to serious adverse consequences due to the lack of knowledge on the clinical characteristics of PSS; on the other hand, most cases of PSS combined with primary glaucoma especially those with primary angle-closed glaucoma were failed to be diagnosed correctly without delay,

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In recent decades, although there were some clinical observations reported by a number of authors on these clinical problems mentioned above, no report of continuous and systematic study was found. A mountain of work in this field had been done in our hospital and some research results were obtained. A brief introduction of our results will be shown in this chapter

The main results of our clinical research included 4 fields as follows: the clinical characteristics of PSS; the glaucomatous optic nerve damage in PSS patients; the clinical approach of optic

The research about clinical characteristics of the PSS included four aspects: clinical observation and analysis of monocular primary open-angle glaucoma(POAG) and binocular PSS; clinical features of elderly PSS patients; characteristics and clinical value of the intraocular pressure and the C-value in PSS patients ; the characteristic of postural intraocular pressure change in

*2.1.1. Clinical observation and analysis of monocular primary open-angle glaucoma and binocular PSS*

**Background:** As we knew, most of POAG patients are binocularly involved, while monocular attack is one of typical features of PSS. However, clinically suspected monocular POAG patients are not rare and binocular PSS cases are often reported. So following questions should be put forward based on the facts as follows [3, 11, 14]: Does monocular POAG really exist? What are the differences between monocular and binocularly involved PSS cases? Is there any

**Figure 1.** Anterior segment of a case with PSS in episodes. Arrows indicate the typital hoar and suet-shaped KP.

### **Typical case**

A patient complained of her blurred vision two months ago, examination in other hospital showed: conjunctiva of her left eye wasn't congestive and the cornea was edematous mildly, IOP: 34/ 18(R/L) mmHg; there were some round lipid-like KP in the left cornea, aqueous flare(-). She came to our hospital on June 7, 2012, ophthalmologic examination: vision was 0.5/ 1.5(R/L), best corrected vision of left eye was 1.2(-1.25DS), IOP: 18/ 13 (R/L) mmHg. Her right eye was normal, conjunctiva of her left eye wasn't congestive and there were five rounds lipidlike KP in the left cornea, binocular C/D was 0.4. Her KP faded away after the treatment of chloromethyl and pranopulin (three times a day) for three weeks. Examination of FFA, ICGA and Virus screening were normal on July 10.The measurement of her 24 hours IOP performed two weeks after she ceased the drugs was 20-14mmHg(R), 15-12 mmHg (L). The result of her visual field and the OCT for glaucoma was normal. She was diagnosed as PSS in left eye and suggested to be observed and treated timely.

### **1.5. Treatment of typical cases in episodes**


### **1.6. The outstanding clinical questions and the main points of the chapter**

It was considered in the early years that PSS have a favorable prognosis without glaucom‐ atous damage of optic disk and visual field, however, a number of authors have con‐ firmed that part of the PSS cases suffered from glaucomatous damage similar to that in primary glaucoma patients in recent years. A lot of questions remained vague such as monocular or binocular explode, age of onset, the detailed features of its IOP and KP, the incidence and degree and relating factors of glaucomatous damage, especially the clinical approaches via which the damage occurred and disease complicated with PSS. These brought about to two undesirable consequences: on the one hand, PSS patients were misdiagnosed as primary glaucoma and received incorrect treatment even led to serious adverse consequences due to the lack of knowledge on the clinical characteristics of PSS; on the other hand, most cases of PSS combined with primary glaucoma especially those with primary angle-closed glaucoma were failed to be diagnosed correctly without delay, thus the best opportunity of treatment was lost ; severe damage occurred.

In recent decades, although there were some clinical observations reported by a number of authors on these clinical problems mentioned above, no report of continuous and systematic study was found. A mountain of work in this field had been done in our hospital and some research results were obtained. A brief introduction of our results will be shown in this chapter in combination with the research achievements of other authors.

### **2. The main results of our clinical research**

**Figure 1.** Anterior segment of a case with PSS in episodes. Arrows indicate the typital hoar and suet-shaped KP.

A patient complained of her blurred vision two months ago, examination in other hospital showed: conjunctiva of her left eye wasn't congestive and the cornea was edematous mildly, IOP: 34/ 18(R/L) mmHg; there were some round lipid-like KP in the left cornea, aqueous flare(-). She came to our hospital on June 7, 2012, ophthalmologic examination: vision was 0.5/ 1.5(R/L), best corrected vision of left eye was 1.2(-1.25DS), IOP: 18/ 13 (R/L) mmHg. Her right eye was normal, conjunctiva of her left eye wasn't congestive and there were five rounds lipidlike KP in the left cornea, binocular C/D was 0.4. Her KP faded away after the treatment of chloromethyl and pranopulin (three times a day) for three weeks. Examination of FFA, ICGA and Virus screening were normal on July 10.The measurement of her 24 hours IOP performed two weeks after she ceased the drugs was 20-14mmHg(R), 15-12 mmHg (L). The result of her visual field and the OCT for glaucoma was normal. She was diagnosed as PSS in left eye and

**1.** Anti-inflammation: Corticosteroid drugs is needed in most cases, but it should not be used

**2.** It is a better select in some cases to apply non-steroidal anti-inflammatory drugs (NSAIDs)

**3.** Reducing IOP: Eye drops of epinephrine, timolol, or clonidine was needed singly or jointly for common patient, carbonic anhydrase inhibitor orally when the IOP is higher than 30mmHg and mannitol of intravenous drip when the IOP is higher than 40mmHg.

**4.** The antiviral treatment systemically or implanting long-acting agents may be helpful to reduce the frequency of attack, but it has worrying and serious side effects and costs too

too long at a time, so as not to cause the corticosteroid glaucoma.

such as eye drops of pranoprofen, indomethacin and flufenamic acid.

**Typical case**

suggested to be observed and treated timely.

482 Ophthalmology - Current Clinical and Research Updates

**1.5. Treatment of typical cases in episodes**

much. [12]

The main results of our clinical research included 4 fields as follows: the clinical characteristics of PSS; the glaucomatous optic nerve damage in PSS patients; the clinical approach of optic nerve damage in PSS patients; other diseases concomitant with PSS.

### **2.1. Study on the clinical characteristics of the PSS**

The research about clinical characteristics of the PSS included four aspects: clinical observation and analysis of monocular primary open-angle glaucoma(POAG) and binocular PSS; clinical features of elderly PSS patients; characteristics and clinical value of the intraocular pressure and the C-value in PSS patients ; the characteristic of postural intraocular pressure change in PSS patients.

#### *2.1.1. Clinical observation and analysis of monocular primary open-angle glaucoma and binocular PSS*

**Background:** As we knew, most of POAG patients are binocularly involved, while monocular attack is one of typical features of PSS. However, clinically suspected monocular POAG patients are not rare and binocular PSS cases are often reported. So following questions should be put forward based on the facts as follows [3, 11, 14]: Does monocular POAG really exist? What are the differences between monocular and binocularly involved PSS cases? Is there any relationship between the monocular POAG and binocular PSS?

**Objects and methods**: A long-term, systematic clinical observation and analysis were com‐ pleted on 121 cases with tentative diagnosis of POAG (22 cases of monocular) and 126 cases of PSS (17 cases of which was binocular). (See figure2)

**Figure 2.** Distribution of monocular and binocular cases in PSS and POAG

### **Results**

**1.** Glaucomatous visual field damage of monocular/ binocular PSS and binocular POAG

clinical manifestations contradictory with POAG were found in most cases, 3 of them were

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The result suggests that the diagnosis of monocular POAG should be very careful, in addition to angle closure glaucoma and other secondary glaucoma, PSS which appears late or last transitorily should not be ignored. Close attention to slit lamp examination for KP and its

All in all, it cannot be stated too strongly: we should be very deliberative when making a diagnosis of monocular POAG or binocular PSS, as half part of suspicious monocular POAG cases were confirmed with PSS after clinical follow-up, and there was a closer connection

**Background:** Among the cases of PSS, the 50s are rare; the 60s are seldom. What is the feature

suspected of PSS.(See Figure4)

**Figure 3.** Results of visual field examination and defect in binocular PSS.

**Figure 4.** Results of clinical follow-up to monocular POAG.

between binocular PSS and POAG. [15]

*2.1.2. Clinical observation of aged PSS cases*

of the aged PSS cases?

relationship with IOP should be paid for such cases.

analysis of the clinical data of patients without doubt with the chi-square test showed: (1) The incidence of glaucomatous visual field damage in binocular PSS (15/16) was much higher than that in monocular cases(30/85), (*X2* =27.43, P<0.01). (2) The damage in 26 of 30 monocular cases were in early stage, while that in 9 of 15 binocular cases were in middle/ last stage, the difference was significant(*X2* =3.53, P<0.01). (3) There is no significant difference in incidence and degree of glaucomatous visual field damage between binocular PSS and binocular POAG.(See Table 2)

**2.** Visual field damage in binocular PSS

15 of 17 binocular PSS cases were confirmed with glaucomatous visual field damage, that was much more serious than in monocular cases; however, no remarkable difference was found between the course of disease in monocular and binocular cases. (See Figure3)

The result suggests that the course of disease cannot explain the severity of visual field damage in binocular PSS. We speculate that binocular PSS may be more relevant to POAG essentially through the following two ways. First, the insufficiency in adjusting IOP results in combination with POAG in some cases; secondly, the weak resistance of optic nerve to high IOP make it easy for a cumulative effect of high intraocular pressure during attacks of pure PSS to bring about visual field damage.

**2.** Results of clinical follow-up to monocular POAG

The results of clinical follow-up observation on the 22 cases with clinically suspected monoc‐ ular POAG are as follows: 15 of the 22 cases were confirmed not to be POAG, 9 of them had been proved to be PSS. Although no definite diagnoses were made in the other 7 cases, but

**Figure 3.** Results of visual field examination and defect in binocular PSS.

**Objects and methods**: A long-term, systematic clinical observation and analysis were com‐ pleted on 121 cases with tentative diagnosis of POAG (22 cases of monocular) and 126 cases

**1.** Glaucomatous visual field damage of monocular/ binocular PSS and binocular POAG

analysis of the clinical data of patients without doubt with the chi-square test showed: (1) The incidence of glaucomatous visual field damage in binocular PSS (15/16) was much higher than

were in early stage, while that in 9 of 15 binocular cases were in middle/ last stage, the difference

of glaucomatous visual field damage between binocular PSS and binocular POAG.(See Table

15 of 17 binocular PSS cases were confirmed with glaucomatous visual field damage, that was much more serious than in monocular cases; however, no remarkable difference was found

The result suggests that the course of disease cannot explain the severity of visual field damage in binocular PSS. We speculate that binocular PSS may be more relevant to POAG essentially through the following two ways. First, the insufficiency in adjusting IOP results in combination with POAG in some cases; secondly, the weak resistance of optic nerve to high IOP make it easy for a cumulative effect of high intraocular pressure during attacks of pure PSS to bring

The results of clinical follow-up observation on the 22 cases with clinically suspected monoc‐ ular POAG are as follows: 15 of the 22 cases were confirmed not to be POAG, 9 of them had been proved to be PSS. Although no definite diagnoses were made in the other 7 cases, but

between the course of disease in monocular and binocular cases. (See Figure3)

=27.43, P<0.01). (2) The damage in 26 of 30 monocular cases

=3.53, P<0.01). (3) There is no significant difference in incidence and degree

of PSS (17 cases of which was binocular). (See figure2)

484 Ophthalmology - Current Clinical and Research Updates

**Figure 2.** Distribution of monocular and binocular cases in PSS and POAG

that in monocular cases(30/85), (*X2*

**2.** Visual field damage in binocular PSS

**2.** Results of clinical follow-up to monocular POAG

was significant(*X2*

about visual field damage.

**Results**

2)

clinical manifestations contradictory with POAG were found in most cases, 3 of them were suspected of PSS.(See Figure4)

**Figure 4.** Results of clinical follow-up to monocular POAG.

The result suggests that the diagnosis of monocular POAG should be very careful, in addition to angle closure glaucoma and other secondary glaucoma, PSS which appears late or last transitorily should not be ignored. Close attention to slit lamp examination for KP and its relationship with IOP should be paid for such cases.

All in all, it cannot be stated too strongly: we should be very deliberative when making a diagnosis of monocular POAG or binocular PSS, as half part of suspicious monocular POAG cases were confirmed with PSS after clinical follow-up, and there was a closer connection between binocular PSS and POAG. [15]

#### *2.1.2. Clinical observation of aged PSS cases*

**Background:** Among the cases of PSS, the 50s are rare; the 60s are seldom. What is the feature of the aged PSS cases?

**Objects and methods:** The clinical data of 14 cases aged above 50 with a definite diagnosis of PSS collected in the past 4 years were summarized and analyzed. Clinical data met all the requirements were obtained in 11cases. The cases aged from 50 to 73 years old, with an average of 61.4 years. One case had a course of the disease beyond 30 years, 4 beyond 10 years and 6 beyond 5 years.

**Results:** Visual acuity of more than half of the cases was inferior to 0.5, 9 of 11 cases had visual field damage that was of moderate or advanced stage in most cases.

**Conclusion:** The aged PSS cases had a longer course of the disease and much more frequent and serious visual function damage. [16, 17, 18]

### *2.1.3. The characteristics and clinical value of the intraocular pressure and the C-value in PSS cases*

**Background:** It is generally acknowledged that IOP of the attacked eye increased and C-value of attack eye decreased in episodes, and both were normal in intermission. Individual author reported that the IOP of the affected eye was lower than that of the fellow one in part of cases, and C-value was higher. It was not confirmed that whether this phenomenon could be considered as the unique characteristic of PSS and what clinical significance should it mean. [3, 19, 20]

**Figure 5.** The difference of C-value and its dynamic changes between 3 PSS groups (A, B, C) and primary glaucoma

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**Figure 6.** The difference of IOP and its dynamic changes between 3 PSS groups (A, B, C) and primary glaucoma

people; however, such an IOP change in PSS cases was not reported so far.

**Background:** It is well known that the recumbent IOP is higher than sedentary one in most of

**Objective:** The cases of PSS with regular IOP change, 42 cases of POAG and 61 cases of PACG

*2.1.4. The characteristics of postural IOP change in PSS cases*

with a great wave in IOP level. [21]

**Objective and methods:** Binocular IOP measurement and tonography were done in 90 cases of PSS; According to the symptom, sign and results of examination for IOP, fundus, visual field, our cases were divided into 3 groups. Group A (typical type): with a normal optic disc, visual field and the diagnostic tests for glaucoma in intermission. Group B (development type): with a damaged optic disc and visual field; except for high intraocular pressure in episodes, binocular IOP and C values were normal. Group C (mixed type): with a damaged optic disc, visual field and abnormal results of binocular IOP, IOP diurnal variation and C value in both episodes and intermission. Another group case of primary glaucoma with a great fluctuation and difference in IOP level between his or her right and left eye was taken as the control group.

**Results:** IOP of PSS cases in group A and B increased in episodes, and were obviously higher than that of the fellow eye; C-value of them decreased and was lower. In intermission, binocular IOP and C-value turned normal, moreover, IOP of attacked eye was lower than that of the fellow one, and its C-value was higher. It means that binocular IOP and C-value in episodes and intermission were crossed-over.

Crossed-over phenomenon of binocular IOP and C-value had not appeared in the control group (primary glaucoma) as well as Group C (PSS combined with POAG).

**Conclusion:** Such an inference could be deduced based on our results that Crossed-over phenomenon of IOP and C-value was one characteristic for pure PSS cases, it is conducive to distinguish pure PSS from primary glaucoma and PSS combined with POAG to observe this phenomenon.

**Objects and methods:** The clinical data of 14 cases aged above 50 with a definite diagnosis of PSS collected in the past 4 years were summarized and analyzed. Clinical data met all the requirements were obtained in 11cases. The cases aged from 50 to 73 years old, with an average of 61.4 years. One case had a course of the disease beyond 30 years, 4 beyond 10 years and 6

**Results:** Visual acuity of more than half of the cases was inferior to 0.5, 9 of 11 cases had visual

**Conclusion:** The aged PSS cases had a longer course of the disease and much more frequent

*2.1.3. The characteristics and clinical value of the intraocular pressure and the C-value in PSS cases*

**Background:** It is generally acknowledged that IOP of the attacked eye increased and C-value of attack eye decreased in episodes, and both were normal in intermission. Individual author reported that the IOP of the affected eye was lower than that of the fellow one in part of cases, and C-value was higher. It was not confirmed that whether this phenomenon could be considered as the unique characteristic of PSS and what clinical significance should it mean.

**Objective and methods:** Binocular IOP measurement and tonography were done in 90 cases of PSS; According to the symptom, sign and results of examination for IOP, fundus, visual field, our cases were divided into 3 groups. Group A (typical type): with a normal optic disc, visual field and the diagnostic tests for glaucoma in intermission. Group B (development type): with a damaged optic disc and visual field; except for high intraocular pressure in episodes, binocular IOP and C values were normal. Group C (mixed type): with a damaged optic disc, visual field and abnormal results of binocular IOP, IOP diurnal variation and C value in both episodes and intermission. Another group case of primary glaucoma with a great fluctuation and difference in IOP level between his or her right and left eye was taken as the control group.

**Results:** IOP of PSS cases in group A and B increased in episodes, and were obviously higher than that of the fellow eye; C-value of them decreased and was lower. In intermission, binocular IOP and C-value turned normal, moreover, IOP of attacked eye was lower than that of the fellow one, and its C-value was higher. It means that binocular IOP and C-value in

Crossed-over phenomenon of binocular IOP and C-value had not appeared in the control

**Conclusion:** Such an inference could be deduced based on our results that Crossed-over phenomenon of IOP and C-value was one characteristic for pure PSS cases, it is conducive to distinguish pure PSS from primary glaucoma and PSS combined with POAG to observe this

group (primary glaucoma) as well as Group C (PSS combined with POAG).

field damage that was of moderate or advanced stage in most cases.

and serious visual function damage. [16, 17, 18]

486 Ophthalmology - Current Clinical and Research Updates

episodes and intermission were crossed-over.

beyond 5 years.

[3, 19, 20]

phenomenon.

**Figure 5.** The difference of C-value and its dynamic changes between 3 PSS groups (A, B, C) and primary glaucoma

**Figure 6.** The difference of IOP and its dynamic changes between 3 PSS groups (A, B, C) and primary glaucoma

#### *2.1.4. The characteristics of postural IOP change in PSS cases*

**Background:** It is well known that the recumbent IOP is higher than sedentary one in most of people; however, such an IOP change in PSS cases was not reported so far.

**Objective:** The cases of PSS with regular IOP change, 42 cases of POAG and 61 cases of PACG with a great wave in IOP level. [21]

**Methods:** IOP measurement was performed with a handheld applanation tonometer before and after lying for five and thirty minutes, and a tonography was finished 1~3 days before or after postural IOP measurement. (See Figure7)

IOP is high or low as the adjustability for IOP had been declining eventually. PSS is a secondary glaucoma for which the intermittent increased release of PGs maybe the primary mechanism. Increases PGs may expand the blood vessels and recedes eduction function of trabecular meshwork. On the contrary, the diluent PGs in remission promotes eduction function of aqueous humour and inturn IOP and C value to normal or even better. Therefore, there is no significant correlation between the IOP increment and C value no matter IOP was high or

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Although reports about that glaucomatous optical neural damage occurred in some cases of PSS were constantly released for past twenty years, we saw little of the systematic research

aimed at the incidence, severity and probable relating facts of the damage. [3, 9]

**Objective:** To study the incidence and severity of the visual field damage in PSS cases.

**Methods:** Visual field examinations at regular intervals with perimeter of Goldmann or Humphrey 750 type were completed in 145 cases of PSS followed up for 5 to 15 years and 166

**Results:** The prevalence of visual field damage in PSS and POAG was 35.43% and 93.42% (P<0.001), 72.11% of the field damage in PSS cases was of early or suspected stage, 78.92% of that in POAG cases was of middle or late stage(P<0.001), 10% of PSS cases suffered a field damage of middle or late stage, 2 became absolute blind and one case had developed into

**Conclusions:** Even though the visual field damage in cases of PSS was less and slighter than that in cases of POAG, it is necessary to treat PSS efficiently and timely, as recurrent attacks of

normal. [20, 22, 23]

**2.2. The visual field damage in PSS cases**

*2.2.1. Incidence and severity of the damage*

bullous keratitis at last.(See Figure8)

cases of POAG observed meanwhile (as the control). [17]

**Figure 8.** The stage distribution of visual field damage in PSS and POAG.

PSS for long period would result in a sad outcome like POAG.

**Results:** 1) Recumbent IOP is much higher than sedentary one in cases of all groups, however, their rising degrees after lying were different.2) There was no significant difference in rising degrees after lying in three kinds of glaucoma when IOP was high; when the IOP turned normal, however, the rising degrees in POAG, PACG were much higher than in PSS. 3) When the sedentary IOP is higher than 24mmHg, the number of cases with recumbent IOP elevated more than 5mmHg in three kinds glaucoma wasn't different statistically; When the sedentary IOP is lower than 24mmHg, cases with recumbent IOP elevated more than 5mmHg were rare in PSS group, much less than that in the other two groups. 4) The IOP increment after lying in the attacked eye of PSS cases in episodes was much higher than that of the fellow eye and the both eye in intermission. 5) The IOP increment was related to C value significantly for POAG when IOP was high and normal, for PACG when IOP was normal only; but wasn't related for PSS no matter IOP was high or normal.

**Conclusion:** Measurement of postural IOP change is beneficial to diagnose suspicious glaucoma cases with a normal or slightly elevated IOP, it may be as valuable as tonography clinically but more convenient, comfort and safer than tonography, complications such as corneal scratches were rarely seen in the measurement of postural IOP change

**Discussion:** Different pathogenesis of the three kinds of glaucoma brought about the different pattern in correlation between the IOP increment and C value in different conditions. PACG is caused by the closed anterior chamber angle, when the IOP is high, the increased IOP is related to C value significantly as the closed anterior chamber angle loses the ability to reduce IOP, however, the adjustability recovery as the anterior chamber angle open partly when the IOP is low. Degeneration of trabecular meshwork which result in more and more futile eduction function of aqueous humour was the primary mechanism for the increased IOP in POAG, so the IOP increment in POAG cases is related to C value significantly whenever the IOP is high or low as the adjustability for IOP had been declining eventually. PSS is a secondary glaucoma for which the intermittent increased release of PGs maybe the primary mechanism. Increases PGs may expand the blood vessels and recedes eduction function of trabecular meshwork. On the contrary, the diluent PGs in remission promotes eduction function of aqueous humour and inturn IOP and C value to normal or even better. Therefore, there is no significant correlation between the IOP increment and C value no matter IOP was high or normal. [20, 22, 23]

### **2.2. The visual field damage in PSS cases**

**Methods:** IOP measurement was performed with a handheld applanation tonometer before and after lying for five and thirty minutes, and a tonography was finished 1~3 days before or

**Results:** 1) Recumbent IOP is much higher than sedentary one in cases of all groups, however, their rising degrees after lying were different.2) There was no significant difference in rising degrees after lying in three kinds of glaucoma when IOP was high; when the IOP turned normal, however, the rising degrees in POAG, PACG were much higher than in PSS. 3) When the sedentary IOP is higher than 24mmHg, the number of cases with recumbent IOP elevated more than 5mmHg in three kinds glaucoma wasn't different statistically; When the sedentary IOP is lower than 24mmHg, cases with recumbent IOP elevated more than 5mmHg were rare in PSS group, much less than that in the other two groups. 4) The IOP increment after lying in the attacked eye of PSS cases in episodes was much higher than that of the fellow eye and the both eye in intermission. 5) The IOP increment was related to C value significantly for POAG when IOP was high and normal, for PACG when IOP was normal only; but wasn't related for

**Conclusion:** Measurement of postural IOP change is beneficial to diagnose suspicious glaucoma cases with a normal or slightly elevated IOP, it may be as valuable as tonography clinically but more convenient, comfort and safer than tonography, complications such as

**Discussion:** Different pathogenesis of the three kinds of glaucoma brought about the different pattern in correlation between the IOP increment and C value in different conditions. PACG is caused by the closed anterior chamber angle, when the IOP is high, the increased IOP is related to C value significantly as the closed anterior chamber angle loses the ability to reduce IOP, however, the adjustability recovery as the anterior chamber angle open partly when the IOP is low. Degeneration of trabecular meshwork which result in more and more futile eduction function of aqueous humour was the primary mechanism for the increased IOP in POAG, so the IOP increment in POAG cases is related to C value significantly whenever the

corneal scratches were rarely seen in the measurement of postural IOP change

after postural IOP measurement. (See Figure7)

488 Ophthalmology - Current Clinical and Research Updates

**Figure 7.** Handheld applanation tonometer.

PSS no matter IOP was high or normal.

Although reports about that glaucomatous optical neural damage occurred in some cases of PSS were constantly released for past twenty years, we saw little of the systematic research aimed at the incidence, severity and probable relating facts of the damage. [3, 9]

#### *2.2.1. Incidence and severity of the damage*

**Objective:** To study the incidence and severity of the visual field damage in PSS cases.

**Methods:** Visual field examinations at regular intervals with perimeter of Goldmann or Humphrey 750 type were completed in 145 cases of PSS followed up for 5 to 15 years and 166 cases of POAG observed meanwhile (as the control). [17]

**Results:** The prevalence of visual field damage in PSS and POAG was 35.43% and 93.42% (P<0.001), 72.11% of the field damage in PSS cases was of early or suspected stage, 78.92% of that in POAG cases was of middle or late stage(P<0.001), 10% of PSS cases suffered a field damage of middle or late stage, 2 became absolute blind and one case had developed into bullous keratitis at last.(See Figure8)

**Figure 8.** The stage distribution of visual field damage in PSS and POAG.

**Conclusions:** Even though the visual field damage in cases of PSS was less and slighter than that in cases of POAG, it is necessary to treat PSS efficiently and timely, as recurrent attacks of PSS for long period would result in a sad outcome like POAG.

#### *2.2.2. The characteristic of the visual field damage in PSS*

**Objective:** To study the characteristic of the visual field damage in PSS.

**Methods:** Compare the visual field damage in glaucoma cases with higher and lower IOP (PSS belongs to that with higher IOP). [24]

**Conclusions:** There are difference in visual field defects between higher IOP patients and

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**Methods:** Analysis the clinical data of 145 PSS cases and 166 POAG cases for recent 15 years.Results about the incidence and severity of visual field damage in the two kinds of

**Results:** 1) Compared with the undamaged group of PSS, the damaged cases were older and with longer course of the disease while there was no remarkable difference in the averaged IOP value during crisis. 2) There was a much higher risk for the visual field damage in binocular cases of PSS. Most of the cases of PSS reported were monocular affected, but later, there were reports about some binocularly affected cases. In our study, 15 of the 35 cases with definite damage were binocularly affected while only one of the 82 cases without damage was affected binocularly. It needs further study to determine whether there is different pathological mechanism for the monocular and binocularly involved cases of PSS. 3) IOP manifestation: although no great difference in the average IOP value during crisis was found between the two groups of PSS, the damage group showed a higher average IOP between crises and included much more cases with an abnormal diurnal and nocturnal variance of IOP or without the IOP crossed-over phenomenon than the undamaged group. These data indicated that the adjustment of IOP between crises was insufficient in those PSS patients with visual field damage. Loss of IOP crossed-over phenomenon meant that other than PSS there were some

**Conclusions:** These data indicated that the harmful effect of the raised IOP during crises of

In recent years a number of authors have confirmed that glaucomatous optic nerve damage similar to that in primary glaucoma cases occurred in part of the PSS cases, but the clinical approach of the occurrence was not reported. Clinical data of cases with PSS during a period of 25 years in our hospital was collected and analyzed, and four clinical approaches via which

208 cases with PSS during the recent 25 years collected in our hospital(male 124 cases, female84 cases), from 9 to 71 years old, with an average of 39.56±12.80. Diagnosis standard for PSS was basically accorded to clinical features described by Posner and Schlossman, except for the cases

**2.3. The clinical approach of optic nerve damage in Posner Schlossman syndrome**

To investigate the clinical approaches of optic nerve damage in PSS patients.

who suffered binocularly or had damage were contained in. [23, 26]

lower IOP patients.

*2.2.3. Relating factors of the visual field damage in PSS*

glaucoma had been showed above.

factors affecting the IOP. [25]

**Propose**

**Methods**

PSS on the optic disc could be accumulated.

the damage occurred in PSS cases were deduced.

**Objective:** To study the relating factors of the visual field damage in PSS.

**Results:** 1) The visual field damage in cases with lower IOP is less and slighter than that in cases with higher IOP. 2) Paracentral, arcuate and ring scotoma was more seen in cases with normal IOP, while constriction of visual field and nasal field were more common in cases with higher IOP. 3) Most of the visual field damages in cases with higher IOP come from the periphery. (See Figure 9)

**Figure 9.** Visual field of a PSS case and a LTG case. The visual field damages in PSS case exist in the periphery area(A), on the contrary, those in glaucoma case with normal IOP exist in the centre area(B).

**Conclusions:** There are difference in visual field defects between higher IOP patients and lower IOP patients.

### *2.2.3. Relating factors of the visual field damage in PSS*

**Objective:** To study the relating factors of the visual field damage in PSS.

**Methods:** Analysis the clinical data of 145 PSS cases and 166 POAG cases for recent 15 years.Results about the incidence and severity of visual field damage in the two kinds of glaucoma had been showed above.

**Results:** 1) Compared with the undamaged group of PSS, the damaged cases were older and with longer course of the disease while there was no remarkable difference in the averaged IOP value during crisis. 2) There was a much higher risk for the visual field damage in binocular cases of PSS. Most of the cases of PSS reported were monocular affected, but later, there were reports about some binocularly affected cases. In our study, 15 of the 35 cases with definite damage were binocularly affected while only one of the 82 cases without damage was affected binocularly. It needs further study to determine whether there is different pathological mechanism for the monocular and binocularly involved cases of PSS. 3) IOP manifestation: although no great difference in the average IOP value during crisis was found between the two groups of PSS, the damage group showed a higher average IOP between crises and included much more cases with an abnormal diurnal and nocturnal variance of IOP or without the IOP crossed-over phenomenon than the undamaged group. These data indicated that the adjustment of IOP between crises was insufficient in those PSS patients with visual field damage. Loss of IOP crossed-over phenomenon meant that other than PSS there were some factors affecting the IOP. [25]

**Conclusions:** These data indicated that the harmful effect of the raised IOP during crises of PSS on the optic disc could be accumulated.

#### **2.3. The clinical approach of optic nerve damage in Posner Schlossman syndrome**

In recent years a number of authors have confirmed that glaucomatous optic nerve damage similar to that in primary glaucoma cases occurred in part of the PSS cases, but the clinical approach of the occurrence was not reported. Clinical data of cases with PSS during a period of 25 years in our hospital was collected and analyzed, and four clinical approaches via which the damage occurred in PSS cases were deduced.

#### **Propose**

*2.2.2. The characteristic of the visual field damage in PSS*

belongs to that with higher IOP). [24]

490 Ophthalmology - Current Clinical and Research Updates

periphery. (See Figure 9)

**Objective:** To study the characteristic of the visual field damage in PSS.

**Methods:** Compare the visual field damage in glaucoma cases with higher and lower IOP (PSS

**Results:** 1) The visual field damage in cases with lower IOP is less and slighter than that in cases with higher IOP. 2) Paracentral, arcuate and ring scotoma was more seen in cases with normal IOP, while constriction of visual field and nasal field were more common in cases with higher IOP. 3) Most of the visual field damages in cases with higher IOP come from the

**Figure 9.** Visual field of a PSS case and a LTG case. The visual field damages in PSS case exist in the periphery area(A),

on the contrary, those in glaucoma case with normal IOP exist in the centre area(B).

To investigate the clinical approaches of optic nerve damage in PSS patients.

#### **Methods**

208 cases with PSS during the recent 25 years collected in our hospital(male 124 cases, female84 cases), from 9 to 71 years old, with an average of 39.56±12.80. Diagnosis standard for PSS was basically accorded to clinical features described by Posner and Schlossman, except for the cases who suffered binocularly or had damage were contained in. [23, 26]

#### **Research project of first diagnosis at the first attendance in our hospital**

History, eyesight, intraocular pressure of episode and intermission, depth of anterior chamber, gonioscope or UBM, intraocular pressure during 24 hours in intermission without eyedrops more than five days, panretinal scope or OCT, FFA in episode of part cases, and so on.

**A B C D**

Sick eye rise rise rise rise higher higher rise rise another eye normal normal normal normal high high high\*/normal high\*/normal

Sick eye normal normal normal rise high high high\*/normal high\*/normal another eye normal normal normal normal high high high\*/normal high\*/normal

positive negative negative negative

width medium width

**stage Early stage later stage Early stage later stage Early stage later stage**

positive \*/ negative

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abnormal \*/ normal

width narrow II-III narrow III-IV

medium

positive \*/ negative

493

abnormal \*/ normal

**Early stage**

IOP

**Results**

Episodes

Intermission

Cross phenomenon of IOP

IOP of 24 hours in period

Anterior chamber angle

**Later**

positive

medium width

**Table 3.** Classification method of the clinical approach for optic nerve damage in PSS

medium width

cases(83.1%) regarded as definite damage.

**2.** The clinical approach of optic nerve damage

causes secondary open-angle glaucoma: 6 cases

represented as Type A, B, C and D.

to visual field damage: 27 cases

of intermittent normal normal normal abnormal abnormal abnormal

medium width

**1.** Incidence and stage distribution of glaucomatous optic nerve damage

Stage distribution of glaucomatous optic nerve damage was shown in Table 4:

**Early stage Moderate stage Advanced stage Absolute stage total** 35 11 11 2 59 59.32% 18.64% 18.64% 3.39% 100%

**Table 4.** Stage of glaucomatous optic nerve damage in 59 cases regarded as clear damage

Type C PSS combined with primary open-angle glaucoma: 19 cases Type D PSS combined with primary closed-angle glaucoma: 7 cases

Anterior chamber depth normal normal normal normal normal normal A little shallow Very shallow

medium

190 cases of 208 patients with PSS had a set of complete material. There were 71 cases (34.1%) with optic nerve damage, in which 12 cases (16.9%) regarded as suspicious damage, 59

Four clinical approaches via which the damage occurred in PSS were deduced, they were

Type A Cumulative effect of repeated episode of high intraocular pressure of pure PSS leads

Type B Recurrent attacks of PSS which results in secondary trabecular meshwork damage

### **Analytical methods**

**1.** Analysis for damage

Standard: repeatable glaucomatous visual field damage and corresponding fundus perform‐ ance

**2.** Stage division standard of glaucomatous visual field damage(see Table2)


**Table 2.** Staging standard of glaucomatous visual field defect

#### **3.** Classification method

According to the results of comprehensive and dynamical analysis of the clinical data of each cases and classification method as shown in table 3, each case was discriminated for the clinical approach of optic nerve damage. [20,21,22,24,27,28]



**Table 3.** Classification method of the clinical approach for optic nerve damage in PSS

#### **Results**

**Research project of first diagnosis at the first attendance in our hospital**

**2.** Stage division standard of glaucomatous visual field damage(see Table2)

refractive interstitial lesions and retinopathy)

Advanced stage tubular visual field Absolute stage no light perception

**Table 2.** Staging standard of glaucomatous visual field defect

approach of optic nerve damage. [20,21,22,24,27,28]

**Early stage**

Age of onset middle-aged and

**Later**

aged people

Typical PSS course positive positive positive negative

Monocular/ binoculus monocular monocular

**3.** Classification method

**Analytical methods**

Without defect

ance

**1.** Analysis for damage

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History, eyesight, intraocular pressure of episode and intermission, depth of anterior chamber, gonioscope or UBM, intraocular pressure during 24 hours in intermission without eyedrops more than five days, panretinal scope or OCT, FFA in episode of part cases, and so on.

Standard: repeatable glaucomatous visual field damage and corresponding fundus perform‐

Early stage paracentral scotoma, nasal step, temporal quadrantanopsia, arcuate scotoma not linked with

Moderate stage arcuate scotoma linked with physiological blind spot, nasal hemianopsia,ring scotoma,

According to the results of comprehensive and dynamical analysis of the clinical data of each cases and classification method as shown in table 3, each case was discriminated for the clinical

> middle-aged and aged people

Family history of glaucoma usually not usually not sometimes have most have

static visual field: no more than 2 clusters of spots with sensitivity reduces more than 5dB, no spot with sensitivity reduces more than 5dB; dynamic visual field: no nasal step and temporal quadrantanopsia more than 10 degrees, no significantly constriction of visual field (except for

physiological blind spot

constriction of visual field more than 30 degrees,

**A B C D**

**stage Early stage later stage Early stage later stage Early stage later stage**

most middle-aged and

monocular KP, binocular

Intermittent attack with binocular high IOP

aged people middle-aged and aged people

high IOP or eyes alternate monocular KP,binocular high IOP

positive negative

**1.** Incidence and stage distribution of glaucomatous optic nerve damage

190 cases of 208 patients with PSS had a set of complete material. There were 71 cases (34.1%) with optic nerve damage, in which 12 cases (16.9%) regarded as suspicious damage, 59 cases(83.1%) regarded as definite damage.

Stage distribution of glaucomatous optic nerve damage was shown in Table 4:


**Table 4.** Stage of glaucomatous optic nerve damage in 59 cases regarded as clear damage

**2.** The clinical approach of optic nerve damage

Four clinical approaches via which the damage occurred in PSS were deduced, they were represented as Type A, B, C and D.

Type A Cumulative effect of repeated episode of high intraocular pressure of pure PSS leads to visual field damage: 27 cases

Type B Recurrent attacks of PSS which results in secondary trabecular meshwork damage causes secondary open-angle glaucoma: 6 cases

Type C PSS combined with primary open-angle glaucoma: 19 cases

Type D PSS combined with primary closed-angle glaucoma: 7 cases

Composition of the clinical approach in 59 cases regarded as definite glaucomatous optic nerve damage was showed in Figure10

**Discussion**

approach

leads to damage **Clinical features**

**Treatment principle**

**1.** The clinical approach of optic nerve damage in Posner-Schlossman syndrome.

of our study may be a wind vane for the further researches.

stage in some cases. (See Figure11) [20, 22, 29]

In the past PSS was considered to be a self-limited disease and has a favorable prognosis, however, in recent years a number of authors have confirmed that part of the PSS cases suffered glaucomatous optic nerve damage similar to those in primary glaucoma cases, but the incidence, degree, related factors and clinical approach of the occurrence is unknown. This part focused on the clinical approach of optic nerve damage in Posner-Schlossman syndrome after aforementioned researches. Reports about optic nerve damage caused by PSS combined with primary open-angle glaucoma were common; the other types were seldom reported. Systematic research aiming at this question has never been seen so far at home and abroad. We determined the damage approach by analyzing each patient's clinical data dynamically and comprehensively according to the discrimination method established on the basis of relating literatures and the results of our long-term systematic study, and got the conclusion that there were four clinical approaches via which the damage occurred. Beyond all question, further research, supplement and correct is necessary in this field, but the method and result

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**2.** Clinical features and treatment principle for cases with damage from different clinical

(1) Type A Cumulative effect of repeated episodes of high intraocular pressure of pure PSS

Except for visual field damage, type A cases complied with the basic characteristics of typical PSS: monocular attacked; intermittently onset of high intraocular pressure with hoar and suetshaped KP ; normal intraocular pressure(including 24 hours intraocular pressure) of the fellow eye in episode and the both eyes in intermission ; Crossed-over phenomenon and postural changes of IOP; normal anterior chamber depth; wide anterior chamber angle; visual field change of vascular shadow usually appears in episode and recover in intermission at the initial in most cases, and true visual field damage is of mild and early stage usually, but loss of light perception can be seen in a few cases; the attack lasts a long time frequently in middle-aged and aged people for long course, also with higher IOP; heterochromia iridis occurred in later

Enough attention should be paid to treatment for each attack, in which the most important is controlling intraocular pressure timely and effectively. Surgery is necessary for the cases with

The surgery method and the time: glaucoma valve or EX-press glaucoma filtration device implantation may be suit for cases with excessive frequent attack, high IOP but light inflam‐ mation (intermission or episodes); trabeculectomy could be selected for cases with low attack

excessive frequent attacks, heavy damage or obvious progress of his damage.

frequency, high IOP as well as severe inflammation (intermission only).

**Figure 10.** The distribution of clinical approach of optic nerve damage in PSS.

Distribution of stage of visual field damage in different optic nerve damage approacheswas showed in Table 5.


**Table 5.** Visual field damage in different type of PSS patients

There is no significant difference in the stage distribution of visual field damage in different type of PSS patients. (*X*<sup>2</sup> =6.904, P>0.05).Make the early and moderate stage as one group, advanced and absolute stage as another group, Statistical result shows that there is significant difference in the stage distribution of visual field damage in different type of PSS patients. The incidence of early stage of glaucomatous visual field damage in Type A (63%) was higher. While 7 of 19 Type C cases were in advanced stage.

**Conclusion:** Most cases in type A suffered an early stage damage, and most in other types suffered a moderate or advanced stage damage, but there were 2 cases in type A who had gone to absolute stage.

### **Discussion**

Composition of the clinical approach in 59 cases regarded as definite glaucomatous optic nerve

Distribution of stage of visual field damage in different optic nerve damage approacheswas

**stage**

There is no significant difference in the stage distribution of visual field damage in different

advanced and absolute stage as another group, Statistical result shows that there is significant difference in the stage distribution of visual field damage in different type of PSS patients. The incidence of early stage of glaucomatous visual field damage in Type A (63%) was higher.

**Conclusion:** Most cases in type A suffered an early stage damage, and most in other types suffered a moderate or advanced stage damage, but there were 2 cases in type A who had gone

=6.904, P>0.05).Make the early and moderate stage as one group,

**absolute stage total**

**moderate stage advanced**

Type A 17 7 1 2 27

Type B 2 2 2 0 6

Type C 5 7 7 0 19

Type D 2 3 2 0 7

damage was showed in Figure10

494 Ophthalmology - Current Clinical and Research Updates

showed in Table 5.

**Early stage**

type of PSS patients. (*X*<sup>2</sup>

to absolute stage.

**Table 5.** Visual field damage in different type of PSS patients

While 7 of 19 Type C cases were in advanced stage.

**Figure 10.** The distribution of clinical approach of optic nerve damage in PSS.

**1.** The clinical approach of optic nerve damage in Posner-Schlossman syndrome.

In the past PSS was considered to be a self-limited disease and has a favorable prognosis, however, in recent years a number of authors have confirmed that part of the PSS cases suffered glaucomatous optic nerve damage similar to those in primary glaucoma cases, but the incidence, degree, related factors and clinical approach of the occurrence is unknown. This part focused on the clinical approach of optic nerve damage in Posner-Schlossman syndrome after aforementioned researches. Reports about optic nerve damage caused by PSS combined with primary open-angle glaucoma were common; the other types were seldom reported. Systematic research aiming at this question has never been seen so far at home and abroad. We determined the damage approach by analyzing each patient's clinical data dynamically and comprehensively according to the discrimination method established on the basis of relating literatures and the results of our long-term systematic study, and got the conclusion that there were four clinical approaches via which the damage occurred. Beyond all question, further research, supplement and correct is necessary in this field, but the method and result of our study may be a wind vane for the further researches.

**2.** Clinical features and treatment principle for cases with damage from different clinical approach

(1) Type A Cumulative effect of repeated episodes of high intraocular pressure of pure PSS leads to damage

#### **Clinical features**

Except for visual field damage, type A cases complied with the basic characteristics of typical PSS: monocular attacked; intermittently onset of high intraocular pressure with hoar and suetshaped KP ; normal intraocular pressure(including 24 hours intraocular pressure) of the fellow

eye in episode and the both eyes in intermission ; Crossed-over phenomenon and postural changes of IOP; normal anterior chamber depth; wide anterior chamber angle; visual field change of vascular shadow usually appears in episode and recover in intermission at the initial in most cases, and true visual field damage is of mild and early stage usually, but loss of light perception can be seen in a few cases; the attack lasts a long time frequently in middle-aged and aged people for long course, also with higher IOP; heterochromia iridis occurred in later stage in some cases. (See Figure11) [20, 22, 29]

#### **Treatment principle**

Enough attention should be paid to treatment for each attack, in which the most important is controlling intraocular pressure timely and effectively. Surgery is necessary for the cases with excessive frequent attacks, heavy damage or obvious progress of his damage.

The surgery method and the time: glaucoma valve or EX-press glaucoma filtration device implantation may be suit for cases with excessive frequent attack, high IOP but light inflam‐ mation (intermission or episodes); trabeculectomy could be selected for cases with low attack frequency, high IOP as well as severe inflammation (intermission only).

Eye: 14-19mmHg, left Eye: 23-29mmHg; iris depigmentation of her left eye exacerbated, no abnormal was found with fundus angiography. The recent onset occurred in September this year, the medication of hormone and pranopulin continued for 3 months, with another

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She made another visit to our hospital one year later. It was found that the iris of her left eye appeared a typical "rain dozen sand samples", meanwhile, there were two off-white round medium-sized lipid-like KP and she was diagnosed as "left eye glaucomatocyclitic crisis with heterochromatic iris." Since then, the attack occurred more frequently, with frequency of 1 to 2 times per month, the visual field damage exacerbated. She was hospitalized in our depart‐ ment, and the surgery of glaucoma valve implantation was performed. Postoperative intra‐ ocular pressure: 19mmHg for her right eye and 6mmHg for her left eye:, visual acuity1.0 left eye (with pin hole) for her both eye, and the syndrome did not attack postoperation. (Clinical

A patient was hospitalized in our hospital for the reason of "intermittent pain of left eye for 25years, decrease of vision for 20 years, blind for 1 year". The patient had a history of intermittent episodes of pain and blurred vision with his left eye for 25 years, which occurred 1 to 2 times per month with the duration of 3 to 5 days, and than self-cured. In many hospitals he was diagnosed as "glaucomatocyclitic crisis" and treated with medica‐ tion irregularly The occurrence becomes more frequently in the recent 10 years, and the duration longer, and the vision recessions gradually. In the intermittent period, he was hospitalized for systematic examination. The visual acuity was 1.0 for his right eye and no light perception for his left eye. All the results of IOP, tonography, 24 hours IOP measure‐ ment and other tests during the intermittent period were normal for his both eyes. The result of the medical examination at this hospitalization showed as following: his right eye had a corrected visual acuity of 1.0, IOP 14mmHg, C/D 0.4, wide anterior chamber angle; his left eye had no light perception, intraocular pressure 56mmHg, C / D1.0, width of N1 ~ N3 for the anterior chamber angle with some small limited adhesions; corneal edema, a

Without any treatment, the IOP of his fell to 14mmHg within one week. All results of exami‐ nations including 24 hours IOP measurement, drinking water experiment, dark room prone test for his right eye were normal. Laboratory results of systemic body check were normal.

His left eye still had attacks of PSS after he left hospital and each attack was self-limited. The IOP and 24-hour IOP during the intermittent period were measured to be normal, and his left eye had an IOP lower than that of his right eye, a typical IOP cross phenomenon appeared every time. Three years later, the fundus and visual field of his right eye kept normal. (Clinical

minor attack during thatthis period.

data please see Figure 12)

dozen of round lipid-like KP.

data see Figure 13)

**Typical** Case 2)

**Figure 11.** The iridis of a PSS patient.(A)is that of the normal eye,(B) is that of the affected eye.

**Typical cases** 1) A patient visited our hospital and was diagnosed as glaucomatocyclitis crisis of left eye in other hospital six years ago. In the initial stage, she attacked once or twice per year with duration of 3~7 days for each attack and ceased spontaneously, then the frequency of attack increased and the duration extended. This attack happened one month before this visits to our hospital and stop one week ago without use of any drug. Examination at first visit: Vision 1.0(OU), IOP19.7mmHg(R), 12mmHg (L), anterior chambers of both eyes were not shallow, iris color was symmetrical, KP (-).Fundus examination: C/D0.3(R) 0.6(L), there wasn't other abnormalities. She was diagnosed as secondary glaucoma of left eye. On September 13 (10 days after withdrawal), the 24 hours IOP of both eyes were measured: right eye: 14-18mmHg, left eye 12-14mmHg, Corneal thickness: right eye: 584µm, left eye: 575µm. She was diagnosed as "glaucomatocyclitis crisis in left eye." Another onset lasted for more than 10 days, IOP of the left eye was 43mmHg, there was 2hoar and suet--like KP and faded iris pigment in left eye. There were total seven attacks in one year, with the duration from 1 week to 20 days, during one of which the KP appeared 9day after the occurrence. 24 hours IOP during this episode: right

Eye: 14-19mmHg, left Eye: 23-29mmHg; iris depigmentation of her left eye exacerbated, no abnormal was found with fundus angiography. The recent onset occurred in September this year, the medication of hormone and pranopulin continued for 3 months, with another minor attack during thatthis period.

She made another visit to our hospital one year later. It was found that the iris of her left eye appeared a typical "rain dozen sand samples", meanwhile, there were two off-white round medium-sized lipid-like KP and she was diagnosed as "left eye glaucomatocyclitic crisis with heterochromatic iris." Since then, the attack occurred more frequently, with frequency of 1 to 2 times per month, the visual field damage exacerbated. She was hospitalized in our depart‐ ment, and the surgery of glaucoma valve implantation was performed. Postoperative intra‐ ocular pressure: 19mmHg for her right eye and 6mmHg for her left eye:, visual acuity1.0 left eye (with pin hole) for her both eye, and the syndrome did not attack postoperation. (Clinical data please see Figure 12)

### **Typical** Case 2)

**Typical cases** 1) A patient visited our hospital and was diagnosed as glaucomatocyclitis crisis of left eye in other hospital six years ago. In the initial stage, she attacked once or twice per year with duration of 3~7 days for each attack and ceased spontaneously, then the frequency of attack increased and the duration extended. This attack happened one month before this visits to our hospital and stop one week ago without use of any drug. Examination at first visit: Vision 1.0(OU), IOP19.7mmHg(R), 12mmHg (L), anterior chambers of both eyes were not shallow, iris color was symmetrical, KP (-).Fundus examination: C/D0.3(R) 0.6(L), there wasn't other abnormalities. She was diagnosed as secondary glaucoma of left eye. On September 13 (10 days after withdrawal), the 24 hours IOP of both eyes were measured: right eye: 14-18mmHg, left eye 12-14mmHg, Corneal thickness: right eye: 584µm, left eye: 575µm. She was diagnosed as "glaucomatocyclitis crisis in left eye." Another onset lasted for more than 10 days, IOP of the left eye was 43mmHg, there was 2hoar and suet--like KP and faded iris pigment in left eye. There were total seven attacks in one year, with the duration from 1 week to 20 days, during one of which the KP appeared 9day after the occurrence. 24 hours IOP during this episode: right

**Figure 11.** The iridis of a PSS patient.(A)is that of the normal eye,(B) is that of the affected eye.

496 Ophthalmology - Current Clinical and Research Updates

A patient was hospitalized in our hospital for the reason of "intermittent pain of left eye for 25years, decrease of vision for 20 years, blind for 1 year". The patient had a history of intermittent episodes of pain and blurred vision with his left eye for 25 years, which occurred 1 to 2 times per month with the duration of 3 to 5 days, and than self-cured. In many hospitals he was diagnosed as "glaucomatocyclitic crisis" and treated with medica‐ tion irregularly The occurrence becomes more frequently in the recent 10 years, and the duration longer, and the vision recessions gradually. In the intermittent period, he was hospitalized for systematic examination. The visual acuity was 1.0 for his right eye and no light perception for his left eye. All the results of IOP, tonography, 24 hours IOP measure‐ ment and other tests during the intermittent period were normal for his both eyes. The result of the medical examination at this hospitalization showed as following: his right eye had a corrected visual acuity of 1.0, IOP 14mmHg, C/D 0.4, wide anterior chamber angle; his left eye had no light perception, intraocular pressure 56mmHg, C / D1.0, width of N1 ~ N3 for the anterior chamber angle with some small limited adhesions; corneal edema, a dozen of round lipid-like KP.

Without any treatment, the IOP of his fell to 14mmHg within one week. All results of exami‐ nations including 24 hours IOP measurement, drinking water experiment, dark room prone test for his right eye were normal. Laboratory results of systemic body check were normal.

His left eye still had attacks of PSS after he left hospital and each attack was self-limited. The IOP and 24-hour IOP during the intermittent period were measured to be normal, and his left eye had an IOP lower than that of his right eye, a typical IOP cross phenomenon appeared every time. Three years later, the fundus and visual field of his right eye kept normal. (Clinical data see Figure 13)

**Figure 13.** Visual field of the right eye of patient (Clinical number 241163).PSS results in blind of his left eye, but the

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(2) Type B secondary open-angle glaucoma from secondary damage to trabecular meshwork

Type B cases complied with the basic characteristics (above mentioned) of typical PSS in early stage. These characteristics lost eventually as the damage to trabecular meshwork gradually accelerated, the attack takes place more frequently and lasts a longer and longer time with a higher and higher IOP, and serious visual field damage developed at last.[30, 31] However, the fundus, visual field, IOP in intermittent and episode of the fellow eye maintained normal.

It is necessary to reduce IOP with drugs according to extent and characteristics of elevated IOP and diminish inflammation with hormone of weak effect on elevating IOP for short time, for example, lotemax. PGA is useful and myotic is prohibitive. Surgery or other treatment (SLT,

trabeculectomy, glaucoma valve or EX-press implantation) should be taken into account according to the IOP level controlled by drugs in intermittent and the situation of visual field

Patients of this type usually had a long course of the disease with an older age.

visual field of his right eye without PSS is normal.

by recurrent attacks of PSS

**Clinical features**

**Treatment principle**

damage.

**Figure 12.** Clinical data of a cases suffered from PSS with glaucomatous optic nerve damage combined with hetero‐ chromia iris (Clinical number 488368).Visual field (A) and Optical Coherence Tomography (B) indicate glaucoma dam‐ ages;Anterio segment of normal right eye(C) and left eye(D),arrow shows heterochmia iris and KP in the attacked eye(E).

**Figure 13.** Visual field of the right eye of patient (Clinical number 241163).PSS results in blind of his left eye, but the visual field of his right eye without PSS is normal.

(2) Type B secondary open-angle glaucoma from secondary damage to trabecular meshwork by recurrent attacks of PSS

### **Clinical features**

Type B cases complied with the basic characteristics (above mentioned) of typical PSS in early stage. These characteristics lost eventually as the damage to trabecular meshwork gradually accelerated, the attack takes place more frequently and lasts a longer and longer time with a higher and higher IOP, and serious visual field damage developed at last.[30, 31] However, the fundus, visual field, IOP in intermittent and episode of the fellow eye maintained normal. Patients of this type usually had a long course of the disease with an older age.

#### **Treatment principle**

**Figure 12.** Clinical data of a cases suffered from PSS with glaucomatous optic nerve damage combined with hetero‐ chromia iris (Clinical number 488368).Visual field (A) and Optical Coherence Tomography (B) indicate glaucoma dam‐ ages;Anterio segment of normal right eye(C) and left eye(D),arrow shows heterochmia iris and KP in the attacked

eye(E).

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It is necessary to reduce IOP with drugs according to extent and characteristics of elevated IOP and diminish inflammation with hormone of weak effect on elevating IOP for short time, for example, lotemax. PGA is useful and myotic is prohibitive. Surgery or other treatment (SLT,

trabeculectomy, glaucoma valve or EX-press implantation) should be taken into account according to the IOP level controlled by drugs in intermittent and the situation of visual field damage.

### **Typical case**

A patient was diagnosed as "left eye PSS" with the complain of vision decline associated with distending pain of his left eye in other hospitals five years ago. The medical records of other hospitals showed: IOP and other relating examinations of the right eye in episode and these in intermittent period of his both eyes was normal at the initial stage. The visual acuity decreased gradually, IOP fluctuated from 32 to 48 mmHg in recent years. He was hospitalized in our hospital three times, the results of clinical observation showed: IOP including 24 hours IOP in intermittent period, the fundus and visual field of his right eye appeared normal; while IOP of his left eye was high frequently and higher when PSS attacked, 24 hours IOP in intermittent period appeared abnormal including the highest IOP and IOP variation. The left eye was diagnosed as secondary open-angle glaucoma from secondary damage to trabecular meshwork by recurrent attacks of PSS, and then a trabecuectomy was performed on his left eye. Postoperative IOP of his left eye was from 12 to 10mmHg in intermittent period, 20 to 31 mmHg in episodes, while his right eye kept normal in all ways. (Clinical data see Figure 14)

(3) Type C PSS combined with primary open-angle glaucoma

### **Clinical features**

Monocular/ binocular paroxysmal increased IOP with mild cyclitis; wide anterior chamber angle; binocular abnormal IOP and visual field damage; high average IOP; great fluctuation of IOP level; absence of IOP cross phenomenon; PSS attacks at the same eye in most cases; at the two eyes alternately or at the same time in a few cases; visual field damage was serious, and more serious in the eye often attacked by PSS.[27, 32]

### **Treatment principle**

Enough attention should be given to the treatment for cases of this type, whose incidence reached up to 31% as reported. Drug treatment is similar to that of POAG, but in epi‐ sode of PSS, corticosteroid is useful transitorily, while PGA and myotic is prohibitive. Indication of surgery is similar to that of POAG, but classical trabeculectomy should be performed in intermission, and the effect and safety of non-penetrating trabeculectomy, implantation of Ahmed glaucoma valve or EX-PRESS Glaucoma Filtration Device has not been confirmed. Laser trabeculoplasty(ALT), Selective laser trabeculoplasty (SLT) or Pneumatic trabeculoplasty (PNT) should be adopted in intermission, however, there has no related report. [11, 33, 34, 35]

### **Typical cases**

A patient reported of discomfort and blurred vision of her left eye for more than 1 year, the patient was diagnosed as POAG in other hospital 10 days ago. Clinical date of that time showed: KP (-), IOP16.3/42.7(R/L), and she was treated with Travoprost Eye Drops to her left eye and brimonidine and brinzolamide to the both eye. 1 week after treatment, her IOP turned to 36/17(R/L), the treatment had been changed to travoprost, brimonidine and brinzolamide for the both eye. The results of examination in our hospital showed as follows: visual acuity R1.0 (-1.25DS),L0.05(-3.75DS), IOP17(OU); absence of conjunctiva hyperemia; cup/disc ratios 0.8 OD and0.9OS,and inferior RNFLD(by OCT:) in the both eye; severe glaucomatous visual

field damage in both eye, extended latent time and descended amplitude on VEP; CCT:540/520 (R/L),corneal endothelium cells 1730/2747(R/L); center anterior chamber depth ≥3.0mm and open anterior chamber angle in every direction for the both eye by UBM. She was diagnosed as binocular POAG, and treated successively with travatan, alphagan and brinzolamide to binoculus, but her IOP was not controlled well. Thus, a trabeculectomy was performed the left eye. Two weeksafter the operation, the filtration bubble turned fibrosed, and IOP increased. By 3 times of pin-delamination with 5-fluorouracil and eyeball massage, IOP was controlled

**Figure 14.** Clinical data of a patient suffered from PSS with glaucomatous optic nerve damange due to secondary open angle glaucoma (Clinical number 813064).Normal visual field in right eye(A) and advanced visual field defect in

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left eye (B);UBM shows the normol right eye and the affected left eye post-operation(C).

**Typical case**

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**Clinical features**

**Treatment principle**

related report. [11, 33, 34, 35]

**Typical cases**

A patient was diagnosed as "left eye PSS" with the complain of vision decline associated with distending pain of his left eye in other hospitals five years ago. The medical records of other hospitals showed: IOP and other relating examinations of the right eye in episode and these in intermittent period of his both eyes was normal at the initial stage. The visual acuity decreased gradually, IOP fluctuated from 32 to 48 mmHg in recent years. He was hospitalized in our hospital three times, the results of clinical observation showed: IOP including 24 hours IOP in intermittent period, the fundus and visual field of his right eye appeared normal; while IOP of his left eye was high frequently and higher when PSS attacked, 24 hours IOP in intermittent period appeared abnormal including the highest IOP and IOP variation. The left eye was diagnosed as secondary open-angle glaucoma from secondary damage to trabecular meshwork by recurrent attacks of PSS, and then a trabecuectomy was performed on his left eye. Postoperative IOP of his left eye was from 12 to 10mmHg in intermittent period, 20 to 31 mmHg in episodes, while his right eye kept normal in all ways. (Clinical data see Figure 14)

Monocular/ binocular paroxysmal increased IOP with mild cyclitis; wide anterior chamber angle; binocular abnormal IOP and visual field damage; high average IOP; great fluctuation of IOP level; absence of IOP cross phenomenon; PSS attacks at the same eye in most cases; at the two eyes alternately or at the same time in a few cases; visual field damage was serious,

Enough attention should be given to the treatment for cases of this type, whose incidence reached up to 31% as reported. Drug treatment is similar to that of POAG, but in epi‐ sode of PSS, corticosteroid is useful transitorily, while PGA and myotic is prohibitive. Indication of surgery is similar to that of POAG, but classical trabeculectomy should be performed in intermission, and the effect and safety of non-penetrating trabeculectomy, implantation of Ahmed glaucoma valve or EX-PRESS Glaucoma Filtration Device has not been confirmed. Laser trabeculoplasty(ALT), Selective laser trabeculoplasty (SLT) or Pneumatic trabeculoplasty (PNT) should be adopted in intermission, however, there has no

A patient reported of discomfort and blurred vision of her left eye for more than 1 year, the patient was diagnosed as POAG in other hospital 10 days ago. Clinical date of that time showed: KP (-), IOP16.3/42.7(R/L), and she was treated with Travoprost Eye Drops to her left eye and brimonidine and brinzolamide to the both eye. 1 week after treatment, her IOP turned to 36/17(R/L), the treatment had been changed to travoprost, brimonidine and brinzolamide for the both eye. The results of examination in our hospital showed as follows: visual acuity R1.0 (-1.25DS),L0.05(-3.75DS), IOP17(OU); absence of conjunctiva hyperemia; cup/disc ratios 0.8 OD and0.9OS,and inferior RNFLD(by OCT:) in the both eye; severe glaucomatous visual

(3) Type C PSS combined with primary open-angle glaucoma

and more serious in the eye often attacked by PSS.[27, 32]

**Figure 14.** Clinical data of a patient suffered from PSS with glaucomatous optic nerve damange due to secondary open angle glaucoma (Clinical number 813064).Normal visual field in right eye(A) and advanced visual field defect in left eye (B);UBM shows the normol right eye and the affected left eye post-operation(C).

field damage in both eye, extended latent time and descended amplitude on VEP; CCT:540/520 (R/L),corneal endothelium cells 1730/2747(R/L); center anterior chamber depth ≥3.0mm and open anterior chamber angle in every direction for the both eye by UBM. She was diagnosed as binocular POAG, and treated successively with travatan, alphagan and brinzolamide to binoculus, but her IOP was not controlled well. Thus, a trabeculectomy was performed the left eye. Two weeksafter the operation, the filtration bubble turned fibrosed, and IOP increased. By 3 times of pin-delamination with 5-fluorouracil and eyeball massage, IOP was controlled on 12 to 14 mmHg. Her right eye was treated with travatan, carteolol hydrochloride and brimonidine, IOP wascontrolled from 12 to 14 mmHg. She was discharged from hospital. Four months later, the right eye appeared 5 small rounds and mutton-fat like KP, IOP increased to 19mmHg. A week later, KP played down, IOP descended to 12 mmHg. A month later; KP appeared again, IOP increased to 37, after treatment in hospital for a week, the IOP decreased to 12 mmHg. She was diagnosed as POAG combined with PSS. Two months later PSS of her right attacked again, IOP increased to 44 mmHg; visual field damage has progressed remark‐ ably. FFA showed optic atrophy without any other abnormal. She was hospitalized again, and a implantation of Ahmed valve to her right eye was done on the next day. During the operation, the valve appeared out of control; we dealt it well with removable restraint line processing; the IOP and anterior chamber stability was controlled. 2 month after the operation, the IOP increased to 22 mmHg because of the draining disc was packaged. By pin-delamination and eyeball massage, IOP was controlled near to 20mmHg. Carteolol hydrochloride was added and the IOP was controlled well in intermittent, but PSS attacked frequently and the IOP was out of control during episode. She was hospitalized once more and the right eye was treated with no-penetrating glaucoma surgery. One month after surgery, the IOP was controlled well, binocular IOP was 10mmHg. 2 month after surgery, PSS attackwas seen in her right eye again, IOP increased to 20 mmHg. This attack faded a week later and IOP of her both maintained 14mmHg below until now. (Clinical data please see Figure 15)

(4) Type D PSS combined with primary closed-angle glaucoma

### **Research status**

Except for our data, there had been only two individual reports about PSS combined with PCAG in China and none in abroad. Cases of PSS combined with PCAG at home are much more than those in abroad due to the higher incidence of PCAG as well as PSS at home. In 2004 we reported 6 cases and completed a systematic clinical analysis. It was often reminded by many ophthalmologists that cases of PSS had be mistaken as PACG, but enough attention has not been paid to this type of PSS. [18, 28, 36, 37, 38]

### **Clinical features**

There is a typical history of PSS attack with binocular shallow anterior chamber and narrow or closed anterior chamber angle. PSS hardly attacked synchronously with PACG, the anterior chamber angle is open in episodes of PSS. Type D cases complied with the basic characteristics of typical PSS in early stage: binocular IOP is normal in intermission; with cross phenomenon of IOP; however, when PACG became more advanced, although the IOP of the PSS attacked eye was much higher than that of the unattacked eye in the episode of PSS, binocular IOP turned higher than normal even in intermission of PSS without obvious cross phenomenon. Most cases were diagnosed as PACG previously, PSS appeared after the treatment for PACG had been completed and the anterior chamber angle been opened, a few cases were typical PSS with narrow anterior chamber angle when they were young; PACG appeared as anterior chamber angle became narrower and narrower with age. Most of the cases of this type were elder with a longer course of PSS and a more advanced visual field damage.

**Figure 15.** Clinical data of patient suffered from PSS(right eye) with glaucomatous optic nerve damange combined with POAG(both eye),the right eye is treated with Ahmed value implantation surgery(A),the left eye is treated with normal trabeculectomy(B), visual field of right eye(C) and left eye(D)show typical glaucoma damages,the fundus an‐ giography indicates no vasular disorder except of optic atrophy(E) and the optic cups of right eye and lefr eye are non-

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symmetrical.

on 12 to 14 mmHg. Her right eye was treated with travatan, carteolol hydrochloride and brimonidine, IOP wascontrolled from 12 to 14 mmHg. She was discharged from hospital. Four months later, the right eye appeared 5 small rounds and mutton-fat like KP, IOP increased to 19mmHg. A week later, KP played down, IOP descended to 12 mmHg. A month later; KP appeared again, IOP increased to 37, after treatment in hospital for a week, the IOP decreased to 12 mmHg. She was diagnosed as POAG combined with PSS. Two months later PSS of her right attacked again, IOP increased to 44 mmHg; visual field damage has progressed remark‐ ably. FFA showed optic atrophy without any other abnormal. She was hospitalized again, and a implantation of Ahmed valve to her right eye was done on the next day. During the operation, the valve appeared out of control; we dealt it well with removable restraint line processing; the IOP and anterior chamber stability was controlled. 2 month after the operation, the IOP increased to 22 mmHg because of the draining disc was packaged. By pin-delamination and eyeball massage, IOP was controlled near to 20mmHg. Carteolol hydrochloride was added and the IOP was controlled well in intermittent, but PSS attacked frequently and the IOP was out of control during episode. She was hospitalized once more and the right eye was treated with no-penetrating glaucoma surgery. One month after surgery, the IOP was controlled well, binocular IOP was 10mmHg. 2 month after surgery, PSS attackwas seen in her right eye again, IOP increased to 20 mmHg. This attack faded a week later and IOP of her both maintained

Except for our data, there had been only two individual reports about PSS combined with PCAG in China and none in abroad. Cases of PSS combined with PCAG at home are much more than those in abroad due to the higher incidence of PCAG as well as PSS at home. In 2004 we reported 6 cases and completed a systematic clinical analysis. It was often reminded by many ophthalmologists that cases of PSS had be mistaken as PACG, but enough attention has

There is a typical history of PSS attack with binocular shallow anterior chamber and narrow or closed anterior chamber angle. PSS hardly attacked synchronously with PACG, the anterior chamber angle is open in episodes of PSS. Type D cases complied with the basic characteristics of typical PSS in early stage: binocular IOP is normal in intermission; with cross phenomenon of IOP; however, when PACG became more advanced, although the IOP of the PSS attacked eye was much higher than that of the unattacked eye in the episode of PSS, binocular IOP turned higher than normal even in intermission of PSS without obvious cross phenomenon. Most cases were diagnosed as PACG previously, PSS appeared after the treatment for PACG had been completed and the anterior chamber angle been opened, a few cases were typical PSS with narrow anterior chamber angle when they were young; PACG appeared as anterior chamber angle became narrower and narrower with age. Most of the cases of this type were

elder with a longer course of PSS and a more advanced visual field damage.

14mmHg below until now. (Clinical data please see Figure 15)

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(4) Type D PSS combined with primary closed-angle glaucoma

not been paid to this type of PSS. [18, 28, 36, 37, 38]

**Research status**

**Clinical features**

**Figure 15.** Clinical data of patient suffered from PSS(right eye) with glaucomatous optic nerve damange combined with POAG(both eye),the right eye is treated with Ahmed value implantation surgery(A),the left eye is treated with normal trabeculectomy(B), visual field of right eye(C) and left eye(D)show typical glaucoma damages,the fundus an‐ giography indicates no vasular disorder except of optic atrophy(E) and the optic cups of right eye and lefr eye are nonsymmetrical.

when the IOP is higher, and to make clinical follow-up observations for KP and its relationship with IOP, so as to ascertain whether PSS is the cause of elevating IOP, so that unnecessary

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According to condition of PACG, laser and/or surgery and/or drugs may become options.

**1.** Indications of that for cases of PSS combined with PACG is similar to that PACG patients, except for that examination and treatment should be done in the intermission of PSS;

**3.** The iris surrounding excision mouth by laser must be thoroughly penetrated and the hole

**4.** Corticosteroids and drugs for reducing IOP should be sufficient after laser operation;

**5.** It is import to pay attention to the treatment for PSS which continue to attack after laser therapy, and to the monitor of IOP and its dynamic change. Additional drug treatment

It is necessary to prevent the attack of PACG in either episodes or intermission of PSS for these

A patient was diagnosed as "PSS" in our hospital because of pain and discomfort of his right eye, then he was diagnosed as "acute angle-closure glaucoma " in other hospital because of severe sore of his both eyes and switched to our hospital after remission seven years later.

Examination revealed mutton-fat like KP in the right eye. His right eye was diagnosed as PSS combined with PACG with analysis by synthesis combining history and test results of IOP, fundus, visual field and anterior chamber angle. The right eye was treated with "glaucoma

IOP of his both appeared stable for six months after operation, then the right eye was attacked by PSS once again. This attack of PSS appeared as typical KP, open angle and slightly increased

A patient came to our clinic because of "repeated intermittent attacks of eye pain and impaired vision for her left eye and right eye as well for more than 14 years". She was treated with YAG laser iridotomy in other hospital for PACG binocularly twice each. Her left eye had been still attacked intermittently ever since. Clinical date from her medical record showed that KP and IOP rising appeared nearly simultaneously on each episode and the IOP turned persistently higher than normal even if in intermission since 2 years ago and the drugs could not control the IOP well. Examination at this time showed: Vision R 1.0, L 0.4; IOP R 14 mmHg and L 46

**2.** Curative effect on cases with typical cross phenomenon of IOP should be better;

even trabeculectomy should be adopted timely when necessary;[27]

untreated PACG cases with the appropriate use of miosis drug.

drainage surgery" and the left eye with "YAG laser iridectomy ".

IOP. (Clinical data please see Figure 17)

surgery can be avoided.

should be big enough;

**Treatment principles**

Laser treatment:

**Typical cases 1)**

**Typical cases 2)**

**Figure 16.** Visual field of patient (Clinical number 232036)with binocular PSS combined with POAG. After drug treat‐ ment,the damage of binocular visual field between 1991(A) and 1998(B) has no significant advance.

### **Diagnosis standard**

The first is that the anterior chamber angle is open when PSS is diagnosed at episode, either in the intermission of PACG or after PACG was treated with Laser/surgery/drug; the second is that the cases complied with the basic characteristics of typical PSS described by Posner-Schlossman. In our study, 2 cases was diagnosed as PSS at a younger age with binocular narrow anterior chamber angle (first was narrow II, narrow III-IV four years later), 5 cases was diagnosed as PSS after treatment of PACG (similar to the two cases reported at home).[28, 39]

#### **Diagnostic summary**

To find out PACG complicated with PSS as soon as possible, it is necessary to carry out a set of comprehensive and careful examinations relating to PACG in the intermission of PSS for PSS patients with factors as follows: the old-aged, with a serious visual field damage, longer course of the disease, with a shallow anterior chamber or an narrow anterior chamber angle, and binocularly attacked.

When IOP appeared as repeated, intermittent and sudden elevation in a patient with PACG whose anterior chamber angle had been opened and the IOP been controlled well for a period after treatment by means of laser and/or surgery and/or drugs, it is very important to pay sufficient attention to the depth of the binocular anterior chamber and anterior chamber angle when the IOP is higher, and to make clinical follow-up observations for KP and its relationship with IOP, so as to ascertain whether PSS is the cause of elevating IOP, so that unnecessary surgery can be avoided.

### **Treatment principles**

According to condition of PACG, laser and/or surgery and/or drugs may become options.

Laser treatment:


It is necessary to prevent the attack of PACG in either episodes or intermission of PSS for these untreated PACG cases with the appropriate use of miosis drug.

### **Typical cases 1)**

**Figure 16.** Visual field of patient (Clinical number 232036)with binocular PSS combined with POAG. After drug treat‐

The first is that the anterior chamber angle is open when PSS is diagnosed at episode, either in the intermission of PACG or after PACG was treated with Laser/surgery/drug; the second is that the cases complied with the basic characteristics of typical PSS described by Posner-Schlossman. In our study, 2 cases was diagnosed as PSS at a younger age with binocular narrow anterior chamber angle (first was narrow II, narrow III-IV four years later), 5 cases was diagnosed as PSS after treatment of PACG (similar to the two cases reported at home).[28, 39]

To find out PACG complicated with PSS as soon as possible, it is necessary to carry out a set of comprehensive and careful examinations relating to PACG in the intermission of PSS for PSS patients with factors as follows: the old-aged, with a serious visual field damage, longer course of the disease, with a shallow anterior chamber or an narrow anterior chamber angle,

When IOP appeared as repeated, intermittent and sudden elevation in a patient with PACG whose anterior chamber angle had been opened and the IOP been controlled well for a period after treatment by means of laser and/or surgery and/or drugs, it is very important to pay sufficient attention to the depth of the binocular anterior chamber and anterior chamber angle

ment,the damage of binocular visual field between 1991(A) and 1998(B) has no significant advance.

**Diagnosis standard**

504 Ophthalmology - Current Clinical and Research Updates

**Diagnostic summary**

and binocularly attacked.

A patient was diagnosed as "PSS" in our hospital because of pain and discomfort of his right eye, then he was diagnosed as "acute angle-closure glaucoma " in other hospital because of severe sore of his both eyes and switched to our hospital after remission seven years later.

Examination revealed mutton-fat like KP in the right eye. His right eye was diagnosed as PSS combined with PACG with analysis by synthesis combining history and test results of IOP, fundus, visual field and anterior chamber angle. The right eye was treated with "glaucoma drainage surgery" and the left eye with "YAG laser iridectomy ".

IOP of his both appeared stable for six months after operation, then the right eye was attacked by PSS once again. This attack of PSS appeared as typical KP, open angle and slightly increased IOP. (Clinical data please see Figure 17)

### **Typical cases 2)**

A patient came to our clinic because of "repeated intermittent attacks of eye pain and impaired vision for her left eye and right eye as well for more than 14 years". She was treated with YAG laser iridotomy in other hospital for PACG binocularly twice each. Her left eye had been still attacked intermittently ever since. Clinical date from her medical record showed that KP and IOP rising appeared nearly simultaneously on each episode and the IOP turned persistently higher than normal even if in intermission since 2 years ago and the drugs could not control the IOP well. Examination at this time showed: Vision R 1.0, L 0.4; IOP R 14 mmHg and L 46

the left eye during episode of PSS. IOP of the both eye maintained15mmHg or below, and the visual field maintained stable in the 3 years. Several attacks of PSS had been recorded with a IOP up to 40mmHg, and her visual field turned worsen, and "rain dozen sand-like" appear‐ ance in the iris of her left eye got more pronounced in the last 2 years. She was hospitalized once more, and another trabeculectomy was performedon the left eye near the first one, at the end of which the two filtering blebs (an original and a just manufactured) were merged into one. She was discharged with an IOP of 12mmHg; the left eye was no longer attacked after

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**Figure 18.** Typical clinical data of patient (Clinical number :341555)with diagnosis of left PSS combined with binocular closed-angle glaucoma. The visual fields of right eye(A) and left eye(B) become worse 4years later(C) and (D),UBM in‐ dicate binocular aqueous humour outflow after the 1 st trabeculectomy(E) and the OCT results show serious retinal

nerve fiber layer defect in left eye(F).

this trabeculectomy, and the IOP kept stable.(Clinical data see Figure 18)

**Figure 17.** Typical clinical data of patient (Clinical number :406013)with diagnosis of right PSS combined with binocu‐ lar PACG and treatment with classical trabeculectomy.The visual field show advanced glaucoma damange (A),OCT(C) also shows retinal nerve fiber layer defect.UBM indicate binocular closed angle(B).

mmHg; two mutton-fat like KP in the left eye ; shallow anterior chamber and angle multiple adhesions in both eyes; several trace of laser therapy on iris of her both eye, the only peetrated hole on the right eye be covered with fibrous membrane, and that on the left eye be too small; cup/disc ratios R 0.4and L 0.8.A diagnosis of "binocular PACG complicated with PSS in left eye" was established. A complementary laser therapy was given to her right eye just at that moment; after this laser therapy, her right had been kept well until now with only the help of 2% Carteolol Hydrochloride eye drops twice a day. Three weeks later, when this attack of PSS faded away, she was hospitalized in our hospital, and a trabeculectomy was performed on her left eye, and she was discharged 10 days after a IOP of 14mmHg. Six weeks after the surgery, an attack of PSS occurred with a IOP of 32mmHg and lasted a week; such attack occurred once or twice a year after that with a maximal IOP of 25mmHg. The IOP in intermission had maintained near 15mmHg during the first 4 years, but the result of 24h IOP measurement showed 13~20mmHg in the right eye and 15~24mmHg in the left eye. Iris heterochromia appeared in the left eye. Such a therapeutic schedule was established and kept 3 years since then: 2% Carteolol Hydrochloride Eye Drops twice a day to the both eye in intermission of PSS; 2% Carteolol twice a day plus brimonidine 3 times a day with shortly use of Lotemax for the left eye during episode of PSS. IOP of the both eye maintained15mmHg or below, and the visual field maintained stable in the 3 years. Several attacks of PSS had been recorded with a IOP up to 40mmHg, and her visual field turned worsen, and "rain dozen sand-like" appear‐ ance in the iris of her left eye got more pronounced in the last 2 years. She was hospitalized once more, and another trabeculectomy was performedon the left eye near the first one, at the end of which the two filtering blebs (an original and a just manufactured) were merged into one. She was discharged with an IOP of 12mmHg; the left eye was no longer attacked after this trabeculectomy, and the IOP kept stable.(Clinical data see Figure 18)

mmHg; two mutton-fat like KP in the left eye ; shallow anterior chamber and angle multiple adhesions in both eyes; several trace of laser therapy on iris of her both eye, the only peetrated hole on the right eye be covered with fibrous membrane, and that on the left eye be too small; cup/disc ratios R 0.4and L 0.8.A diagnosis of "binocular PACG complicated with PSS in left eye" was established. A complementary laser therapy was given to her right eye just at that moment; after this laser therapy, her right had been kept well until now with only the help of 2% Carteolol Hydrochloride eye drops twice a day. Three weeks later, when this attack of PSS faded away, she was hospitalized in our hospital, and a trabeculectomy was performed on her left eye, and she was discharged 10 days after a IOP of 14mmHg. Six weeks after the surgery, an attack of PSS occurred with a IOP of 32mmHg and lasted a week; such attack occurred once or twice a year after that with a maximal IOP of 25mmHg. The IOP in intermission had maintained near 15mmHg during the first 4 years, but the result of 24h IOP measurement showed 13~20mmHg in the right eye and 15~24mmHg in the left eye. Iris heterochromia appeared in the left eye. Such a therapeutic schedule was established and kept 3 years since then: 2% Carteolol Hydrochloride Eye Drops twice a day to the both eye in intermission of PSS; 2% Carteolol twice a day plus brimonidine 3 times a day with shortly use of Lotemax for

**Figure 17.** Typical clinical data of patient (Clinical number :406013)with diagnosis of right PSS combined with binocu‐ lar PACG and treatment with classical trabeculectomy.The visual field show advanced glaucoma damange (A),OCT(C)

also shows retinal nerve fiber layer defect.UBM indicate binocular closed angle(B).

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**Figure 18.** Typical clinical data of patient (Clinical number :341555)with diagnosis of left PSS combined with binocular closed-angle glaucoma. The visual fields of right eye(A) and left eye(B) become worse 4years later(C) and (D),UBM in‐ dicate binocular aqueous humour outflow after the 1 st trabeculectomy(E) and the OCT results show serious retinal nerve fiber layer defect in left eye(F).

### **3. Differential diagnosis and main points in diagnosis and treatment of complications of PSS**

On the one hand, PSS is often misdiagnosed as other diseases, other diseases are often misdiagnosed as PSS; on the other hand, PSS can also be merged with or cause other diseases. Although the differential diagnosis of these conditions is complex, but we should be able to complete the work well through a careful clinical observation and analyzation rely on the basic characteristics of PSS described by Posner and Schlossman and new discoveries introduced above.,,. Figure 18. Typical clinical data of patient (Clinical number :341555)with diagnosis of left PSS combined with binocular closed-angle glaucoma. The visual fields of right eye(A) and left eye(B) become worse 4years later(C) and (D),UBM indicate binocular aqueous humour outflow after the 1 st trabeculectomy(E) and the OCT results show serious retinal nerve fiber layer defect in left eye(F). 4 Differential diagnosis and main points in diagnosis and treatment of complications of

#### **3.1. The differential diagnosis of PSS and other diseases.** PSS On the one hand, PSS is often misdiagnosed as other diseases, other diseases are often

#### *3.1.1. Analysis the situation of misdiagnosis* misdiagnosed as PSS; on the other hand, PSS can also be merged with or cause other diseases. Although the differential diagnosis of these conditions is complex, but we should be able to

There were a total of 37 articles about misdiagnosis of PSS among the domestic documents about PSS since 1990. Here are the results of our analysis of these documents. complete the work well through a careful clinical observation and analyzation rely on the basic characteristics of PSS described by Posner and Schlossman and new discoveries introduced

**1.** Other diseases misdiagnosed as PSS above., ,. 4.1 The differential diagnosis of PSS and other diseases.

There were 5 cases in which Fuchs syndrome was misdiagnosed as PSS, in 5 cases viral keratitis misdiagnosed as PSS and in 4 cases acute retinal necrosis misdiagnosed as PSS. 4.1.1 Analysis the situation of misdiagnosis There were a total of 37 articles about misdiagnosis of PSS among the domestic documents about

**2.** PSS misdiagnosed as other diseases PSS since 1990. Here are the results of our analysis of these documents. (1)Other diseases misdiagnosed as PSS

There were 76 cases of PSS misdiagnosed as acute angle-closure glaucoma, 42 misdiagnosed as iridocyclitis, 42 cases misdiagnosed as primary open-angle glaucoma, 22 cases misdiag‐ nosed as uveitis, 4 cases misdiagnosed as conjunctivitis, 4 cases misdiagnosed as Fuch's syndrome, 1 case misdiagnosed as high intraocular pressure and1 case misdiagnosed as keratitis. There were 5 cases in which Fuchs syndrome was misdiagnosed as PSS,in 5 cases viral keratitis misdiagnosed as PSS and in 4 cases acute retinal necrosis misdiagnosed as PSS.(2)PSS misdiagnosed as other diseases There were 76 cases of PSS misdiagnosed as acute angle-closure glaucoma, 42 misdiagnosed as iridocyclitis, 42 cases misdiagnosed as primary open-angle glaucoma, 22 cases misdiagnosed as uveitis, 4 cases misdiagnosed as conjunctivitis, 4 cases misdiagnosed as Fuch 's syndrome, 1 case

(3)About the harms of misdiagnosis for the patients.PSS patients were misdiagnosed as primary glaucoma and inappropriate treated, even the surgery that should not be done had been performed.

misdiagnosed as high intraocular pressure and1 case misdiagnosed as keratitis.


**3.** About the harms of misdiagnosis for the patients.PSS patients were misdiagnosed as primary glaucoma and inappropriate treated, even the surgery that should not be done had been performed. Primary glaucoma merged with PSS were missed diagnosis, result in the lost the optimal timing of treatment. Such diseases as Fuch's syndrome, acute retinal necrosis and viral keratitis were misdiagnosed as PSS, lead to the delay of treatment.

**PSS POAG PCAG**

Affected eye most most binocular binocular, usually

usually binocular and centrally

Related to C value no matter

intermission both eyes are normal invariably Invariably or paroxysmal

IOP is high or low

**1.** The differential diagnosis of PSS and other glaucomaThe differential diagnosis between PSS and POAG or PACG can be carried out in reference to table 7. [23 24, 27, 28, 40]

**Iridocyclitis:** Ciliary hyperemia, eyesight drops significantly, smaller KP, aqueous humor of

**Choroiditis:** significantly dropped vision, with or without KP, vitreous of turbidity, no iris adhesion usually, lower IOP, corresponding pathological changes in retinal and choroiditis. **All uveitis:** ciliary hyperemia, significantly dropped vision, KP in most cases, muddy aqueous humor, vitreous of turbidity, fast and heavy adhesion of iris, higher or lower IOP, correspond‐

**Intermediate uveitis:** a kind of uveitis limited in the pars plana of ciliary body, peripheral retina and vitreous base, without any clinical symptoms in some cases or with muscae volitantes, blurred vision and temporary myopia in most cases, normal or mild declined vision in most cases but significant vision loss in case with cystoid macular edema and other

pigmented KP sometimes

No in chronic cases, Yes in acute cases sometimes after an outburst

Related to C value only when IOP is high

after a outburst

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or closed

located more binocular, often irregular

age at first onset usually under the age of 50 years middle-aged or older

KP Yes, accompany with elevated IOP No

Visual field damage Little and light, more began in the peripheral, usually

IOP cross Yes No

IOP is high or low

**The characteristics of common uveitis**

In episodes the is normal, in

Not related to C value no matter

**2.** The differential diagnosis of PSS and other uveitis

ing pathological changes in retinal and choroiditis.

**Table 6.** The key points about differential diagnosis between PSS and POAG or PACG

*3.1.2. The differential diagnosis of several kinds of common diseases*

turbidity, fast and heavy adhesion of iris, higher or lower IOP.

Anterior chamber

angle

IOP

postrualar IOP change

Figure 19. Number of cases of PSS misdiagnosed as other diseases **Figure 19.** Number of cases of PSS misdiagnosed as other diseases

**3.** About the harms of misdiagnosis for the patients.PSS patients were misdiagnosed as primary glaucoma and inappropriate treated, even the surgery that should not be done had been performed. Primary glaucoma merged with PSS were missed diagnosis, result in the lost the optimal timing of treatment. Such diseases as Fuch's syndrome, acute retinal necrosis and viral keratitis were misdiagnosed as PSS, lead to the delay of treatment.


**Table 6.** The key points about differential diagnosis between PSS and POAG or PACG

### *3.1.2. The differential diagnosis of several kinds of common diseases*


#### **The characteristics of common uveitis**

**3. Differential diagnosis and main points in diagnosis and treatment of**

On the one hand, PSS is often misdiagnosed as other diseases, other diseases are often misdiagnosed as PSS; on the other hand, PSS can also be merged with or cause other diseases. Although the differential diagnosis of these conditions is complex, but we should be able to complete the work well through a careful clinical observation and analyzation rely on the basic characteristics of PSS described by Posner and Schlossman and new discoveries introduced

Figure 18. Typical clinical data of patient (Clinical number :341555)with diagnosis of left PSS combined with binocular closed-angle glaucoma. The visual fields of right eye(A) and left eye(B) become worse 4years later(C) and (D),UBM indicate binocular aqueous humour outflow after the 1 st trabeculectomy(E) and the OCT results show serious retinal nerve fiber layer defect in left

4 Differential diagnosis and main points in diagnosis and treatment of complications of

On the one hand, PSS is often misdiagnosed as other diseases, other diseases are often misdiagnosed as PSS; on the other hand, PSS can also be merged with or cause other diseases. Although the differential diagnosis of these conditions is complex, but we should be able to complete the work well through a careful clinical observation and analyzation rely on the basic characteristics of PSS described by Posner and Schlossman and new discoveries introduced

There were a total of 37 articles about misdiagnosis of PSS among the domestic documents

There were 5 cases in which Fuchs syndrome was misdiagnosed as PSS, in 5 cases viral keratitis

There were a total of 37 articles about misdiagnosis of PSS among the domestic documents about

There were 5 cases in which Fuchs syndrome was misdiagnosed as PSS,in 5 cases viral keratitis misdiagnosed as PSS and in 4 cases acute retinal necrosis misdiagnosed as PSS.(2)PSS

There were 76 cases of PSS misdiagnosed as acute angle-closure glaucoma, 42 misdiagnosed as iridocyclitis, 42 cases misdiagnosed as primary open-angle glaucoma, 22 cases misdiagnosed as uveitis, 4 cases misdiagnosed as conjunctivitis, 4 cases misdiagnosed as Fuch 's syndrome, 1 case

> 1. misdiagnosed as acute angle-closure glaucoma 2. misdiagnosed as iridocyclitis 3. misdiagnosed as POAG 4. misdiagnosed as uveitis 5. misdiagnosed as conjunctivitis 6. misdiagnosed as Fuch 's syndrome

7. misdiagnosed as high intraocular

8. misdiagnosed as keratitis

pressure

(3)About the harms of misdiagnosis for the patients.PSS patients were misdiagnosed as primary glaucoma and inappropriate treated, even the surgery that should not be done had been performed.

There were 76 cases of PSS misdiagnosed as acute angle-closure glaucoma, 42 misdiagnosed as iridocyclitis, 42 cases misdiagnosed as primary open-angle glaucoma, 22 cases misdiag‐ nosed as uveitis, 4 cases misdiagnosed as conjunctivitis, 4 cases misdiagnosed as Fuch's syndrome, 1 case misdiagnosed as high intraocular pressure and1 case misdiagnosed as

about PSS since 1990. Here are the results of our analysis of these documents.

4.1 The differential diagnosis of PSS and other diseases.

misdiagnosed as PSS and in 4 cases acute retinal necrosis misdiagnosed as PSS.

misdiagnosed as high intraocular pressure and1 case misdiagnosed as keratitis.

Figure 19. Number of cases of PSS misdiagnosed as other diseases

**Figure 19.** Number of cases of PSS misdiagnosed as other diseases

PSS since 1990. Here are the results of our analysis of these documents.

**3.1. The differential diagnosis of PSS and other diseases.**

*3.1.1. Analysis the situation of misdiagnosis*

**1.** Other diseases misdiagnosed as PSS

4.1.1 Analysis the situation of misdiagnosis

(1)Other diseases misdiagnosed as PSS

**2.** PSS misdiagnosed as other diseases

misdiagnosed as other diseases

**complications of PSS**

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eye(F).

PSS

above., ,.

above.,,.

keratitis.

**Iridocyclitis:** Ciliary hyperemia, eyesight drops significantly, smaller KP, aqueous humor of turbidity, fast and heavy adhesion of iris, higher or lower IOP.

**Choroiditis:** significantly dropped vision, with or without KP, vitreous of turbidity, no iris adhesion usually, lower IOP, corresponding pathological changes in retinal and choroiditis.

**All uveitis:** ciliary hyperemia, significantly dropped vision, KP in most cases, muddy aqueous humor, vitreous of turbidity, fast and heavy adhesion of iris, higher or lower IOP, correspond‐ ing pathological changes in retinal and choroiditis.

**Intermediate uveitis:** a kind of uveitis limited in the pars plana of ciliary body, peripheral retina and vitreous base, without any clinical symptoms in some cases or with muscae volitantes, blurred vision and temporary myopia in most cases, normal or mild declined vision in most cases but significant vision loss in case with cystoid macular edema and other complications or sudden severe vision loss in case with acute vitreous hemorrhage, retinal detachment,, mild to moderate anterior segment inflammation in most cases but severe ciliary hyperemia, a large number of KP, obvious aqueous flare and a lot of inflammatory cells in the anterior chamber in a few cases at first onset with severe anterior segment reaction occasion‐ ally, change in the vitreous and the pars plana of ciliary body (the most common and important performance of the disease) such as vitreous inflammatory cells, snow ball turbidity due to cell agglutination, snowbank like lesion stretches from the pars plana and vitreous base into vitreous cavity, vitreous degeneration, hemorrhage and hyperplastic vitreous retinopathy at late stage, a variety of retinopathy, such as macular edema, diffuse retinal edema, retinal vasculitis and perivascular inflammation, exudation, hemorrhage, retinal neovascularization, hyperplastic retinopathy, retinal detachment, usually normal IOP in early time but a persistent high IOP once elevated, sporadic KP with no association with IOP.

**3.** The differential diagnosis of PSS and keratitis

### **Keratitis**

**Sign** Obvious hyperaemia, matrix and endothelial change, KP with different forms mainly distributed in lesion site of the cornealand seldom inhealthy area.

**Characteristics** The eye with angle-closure glaucoma induced by keratitis have the basic characteristics of angle-closure glaucoma; A monocular open-angle glaucoma would occurred in the affected eye if keratitis spread to the trabecular meshwork with an intraocular pressure changes over the cornea edema.

Course of disease:They are not self-limited and repeated outbreaks tend to occur.

### **3.2. Main points in diagnosis and treatment of complications of PSS**

Other kinds of glaucoma which PSS concurred with or lead to were not introduced before. PSS can also concur with or cause iris heterochromia, ischemic optic neuropathy, complicated cataract and other diseases, such as retinal detachment. Main points in diagnosis and treatment of these complications were briefly introduced as follows:

both eyes, IOP 17/15(R/L)mmHg, a lot of small lipid-like KP in the inferior of the left cornea, "rain dozen sand-like" appearance in the iris of his left eye, C/D rate 0.6/0.7(R/L),CCT 553/560(R/L). Results of his visual field and OCT showed in Figure below. UBM showed wideangle in the both eyes. Fundus fluorescein angiography and contrast sensitivity revealed no special finds. 24 hours IOP measurements (2 weeks after KP disappeared): 13~16/ 12~15(R/ L)mmHg. Diagnosis of "PSS complicated with iris heterochromia" for his left eye was confirmed than. He was asked to treat every onset of the disease in time with drugs dropping

**Figure 20.** Typical clinical data of patient (ID :11041302)with diagnosis of left PSS combined with iris heterochromia. The visual fields of left eye show nasal defect (A) ,binocular OCTresults indicate ocular cups expand (B)and (C) obvious

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**Case 2)** A patient was admitted to our hospital because her right eye suffered from repeated episodes of pain with blurred vision for more than nine years, and her vision decreased 3 months, with a primary diagnosis of "secondary glaucoma" for her right eye. A lot of inter‐ mittent recurrent pain and blurred vision had attacked her right eye from nine years ago, 2 or 3 times a year. Each attack lasted about one week, than resolved spontaneously. Three months ago her sense of vision went to recession. She felt that her right eye was attacked again recent days, so she can to our hospital. Ophthalmologic examination in this time showed: visual

IOP as well as anti-inflammatory medicine. (Clinical data see Figure 20)

retinal nerve fiber layer defect (C).

#### *3.2.1. PSS combined with iris heterochromia*

### **Typical cases**

Case 1) A patient consulted at our hospital because his left eye suffered from intermittent recurrent pain and blurred vision for more than one year. Intraday examinations showed: best corrected visual acuity is 1.0/ 0.6(R/L), IOP: 16.7/ 13.7(R/L) mmHg, FFA in both eyes are normal, optic cup in his left eye is expand. He was suspected of glaucoma. Intermittent recurrent pain and blurred vision kept to attack his left eye for more than half a year after then. These attacks usually ceased a few days late, with or without the help of 0.5% timolol eye drop and other drugs. During this period, the highest IOP record of his left eye was 35mmHg with a normal record of his right eye. The patient returned to our hospital one year later after stopping use of any drugs for two weeks. Ophthalmologic examination at this time showed: visual acuity1.2

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complications or sudden severe vision loss in case with acute vitreous hemorrhage, retinal detachment,, mild to moderate anterior segment inflammation in most cases but severe ciliary hyperemia, a large number of KP, obvious aqueous flare and a lot of inflammatory cells in the anterior chamber in a few cases at first onset with severe anterior segment reaction occasion‐ ally, change in the vitreous and the pars plana of ciliary body (the most common and important performance of the disease) such as vitreous inflammatory cells, snow ball turbidity due to cell agglutination, snowbank like lesion stretches from the pars plana and vitreous base into vitreous cavity, vitreous degeneration, hemorrhage and hyperplastic vitreous retinopathy at late stage, a variety of retinopathy, such as macular edema, diffuse retinal edema, retinal vasculitis and perivascular inflammation, exudation, hemorrhage, retinal neovascularization, hyperplastic retinopathy, retinal detachment, usually normal IOP in early time but a persistent

**Sign** Obvious hyperaemia, matrix and endothelial change, KP with different forms mainly

**Characteristics** The eye with angle-closure glaucoma induced by keratitis have the basic characteristics of angle-closure glaucoma; A monocular open-angle glaucoma would occurred in the affected eye if keratitis spread to the trabecular meshwork with an intraocular pressure

Other kinds of glaucoma which PSS concurred with or lead to were not introduced before. PSS can also concur with or cause iris heterochromia, ischemic optic neuropathy, complicated cataract and other diseases, such as retinal detachment. Main points in diagnosis and treatment

Case 1) A patient consulted at our hospital because his left eye suffered from intermittent recurrent pain and blurred vision for more than one year. Intraday examinations showed: best corrected visual acuity is 1.0/ 0.6(R/L), IOP: 16.7/ 13.7(R/L) mmHg, FFA in both eyes are normal, optic cup in his left eye is expand. He was suspected of glaucoma. Intermittent recurrent pain and blurred vision kept to attack his left eye for more than half a year after then. These attacks usually ceased a few days late, with or without the help of 0.5% timolol eye drop and other drugs. During this period, the highest IOP record of his left eye was 35mmHg with a normal record of his right eye. The patient returned to our hospital one year later after stopping use of any drugs for two weeks. Ophthalmologic examination at this time showed: visual acuity1.2

Course of disease:They are not self-limited and repeated outbreaks tend to occur.

**3.2. Main points in diagnosis and treatment of complications of PSS**

of these complications were briefly introduced as follows:

*3.2.1. PSS combined with iris heterochromia*

high IOP once elevated, sporadic KP with no association with IOP.

distributed in lesion site of the cornealand seldom inhealthy area.

**3.** The differential diagnosis of PSS and keratitis

510 Ophthalmology - Current Clinical and Research Updates

changes over the cornea edema.

**Keratitis**

**Typical cases**

**Figure 20.** Typical clinical data of patient (ID :11041302)with diagnosis of left PSS combined with iris heterochromia. The visual fields of left eye show nasal defect (A) ,binocular OCTresults indicate ocular cups expand (B)and (C) obvious retinal nerve fiber layer defect (C).

both eyes, IOP 17/15(R/L)mmHg, a lot of small lipid-like KP in the inferior of the left cornea, "rain dozen sand-like" appearance in the iris of his left eye, C/D rate 0.6/0.7(R/L),CCT 553/560(R/L). Results of his visual field and OCT showed in Figure below. UBM showed wideangle in the both eyes. Fundus fluorescein angiography and contrast sensitivity revealed no special finds. 24 hours IOP measurements (2 weeks after KP disappeared): 13~16/ 12~15(R/ L)mmHg. Diagnosis of "PSS complicated with iris heterochromia" for his left eye was confirmed than. He was asked to treat every onset of the disease in time with drugs dropping IOP as well as anti-inflammatory medicine. (Clinical data see Figure 20)

**Case 2)** A patient was admitted to our hospital because her right eye suffered from repeated episodes of pain with blurred vision for more than nine years, and her vision decreased 3 months, with a primary diagnosis of "secondary glaucoma" for her right eye. A lot of inter‐ mittent recurrent pain and blurred vision had attacked her right eye from nine years ago, 2 or 3 times a year. Each attack lasted about one week, than resolved spontaneously. Three months ago her sense of vision went to recession. She felt that her right eye was attacked again recent days, so she can to our hospital. Ophthalmologic examination in this time showed: visual

chamber was not shallow, ultrasound biomicroscopy (UBM) showed a wide angle in both eye. Her left eye showed no KP with a C/D less 0.3. Her systemic examination and routine inspec‐ tion and examination showed no special finds. Treatment with drugs dropping IOP such as carteolol and brimonidine and mannitol as well as steroids loteprednol kept about a week, KP significantly reduced but the intraocular pressure is still high. Operation of Ahmed valve implantation was performed on her right eye two weeks later. She was discharged a week postoperative with an IOP of 9mmHg in the operated eye. Her IOP was controlled well with fewer attacks of PSS and a stable visual field in the recent 3 years after the surgery. (Clinical

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**Figure 22.** Typical clinical data of patient (Clinical number :437614)with diagnosis of right PSS combined with iris dis‐ order. The right eye is after Ahmed implantation and arrow indicate iris heterochromia(A),the left eye is nor‐

mal(B).UBM indicate a wild angle in right eye (C),but the visual field show serious damanges in right eye(D).

data see Figure 21)

**Figure 21.** Typical clinical data of patient (ID :11041302)with diagnosis of left PSS combined with iris heterochromia. The visual fields of left eye show nasal defect(A),binocular OCT results indicate ocular cups expand(B) and (C) obvious retinal nerve fiber layer defect (C).

acuity: 0.15/ 1.0(R/L), IOP: 43/12(R/L) mmHg, mist edema in her cornea of her right eye with a lot of fat-like KP, pale and "rain scatting beach-like" appearance in her left iris with a round pupil about 3mm in diameter, her optic disk appeared pale in color with a C/D 0.9, her anterior chamber was not shallow, ultrasound biomicroscopy (UBM) showed a wide angle in both eye. Her left eye showed no KP with a C/D less 0.3. Her systemic examination and routine inspec‐ tion and examination showed no special finds. Treatment with drugs dropping IOP such as carteolol and brimonidine and mannitol as well as steroids loteprednol kept about a week, KP significantly reduced but the intraocular pressure is still high. Operation of Ahmed valve implantation was performed on her right eye two weeks later. She was discharged a week postoperative with an IOP of 9mmHg in the operated eye. Her IOP was controlled well with fewer attacks of PSS and a stable visual field in the recent 3 years after the surgery. (Clinical data see Figure 21)

**Figure 22.** Typical clinical data of patient (Clinical number :437614)with diagnosis of right PSS combined with iris dis‐ order. The right eye is after Ahmed implantation and arrow indicate iris heterochromia(A),the left eye is nor‐ mal(B).UBM indicate a wild angle in right eye (C),but the visual field show serious damanges in right eye(D).

acuity: 0.15/ 1.0(R/L), IOP: 43/12(R/L) mmHg, mist edema in her cornea of her right eye with a lot of fat-like KP, pale and "rain scatting beach-like" appearance in her left iris with a round pupil about 3mm in diameter, her optic disk appeared pale in color with a C/D 0.9, her anterior

**Figure 21.** Typical clinical data of patient (ID :11041302)with diagnosis of left PSS combined with iris heterochromia. The visual fields of left eye show nasal defect(A),binocular OCT results indicate ocular cups expand(B) and (C) obvious

retinal nerve fiber layer defect (C).

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### **Discussion**

**1.** Clinical performance of PSS complicated with iris heterochromia

Four cases of PSS complicated with iris heterochromia were reported [40]. They were two males and two females aged 35 to 45 years. In addition to typical PSS performance, the iris showed "rain scatting sand-like" appearance in all of the 4 patients. All of them are monocular repeatedly attacked at the same eye. Each attack kept 3 to 7 days with a significantly increased IOP up to30.00 ~ 60.00mnHg and a few of fat-like KP, than relieve itself or extinct with the help of medication. Intraocular pressure (including 24 hours intraocular pressure) in intermittent period appeared normal after discontinuation of all medication with a typical crossed-over phenomenon.

the cornea, usually disappeared naturally within a few days after or before IOP reduction. On the contrary, KP in patients with Fuchs syndrome has different characteristics as following: persistence for very long time even always in most cases, white transparent small dot or starlike coexisting with pigmented KP, diffuse distribution in the cornea, sometimes connected each other with fibrous filaments, poor response to corticosteroids therapy. (Clinical data see

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**Figure 23.** Heterochromatic iris and KP in FHI. There is a typical iris such as "rain dozen sand-like"(A) arrow shows a lot

Fuchs syndrome complicated with cataract is common at later stage; however the complicated

Glaucomatous damage in PSS cases appeared later and to a lesser extent, however that of FH

A patient came to our hospital because her vision of the left eye sudden dropped 2 months ago. She was examined 2 months ago: visual acuity: 1.0/ 0.5(R/L) IOP: 17.3/ 15(R/L) mmHg. The optic disc of her left eye was pale, visual field showed an inferior fan like defect. Fundus fluorescein angiography(FFA) of her left eye showed ischemic optic neuropathy. The anterior segment, fundus, vision, and FFA of her right eye were normal. She was diagnosed as "left eye ischemic optic neuropathy". She was admitted to our hospital, and examinations showed: visual acuity: 1.0/ 0.15(R/L). IOP: 17.3/ 50.62(R/L), anterior chamber of both eyes were not shallow, Right eye showed no abnormality. Left cornea had mild edema and there was a medium size fat-like KP below the pupil. The boundary of optic papillae in left eye was clear, the color was off white, and the C / D was about 0.3,the angle of left eye was N1 ~ N2. Systemic

cataract is uncommon in the PSS cases with iris heterochromia.

**(5) Glaucomatous retinal and visual damage**

*3.2.2. PSS combined with ischemic optic neuropathy*

cases occur earlier and quicker.

Figure 22)

of star-like KPs(B).

**Typical cases**

**(4) Lens situation**

**2.** Key-points in the differential diagnosis between PSS complicated with iris heterochro‐ matic and FHI (Fuchs heterochromic iridicyclitis).The two diseases are different clinically in the following five aspects: the attacked eye and sex of patients, manifestation of intraocular pressure, character of KP, appearance of the Lens and glaucomatous damage of optic nerve and visual field.

### **(1) The attacked eye and sex of patients**

Most of PSS cases had monocular presentation, a few of cases were binocular, but usually one eye was affected at a time, in extremely rare cases was binocularly attacked simultaneously. Male patients were more common than female in PSS. FH is generally believed that no gender more predisposed than the other more than 90% of the cases were monocularly affected.

#### **(2) Manifestation of intraocular pressure**

The IOP in patients of PSS with iris heterochromatic appeared as an intermittent and abruptly rising when the attack comes with the appearance of typical KP in pure PSS patients. IOP elevation in patients of PSS with iris heterochromatic usually lasted 3 ~ 10days, and then turned to subside spontaneously with the disappearance of the KP after this period, it is also sensitive to drugs dropping IOP and anti-inflammatory medicine. On the contrary, IOP of patient with FH appeared normal in the initial stage for a long time, after that, elevated in part of the cases gradually; however, once the intraocular pressure elevated, it often appeared persistently higher, although there maybe some fluctuations. The elevated IOP and KP in patient with FH had no characteristic of intermittent, were difficult to be controlled and poorly responded to corticosteroids therapy. The IOP in patients with PSS complicated with iris heterochromia kept the characteristic of crossed-over, that is, the IOP of the attacked eye was higher than that of contra lateral eye during the episode but lower(3 ~ 5mmHg) than the other eye between attacks. IOP in patients with Fuchs syndrome had no such characteristic, once elevated; it is always higher if untreated.

### **(3) Keratic Precipitates**

The KP in patient with PSS complicated with iris heterochromia appeared only in a short period during the attack in most cases. This KP is of following characteristics: small round suet-like, medium sized, isolated, with no pigment in initial stage, mainly located in the lower part of the cornea, usually disappeared naturally within a few days after or before IOP reduction. On the contrary, KP in patients with Fuchs syndrome has different characteristics as following: persistence for very long time even always in most cases, white transparent small dot or starlike coexisting with pigmented KP, diffuse distribution in the cornea, sometimes connected each other with fibrous filaments, poor response to corticosteroids therapy. (Clinical data see Figure 22)

**Figure 23.** Heterochromatic iris and KP in FHI. There is a typical iris such as "rain dozen sand-like"(A) arrow shows a lot of star-like KPs(B).

#### **(4) Lens situation**

**Discussion**

phenomenon.

higher if untreated.

**(3) Keratic Precipitates**

of optic nerve and visual field. **(1) The attacked eye and sex of patients**

514 Ophthalmology - Current Clinical and Research Updates

**(2) Manifestation of intraocular pressure**

**1.** Clinical performance of PSS complicated with iris heterochromia

Four cases of PSS complicated with iris heterochromia were reported [40]. They were two males and two females aged 35 to 45 years. In addition to typical PSS performance, the iris showed "rain scatting sand-like" appearance in all of the 4 patients. All of them are monocular repeatedly attacked at the same eye. Each attack kept 3 to 7 days with a significantly increased IOP up to30.00 ~ 60.00mnHg and a few of fat-like KP, than relieve itself or extinct with the help of medication. Intraocular pressure (including 24 hours intraocular pressure) in intermittent period appeared normal after discontinuation of all medication with a typical crossed-over

**2.** Key-points in the differential diagnosis between PSS complicated with iris heterochro‐ matic and FHI (Fuchs heterochromic iridicyclitis).The two diseases are different clinically in the following five aspects: the attacked eye and sex of patients, manifestation of intraocular pressure, character of KP, appearance of the Lens and glaucomatous damage

Most of PSS cases had monocular presentation, a few of cases were binocular, but usually one eye was affected at a time, in extremely rare cases was binocularly attacked simultaneously. Male patients were more common than female in PSS. FH is generally believed that no gender more predisposed than the other more than 90% of the cases were monocularly affected.

The IOP in patients of PSS with iris heterochromatic appeared as an intermittent and abruptly rising when the attack comes with the appearance of typical KP in pure PSS patients. IOP elevation in patients of PSS with iris heterochromatic usually lasted 3 ~ 10days, and then turned to subside spontaneously with the disappearance of the KP after this period, it is also sensitive to drugs dropping IOP and anti-inflammatory medicine. On the contrary, IOP of patient with FH appeared normal in the initial stage for a long time, after that, elevated in part of the cases gradually; however, once the intraocular pressure elevated, it often appeared persistently higher, although there maybe some fluctuations. The elevated IOP and KP in patient with FH had no characteristic of intermittent, were difficult to be controlled and poorly responded to corticosteroids therapy. The IOP in patients with PSS complicated with iris heterochromia kept the characteristic of crossed-over, that is, the IOP of the attacked eye was higher than that of contra lateral eye during the episode but lower(3 ~ 5mmHg) than the other eye between attacks. IOP in patients with Fuchs syndrome had no such characteristic, once elevated; it is always

The KP in patient with PSS complicated with iris heterochromia appeared only in a short period during the attack in most cases. This KP is of following characteristics: small round suet-like, medium sized, isolated, with no pigment in initial stage, mainly located in the lower part of Fuchs syndrome complicated with cataract is common at later stage; however the complicated cataract is uncommon in the PSS cases with iris heterochromia.

### **(5) Glaucomatous retinal and visual damage**

Glaucomatous damage in PSS cases appeared later and to a lesser extent, however that of FH cases occur earlier and quicker.

### *3.2.2. PSS combined with ischemic optic neuropathy*

### **Typical cases**

A patient came to our hospital because her vision of the left eye sudden dropped 2 months ago. She was examined 2 months ago: visual acuity: 1.0/ 0.5(R/L) IOP: 17.3/ 15(R/L) mmHg. The optic disc of her left eye was pale, visual field showed an inferior fan like defect. Fundus fluorescein angiography(FFA) of her left eye showed ischemic optic neuropathy. The anterior segment, fundus, vision, and FFA of her right eye were normal. She was diagnosed as "left eye ischemic optic neuropathy". She was admitted to our hospital, and examinations showed: visual acuity: 1.0/ 0.15(R/L). IOP: 17.3/ 50.62(R/L), anterior chamber of both eyes were not shallow, Right eye showed no abnormality. Left cornea had mild edema and there was a medium size fat-like KP below the pupil. The boundary of optic papillae in left eye was clear, the color was off white, and the C / D was about 0.3,the angle of left eye was N1 ~ N2. Systemic examination such as X-ray, electrocardiogram and routine laboratory tests were normal. Visual field of right eye was normal and that of the left eye showed a centripetal narrow with an inferior fan like defect. She was diagnosed as "Left eye PSS, complicated with ischemic optic neuropathy", and treated with drugs for reducing IOP and nutrition curing to optic nerve for about a weak. She was discharged with IOP 12mmHg disappeared KP, vision 0.2 of her left eye. (Clinical data see Figure 23)

to 29 mmHg 3 days after hospitalization and a fat-like KP appeared in his right eye, than he was diagnosed as rhegmatogenous retinal detachment combined with PSS. Retinal detach‐ ment surgery (Condensation+cerclage+scleral pressure technique) were done after reducing IOP with the treatment of drugs. Postoperative recovery was good. PSS recurred 4 months

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The pathogenesis of PSS combined with rhegmatogenous retinal detachment is unknown. Increased concentration of PG (especially PGE) resulted from retinal S-antigen entered into the vitreous cavity after blood-eye barrier breakdown during the formation of retinal breaks may leads to the inflammation of the uvea, and the higher concentration of PGs and inflam‐

A patient complained of recurrent pain and decreased vision of her right eye for four years. Results of examinations intraday showed: visual acuity:0.08/ 0.4(R/L); corrected visual acuityR: 0.3(-0.75DS/1.50DC\*111),L: 0.9(-1.25DS/-0.50DC\*83) ;IOP: 12/ 14(R/L) mmHg; a few of time worn pigmented KP on the central and lower part of her clear corneal; round pupil about3mm in diameter; normal iris, opacification of posterior capsule of lens; C/D of optic papillaeo.4.Her left eye appeared normal. She was hospitalized with the diagnosis of PSS and was treated with carteolol, brimonidine, mannitol for reducing IOP, tobradex for anti-inflammation and methycobal to maintain optic nerve. She was discharged once the attack of PSS faded away every time. The PSS attacked her1 to 2 month a time, her vision of right eye declined gradually

**Figure 25.** Anterior segment slit-lamp photography of patient (Clinical number 394998) with the diagnosis of PSS combined with cataract.Arrows show an opacities area at posterior capsule (A) and few typical fat-shaped KPs(B).

later and recovered 5 days late.

*3.2.4. PSS combined with cataract*

matory products results in the IOP elevation.

without other discomfort. (Clinical data see Figure 24)

**Discussion**

**Typical cases**

**Figure 24.** visual field of patient (Clinical number :294450) The case suffered from left eye PSS combined with ische‐ mic optic neuropathy. inferior visual field defect and serious contraction of left(A),and that of the normal right eye(B).

### **Discussion**

In 2003 1 case of PSS complicated with non-arteritic anterior ischemic optic neuropathy (AION) was reported. The vision of the case improved significantly after the attack of PSS had been controlled, but the vision and optic neuropathy damaged continually. The authors emphasized that the IOP of PSS patients complicated with AION should be promptly controlled as it is one of the risk factors [41]. It is useful to use drugs with dual role of reducing IOP and improving retinal blood supply in intermittent period. Our case appeared a sudden vision loss and significant discomfort two months ago. The result of examinations in other hospital such as visual field defect of arcuate below and FFA supported the diagnosis of left eye ischemic optic neuropathy. Results of examinations, reaction to treatment and course of the disease during her hospitalization in our hospital In July 2000 conformed with diagnostic criteria of PSS. The structure of the optic nerve, damage of blood vessels and blood state are related to ischemic optic neuropathy, the severely sudden rising of IOP during attack of PSS maybe the inducing factors. So it is necessary to reduce the IOP during each attack of PSS as soon and effective as possible for the cases of PSS combined with ischemic optic neuropathy or with the risk factors for that.

#### *3.2.3. PSS combined with rhegmatogenous retinal detachment*

#### **Typical cases**

A patient was hospitalized in our hospital for the reason that there was shadow before his right eye with a diagnose of rhegmatogenous retinal detachment. The IOP of his right eye elevated to 29 mmHg 3 days after hospitalization and a fat-like KP appeared in his right eye, than he was diagnosed as rhegmatogenous retinal detachment combined with PSS. Retinal detach‐ ment surgery (Condensation+cerclage+scleral pressure technique) were done after reducing IOP with the treatment of drugs. Postoperative recovery was good. PSS recurred 4 months later and recovered 5 days late.

### **Discussion**

examination such as X-ray, electrocardiogram and routine laboratory tests were normal. Visual field of right eye was normal and that of the left eye showed a centripetal narrow with an inferior fan like defect. She was diagnosed as "Left eye PSS, complicated with ischemic optic neuropathy", and treated with drugs for reducing IOP and nutrition curing to optic nerve for about a weak. She was discharged with IOP 12mmHg disappeared KP, vision 0.2 of her left

**Figure 24.** visual field of patient (Clinical number :294450) The case suffered from left eye PSS combined with ische‐ mic optic neuropathy. inferior visual field defect and serious contraction of left(A),and that of the normal right eye(B).

In 2003 1 case of PSS complicated with non-arteritic anterior ischemic optic neuropathy (AION) was reported. The vision of the case improved significantly after the attack of PSS had been controlled, but the vision and optic neuropathy damaged continually. The authors emphasized that the IOP of PSS patients complicated with AION should be promptly controlled as it is one of the risk factors [41]. It is useful to use drugs with dual role of reducing IOP and improving retinal blood supply in intermittent period. Our case appeared a sudden vision loss and significant discomfort two months ago. The result of examinations in other hospital such as visual field defect of arcuate below and FFA supported the diagnosis of left eye ischemic optic neuropathy. Results of examinations, reaction to treatment and course of the disease during her hospitalization in our hospital In July 2000 conformed with diagnostic criteria of PSS. The structure of the optic nerve, damage of blood vessels and blood state are related to ischemic optic neuropathy, the severely sudden rising of IOP during attack of PSS maybe the inducing factors. So it is necessary to reduce the IOP during each attack of PSS as soon and effective as possible for the cases of PSS combined with ischemic optic neuropathy or with the risk factors

A patient was hospitalized in our hospital for the reason that there was shadow before his right eye with a diagnose of rhegmatogenous retinal detachment. The IOP of his right eye elevated

eye. (Clinical data see Figure 23)

516 Ophthalmology - Current Clinical and Research Updates

**Discussion**

for that.

**Typical cases**

*3.2.3. PSS combined with rhegmatogenous retinal detachment*

The pathogenesis of PSS combined with rhegmatogenous retinal detachment is unknown. Increased concentration of PG (especially PGE) resulted from retinal S-antigen entered into the vitreous cavity after blood-eye barrier breakdown during the formation of retinal breaks may leads to the inflammation of the uvea, and the higher concentration of PGs and inflam‐ matory products results in the IOP elevation.

#### *3.2.4. PSS combined with cataract*

### **Typical cases**

A patient complained of recurrent pain and decreased vision of her right eye for four years. Results of examinations intraday showed: visual acuity:0.08/ 0.4(R/L); corrected visual acuityR: 0.3(-0.75DS/1.50DC\*111),L: 0.9(-1.25DS/-0.50DC\*83) ;IOP: 12/ 14(R/L) mmHg; a few of time worn pigmented KP on the central and lower part of her clear corneal; round pupil about3mm in diameter; normal iris, opacification of posterior capsule of lens; C/D of optic papillaeo.4.Her left eye appeared normal. She was hospitalized with the diagnosis of PSS and was treated with carteolol, brimonidine, mannitol for reducing IOP, tobradex for anti-inflammation and methycobal to maintain optic nerve. She was discharged once the attack of PSS faded away every time. The PSS attacked her1 to 2 month a time, her vision of right eye declined gradually without other discomfort. (Clinical data see Figure 24)

**Figure 25.** Anterior segment slit-lamp photography of patient (Clinical number 394998) with the diagnosis of PSS combined with cataract.Arrows show an opacities area at posterior capsule (A) and few typical fat-shaped KPs(B).

### **Discussion**

The possible pathogenesis: repeated onset of IOP elevation and anterior segment inflammation cause disorders of nutrition and metabolism of the lens.

[4] Paivonsalo HT, Tuminen J, Vaahtoranta LH, et al. Incidence and prevalence of differ‐

Clinical Research Progress of Glaucomatocyclitic Crisis

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519

[5] Kanjiro M. The relationship between elevation of intraocular pressure and prosta‐ glandin in cases with glaucomatocyclitic crisis. clinical ophthalmology.

[6] Yamamoto S, Pavan-Langston D, Tada R, et al. Possible role of herpes simplex viru‐ sin the origin of Posner-Schlossman syndrome. Am J Ophthalmol.1995, 119: 796-798

[7] Yang SY, Chen MJ, Chen KH, et al. Cytomegalovirus and herpes simplex virus as‐ causes of bilateral anterior uveitis in an immunocompetent patient. J Chin Med As‐

[8] Blich-Michel E, Dussaix E, Cerqueti P, et al. Possible role of cytomegalovirus infec‐ tion in the etiology of the Posner-Schlossman syndrome. IntOphthalmol.

[9] Chee SP, Jap A. Presumed Fuchs heterochromiciridocyclitis and Posner-Schlossman‐ syndrome: comparison of cytomegalovirus-positive and negative eyes.

[10] CY Choi, MS Kim, JM Kim, SH Park, KH Park, C Hong. Association between Helico‐ bacter pylori infection and Posner–Schlossman syndrome. Eye. 2010, [11] Zhi-Hui Li, Xun-ChuanJi, Shu-Chu Chen, et al. [The Long-term follow-up of PosnerSchloddman

[11] Nan-Xiang Peng. [Clinical analyzation of 52 cases with Posner Schloddman Syn‐

[12] Wen-Xue Hu. [Clinical observation of early stage of Posner-Schlossman syn‐

[13] Puri P, Verma D. Bilateral glaucomatocyclitic crisis in a patient with Holmes Adie‐

[14] Yu-Hong Wang, Xing-Huai Sun. [Clinical analysization of the the operative effect in‐ patients with glaucomatocyclitic crisis]. Chinese Journal of Practical Ophthalmology.

[15] Wen-Bing Zhou, Shou-Xiong Peng. [glaucomatocyclitic crisis and Primary Open-an‐

[16] He-Zheng Zhou, Yuan-Hong Du. [The related factors about Posner-Schlossman syn‐ drome damage of visual field].Chinese Journal of Practical Ophthalmology.

[17] Hua-Xin Chen, He-Zheng Zhou, Bai-Chuan Wang et al.[The Clinical Observation of14 cases elderly Posner-Schlossmansyndrome]. Military medical journal of South‐

Syndrome]. Chin J Ophthalmology. 1982,18:306-308

drome].Contemporary Medicine.2008, 5:141-141

drome].Int J Ophthalmology. 2011; 11: 1980-1982

gle Glaucoma]. Chinese Ophthalmic Res.1994,12:34-36

syndrome. J Postgrad Med.1998,44:76-77

entuneitis,entilies in Filand. Acta Ophthalmology Scand.1997, 75:76~81.

1975,29:689-692

soc. 2011,74:48-50

1987,11:95-96

2005, 10:23-30

2002,10:768~769

China. 2007; 21: 43-45

Am2008,146:883-889

Surgical opportunity: Cataract surgery should be done after the inflammation has been subsidized for more than 3 months. The rest of the indication is the same to the convention‐ al cataract. Considering the PSS is an inflammation of the nature of the disease and the literature PSS patients of corneal endothelial cell density is low, PSS patients combined cataract surgery methods should also do more thinking. Femtosecond laser cataract surgery with accurate positioning, and the advantage of less influence on corneal endothelial, compared with the phaco, whether merger of cataract in patients with PSS has advantag‐ es, is worth our discussion.[42]

#### **Prospect**

With the deepening of the research on PSS, the pathogenic factors, pathogenesis, clinical characteristics, especially the clinical pathway via which the glaucoma optic nerve damage occurred in PSS cases will become clearer. For example, if hormone treatment was used excessively in PSS cases, would glueoeortieoid-induced glaucoma take place? If a poor blood supply to the optic disc of a patient with PSS or a weak structure of the papilla of optic nerve or a lower intracranial pressure, in such cases, would a normal-tension glaucoma appear? All these problems need to be continuously explored through our joint efforts.

### **Author details**

He-Zheng Zhou\* , Wen-Shan Jiang, Han-Guang Jie, Chang Feng, Wen-Qiang Zhang, Qian Ye, Jian-Guo Wu, Yan-Ping Song and Qin Ding

\*Address all correspondence to: zhoueye@qq.com

Department of Ophthalmology, Wuhan General Hospital of Guangzhou Command, China

### **References**


[4] Paivonsalo HT, Tuminen J, Vaahtoranta LH, et al. Incidence and prevalence of differ‐ entuneitis,entilies in Filand. Acta Ophthalmology Scand.1997, 75:76~81.

**Discussion**

**Prospect**

**Author details**

He-Zheng Zhou\*

**References**

Jian-Guo Wu, Yan-Ping Song and Qin Ding

\*Address all correspondence to: zhoueye@qq.com

symptoms. Arch opthalmol.1948,39:5-28

drome).Br J Ophthalmol.1952,36:207-213

manSyndrome]. Chin J Ophthalmology. 1982,18:34-37

es, is worth our discussion.[42]

The possible pathogenesis: repeated onset of IOP elevation and anterior segment inflammation

Surgical opportunity: Cataract surgery should be done after the inflammation has been subsidized for more than 3 months. The rest of the indication is the same to the convention‐ al cataract. Considering the PSS is an inflammation of the nature of the disease and the literature PSS patients of corneal endothelial cell density is low, PSS patients combined cataract surgery methods should also do more thinking. Femtosecond laser cataract surgery with accurate positioning, and the advantage of less influence on corneal endothelial, compared with the phaco, whether merger of cataract in patients with PSS has advantag‐

With the deepening of the research on PSS, the pathogenic factors, pathogenesis, clinical characteristics, especially the clinical pathway via which the glaucoma optic nerve damage occurred in PSS cases will become clearer. For example, if hormone treatment was used excessively in PSS cases, would glueoeortieoid-induced glaucoma take place? If a poor blood supply to the optic disc of a patient with PSS or a weak structure of the papilla of optic nerve or a lower intracranial pressure, in such cases, would a normal-tension glaucoma appear? All

Department of Ophthalmology, Wuhan General Hospital of Guangzhou Command, China

[1] Posener A, Schlossman A. Syndrome of unilateral attacks of glaucoma with cyclic‐

[2] Theodore FH. Observation on glaucomatocycliticcrisis(Posner Schloddman Syn‐

[3] Dao-Ping Lu, Ran-Ran Xi. [Clinical analyzation of 177 cases with Posner Schlodd‐

, Wen-Shan Jiang, Han-Guang Jie, Chang Feng, Wen-Qiang Zhang, Qian Ye,

these problems need to be continuously explored through our joint efforts.

cause disorders of nutrition and metabolism of the lens.

518 Ophthalmology - Current Clinical and Research Updates


[18] Raitta C, Vannas A. Glaucomatocyclitic crisis. Arch Ophthalmology. 1977, 95:608-612

[34] Stavrou P, Murray PI. Does trabeculectomy influence the course of uveitis? OculIm‐

Clinical Research Progress of Glaucomatocyclitic Crisis

http://dx.doi.org/10.5772/58348

521

[35] Xiao-Ping Zhang, Ji-Zhong Chen, Ru-Yong Song,[Analyze the Diagnostic of Posner-Schlossman syndrome]. Journal of clinical ophthalmology.2002,10:137-139

[36] Jin-Fu Ying, Ling-Ling Wu, [Posner-Schlossman syndrome complicated with Pri‐ mary Closed-Angle Glaucoma]. Chinese Journal of Practical Ophthalmology.

[37] Chang-lin Zhao, Han-Ping Xie. [A case report of primary angle closure glaucoma ac‐ companied by glaucomatocyclitic crisis]. Acta Academiae Medicinae Militaris Ter‐

[38] Li-Hong Guan. [2 cases of Posner-Schlossman syndrome complicated with Primary

[39] Wen-Shan Jiang, He-ZhengZhou,Yun-Hui Chen, Ling Hong [Differential diagnosisof the Posner-Schlossman syndrome with heterochromic iris and the Fuchs syndrome clinial report about three cases]. International Journal of Ophthalmology, 2009; 9 (9):

[40] Irak I, Katz BJ, Zabriskie NA, Zimmerman PL.Posner-Schlossman syndrome andno‐ narteritic anterior ischemic optic neuropathy. J Neuroophthalmol. 2003,23: 264-267

[41] Schultz T, Conrad – Hengerer I, Hengerer FH, et al. Intraocular pressure variation during femtosecond laser – assisted cataract surgery using a fluid–filled interface. J

Closed-Angle Glaucoma]. Modern Medicine & Health. 2008, 24: 152

munolInflamm. 1999,7:103-108

1993.11:491-492

1762-1763

tiae. 2004.10.25; 26: 1798

Cataract Refract Surg 2013; 39 (1): 22–27


[34] Stavrou P, Murray PI. Does trabeculectomy influence the course of uveitis? OculIm‐ munolInflamm. 1999,7:103-108

[18] Raitta C, Vannas A. Glaucomatocyclitic crisis. Arch Ophthalmology. 1977, 95:608-612 [19] He-Zheng Zhou, Yi-Jia Yang. [Characteristics and clinical value of the intraocular‐ pressure and the C-value in Posner Schloddman Syndrome]. Chinese Journal ofPrac‐

[20] Ying-Bo Shui, Hou-Ren Wei. [Influence of Postural Change on Intraocular Pressureof

[21] He-Zheng Zhou. [Tonography and postural change of intraocular pressure in pa‐ tients with glaucoma]. Chinese Journal of Practical Ophthalmology.1991,9:598-602

[22] He-Zheng Zhou, Wen-Shan Jiang. [Differential diagnosis of Posner-Schlossman syn‐

[23] He-Zheng Zhou, Yuan-Hong Du, Yan-Ping Song, Guang-Jie Wang, Jian-Guo Wu. [Visual field damage of glaucomatocyclitic crisis and its relating factors]. Fourth

[24] Yi-Lin Tang. [Clinical analysis of damage of visual field with Posner Schlossmanps‐

[25] Jap A, Sivakumar M, Chee SP. Is Posner-Schlossman syndrome benign? Ophthalmol‐

[26] He-Zheng Zhou, Bai-Chuan Wang, Xiong Zhou. [Unilateral Primary Open-Angle‐ Glaucomaand BilateralPosner-Schlossman syndrome]. Chin J Misdiagn.

[27] He-Zheng Zhou, Wen-Qiang Zhang, Bai-ChuanWang. [Glaucomatocyclitic crisiswith primary close-Angle glaucoma]. International Journal of Ophthalmology,2004,4(5):

[28] Darchuk V, Sampaolesi J, Mato L, Nicoli C, SampaolesiR.Optic nerve head behavior‐

[29] Rong-Xin Wu. [Operative effect in 1 Case with Posner-Schlossman syndrome].Ocu‐

[30] Lei Sheng, Yu-Pu Li, Gui-LanLan. [1 Case of Posner-Schlossmansyndrome].Chinese‐

[31] Bo Zhao, Da-Yong Bai, Hui Zhao.et al. [Posner-Schlossman syndrome and pri‐ maryopen-angle glaucoma]. Chin J Pract Ophthalmology. 2004,22:142-143

[32] Xiu-Feng Ke, Dan-Ning Z, Li Yuan. [Observation the clinical operation curative effec‐ tof Posner-Schlossman syndrome]. Chinese Journal of Practical Ophthalmology.

[33] Dinakaran S, Kayarkar V. Trabeculectomy in the management of Posner-Schlossman‐

in Posner-Schlossman syndrome. IntOphthalmol,2001;23:373-379

lartrauma professional eye disease magazine. 2002,24:328

Journal of Practical Ophthalmology.2008,26:572

syndrome. Ophthalmic SurgLasers.2002,33:321-322

syndrome]. International Journal of Ophthalmology. 2010,10:1204-1205

tical Ophthalmology.1992, 10:143-145

520 Ophthalmology - Current Clinical and Research Updates

MilMed Univ.2001,22:1674-1677

ogy.2001,108:913-991

2001,1:334-336

2007,6:642-643

844-847

Normal Eyes]. Chinese Ophthalmic Res. 1987; 3 : 182-185

drome]. Military medical journal of South China.2012,2:32-35


**Chapter 21**

**Excitotoxicity and Glaucoma**

Makoto Ishikawa, Takeshi Yoshitomi and

Additional information is available at the end of the chapter

Glutamate is a major excitatory neurotransmitter in the visual perception pathway. In the retina, rod and cone photoreceptor cells continuously release glutamate and partially depo‐ larized in darkness, and light decreases the glutamate release in a graded manner. The photoreceptor signals are transmitted to bipolar cells and horizontal cells. The two-types of bipolar cells, ON-and OFF-bipolar cells, continuously release glutamate in lightness and in darkness, respectively [1,2]. Bipolar cells respond to light with sustained and graded potential as photoreceptor cells do. Bipolar cell signals are then transmitted to ganglion cells, which produce action potentials as a signal transduction to the brain via the axon of the ganglion cell. Glutamate released from the presynaptic terminals diffuse to bind to the glutamate receptors on the postsynaptic membrane via the synaptic cleft. Retinal glutamate receptors are mainly located in the outer plexiform layer where glutamatergic synapses connect photoreceptors to bipolar and horizontal cells; and also in the inner plexiform layer which contains the bulk of

glutamatergic synapses from bipolar cells to ganglion cells and amacrine cells [3-6].

Multiple glutamate receptor types have been identified. Though glutamate will bind onto all glutamate receptors, each receptor is characterized by its sensitivity to specific glutamate analogues and by the features of the glutamate-elicited current. Glutamate receptors are divided into three groups, N-methyl-D-aspartate (NMDA) receptors, AMPA (α-amino-3 hydroxyl-5-methyl-4-isoxazole-propionate)/kainic acid receptors (non-NMDA receptors), and metabotropic receptors. NMDA and non-NMDA receptors are called ionotropic glutamate receptors, and form ion channel pores for ion influx and efflux, when glutamate binds to the

When glutamate is in excess, glutamate binds to cell surface ionotropic glutamate receptors, triggering massive Ca2+influx and activation of pro-apoptotic signaling cascades. It can become

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Yukitoshi Izumi

**1. Introduction**

receptor [7-9].

http://dx.doi.org/10.5772/57605

### **Chapter 21**

## **Excitotoxicity and Glaucoma**

Makoto Ishikawa, Takeshi Yoshitomi and Yukitoshi Izumi

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57605

### **1. Introduction**

Glutamate is a major excitatory neurotransmitter in the visual perception pathway. In the retina, rod and cone photoreceptor cells continuously release glutamate and partially depo‐ larized in darkness, and light decreases the glutamate release in a graded manner. The photoreceptor signals are transmitted to bipolar cells and horizontal cells. The two-types of bipolar cells, ON-and OFF-bipolar cells, continuously release glutamate in lightness and in darkness, respectively [1,2]. Bipolar cells respond to light with sustained and graded potential as photoreceptor cells do. Bipolar cell signals are then transmitted to ganglion cells, which produce action potentials as a signal transduction to the brain via the axon of the ganglion cell.

Glutamate released from the presynaptic terminals diffuse to bind to the glutamate receptors on the postsynaptic membrane via the synaptic cleft. Retinal glutamate receptors are mainly located in the outer plexiform layer where glutamatergic synapses connect photoreceptors to bipolar and horizontal cells; and also in the inner plexiform layer which contains the bulk of glutamatergic synapses from bipolar cells to ganglion cells and amacrine cells [3-6].

Multiple glutamate receptor types have been identified. Though glutamate will bind onto all glutamate receptors, each receptor is characterized by its sensitivity to specific glutamate analogues and by the features of the glutamate-elicited current. Glutamate receptors are divided into three groups, N-methyl-D-aspartate (NMDA) receptors, AMPA (α-amino-3 hydroxyl-5-methyl-4-isoxazole-propionate)/kainic acid receptors (non-NMDA receptors), and metabotropic receptors. NMDA and non-NMDA receptors are called ionotropic glutamate receptors, and form ion channel pores for ion influx and efflux, when glutamate binds to the receptor [7-9].

When glutamate is in excess, glutamate binds to cell surface ionotropic glutamate receptors, triggering massive Ca2+influx and activation of pro-apoptotic signaling cascades. It can become

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

toxic to the retinal neurons [10-13]. Olney (1969)coined the term excitotoxicity to describe the process of neuronal death caused by excessive or prolonged activation of receptors for excitatory amino acid neurotransmitters [14]. Like excitotoxicity has been considered as an important contributor to the retinal ganglion cell death in ischemic retinal diseases such as vascular occlusions [15] or diabetic retinopathy [16-18] excitotoxicity may be involved in ganglion cell death in glaucoma [19].

Although massive glutamate release is characteristic for the ischemic retinal diseases [20-22], this is not necessarily required for pathogenesis of glaucoma. In fact, several studies were unable to detect the elevation of extracellular concentration of glutamate in vitreous humor samples from experimental animals with ocular hypertension, and in human glaucoma [23-27]. Correspondingly, it has been revealed that retinal glial cells play critical roles in the prevention of excitotoxocity. For example, Müller cells are responsible for the uptake of excess glutamate via GLAST (Glutamate Aspartate Transporter) [28.29], which is essential to maintain physio‐ logical concentrations of glutamate. Glutamate at physiological levels can be neurotoxic, if glutamate metabolism is impaired. Therefore, it is considered that impaired metabolism of glutamate more likely contributes to the excitotoxic injury even if glutamate is not in excess.

This review summarizes the present knowledge regarding the glutamate metabolism in glaucoma and the possible neuroprotective therapy of glaucoma.

### **2. Glutamate uptake and glaucoma**

Glutamate released from the presynaptic terminals reaches the receptor molecules of the postsynaptic plasma membrane; but majority of glutamate are taken up by Müller glia or by retinal neurons via glutamate transporters. Glutamate transported into Müller glia is amidated to glutamine by a glutamate degrading enzyme, glutamine synthetase [30-33] (Figure 1).

### **2.1. Physiology of glutamate transporters**

Glutamate uptake is mediated by five distinct glutamate transporters (EAAT1-5): GLAST (EAAT1) [34], GLT-1 (EAAT2) [35], EAAC1 (EAAT3) [36], EAAT4 [37] and EAAT5 [38]. In five EAATs, GLAST (EAAT1) and GLT-1 (EAAT2) are the major glutamate transporters in the retina. GLAST is mainly expressed in the Müller cells, whereas GLT1 and EAAC1 are in retinal neurons. We describe the physiological roles of GLAST and GLT-1, respectively.

transporters or exchangers [50]. Although antisense GLAST fails to induce apparent excito‐ toxicity [51], antisense suppresses the b-wave and oscillatory potentials of electrocardiogram [46, 51], and doubles total glutamate levels in the retina [50]. These results indicate that GLAST is essential to maintain the homeostasis of glutamate metabolism and physiological neural functions. In support of this, it has been shown that retinas from mice with targeted deletions

**Figure 1.** After release from the presynaptic terminal, glutamate binds to the post-synaptic glutamate receptors.Then, excess of glutamate is transported into the Mulller glia via glial glutamate transporter, GLAST, and catalyzed by gluta‐ mine synthetase to the nontoxic amino acid glutamine. Glutamate is also transported into retinal neurons via neuro‐

**Glutamate** 

**GLAST**

**GLAST**

**Glutamine**

**Glutamine 
 synthetase**

Excitotoxicity and Glaucoma http://dx.doi.org/10.5772/57605 525

GLT-1 (EAAT2) is the neuronal glutamate transporter, and exists in several distinct forms, including the originally described form (GLT-1, also referred as GLT-1a), along with GLT-1b (also called GLT1v) and GLT1c [48]. GLT-1a appears to be associated mainly with a population of amacrine cells and bipolor cells, whereas GLT-1b is associated with cone photoreceptors and subpopulations of bipolar cells [52,53]. GLT-1c is normally only expressed by the photo‐ receptors in the mammalian retina [54]. GLT1 knockout mice appear to exhibit minimal

of GLAST are extremely sensitive to ischemic insults [46].

**NMDAR 

 non-‐NMDAR 

 mR**

・ ・ 

・ 

・ ・ 

・ 

・ 

・ ・ ・ 

・ ・ ・ 

**Postsynap;c 
 neuron** 

Glu

・ ・ 

**Presynap;c 
 terminal**

Glu Glu

・ 

・ ・ 

・ 

・ ・ 

・ ・ 

・ 

nal glutamate transporter, GLT-1.

・ 

・ ・ ・ 

・ 

Glu

・ 

・ 

・ **Glutamate**

・ 

・ 

・ 

・ 

・ 

**b. GLT-1**

**Fig. 
 1**

### **a. GLAST**

GLAST is the prominent glutamate transporter in the retina, and mainly expressed in the Müller cells [10, 31-33, 39, 40]. Müller cells remove the majority of glutamate from extracellular sites [41-47]. When Müller glial uptake is pharmacologically blocked, extracellular glutamate concentration increase [48], and severe excitotoxicity is induced [48, 49]. In GLAST KO mice, the Vmax for Müller glial glutamate transport is suppressed by 50%, suggesting that approx‐ imately 50% of glutamate is taken up via GLAST, another 40% through electroneutral, sodiumdependent (presently undefined) glutamate transporters, and 10% via sodium-independent

**Figure 1.** After release from the presynaptic terminal, glutamate binds to the post-synaptic glutamate receptors.Then, excess of glutamate is transported into the Mulller glia via glial glutamate transporter, GLAST, and catalyzed by gluta‐ mine synthetase to the nontoxic amino acid glutamine. Glutamate is also transported into retinal neurons via neuro‐ nal glutamate transporter, GLT-1.

transporters or exchangers [50]. Although antisense GLAST fails to induce apparent excito‐ toxicity [51], antisense suppresses the b-wave and oscillatory potentials of electrocardiogram [46, 51], and doubles total glutamate levels in the retina [50]. These results indicate that GLAST is essential to maintain the homeostasis of glutamate metabolism and physiological neural functions. In support of this, it has been shown that retinas from mice with targeted deletions of GLAST are extremely sensitive to ischemic insults [46].

### **b. GLT-1**

toxic to the retinal neurons [10-13]. Olney (1969)coined the term excitotoxicity to describe the process of neuronal death caused by excessive or prolonged activation of receptors for excitatory amino acid neurotransmitters [14]. Like excitotoxicity has been considered as an important contributor to the retinal ganglion cell death in ischemic retinal diseases such as vascular occlusions [15] or diabetic retinopathy [16-18] excitotoxicity may be involved in

Although massive glutamate release is characteristic for the ischemic retinal diseases [20-22], this is not necessarily required for pathogenesis of glaucoma. In fact, several studies were unable to detect the elevation of extracellular concentration of glutamate in vitreous humor samples from experimental animals with ocular hypertension, and in human glaucoma [23-27]. Correspondingly, it has been revealed that retinal glial cells play critical roles in the prevention of excitotoxocity. For example, Müller cells are responsible for the uptake of excess glutamate via GLAST (Glutamate Aspartate Transporter) [28.29], which is essential to maintain physio‐ logical concentrations of glutamate. Glutamate at physiological levels can be neurotoxic, if glutamate metabolism is impaired. Therefore, it is considered that impaired metabolism of glutamate more likely contributes to the excitotoxic injury even if glutamate is not in excess. This review summarizes the present knowledge regarding the glutamate metabolism in

Glutamate released from the presynaptic terminals reaches the receptor molecules of the postsynaptic plasma membrane; but majority of glutamate are taken up by Müller glia or by retinal neurons via glutamate transporters. Glutamate transported into Müller glia is amidated to glutamine by a glutamate degrading enzyme, glutamine synthetase [30-33] (Figure 1).

Glutamate uptake is mediated by five distinct glutamate transporters (EAAT1-5): GLAST (EAAT1) [34], GLT-1 (EAAT2) [35], EAAC1 (EAAT3) [36], EAAT4 [37] and EAAT5 [38]. In five EAATs, GLAST (EAAT1) and GLT-1 (EAAT2) are the major glutamate transporters in the retina. GLAST is mainly expressed in the Müller cells, whereas GLT1 and EAAC1 are in retinal

GLAST is the prominent glutamate transporter in the retina, and mainly expressed in the Müller cells [10, 31-33, 39, 40]. Müller cells remove the majority of glutamate from extracellular sites [41-47]. When Müller glial uptake is pharmacologically blocked, extracellular glutamate concentration increase [48], and severe excitotoxicity is induced [48, 49]. In GLAST KO mice, the Vmax for Müller glial glutamate transport is suppressed by 50%, suggesting that approx‐ imately 50% of glutamate is taken up via GLAST, another 40% through electroneutral, sodiumdependent (presently undefined) glutamate transporters, and 10% via sodium-independent

neurons. We describe the physiological roles of GLAST and GLT-1, respectively.

glaucoma and the possible neuroprotective therapy of glaucoma.

**2. Glutamate uptake and glaucoma**

**2.1. Physiology of glutamate transporters**

**a. GLAST**

ganglion cell death in glaucoma [19].

524 Ophthalmology - Current Clinical and Research Updates

GLT-1 (EAAT2) is the neuronal glutamate transporter, and exists in several distinct forms, including the originally described form (GLT-1, also referred as GLT-1a), along with GLT-1b (also called GLT1v) and GLT1c [48]. GLT-1a appears to be associated mainly with a population of amacrine cells and bipolor cells, whereas GLT-1b is associated with cone photoreceptors and subpopulations of bipolar cells [52,53]. GLT-1c is normally only expressed by the photo‐ receptors in the mammalian retina [54]. GLT1 knockout mice appear to exhibit minimal compromise of retinal function, suggesting that GLAST is essential for the maintenance of normal synaptic transmission [46, 49]. However, it is still controversial because other research‐ ers reported that treatment with antisense oligonucleotides against GLT-1 induced the excitotoxic ganglion cell death in the rat retina [42].

Sullivan et al. (2006) [68] reported the expressional changes of the splice variant of GLT-1 (GLT-1c) in the glaucoma eyes. In normal eyes of humans and rats, GLT-1c is expressed only in photoreceptors. In glaucoma, additional robust expression of GLT-1c is detected in retinal ganglion cells, including occasional displaced ganglion cells [106]. The new induction of GLT-1c expression by retinal ganglion cells may imply abnormalities in glutamate homeostasis in glaucomatous RGCs. The same authors said that GLT-1c may be a useful indicator of the extent of stress of the RGCs and thus a tool for examining outcomes of potential therapeutic

Several studies [56, 64] revealed that the expression of the major glutamate transporter, GLAST, decreases after pressure loading. Therefore, agents that effectively enhance glutamate transporter function may serve as potential therapeutics against the pressure-induced injury. Enhancement of glutamate transport is developing into a new strategy for reducing excito‐ toxicity also in brain injury and neurodegenerative disease [69-71]. Lee et al. (2009) [72] reported that tamoxifen, estrogen modulator, possessed neuroprotective properties against excitotoxicity by the up-regulation of GLAST at protein and mRNA levels in the mannganeseinduced excitotoxicity. Estradiol and its derivative also reported to increase GLAST expres‐

Recently, the daily treatment with 17β-estradiol (E2) eye drops resulted in significant E2 concentration in the retina with concomitant profound neuroprotective therapeutic benefits, even in the presence of continually elevated IOP [73]. However, E2 eye drop induces the adverse effect to other organs induced by stimulation of estrogen receptors. It seems safe to apply E2 eye drops to postmenopausal women. Taking all above into consideration, there is a long way to go before topical estrogen drops becomes a new therapeutics of glaucoma.

In the Müller cells, glutamate is rapidly converted into glutamine by the glia-specific enzyme, glutamine synthetase [33]. Glutamine synthetase is specifically localized in the cytosol of

Glutamate <sup>+</sup> *<sup>N</sup> <sup>H</sup>* 4+ <sup>+</sup> *ATP* <sup>→</sup>glutamine <sup>+</sup> *ADP* <sup>+</sup> *Pi* <sup>+</sup> *<sup>H</sup>* <sup>+</sup>

The activity of the glutamine synthetase influences the rate of the glutamate uptake by the Müller cells [41]. The rapid metabolization of glutamate to glutamine causes a stronger driving force for the glutamate uptake in the Müller cells than in neurons, which have intracellular free glutamate concentrations two orders of magnitude higher than the Müller cells [75]. A prerequisite for an effective glutamate-glutamine cycle in Müller cells would be the regulated

,

Excitotoxicity and Glaucoma http://dx.doi.org/10.5772/57605 527

and experimental interventions.

in the presence of Mn2+or Mg2+.

**2.3. Neuroprotection by upregulation of glutamate transporters**

sion, though these drugs have not been applied to glaucoma patients.

**3. Enzymatic degradation of glutamate and glaucoma**

Müller cells [74].Glutamine synthetase catalyzes the following reaction,

coordination between glutamate uptake and glutamate degradation [39].

### **2.2. Impairment of glutamate removal in glaucoma**

### **a. GLAST**

Some studies have shown that GLAST expression diminishes [55-57] or remains stable [58] in experimental glaucoma, whereas others have reported increased expression [59]. Thus, it remains unclear whether elevated intraocular pressure (IOP) alters glutamate uptake by modulating GLAST. After experimental IOP elevation in rats, Holcombe et al. (2008) [47] immunohistochemically determined the glutamate transport activity as aspartate uptake into Müller glia, and found that Müller glial uptake is normal even IOP is as high as 70 mmHg but compromised at 80 mmHg or higher. These results suggest that GLAST is functional as long as retinal perfusion is maintained.

We [60] used a rat *ex vivo* model incubating rat eye cups under hydrostatic pressure at the bottom of a deep cylinder. Such acute high pressures can induce retinal ischemia clinically and in *in vivo* glaucoma models [61-63] but not in this *ex vivo* model. The advantages of *ex vivo* hydrostatic pressure model include better preservation of eyecup samples without ischemia, making it possible to investigate direct effects of pressure-induced retinal injury on glutamate metabolism. In this acute *ex vivo* model, axonal damage of the retinal ganglion cells were prominent, and Western blot and real-time RT-PCR analyses revealed that 75 mm Hg pressure depressed GLAST expression [64]. Administration of glutamate receptor blockers prevented axonal damages, indicating that IOP elevation induces excitotoxicity via depression of GLAST. It should be also noticed that IOP elevation can depress GLAST activity even if retinal perfusion is preserved.

Harada et al. (2007) [65] show that GLAST-deficient mice demonstrate spontaneous RGC loss and optic nerve degeneration in spite of normal IOP. In GLAST-deficient mice, administration of glutamate receptor blockers prevented RGC loss.

These findings suggest that glutamate transporters are necessary to prevent glaucomatous excitotoxic retinal damages.

### **b. GLT-1**

GLT-1, the main neuronal glutamate transporter in the retinal neurons, is reported to be downregulated in glaucomatous eyes in rats [58, 66] and mice [57]. By contrast, Park et al. [58] reported that the expression of GLT-1 was expressed in cone photoreceptors and the level of expression in some cone bipolar cells was significantly increased in *in vivo* glaucoma model. They also demonstrated that GLAST expression in Müller cells remained stable during the experimental period. These results suggest that integrity of GLT-1 may be a prerequisite for the maintenance of glutamate homeostasis in the retina undergoing glaucoma [67].

Sullivan et al. (2006) [68] reported the expressional changes of the splice variant of GLT-1 (GLT-1c) in the glaucoma eyes. In normal eyes of humans and rats, GLT-1c is expressed only in photoreceptors. In glaucoma, additional robust expression of GLT-1c is detected in retinal ganglion cells, including occasional displaced ganglion cells [106]. The new induction of GLT-1c expression by retinal ganglion cells may imply abnormalities in glutamate homeostasis in glaucomatous RGCs. The same authors said that GLT-1c may be a useful indicator of the extent of stress of the RGCs and thus a tool for examining outcomes of potential therapeutic and experimental interventions.

### **2.3. Neuroprotection by upregulation of glutamate transporters**

Several studies [56, 64] revealed that the expression of the major glutamate transporter, GLAST, decreases after pressure loading. Therefore, agents that effectively enhance glutamate transporter function may serve as potential therapeutics against the pressure-induced injury. Enhancement of glutamate transport is developing into a new strategy for reducing excito‐ toxicity also in brain injury and neurodegenerative disease [69-71]. Lee et al. (2009) [72] reported that tamoxifen, estrogen modulator, possessed neuroprotective properties against excitotoxicity by the up-regulation of GLAST at protein and mRNA levels in the mannganeseinduced excitotoxicity. Estradiol and its derivative also reported to increase GLAST expres‐ sion, though these drugs have not been applied to glaucoma patients.

Recently, the daily treatment with 17β-estradiol (E2) eye drops resulted in significant E2 concentration in the retina with concomitant profound neuroprotective therapeutic benefits, even in the presence of continually elevated IOP [73]. However, E2 eye drop induces the adverse effect to other organs induced by stimulation of estrogen receptors. It seems safe to apply E2 eye drops to postmenopausal women. Taking all above into consideration, there is a long way to go before topical estrogen drops becomes a new therapeutics of glaucoma.

### **3. Enzymatic degradation of glutamate and glaucoma**

In the Müller cells, glutamate is rapidly converted into glutamine by the glia-specific enzyme, glutamine synthetase [33]. Glutamine synthetase is specifically localized in the cytosol of Müller cells [74].Glutamine synthetase catalyzes the following reaction,

$$\text{Glutamate + } NH^{4\*} + ATP \rightarrow \text{gluatamine + } ADP + P\_i + H^+ \ .$$

in the presence of Mn2+or Mg2+.

compromise of retinal function, suggesting that GLAST is essential for the maintenance of normal synaptic transmission [46, 49]. However, it is still controversial because other research‐ ers reported that treatment with antisense oligonucleotides against GLT-1 induced the

Some studies have shown that GLAST expression diminishes [55-57] or remains stable [58] in experimental glaucoma, whereas others have reported increased expression [59]. Thus, it remains unclear whether elevated intraocular pressure (IOP) alters glutamate uptake by modulating GLAST. After experimental IOP elevation in rats, Holcombe et al. (2008) [47] immunohistochemically determined the glutamate transport activity as aspartate uptake into Müller glia, and found that Müller glial uptake is normal even IOP is as high as 70 mmHg but compromised at 80 mmHg or higher. These results suggest that GLAST is functional as long

We [60] used a rat *ex vivo* model incubating rat eye cups under hydrostatic pressure at the bottom of a deep cylinder. Such acute high pressures can induce retinal ischemia clinically and in *in vivo* glaucoma models [61-63] but not in this *ex vivo* model. The advantages of *ex vivo* hydrostatic pressure model include better preservation of eyecup samples without ischemia, making it possible to investigate direct effects of pressure-induced retinal injury on glutamate metabolism. In this acute *ex vivo* model, axonal damage of the retinal ganglion cells were prominent, and Western blot and real-time RT-PCR analyses revealed that 75 mm Hg pressure depressed GLAST expression [64]. Administration of glutamate receptor blockers prevented axonal damages, indicating that IOP elevation induces excitotoxicity via depression of GLAST. It should be also noticed that IOP elevation can depress GLAST activity even if retinal perfusion

Harada et al. (2007) [65] show that GLAST-deficient mice demonstrate spontaneous RGC loss and optic nerve degeneration in spite of normal IOP. In GLAST-deficient mice, administration

These findings suggest that glutamate transporters are necessary to prevent glaucomatous

GLT-1, the main neuronal glutamate transporter in the retinal neurons, is reported to be downregulated in glaucomatous eyes in rats [58, 66] and mice [57]. By contrast, Park et al. [58] reported that the expression of GLT-1 was expressed in cone photoreceptors and the level of expression in some cone bipolar cells was significantly increased in *in vivo* glaucoma model. They also demonstrated that GLAST expression in Müller cells remained stable during the experimental period. These results suggest that integrity of GLT-1 may be a prerequisite for

the maintenance of glutamate homeostasis in the retina undergoing glaucoma [67].

excitotoxic ganglion cell death in the rat retina [42].

526 Ophthalmology - Current Clinical and Research Updates

**2.2. Impairment of glutamate removal in glaucoma**

of glutamate receptor blockers prevented RGC loss.

as retinal perfusion is maintained.

**a. GLAST**

is preserved.

**b. GLT-1**

excitotoxic retinal damages.

The activity of the glutamine synthetase influences the rate of the glutamate uptake by the Müller cells [41]. The rapid metabolization of glutamate to glutamine causes a stronger driving force for the glutamate uptake in the Müller cells than in neurons, which have intracellular free glutamate concentrations two orders of magnitude higher than the Müller cells [75]. A prerequisite for an effective glutamate-glutamine cycle in Müller cells would be the regulated coordination between glutamate uptake and glutamate degradation [39].

The activity of glutamine synthetase is stimulated by glucocorticoids [76,77]. In chick embryo retinas the stimulated glutamine synthetase by glucocorticoids is correlated with amounts of released glutamine from Müller glia, suggesting that the activity of glutamine synthetase influences glutamate uptake [78]. Conversely, it is also reported that basic fibrogrowth factor (bFGF) suppresses the activity of glutamine synthetase presumably through inhibition of glucocorticoid actions [79].

**3.2. Neuroprotection by upregulation of glutamine synthetase**

pressure-induced injury.

**4. Glutamate receptors**

and its relation to excitotoxicity.

permit the influx of sodium ions (Na+

**a. NMDA receptors**

elucidated.

(K+ ).

Hydrocortisone, which is shown to increase the expression of glutamine synthetase in the Müller cells, is considered as neuroprotectve against excitotoxicity [87-89]. Upregulation of glutamine synthetase by hydrocortisone may be related to the fact that the upstream region of the glutamine synthetase gene contains a glucocorticoid response element that can bind the glucocorticoid receptor protein [53]. Glutamine synthtase was also reported upregulated by taurine supplementation in the diabetic retina [90]. These agents that effectively enhance glutamine synthetase function and expression may serve as potential therapeutics against the

The excitotoxicity is predominantly mediated by the overstimulation of NMDA receptors due to their extreme permeability to calcium ions [94]. Many researchers have concluded, therefore, that excitotoxicity occurs, in part, via NMDA receptors activation [99,100]. There is still remained a possibility that glutamate acts via non-NMDA receptors to initiate neurotoxicity [101-105]. However, the role of non-NMDA receptorsin pathogenesis of glaucoma has not been

We describe the present knowledge concerning the molecular function of NMDA receptors

Retinal ganglion cells express abundant NMDA receptors [106-109]. A number of studies demonstrated that ganglion cells are extremely vulnerable to exogenously applied NMDA, which inducesganglion cell degeneration.It has been also shown that NMDA receptor antagonists are neuroprotective in experimental glaucoma models [110-117]. NMDA receptors

Although all NMDA receptors express the NR1 subunit [122,123,124], NR2 subunits are major determinants of the functional properties of NMDA receptor [125]. Recently, Bai et al. (2013) [126] reported the roles of the four different NR2 subtypes (NR2a, NR2b, NR2c, NR2d) in NMDA-induced retinal cell death using mice lacking specific NR2 subunits. They also evaluated the neuroprotective effect of 7-hydroxy-6-methoxy-2-methyl-1-(2-(4-(trifluorometh‐ yl)phenyl)ethyl)-1,2,3,4-tetra-hydro-isoquinoline hydrochloride (HON0001) [127], an specific NR2b antagonist, on ganglion cell degeneration due to glutamate excitotoxicity in GLASTdeficient mice. As the results, NR2b-and NR2d-deficiency protected ganglion cells from NMDA-induced excitotoxicity. Pharmacological inhibition of the NR2b subunit by HON0001 attenuated ganglion cell loss in GLAST deficient mice. These findings suggest that NR2b-and NR2d-containing NMDA receptors play a critical role in NMDA receptor-mediated excito‐ toxicity in the retina. Based on these findings,inhibition of NR2b and NR2d activity is a

) and calcium ions (Ca2+) and the efflux of potassium ions

Excitotoxicity and Glaucoma http://dx.doi.org/10.5772/57605 529

Glutamine, synthesized from glutamate in Müller glia, is the major source of glutamate found in retinal neurons. MSO, an inhibitor of glutamine synthetase, rapidly abolish free glutamate from bipolar cells and retinal ganglion cells [80]. Therefore, glutamine synthetase is a key enzyme in glutamate-glutamine cycle.

### **3.1. Impairment of glutamate metabolism and glaucoma**

Several studies have shown increases in the expression of glutamine synthetase [78] after pressure elevation [81,82], whereas others have reported decreases. Thus, it remains contro‐ versial whether elevated IOP alters glial cell glutamate metabolism as a potential mechanism of retinal excitotoxicity [83].

In primary glaucoma in dogs [84], decreases in immunoreactivity of glutamine synthetase were associated with glutamate redistribution. These decreases in glutamine synthetase occurred even in mildly damaged regions of retina before retinal thinning. Reactive Müller cells were seen primarily in chronic primary glaucoma in severely damaged regions. Decreases in glutamine synthetase may potentiate ischemia-induced early glutamate redistribution and neuronal damage in canine primary glaucoma.

We (2010) [60] reported that pressure elevation induced reduction of glutamine synthetase activity compared with control pressure in an acute*ex vivo* model. The result suggests that the neural degeneration observed during pressure elevation is caused by impaired glial glutamate metabolism.

Although GLAST and the activities of glutamine synthetase are intimately intertwined [85], both are simultaneously suppressed by high pressure-loading. Thus, it is also possible that suppression of GLAST and the activities of glutamine synthetase occur separately during pressure-loading [86]. However, a series of observations using acute *ex vivo* model suggest that during pressure-loading, the impairment of GLAST expression precedes the depression of glutamine synthetase activity. Pharmacologic inhibition of glutamine synthetase activity with MSO fails to modulate GLAST expression, whereas inhibition of GLAST with TFB-TBOA substantially suppresses glutamine synthetase activity. Based on these findings, it is hypothe‐ size that during pressure-loading, impairment of GLAST takes place first and results in downregulation of activities of glutamine synthetase as a secondary effect [62], though it is also possible that changes in the activities of glutamine synthetase influence GLAST activities [78].

### **3.2. Neuroprotection by upregulation of glutamine synthetase**

Hydrocortisone, which is shown to increase the expression of glutamine synthetase in the Müller cells, is considered as neuroprotectve against excitotoxicity [87-89]. Upregulation of glutamine synthetase by hydrocortisone may be related to the fact that the upstream region of the glutamine synthetase gene contains a glucocorticoid response element that can bind the glucocorticoid receptor protein [53]. Glutamine synthtase was also reported upregulated by taurine supplementation in the diabetic retina [90]. These agents that effectively enhance glutamine synthetase function and expression may serve as potential therapeutics against the pressure-induced injury.

### **4. Glutamate receptors**

The activity of glutamine synthetase is stimulated by glucocorticoids [76,77]. In chick embryo retinas the stimulated glutamine synthetase by glucocorticoids is correlated with amounts of released glutamine from Müller glia, suggesting that the activity of glutamine synthetase influences glutamate uptake [78]. Conversely, it is also reported that basic fibrogrowth factor (bFGF) suppresses the activity of glutamine synthetase presumably through inhibition of

Glutamine, synthesized from glutamate in Müller glia, is the major source of glutamate found in retinal neurons. MSO, an inhibitor of glutamine synthetase, rapidly abolish free glutamate from bipolar cells and retinal ganglion cells [80]. Therefore, glutamine synthetase is a key

Several studies have shown increases in the expression of glutamine synthetase [78] after pressure elevation [81,82], whereas others have reported decreases. Thus, it remains contro‐ versial whether elevated IOP alters glial cell glutamate metabolism as a potential mechanism

In primary glaucoma in dogs [84], decreases in immunoreactivity of glutamine synthetase were associated with glutamate redistribution. These decreases in glutamine synthetase occurred even in mildly damaged regions of retina before retinal thinning. Reactive Müller cells were seen primarily in chronic primary glaucoma in severely damaged regions. Decreases in glutamine synthetase may potentiate ischemia-induced early glutamate redistribution and

We (2010) [60] reported that pressure elevation induced reduction of glutamine synthetase activity compared with control pressure in an acute*ex vivo* model. The result suggests that the neural degeneration observed during pressure elevation is caused by impaired glial glutamate

Although GLAST and the activities of glutamine synthetase are intimately intertwined [85], both are simultaneously suppressed by high pressure-loading. Thus, it is also possible that suppression of GLAST and the activities of glutamine synthetase occur separately during pressure-loading [86]. However, a series of observations using acute *ex vivo* model suggest that during pressure-loading, the impairment of GLAST expression precedes the depression of glutamine synthetase activity. Pharmacologic inhibition of glutamine synthetase activity with MSO fails to modulate GLAST expression, whereas inhibition of GLAST with TFB-TBOA substantially suppresses glutamine synthetase activity. Based on these findings, it is hypothe‐ size that during pressure-loading, impairment of GLAST takes place first and results in downregulation of activities of glutamine synthetase as a secondary effect [62], though it is also possible that changes in the activities of glutamine synthetase influence GLAST activities

glucocorticoid actions [79].

of retinal excitotoxicity [83].

metabolism.

[78].

enzyme in glutamate-glutamine cycle.

528 Ophthalmology - Current Clinical and Research Updates

**3.1. Impairment of glutamate metabolism and glaucoma**

neuronal damage in canine primary glaucoma.

The excitotoxicity is predominantly mediated by the overstimulation of NMDA receptors due to their extreme permeability to calcium ions [94]. Many researchers have concluded, therefore, that excitotoxicity occurs, in part, via NMDA receptors activation [99,100]. There is still remained a possibility that glutamate acts via non-NMDA receptors to initiate neurotoxicity [101-105]. However, the role of non-NMDA receptorsin pathogenesis of glaucoma has not been elucidated.

We describe the present knowledge concerning the molecular function of NMDA receptors and its relation to excitotoxicity.

#### **a. NMDA receptors**

Retinal ganglion cells express abundant NMDA receptors [106-109]. A number of studies demonstrated that ganglion cells are extremely vulnerable to exogenously applied NMDA, which inducesganglion cell degeneration.It has been also shown that NMDA receptor antagonists are neuroprotective in experimental glaucoma models [110-117]. NMDA receptors permit the influx of sodium ions (Na+ ) and calcium ions (Ca2+) and the efflux of potassium ions (K+ ).

Although all NMDA receptors express the NR1 subunit [122,123,124], NR2 subunits are major determinants of the functional properties of NMDA receptor [125]. Recently, Bai et al. (2013) [126] reported the roles of the four different NR2 subtypes (NR2a, NR2b, NR2c, NR2d) in NMDA-induced retinal cell death using mice lacking specific NR2 subunits. They also evaluated the neuroprotective effect of 7-hydroxy-6-methoxy-2-methyl-1-(2-(4-(trifluorometh‐ yl)phenyl)ethyl)-1,2,3,4-tetra-hydro-isoquinoline hydrochloride (HON0001) [127], an specific NR2b antagonist, on ganglion cell degeneration due to glutamate excitotoxicity in GLASTdeficient mice. As the results, NR2b-and NR2d-deficiency protected ganglion cells from NMDA-induced excitotoxicity. Pharmacological inhibition of the NR2b subunit by HON0001 attenuated ganglion cell loss in GLAST deficient mice. These findings suggest that NR2b-and NR2d-containing NMDA receptors play a critical role in NMDA receptor-mediated excito‐ toxicity in the retina. Based on these findings,inhibition of NR2b and NR2d activity is a potential therapeutic strategy for the treatment of retinal neurodegeneration induced by excitotoxicity.

potential therapeutics against the pressure-induced injury. Enhancement of glutamine

Excitotoxicity and Glaucoma http://dx.doi.org/10.5772/57605 531

I thank Yoko Hayami, and Sanae Takaseki (Department of Ophthalmology Akita Graduate University School of Medicine) for instructions and suggestions. This work was supported by

1 Department of Ophthalmology, Akita Graduate University Faculty of Medicine, Akita,

2 Department of Psychiatry, Washington University School of Medicine, St. Louis, M.O.,

[1] Crevetto, L, & Piccolino, M. Synaptic trans-mission between photoreceptors and hor‐

[2] Dowling, J. E, & Ripps, H. Effect of magnesium on horizontal cell activity in the skate

[3] Gruender, T, Kohler, K, Kaletta, A, & Guenther, E. The distribution and developmen‐ tal regulation of NMDA receptor subunit proteins in the outer and inner retina of the

[4] Lagrèze, W. A, Darstein, M, Feuerstein, T. J, Otto, T, & Landwehrmeyer, G.B. NMDA receptor subunit mRNA expression in human retinal ganglion cells.Graefe's Ar‐

[5] Lukasiewicz, P. Synaptic mechanisms that shape visual signaling at the inner retina.

[6] Peng, Y. W, Blackstone, C. D, Huganir, R. L, &Yau, K. W, Distribution of glutamate receptor subtypes in the vertebrate retina. Neuroscience (1995)., 66, 483-497.

chives of Clinical & Experimental Ophthalmology (2000)., 238, 486-490.

izontal cells in the turtle retina. Science (1974)., 183, 417-419.

and Yukitoshi Izumi2

synthetase may be a therapeutic strategy for reducing excitotoxicity.

JSPS KAKENHI Grant Numbers 24592666 to M.I.

\*Address all correspondence to: mako@med.akita-u.ac.jp

retina. Nature London(1973)., 242, 101-103.

Progress in Brain Research (2005).. 147, 205-218.

rat. J. Neurobiol (2000)., 44, 333-342.

Makoto Ishikawa1\*, Takeshi Yoshitomi1

**Acknowledgements**

**Author details**

Japan

USA

**References**

The same authors demonstrate that NR2d deficiency attenuates ganglion cell loss in GLASTdeficient mice [126]. Furthermore, Dock3, a guanine nucleotide exchange factor, binds to the NR2d C-terminal domain and reduces the expression of NR2d, thereby protects ganglion cells from excitotoxicity. These results suggest that NR2d is involved in the excitotoxic ganglion cell death, and that the interaction between NR2d and Dock3 may have a neuroprotective effect. These findings indicate the possibility that NR2d and Dock3 might be therapeutic targets for glaucoma.

#### **b. Neuroprotection by NMDA receptor antagonists**

Classical pharmacological approaches for reducing excitotoxicity have focused on antagonism of glutamate receptors. Memantine is an uncompetitive NMDA antagonist, binding near the Mg2+site within the ion channel [128]. The degree of blockade of the NMDA receptors is changed according to the concentration of memantine [128]. Memantine is a neuroprotective agent that has completed phase III clinical trial in patients with glaucoma [129, 130]. The trial showed that memantine was ineffective by the primary end point, with the variable mecha‐ nisms of retinal ganglion apoptosis being offered as an explanation [131].

A recent study demonstrated that NR2c-and NR2d-containing NMDA receptors are the primary targets of memantine [132]. It has been reported that memantine prevents the loss of retinal ganglion cells in GLAST knockout mice, a model of normal tension glaucoma (NTG), suggesting that NR2d-containing receptors may be involved in ganglion cell loss in glaucoma [125, 126]. It was also demonstrated that Mg2+regulates the sensitivity of NMDA receptors to memantine [133]. In a physiological concentration (1 mM) of extracellular Mg2+, memantine exerts a more potent blocking effect at NR2c and NR2d subunits than at NR2a and NR2b subunits. These findings suggest that NR2c-and NR2d-containing NMDA receptors are likely to be the main targets of memantine.

### **5. Concluding comments**

Glutamate accumulation in extracellular spaces can be potentially neurotoxic if glutamate is not removed in an appropriate manner. It should be noticed that excitotoxicity does not always due to excess of glutamate. Extracellular glutamate level duringretinal ischemia may not be sufficient to induceneuronal damage under normal conditions. This suggeststhat clearance of glutamate is essential in preventingretinal excitotoxicity. In glaucomatous models, glutamate metabolism can be impaired by inhibition of glutamate transporter and glutamine synthetase, resulting in excitotoxic glaucomatous damages of retinal ganglion cells. A series of observa‐ tions using ex vivo glaucomatous model suggest that during pressure-loading, the impairment of glutamate transporter expression precedes the depression of glutamine synthetase activity. Therefore, it is also possible that changes in the activities of glutamine synthetase influence GLAST activities.Agents that effectively enhance glutamate transporter function may serve as potential therapeutics against the pressure-induced injury. Enhancement of glutamine synthetase may be a therapeutic strategy for reducing excitotoxicity.

### **Acknowledgements**

potential therapeutic strategy for the treatment of retinal neurodegeneration induced by

The same authors demonstrate that NR2d deficiency attenuates ganglion cell loss in GLASTdeficient mice [126]. Furthermore, Dock3, a guanine nucleotide exchange factor, binds to the NR2d C-terminal domain and reduces the expression of NR2d, thereby protects ganglion cells from excitotoxicity. These results suggest that NR2d is involved in the excitotoxic ganglion cell death, and that the interaction between NR2d and Dock3 may have a neuroprotective effect. These findings indicate the possibility that NR2d and Dock3 might be therapeutic targets

Classical pharmacological approaches for reducing excitotoxicity have focused on antagonism of glutamate receptors. Memantine is an uncompetitive NMDA antagonist, binding near the Mg2+site within the ion channel [128]. The degree of blockade of the NMDA receptors is changed according to the concentration of memantine [128]. Memantine is a neuroprotective agent that has completed phase III clinical trial in patients with glaucoma [129, 130]. The trial showed that memantine was ineffective by the primary end point, with the variable mecha‐

A recent study demonstrated that NR2c-and NR2d-containing NMDA receptors are the primary targets of memantine [132]. It has been reported that memantine prevents the loss of retinal ganglion cells in GLAST knockout mice, a model of normal tension glaucoma (NTG), suggesting that NR2d-containing receptors may be involved in ganglion cell loss in glaucoma [125, 126]. It was also demonstrated that Mg2+regulates the sensitivity of NMDA receptors to memantine [133]. In a physiological concentration (1 mM) of extracellular Mg2+, memantine exerts a more potent blocking effect at NR2c and NR2d subunits than at NR2a and NR2b subunits. These findings suggest that NR2c-and NR2d-containing NMDA receptors are likely

Glutamate accumulation in extracellular spaces can be potentially neurotoxic if glutamate is not removed in an appropriate manner. It should be noticed that excitotoxicity does not always due to excess of glutamate. Extracellular glutamate level duringretinal ischemia may not be sufficient to induceneuronal damage under normal conditions. This suggeststhat clearance of glutamate is essential in preventingretinal excitotoxicity. In glaucomatous models, glutamate metabolism can be impaired by inhibition of glutamate transporter and glutamine synthetase, resulting in excitotoxic glaucomatous damages of retinal ganglion cells. A series of observa‐ tions using ex vivo glaucomatous model suggest that during pressure-loading, the impairment of glutamate transporter expression precedes the depression of glutamine synthetase activity. Therefore, it is also possible that changes in the activities of glutamine synthetase influence GLAST activities.Agents that effectively enhance glutamate transporter function may serve as

nisms of retinal ganglion apoptosis being offered as an explanation [131].

excitotoxicity.

530 Ophthalmology - Current Clinical and Research Updates

for glaucoma.

**b. Neuroprotection by NMDA receptor antagonists**

to be the main targets of memantine.

**5. Concluding comments**

I thank Yoko Hayami, and Sanae Takaseki (Department of Ophthalmology Akita Graduate University School of Medicine) for instructions and suggestions. This work was supported by JSPS KAKENHI Grant Numbers 24592666 to M.I.

### **Author details**

Makoto Ishikawa1\*, Takeshi Yoshitomi1 and Yukitoshi Izumi2

\*Address all correspondence to: mako@med.akita-u.ac.jp

1 Department of Ophthalmology, Akita Graduate University Faculty of Medicine, Akita, Japan

2 Department of Psychiatry, Washington University School of Medicine, St. Louis, M.O., USA

### **References**


[7] Thoreson, W. B, & Witkovsky, P. Glutamate receptors and circuits in the vertebrate retina. Progress in Retinal and Eye Research(1999)., 18, 765-810.

[21] Bertram, K. M, Bula, D. V, Pulido, J. S, Shippy, S. A, Gautam, S, Lu, M. J, Hatfield, R. M, Kim, J. H, Quirk, M. T, &Arroyo, J. G. Amino-acid levels in subretinal and vitre‐

Excitotoxicity and Glaucoma http://dx.doi.org/10.5772/57605 533

[22] Diederen, R.M. H, La Heij, E. C, Deutz, N.E. P, Kijlstra, A, Kessels, A.G. H, van Eijk, H.M. H, Liem, A.T. A, Dieudonné, S, & Hendrikse, F. Increased glutamatelevels in the vitreous of patients with retinal detachment. Experimantal Eye Research (2006).,

[23] Carter-Dawson, L, Crawford, M.L. J, Harwerth, R. S, Smith, E. L, Feldman, R, Shen, F. F, Mitchell, C. K, & Whitetree, A. Vitreal glutamate concentration in monkeys with experimental glaucoma. Investigative Ophthalmology & Visual Science(2002)., 43,

[24] Honkanen, R. A, Baruah, S, Zimmerman, M. B, Khanna, C. L, Weaver, Y. K, Narkie‐ wicz, J, Waziri, R, Gehrs, K. M, Weingeist, T. A, Boldt, H. C, Folk, J.C., Russell, S. R, &Kwon, Y. H. Vitreous amino acid concentrations in patients with glaucoma under‐

[25] Kwon, Y. H, Rickman, D. W, Baruah, S, Zimmerman, M. B, Kim, C.S., Boldt, H. C, Russell, S. R, &Hayreh, S. S. Vitreous and retinal amino acid concentrations in experi‐

[26] Levkovitch-Verbin, H, Martin, K. R, Quigley, H. A, Baumrind, L. A, Pease, M. E, & Valenta, D. Measurement of amino acid levels in the vitreous humor of rats after chronic intraocular pressure elevation or optic nerve transection. Journal of Glauco‐

[27] Wamsley, S, Gabelt, B. T. Dahl, D. B, Case, G. L, Sherwood, R. W. May, C.A., Hernan‐ dez, M. R,& Kaufman, P.L. Vitreous glutamate concentration and axon loss in mon‐ keys with experimental glaucoma. Archives of Ophthalmology(2005)., 123, 64-70. [28] Barnett, N. L Pow, D. V, &Bull, N. D. Differential perturbation of neuronal and glial glutamate transport systems in retinal ischemia. Neurochemistry Internation‐

[29] Otori, Y, Shimada, S, Tanaka, K, Ishimoto, I. Tano, Y, & Tohyama, M. Marked in‐ crease in glutamate-aspartate transporter (GLAST/GluT-1) mRNA following transi‐

[30] Derouiche, A, & Rauen, T. Coincidence of L-glutamate/L-aspartate transporter (GLAST) and glutamine synthetase (GS) immunoreactions in retinal glia: evidence for coupling of GLAST and GS in transmitter clearance. Journal of Neuroscience Re‐

[31] Higgs, M. H, & Lukasiewicz, P. D. Glutamate uptake limits synaptic excitation of ret‐

ent retinal ischemia. Molecular Brain Research (1994)., 27, 310–314.

inal ganglion cells. Journal of Neuroscience (2002)., 19, 3691–3700.

mental central retinal artery occlusion in the primate. Eye (2004)., 19, 455-463.

going vitrectomy. Archives of Ophthalmology (2003)., 121, 183-188.

ous fluid of patients with retinal detachment. Eye(2008).,22, 582-589.

83, 45-50.

2633e2637.

ma (2002)., 11, 396-405.

al(2001)., 39(4), 291-299.

search (1995)., 42, 131-143.


[21] Bertram, K. M, Bula, D. V, Pulido, J. S, Shippy, S. A, Gautam, S, Lu, M. J, Hatfield, R. M, Kim, J. H, Quirk, M. T, &Arroyo, J. G. Amino-acid levels in subretinal and vitre‐ ous fluid of patients with retinal detachment. Eye(2008).,22, 582-589.

[7] Thoreson, W. B, & Witkovsky, P. Glutamate receptors and circuits in the vertebrate

[8] Massey, S. C, & Miller, R. F. Excitatory amino acid receptors of rod-and cone-driven horizontal cells in the rabbit retina. Journal of Neurophysiology (1987)., 57, 645-59. [9] Massey, S. C, & Miller, R. F. N-methyl-D-aspartate receptors of ganglion cells in rab‐

[10] Lucas, D. R, & Newhouse, J. P. The toxic effect of sodium l-glutamate on the inner

[11] Sisk, D. R, & Kuwabara, T. Histologic changes in the inner retina of albino rats fol‐ lowing intravitreal injection of monosodium l-glutamate. Graefe's Archives of Clini‐

[12] Olney, J. W. The toxic effects of glutamate and related compounds in the retina and

[13] Vorwerk, C. K, Lipton, S. A, Zurakowski, D, Hyman, B. T, Sabel, B. A, &Dreyer, E. B. Chronic low-dose glutamate is toxic to retinal ganglion cells. Toxicity blocked by memantine. Invest igative Ophthalmology & Visual Science (1996)., 37, 1618–1624. [14] Olney J. W. Glutaate-induced retinal degeneration in neonatal mice. Electron micro‐ scopy of the acutely evolving lesion. Journal of Neuropatholgy & Experimental Neu‐

[15] Ju, W. K, &Kim, K. Y. Measuring glutamate receptor activation-induced apoptotic cell death in ischemic rat retina using the TUNEL assay. Methods in Molecular Biolo‐

[16] Casson, R. J. Possible role of excitotoxicity in the pathogenesis of glaucoma. Clinical

[17] Kaur, C, Foulds, W. S, & Ling, E. A. Hypoxia-ischemia and retinal ganglion cell dam‐

[19] Vorwerk C. K, Gorla M. S, &Dreyer, E. B. An experimental basis for implicating exci‐ totoxicity in glaucomatous optic neuropathy. Survey of Ophthalmology(1999)., 43

[20] Choi, D. W, &Rothman, S. M. The role of glutamate neurotoxicity in hypoxicischemic

neuronal death. Annual Review of Neuroscience (1990)., 13, 171-182.

layers of the retina. Archives of Ophthalmology (1957)., 58, 193–201.

retina. Progress in Retinal and Eye Research(1999)., 18, 765-810.

bit retina. Journal of Neurophysiology (1990)., 63, 16-30.

cal&Experimental Ophthalmology (1985)., 223, 250–258.

& Experimental Ophthalmology (2006)., 34, 54-63.

[18] Hernández, C, & Simó, R. Neuroprotection in diabetic retinopathy.

Clinical Ophthalmology(2008)., 2, 879-889.

Current Diabtes Report (2012).,12, 329-337.

the brain, Retina(1982)., 2, 341–359.

532 Ophthalmology - Current Clinical and Research Updates

rology(1969)., 28(3):455-74.

gy(2011)., 740:149-56.

Suppl 1, S142-150.

age.


[32] Matsui, K, Hosoi, N, & Tachibana, M. Active role of glutamate uptake in the synaptic transmission from retinal nonspiking neurons. Journal of Neuroscience (1999)., 19, 6755–6766.

[45] Ladanyi, M, & Beaudet, A. In-vivo labeling of (3H)D-aspartate uptake sites in mon‐

Excitotoxicity and Glaucoma http://dx.doi.org/10.5772/57605 535

[46] Harada, T, Harada, C, Watanabe, M, Inoue, Y, Sakagawa, T, Nakayama, N, Sasaki, S, Okuyama, S, Watase, K, Wada, K, & Tanaka, K. Functions of the two glutamate transporters GLAST and GLT-1 in the retina. Proceedings ofthe National Acaddemy

[47] Holcombe, D. J, Lengefeld, N, Gole, G. A, &Barnett, N. L. (The effects of acute intra‐ ocular pressure elevation on rat retinal glutamate transport. Acta Ophthalmologica

[48] Sarthy, V. P, Pignataro, L, Pannicke, T. Weick, M, Reichenbach, A, Harada, T, Tana‐ ka, K, &Marc, R. Glutamate transport by retinal Mülle cells in glutamate/aspartate

[49] Barnett, N. L, & Pow, D. V. Antisense knockdown of GLAST, a glial glutamate trans‐ porter, compromises retinal function. Investigative Ophthalmology & Visual Science

[50] Izumi, Y, Shimamoto, K, Benz, A. M, Hammerman, S. B, Olney, J. W, &Zorumski, C. F. Glutamate transporters and retinal excitotoxicity. Glia (2002). 39, 58–68.

[51] Reye, P, Sullivan, R, Fletcher, E. L, & Pow, D. W. Distribution of two splice variants of the glutamate transporter GLT1 in the retinas of humans, monkeys, rabbits, rats,

[52] Reye, P, Sullivan, R, &Pow, D. V. Distribution of two splice variants of the glutamate transporter GLT-1 in the developing rat retina. Journal of Comparative Neurology

[53] Rauen, T, Wiessner, M, Sullivan, R, Lee, A, & Pow, D. V. A new GLT1 splice variant: cloning and immunolocalization of GLT1c in the mammalian retina and brain,. Neu‐

[54] Naskar, R, Vorwerk, C. K, &Dreyer, E. B. Concurrent downregulation of a glutamate transporter and receptor in glaucoma. Investigative Ophthalmology & Visual Science

[55] Martin, K. R, Levkovitch-Verbin, H, Valenta, D., L, Baumrind, L, Pease, M. E, &Quig‐ ley, H. A. Retinal glutamate transporter changes in experimental glaucoma and after optic nerve transection in the rat. Investigative Ophthalmology & Visual Science

[56] Schuettauf, F, Thaler, S. Bolz, S, Kalbacher, S. H, Mankowska, A, Zurakowski, D, Zrenner, E, & Rejdak, R. Alterations of amino acids and glutamate transport in the DBA/2J mouse retina; possible clues to degeneration. Graefe's Archives of Clini‐

cal&Experimental Ophthalmology (2007)., 245, 1157–1168.

cats, and chickens. Journal of Comparative Neurology (2002)., 445, 1–12.

key retina. Cell & Tissue Research (1986)., 243, 59–63.

transporter-knockout mice. Glia(2005)., 49, 184–196.

rochemistry International (2004)., 45, 1095–1106.

Scandinavia, (2008)., 86, 408–414.

(2000)., 41, 585–591.

(2002)., 447, 323–330.

(2000)., 41, 1940–1944.

(2002)., 43, 2236–2243.

of Sciences of the United States of America(1998).,95, 4663–4666.


[45] Ladanyi, M, & Beaudet, A. In-vivo labeling of (3H)D-aspartate uptake sites in mon‐ key retina. Cell & Tissue Research (1986)., 243, 59–63.

[32] Matsui, K, Hosoi, N, & Tachibana, M. Active role of glutamate uptake in the synaptic transmission from retinal nonspiking neurons. Journal of Neuroscience (1999)., 19,

[33] Bringmann, A, Pannicke, T, Biedermann, B, Francke, M, Iandiev, I, Grosche, J, Wiede‐ mann, P, Albrecht, J, & Reichenbach, A. Role of retinal glial cells in neurotransmitter

[34] Storck, T, Schulte, S, Hofmann, K, &Stoffel, W. Structure, expression, and functional analysis of a Na(+)-dependent glutamate/aspartate transporter from rat brain. Pro‐ ceedings ofthe National Acaddemy of Sciences of the United States of Ameri‐

[35] Pines, G, Zhang, Y, & Kanner, B. I. Glutamate 404 is involved in the substrate dis‐ crimination of GLT-1, a (Na++K+)-coupled glutamate transporter from rat brain.

[36] Kanai, Y, & Hediger, M. A. Primary structure and functional characterization of a

[37] Fairman, W. A, Vandenberg, R. J, Arriza, J. L, Kavanaugh, M. P, & Amara, S. G. An excitatory amino-acid transporter with properties of a ligand-gated chloride channel.

[38] Arriza, I. L, Eliasof, S, Kavanaugh, M. P, & Amara, S. G. Excitatory amino acid trans‐ porter 5, a retinal glutamate transporter coupled to a chloride conductance. Proceed‐ ings ofthe National Acaddemy of Sciences of the United States of America(1997)., 94,

[39] Rauen, T, & Wiessner, M. Fine tuning of glutamate uptake and degradation in glial cells: common transcriptional regulation of GLAST1 and GS. Neurochemistry Inter‐

[40] Kanai, Y, & Hediger, M. A. The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects. Pflugers Archiv(2004).,

[41] Rauen, T, Taylor, W. R, Kuhlbrodt, K, & Wiessner, M. High-affinity glutamate trans‐ porters in the rat retina: a major role of the glial glutamate transporter GLAST-1 in

[42] Rauen, T. Diversity of glutamate transporter expression and function in the mamma‐

[43] Pow, D. V, Barnett, N. L, & Penfold, P. Are neuronal transporters relevant in retinal glutamate homeostasis? Neurochemistry International (2000)., 37, 191–198.

[44] White, R. D, & Neal, M. J. The uptake of L-glutamate by the retina. Brain Research

transmitter clearance. Cell &Tissue Research (1998)., 291, 19–31.

lian retina. Amino Acids(2000)., 19, 53–62.

Journal of Biological Chemistry (1995)., 270,17093-17097.

high-affinity glutamate transporter. Nature(1992)., 360, 467-471.

uptake and metabolism. Neurochemistry International (2009)., 54, 143-160.

6755–6766.

ca(1992)., 89:10955–10959.

534 Ophthalmology - Current Clinical and Research Updates

Nature(1995)., 375, 599-603.

national (2000)., 37, 179–189.

4155-4160.

447, 469–479.

(1976)., 111, 79–93.


[57] Park, C. K, Cha, J, Park, S. C, Lee, P. Y, Kim, J. H, Kim, H. S, Kim, S. A, Kim, I. B, & Chun, M. H. "Differential expression of two glutamate transporters, GLAST and GLT-1, in an experimental rat model of glaucoma. Experimental Brain Research (2009).. 197, 101–109.

tension glaucoma-like retinal degeneration in EAAC1-deficient mice. Neuroscience

Excitotoxicity and Glaucoma http://dx.doi.org/10.5772/57605 537

[69] Dhandapani, K. M, & Brann, D. W. Protective effects of estrogen and selective estro‐ gen receptor modulators in the brain. Biology of Reproduction (2002)., 67, 1379–1385.

[70] Lee, E. S, Sidoryk, M, Jiang, H, Yin, Z, & Aschner, M. Estrogen and tamoxifen reverse manganese-induced glutamate transporter impairment in astrocytes. Journal of Neu‐

[71] Prokai-Tatrai, K, Xin, H, Nguyen, V, Szarka, S, Blazics, B, Prokai, L, & Koulen, P. 17βestradiol eye drops protect the retinal ganglion cell layer and preserve visual func‐ tion in an in vivo model of glaucoma. Molecular Pharmacology (2013)., 10, 3253-3261.

[72] Riepe, R. E, &Norenburg, M. D. Müller cell localisation of glutamine synthetase in rat

[73] Marc, R. E, Murry, R. F, & Basinger, S. F. Pattern recognition of amino acid signatures

[74] Gorovits, R, Yakir, A, Fox, L. E, & Vardimon, L. Hormonal and non-hormonal regu‐ lation of glutamine synthetase in the developing neural retina. Brain Research & Mo‐

[75] Vardimon L. Neuroprotection by glutamine synthetase. Israel Medical Association

[76] Shaked, I, Ben-Dror, I, &Vardimon, L. Glutamine synthetase enhances the clearance of extracellular glutamate by the neural retina. Journal of Neurochemistry(2002).,

[77] Kruchkova, Y, Ben-Dror, I, Herschkovitz, A, David, M, Yayon, A, &Vardimon, L. Ba‐ sic fibroblast growth factor: a potential inhibitor of glutamine synthetase expression

[78] Pow, D. V, &Robinson, S. R. Glutamate in some retinal neurons is derived solely

[79] Izumi, Y., Hammerman, S. B., Kirby, C. O., Benz, A. M, Olney, J. W, & Zorumski, C. F. Involvement of glutamate in ischemic neurodegeneration in isolated retina. Visual

[80] Shen, F, Chen, B, J., Danias, J, Lee, K. C, Lee, K. H, Su, Y, Podos, S. M, &Mittag, T. W. Glutamate-induced glutamine synthetase expression in retinal Müller cells after short-term ocular hypertension in the rat. Investigative Ophthalmology & Visual Sci‐

[81] Zeevalk, G. D, &Nicklas, W. J. Evidence that the loss of the voltage-dependent Mg2+block at the N-methyl-D-aspartate receptor underlies receptor activation dur‐

in injured neural tissue. Journal of Neurochemistry (2001).,77(6), 1641-1649.

in retinal neurons. Journal of Neuroscience (1995)., 15, 5106–5129.

Letter (2009)., 465, 160-164.

rochemistry (2009)., 110, 530-544.

retina. Nature(1977)., 268(5621):654-655.

lecular Brain Research (1996)., 43, 321–329,

from glia. Neuroscience. (1994).,60(2), 355-366

Neuroscience (2003)., 20, 97-107.

ence (2004)., 45, 3107–3111.

Journal(2000)., Suppl:46-51

83(3):574-580.


tension glaucoma-like retinal degeneration in EAAC1-deficient mice. Neuroscience Letter (2009)., 465, 160-164.

[69] Dhandapani, K. M, & Brann, D. W. Protective effects of estrogen and selective estro‐ gen receptor modulators in the brain. Biology of Reproduction (2002)., 67, 1379–1385.

[57] Park, C. K, Cha, J, Park, S. C, Lee, P. Y, Kim, J. H, Kim, H. S, Kim, S. A, Kim, I. B, & Chun, M. H. "Differential expression of two glutamate transporters, GLAST and GLT-1, in an experimental rat model of glaucoma. Experimental Brain Research

[58] Ishikawa, M, Yoshitomi, T, Zorumski, C. F, & Izumi, Y. Effects of acutely elevated hydrostatic pressure in a rat ex vivo retinal preparation, Investigative Ophthalmolo‐

[59] Park, S. W., Kim, K. Y, Lindsey, J. D, Dai, Y, Heo, H. Nguyen, D. H, Ellisman, M. H, Weinreb, R. N, & Ju, W. K. A selective inhibitor of drp1, mdivi-1, increases retinal ganglion cell survival in acute ischemic mouse retina. Investigative Ophthalmology

[60] Yoneda, S, Tanaka, E, Goto, W, Ota, T, & Hara, H. Topiramate reduces excitotoxic

[61] Whitlock, N. A, Agarwal, N. Ma, J. X, & Crosson, C. E. Hsp27 upregulation by HIF-1 signaling offers protection against retinal ischemia in rats. Investigative Ophthalmol‐

[62] shikawa, M, Yoshitomi, T, Zorumski, C. F., & Izumi, Y. Downregulation of glutamine synthetase via GLAST suppression induces retinal axonal swelling in a rat ex vivo hydrostatic pressure model. Investigative Ophthalmology & Visual Science (2011)..

[63] Harada T, Harada, C, Nakamura, K, Quah, H. M, Okumura, A, Namekata, Saeki, K, Aihara, M, Yoshida, H, Mitani, A, &Tanaka, K. The potential role of glutamate trans‐ porters in the pathogenesis of normal tension glaucoma. Journal of Clinical Investi‐

[64] Russo, R, Cavaliere, F, Varanom G. P, Milanese, M, Adornetto, A, Nucci, C, Bonanno, G, Morrone, L. A, Corasaniti, M. T, & Bagetta, G. Impairment of Neuronal Glutamate Uptake and Modulation of the Glutamate Transporter GLT-1 Induced by Retinal Is‐

[65] Persson, M, & Rönnbäck, L. Microglial self-defence mediated through GLT-1 and

[66] Sullivan, R. K, Woldemussie, E, Macnab, L, Ruiz, G, Pow, DV. Evoked expression of the glutamate transporter GLT-1c in retinal ganglion cells in human glaucoma and in a rat model. Investigative Ophthalmology & Visual Science(2006)., 47(9):3853-3859.

[67] Shi, J, Zhang, Y. Q, & Simpkins, J. W. Effects of 17beta-estradiol on glucose transport‐ er 1 expression and endothelial cell survival following focal ischemia in the rats. Ex‐

[68] Namekata, K, Harada, C, Guo, X, Kikushima, K, Kimura, A, Fuse, N, Mitamura, Y, Kohyama, K, Matsumoto, Y, Tanaka, K, & Harada, T. Interleukin-1 attenuates normal

and ischemic injury in the rat retina. Brain Research (2003)., 967, 257-266.

(2009).. 197, 101–109.

536 Ophthalmology - Current Clinical and Research Updates

52, 6604-6616.

gation (2007)., 117, 1763–1770.

chemia. PLoS One(2013)., 8, e69250.

glutathione. Amino Acids(2012)., 42, 207-219.

perimantal Brain Research (1997)., 117, 200–206.

gy & Visual Science (2010)., 51,6414-6423.

& Visual Science (2011)., 52, 2837-2843.

ogy & Visual Science (2005)., 46, 1092-1098.


ing inhibition of neuronal metabolism. Journal of Neurochemistry (1992).. 59, 1211– 1220.

cells and the effects of ischaemia to the retina. Experimental Eye Research(1999)., 69,

Excitotoxicity and Glaucoma http://dx.doi.org/10.5772/57605 539

[94] Osborne, N.N, Safa, R, &Nash, M.S. Photoreceptors are preferentially affected in the rat retina following permanent occlusion of the carotid arteries. Vision Research

[95] Osborne, N. N, Ugarte, M, Chao, M, Chidlow, G, Bae, J. H, Wood, J.P.M., &Nash, M. S. Neuroprotection in relation to retinal ischemia and relevance to glaucoma. Survey

[96] Osborne, N. N, Wood, J.P. M, Chidlow, G, Bae, J. H, Melena, J, &Nash, M. S., Gan‐ glion cell death in glaucoma: what do we really know? British Journal of Ophthal‐

[97] Olney, J. W, Price, M. T, Salles, K. S, Labruyere, J, Ryerson, R, Mahan, K, Frierdich, G, & Samson, L. L-homocysteic acid: an endogenous excitotoxic ligand of the NMDA

[98] el-Asrar A. M, Morse P. H, Maimone, D, Torczynski, E, &Reder, A. T. MK-801 pro‐ tects retinal neurons from hypoxia and the toxicity of glutamate and aspartate. Inves‐

[99] Izumi, Y, Hammerman, S. B, Kirby, C. O, Benz, A. M, Olney, J. W, &Zorumski, C. F. Involvement of glutamate in ischemic neurodegeneration in isolated retina. Visual

[100] Romano, C, Price, M. T, Almli, T, Olney, J. W. Excitotoxic neurodegeneration in‐ duced by deprivation of oxygen and glucose in isolated retina. Investigative Oph‐

[101] Lees, G. J, & Leong, W. Differential effects of NBQX on the distal and local toxicity of glutamate agonists administered intrahippocampally. Brain Research (1993).. 628, 1–

[102] Osborne, N. N,&Herrera, A. J. The effect of experimental ischaemia and excitatory amino acid agonists on the GABA and serotonin immunoreactivities in the rabbit ret‐

[103] Weber, M, Bonaventure, N, &Sahel, J. A. Protective role of excitatory amino acid an‐ tagonists in experimental retinal ischemia. Graefes Archives of Clinical & Experimen‐

[104] Massey, S. C. Cell types using glutamate as a neurotransmitter in the vertebrate reti‐ na. In: Osborne, N.N., Chader, G.J. (Eds.), Progress in Retinal Research. Pergamon

331–342.

(1999).. 39, 3995–4002.

mology(1999).83, 980–986.

Neuroscience (2003)., 20, 97-107.

ina. Neuroscience (1994).59,1071–1081.

tal Ophthalmology (1995)., 233, 360–365.

Press, Oxford, (1990)., pp. 399–425.

7.

of Ophthalmology (1999).. 43 (Suppl. 1), 102–128.

receptor. Brain Research Bulletin (1987)., 19, 597–602.

thalmology & Visual Science(1998)., 39(2), 416-23.

tigative Ophthalmology &Visual Science(1992)., 33(12):3463-3468.


cells and the effects of ischaemia to the retina. Experimental Eye Research(1999)., 69, 331–342.

[94] Osborne, N.N, Safa, R, &Nash, M.S. Photoreceptors are preferentially affected in the rat retina following permanent occlusion of the carotid arteries. Vision Research (1999).. 39, 3995–4002.

ing inhibition of neuronal metabolism. Journal of Neurochemistry (1992).. 59, 1211–

[82] Chen, C-H, Alyahya, K, Gionfriddo, J. R, Dubielzig, R. R, &Madl, J. E. Loss of gluta‐ mate synthetase immunoreactivity from the retina in canine primary glaucoma, Vet‐

[83] Derouiche, A, & Rauen, T. Coincidence of L-glutamate/L-aspartate transporter (GLAST) and glutamine synthetase (GS) immunoreactions in retinal glia: evidence for coupling of GLAST and GS in transmitter clearance. Journal of Neuroscience Re‐

[84] Jablonski, M. M, Freeman, N. E, Orr, W. E, Templeton, J. P, Lu, L, Williams, R. W, & Geisert, E. E. Genetic pathways regulating glutamate levels in retinal Mülle cells.

[85] Carter-Dawson, L, Crawford, M. L, Harwerth, R. S, Smith, E. L, Feldman, R, Shen, F. F, Mitchell, C. K, & Whitetree, A. Vitreal glutamate concentration in monkeys with

[86] Louzada-Junior, P, Dias, J. J, Santos, W. F, Lachat, J. J, Bradford, H. F, & J. Coutinho-Netto. Glutamate release in experimental ischaemia of the retina: an approach using

[87] Neal, M. J, Cunningham, J. R, Hutson, P. H, & Hogg,, J. Effects of ischemia on neuro‐ transmitter release from the isolated retina. Journal of Neurochemistry(1994)., 62,

[88] Zeng, K, Xu, H, Mi, M, Zhang, Q, Zhang, Y, Chen, K, Chen, F, Zhu, J, Yu, X. Dietary taurine supplementation prevents glial alterations in retina of diabetic rats. Neuro‐

[89] Zuo, ZF, Zhang, Q, Liu, XZ. Protective effects of curcumin on retinal Müller cell in early diabetic rats. International Journal of Ophthalmology(2013)., 6(4):422-424. [90] El-Remessy, A. B, Khalifa, Y, Ola, S, Ibrahim, A. S, &Liou, GI. Cannabidiol protects retinal neurons by preserving glutamine synthetase activity in diabetes. Molecular

[91] Shen, X, Xie, B, Cheng, Y, Jiao, Q, &Zhong Y. Effect of pigment epithelium derived factor on the expression of glutamine synthetase in early phase of experimental dia‐

[92] Ferreira, I. L, Duarte, C. B, &Carvalho, A. P. Ca2+influx through glutamate receptorassociated channels in retina cells correlates with neuronal cell death.Europian Jour‐

[93] Osborne, N.N, DeSantis, L, Bae, J. H, Ugarte, M, Wood, J.P. M. Nash, M. S, & Chi‐ dlow, G. Topically applied betaxolol attenuates NMDA-induced toxicity to ganglion

betic retinopathy. Ocular Immunology & Inflammation(2011).,19(4), 246-254.

Investigative Ophthalmology & Visual Science (2002).., 43:2633-2637.

microdialysis. Journal of Neurochemistry (1992).,59, 358–363.

erinary Ophthalmology (2008)., 11, 150–157.

Neurochemical Research (2011)., 36, 594–603.

chemical Research(2009)., 34(2), 244-54.

nal of Pharmacology(1996)., 302:153-162.

search (1995)., 42:131–143.

538 Ophthalmology - Current Clinical and Research Updates

experimental glaucoma.

Vision(2010)., 16:1487-95

1025–1033.

1220.


[105] Dixon D. B, &Copenhagen, D. R. Two types of glutamate receptors differentially ex‐ cite amacrine cells in the tiger salamander retina. Journal of Physiology(1992)., 449, 589-606

[116] Kutsuwada, T, Kashiwabuchi, N, Mori, H, Sakimura, K, Kushiya, E, Araki, K, Me‐ guro, H, Masaki, H, Kumanishi, T, Arakawa, M, &Mishina, M. Molecular diversity of

Excitotoxicity and Glaucoma http://dx.doi.org/10.5772/57605 541

[117] Moriyoshi, K, Masu, M, Ishii, T, Shigemoto, R, Mizuno, N, &Nakanishi, S. Molecular cloning and characterization of the rat NMDA receptor. Nature(1991).,354(6348),

[118] Ikeda, K, Nagasawa, M, Mori, H, Araki, K, Sakimura, K, Watanabe, M, Inoue, Y, &Mishina, M. Cloning and expression of the epsilon 4 subunit of the NMDA receptor

[119] Meguro, H, Mori, H, Araki, K, Kushiya, E, Kutsuwada, T, Yamazaki, M, Kumanishi, T, Arakawa, M, Sakimura, K, &Mishina, M. Functional characterization of a hetero‐ meric NMDA receptor channel expressed from cloned cDNAs. Nature(1992) 357

[120] Ishii, T, Moriyoshi, K, Sugihara, H, Sakurada, K, Kadotani, H, Yokoi, M, Akazawa, C, Shigemoto, R, Mizuno, N, Masu, M, &Shigetada N. Molecular characterization of the family of the N-methyl-D-aspartate receptor subunits. Journal of Biological Chemis‐

[121] Monyer, H, Sprengel, R, Schoepfe,r R, Herb, A, Higuchi, M, Lomeli, H, Burnashev, N, Sakmann, B, &Seeburg, P. H. Heteromeric NMDA receptors: molecular and func‐

[122] Nakanishi, S. Molecular diversity of glutamate receptors and implications for brain

[123] Bai, N, Aida, T, Yanagisawa, M, Katou, S, Sakimura, K, Mishina, M, & Tanaka, K. NMDA receptor subunits have different roles in NMDA-induced neurotoxicity in the

[124] Bai, N, Hayashi, H, Aida, T, Namekata, K, Harada, T, Mishina, M, &Tanaka, K. Dock3 interaction with a glutamate-receptor NR2D subunit protects neurons from

[125] Suetake-Koga, S, Shimazaki, T, Takamori, K, Chaki, S, Kanuma, K, Sekiguchi, Y, Su‐ zuki, T., Kikuchi, T, Matsui, Y, & Honda, T. In vitro and antinociceptive profile of HON0001, an orally active NMDA receptor NR2B subunit antagonist. Pharmacology

[126] Lipton, S. A. Possible role for memantine in protecting retinal ganglion cells from glaucomatous damage. Survey of Ophthalmology(2003)., (Suppl 1), S38-S46.

[127] Reisberg, B, Doody, R, Stoffler, A, Schmitt, F, Ferris, S, & Mobius, H. J. Memantine in moderate-to-severe Alzheimer's disease. New England Journal of Medicine (2003).,

tional distinction of subtypes. Science (1992).,256(5060), 1217-21

the NMDA receptor channel. Nature (1992)., 358, 36–41.

channel. FEBS Letter (1992)., 313(1), 34-38.

function. Science(1992).,258(5082), 597-603.

excitotoxicity. Molecular Brain (2013)., 6:22e.

Biochemistry and Behavior (2006)., 84:134-141.

retina. Molecular Brain(2013)., 6:34e

348, 1333–1341.

31-37.

(6373), 70-4.

try(1993).,268(4), 2836-43


[116] Kutsuwada, T, Kashiwabuchi, N, Mori, H, Sakimura, K, Kushiya, E, Araki, K, Me‐ guro, H, Masaki, H, Kumanishi, T, Arakawa, M, &Mishina, M. Molecular diversity of the NMDA receptor channel. Nature (1992)., 358, 36–41.

[105] Dixon D. B, &Copenhagen, D. R. Two types of glutamate receptors differentially ex‐ cite amacrine cells in the tiger salamander retina. Journal of Physiology(1992)., 449,

[106] Diamond, J. S, &Copenhagen, D. R. The contribution of NMDA and non-NMDA re‐ ceptors to the light-evoked input-output characteristics of retinal ganglion cells. Neu‐

[107] Cohen, E. D, &Miller, R. F. The role of NMDA and non-NMDA excitatory amino acid receptors in the functional organization of primate retinal ganglion cells.Visual Neu‐

[108] Dong, C-J, Guo, Y, Agey, P, Wheeler, L, & Hare, W.A, Alpha-2 adrenergic modula‐ tion of NMDA receptor function as a major mechanism of RGC protection in experi‐ mental glaucoma and retinal excitotoxicity. Investigative Ophthalmology & Visual

[109] Hare, W. A, WoldeMussie, E, Lai, R. K, Ton, H, Ruiz, G, Chun, T, & Wheeler, L. Effi‐ cacy and safety of memantine treatment for reduction of changes associatedwith ex‐ perimental glaucoma in monkey, I: functional Measures. Investigative

[110] Lam, T. T, Abler, A.S., Kwong, J.M. K, Tso, M.O. M. N-methyl-D-aspartate (NMDA) induced apoptosis in rat retina. Investigative Ophthalmology & Visual Sci‐

[111] Manabe, S, &Lipton, S. Divergent NMDA signals leading to proapoptotic and antia‐ poptotic pathways in the rat retina. Investigative Ophthalmology & Visual Science

[112] Reichstein, D, Ren, L, Filippopoulos, T, Mittag, T, & Danias, J., Apoptotic retinal gan‐ glion cell death in the DBA/2 mouse model of glaucoma. Experimental Eye Research

[113] Russo, R, Cavaliere, F, Berliocchi, L, Nucci, C, Gliozzi, M, Mazzei, C., Tassorelli, C, Corasaniti, M. T, Rotiroti, D, Bagetta, G, &Morrone, L. A. Modulation of prosurvival and death-associated pathways under retinal ischemia/reperfusion: effects of NMDA

[114] Schuettauf, F, Stein, T, Choragiewicz, T, Rejdak, R, Bolz, S, Zurakowski, D. Varde, M, Laties, A, & Thaler, S. Caspase inhibitors protect against NMDAmediated retinal ganglion cell death. Clinical & Experimental Ophthalmology (2010)., 39, 545-554. [115] Shimazawa, M, Yamashima, T, Agarwal, N, & Hara, H. Neuroprotective effects of minocycline against in vitro and in vivo retinal ganglion cell damage. BrainResearch

receptor blockade. J.ournal of Neurochemistry (2008)., 107, 1347-1357.

Ophthalmology & Visual Science (2004)., 45, 2625-2639.

589-606

ron(1993).,11(4), 725-38.

540 Ophthalmology - Current Clinical and Research Updates

roscience(1994).,11(2), 317-32.

Science(2008)., 49, 4515-4522.

ence(1999)., 40, 2391-2397.

(2003).. 44, 385-392.

(2007)., 84, 13-21.

(2005)., 1053, 185-194


[128] Baltmr, A, Duggan, J, Nizari, S, Salt, T. E & Cordeiro, M. F. Neuroprotection in glau‐ coma-Is there a future role? Experimental Eye Research (2010)., 91, 554-566.

**Chapter 22**

**Regional Immune, Hormonal and Mediatory**

Artashes A. Zilfyan and Arto V. Zilfyan

http://dx.doi.org/10.5772/58229

immune deviation" (ACAID).

insufficiently.

**1. Introduction**

Additional information is available at the end of the chapter

**Mechanisms Responsible for Function of "Immune**

**Privilege of an Eye" at Senile and Complicated Cataracts**

Nowadays, in current biology and medicine the subject of wide discussion present paracrine and autocrine immune, endocrine and mediatory mechanisms functioning of which in all the integrative systems of the organism are realized due to principles of interregulation and interdependence. It is not excluded that similar mechanisms are also engaged in eye tunics, moreover that the hematoophthalmic barrier is characterized by a more stable selective permeability (as compared to other histohematic barriers) towards a wide range of endoge‐

In this concern, to our mind, studies aimed at elucidation of autonomous mechanisms engaged in sustaining the immune and endocrine homeostasis in the eye tunics are rather promising.

Hence, during the last 40 years the subject of special investigation became scientific research works relevant to the aspects of pathogenesis "active immunological tolerance" originating in eye tunics as a response to baring of antigenic determinants in eye tunics and tissues at a wide range of ophthalmological diseases. The entire symptom complex of *in situ* occurring immu‐ nological reactions is defined in modern ophthalmology as "anterior chamber associated

At the same time, regional mechanisms responsible for ACAID function are studied rather

In the mentioned aspect, cells identified in certain eye tunics should become the subject of specific discussion; besides their "main functions' these cells are provided with the immune,

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

nous active biological compounds of immune, hormonal and mediatory origin.

