Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

of radiant energy allows for minimal thermal diffusion and collateral damage (2). Melanin, the target chromophore in trabecular meshwork (TM) cells, has a thermal relaxation time of approximately 1 μs, whereas the pulse duration of the SLT is 3 ns. This disparate relationship between the thermal relaxation time of biological materials and the ultra-short pulse duration of the SLT prevents irradiated melanin particles from releasing heat into surrounding non-pigmented tissues and hence SLT induces no collateral heat damage. Other lasers, including the traditional Nd:YAG, argon, diode, and continuous wave, frequency-doubled Nd:YAG cannot achieve a similar effect because their pulse duration is much longer than the thermal relaxation time of the irradiated tissues. Therefore, heat transfer to surrounding tissue occurs and selectivity cannot be achieved.

HISTOPATHOLOGY

Histopathological study evaluating SLT in human and animal eyes has shown that the principles of selective photothermolysis are observed after irradiation with SLT

(3). Absorption occurs within pigmented granules in the TM cells, which undergo bleaching and disruption upon irradiation by SLT. For particular cells that are loaded heavily with melanin granules, the disruption induced by SLT can be sufficiently intense to result in cell death. However, it is important to be aware that other cells present in the immediate vicinity of such cells disrupted by the SLT remain unaffected as selective photothermolysis induces no thermal diffusion, which could have resulted in collateral cell damage or photocoagulation of the collagenous tissues of the TM. Figure-1a shows phase contrast micrograph of pigmented and non-pigmented TM cells. The photomicrograph in Fig. 1b shows a fluorescent viability/cytotoxicity assay after irradiation with selective laser trabeculoplasty (SLT). Only the pigmented TM cells

Fig. 1. (a) Phase contrast micrograph of pigmented and non-pigmented trabecular meshwork (TM) cells after selective laser trabeculoplasty (SLT). (b) Photomicrograph showing fluorescent viability/cytotoxicity assay after irradiation with SLT. Only the pigmented TM cells exhibit nuclear staining and absence of cytoplasmic staining, which indicates cell death (grey arrow). The non-pigmented TM cells were not affected with SLT, as shown by the presence of cytoplasmic staining and absence of nuclear staining in these cells (white arrow) (courtesy: Mark A Latina, MD).

Fig. 4. Transmission electron microscopy of owl monkey trabecular meshwork (TM) 24 h post-SLT treatment showing healthy trabecular beams and healthy non-pigmented TM cells without evidence of any thermal damage and also showing presence of extracellular pigments. (courtesy: Mark A. Latina, MD).

Biochemical Mediators

The existence of a cell-to-cell signaling mechanism has been described recently, which provides a cellular and molecular basis for the regulation of outflow across the conventional aqueous pathway after SLT (9,10). When cultured human TM endothelial cells (TMEs) are lasered, using the same parameters as during SLT, the TMEs become activated and release a dozen cytokine/chemokine factors. These factors upon binding to Schlemm’s endothelial cells (SCEs) induce an increase in SCE-permeability in vitro. This mechanism is also activated in situ when human TM tissues are lasered using corneal rims remaining after corneal transplantation surgery. Thus, it is postulated that there is a TME-driven mechanism regulating SCE-permeability that can account for the effect of SLT to lower the IOP by promoting flow across the SCE-barrier (9,10).

Monocytes/macrophages are recruited into the TM after both ALT and SLT and likely play an important role in the mechanism of action of both procedures. Alvarado reported in 1992 that monocytes are recruited to the TM after ALT (11). Most recently, Alvarado has determined in collaborative studies with Dr. J. Katz, MD, that there are approximately 15,000 monocytes transiting across the TM under baseline conditions in the adult human eye. This number increases fivefold to approximately 75,000 monocytes in eyes irradiated by SLT (personal communication from J. Alvarado & J. Katz). The reader is reminded of the important studies of Feder and Dueker carried out over two decades ago showing that when autologous monocytes are added into the anterior chamber of rabbit eyes there is a major decrease in the IOP and a concomitant increase in outflow facility (12). It is likely that upon returning to circulation by passing into Schlemm’s canal, monocytes can return to either eye where they become engaged in surveillance and maintenance of aqueous outflow homeostasis. We speculate that monocytes, acting as the most important cell type of the innate immune system, may be responsible for the bilateral effect documented after SLT to only one eye.

In addition, cytokines are also involved in the expression of certain metalloproteinases and stimulate the remodelling of the extracellular matrix of the TM and increase aqueous flow across the extracellular matrix (13). Hence, SLT probably stimulates the intrinsic system to remodel the TM without causing observable mechanical or thermal damage to the lasered area.

TREATMENT TECHNIQUE

The SLT laser has a fixed spot size of 400 μm in diameter, fixed pulse duration of 3 ns, and the power is adjustable from 0.2 to 1.7 mJ (see Table 1). With the help of a goniolens, the helium-neon laser-aiming beam is focused on the pigmented TM and its spot size of 400 μm is large enough to encompass the entire antero-posterior extent of the TM. The visible endpoints typical of conventional ALT, such as blanching of the TM or bubble formation within the TM, are not seen with SLT. To determine the optimum energy level, the SLT laser energy is initially set at 0.8 mJ and then it is adjusted in 0.1 mJ increments until bubble formation is visualized anterior to TM. Standard therapy is to deliver contiguous but non-overlapping 50 laser spots over 180° or 100 laser spots over 360° of TM.

The time required for IOP reduction to be observed after SLT has been found to be highly variable, but a significant response is often seen 1 day post-laser. Frequently, it takes about 4–6 weeks to result in IOP reduction, but in some patients the response may take even longer.

Clinical Use

SLT as initial primary therapy or as an adjunct therapy in different forms of openangle glaucoma (OAG) and OHT has been shown effective in reducing IOP by an average 4.5–8.7 mmHg or by 18–32% depending on duration of follow-up in various studies as shown in Table 2. A prospective, non-randomized study by McIlraith et al. (14) has reported SLT to be equally efficacious to latanoprost 0.005% in reducing IOP in OAG or OHT over 12-month period, reducing IOP by a mean value of 8.3 mmHg (31%) in SLT group and 7.7 mmHg (30.6%) in latanoprost group. Randomized clinical trials have shown efficacy of SLT comparable to that of ALT in reducing IOP in OAG (see Table 3). In these studies, the mean reduction in IOP was 5–6 mmHg or 20–30% with SLT and 4–6 mmHg or 18–21% with ALT. Additional IOP reduction can be

Table 1

Selective Laser Trabeculoplasty (SLT) Laser (Lumenis Inc.)

Specifications

Frequency-doubled Q-switched Nd:YAG Wavelength: 532 nm

Spot size (fixed): 400 μm Pulse duration (fixed): 3 ns

Energy per pulse (variable): 0.2–1.7 mJ usually starts at 0.6 mJ

Applications: 50 spots for 180° angle 100 spots for 360° angle

are typically easy to manage (15–17). As expected, no peripheral anterior synechiae has been reported in eyes treated with SLT.

In summary, SLT has been shown safe and effective treatment modality for various forms of OAG and OHT. The preservation of intact TM architecture with SLT makes it potentially a repeatable procedure. It may be considered for primary treatment for newly diagnosed OAG or OHT in addition to its use as an adjunct modality in various stages of glaucoma management.

REFERENCES

1.Anderson RR, Parrish JA. Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science 1983;220(4596):524–527.

2.Park CH, Latina MA, Schuman JS. Developments in laser trabeculoplasty. Ophthalmic Surg Lasers 2000;31(4):315–322.

3.Latina MA, Park C. Selective targeting of trabecular meshwork cells: in vitro studies of pulsed and CW laser interactions. Exp Eye Res 1995;60:359–372.

4.Noecker RJ, Kramer TR. Comparison of the acute morphologic changes after selective laser trabeculoplasty and argon laser trabeculoplasty in human eye bank eyes. Ophthalmology 2001;108(4):773–779.

5.Hollo G. Argon and low energy pulsed Nd:YAG laser trabeculoplasty. Acta Ophthalmol Scand 1996;74:126–131.

6.Melamed S, Pei J, Epstein DL. Short term effect of argon laser trabeculoplasty in monkeys. Arch Ophthalmol 1985;103(10):1546–1552.

7.Bylsma SS, Samples JR, Acott TS, Van Buskirk EM. Trabecular cell division after argon laser trabeculoplasty. Arch Ophthalmol 1988;106:544–547.

8.Alvarado J, Murphy C, Juster R. Trabecular meshwork cellularity in primary open-angle glaucoma and nonglaucomatous normals. Ophthalmology 1984;91:564–579.

9.Alvarado JA, Alvarado RG, Yeh RF, Franse-Carman L, Marcellino GR, Brownstein MJ. A new insight into the cellular regulation of aqueous outflow: how trabecular meshwork endothelial cells drive a mechanism that regulates the permeability of Schlemm’s canal endothelial cells. Br J Ophthalmol 2005;89(11):1500–1505.

10.Alvarado JA, Yeh RF, Franse-Carman L, Marcellino GR, Brownsein MJ: Interactions between endothelia of the trabecular meshwork and of Schlemm’s canal: a new insight into the regulation of aqueous outflow in the eye. Trans Am Ophthalmol Soc 2005;103:155–170.

11.Alvarado JA, Murphy CG. Outflow obstruction in pigmentary and primary open angle glaucoma. Arch Ophthalmol 1992;110(12):1769–1778.

12.Feder RS, Dueker DK. Can macrophages cause obstruction to aqueous outflow in rabbits? Int Ophthalmol 1984;7(2):87–93.

13.Acott T, Wirtz M. Biochemistry of aqueous outflow. In: Krupin T, ed. The Glaucomas. St Louis: Mosby; 1996:281–305.

14.McIlraith I, Strasfeld M, Colev G, Hutnik CM. Selective laser trabeculoplasty as initial and adjunctive treatment for open-angle glaucoma. J Glaucoma 2006;15(2):124–230.

15.Melamed S, Ben Simon GJ, Levkovitch-Verbin H. Selective laser trabeculoplasty as primary treatment for open-angle glaucoma: a prospective, nonrandomized pilot study. Arch Ophthalmol 2003;121:957–960.

16.Latina MA, Sibayan SA, Shin DH, et al. Q-switched 532-nm Nd: YAG laser trabeculoplasty (selective laser trabeculoplasty): a multi-center, pilot, clinical study. Ophthalmology 1998;105(11):2082–2088.

17.Damji KF, Shah KC, Rock WJ, et al. Selective laser trabeculoplasty vs. argon laser trabeculoplasty. Br J Ophthalmol 1999;83:718–722.

18.Weinand FS, Althen F. Long-term clinical results of selective laser trabeculoplasty in the treatment of primary open angle glaucoma. Eur J Ophthalmol 2006;16(1):100–104.

19.Cvenkel B. One-year follow-up of selective laser trabeculoplasty in open-angle glaucoma. Ophthalmologica 2004;218(1):20–25.

20.Lai JSM, Chua JKH, Tham CCY, Lam DSC. Five-year follow up of selective laser trabeculoplasty in Chinese eyes. Clin Exp Ophthalmol 2004;32(4):368–372.

21.Rozsival P, Kana V, Hovorkova M. [Selective laser trabeculoplasty] Cesk Slov Oftalmol 2004;60(4):267–274.

22.Melamed S, Ben Simon GJ, Levkovitch-Verbin H. Selective laser trabeculoplasty as primary treatment for open-angle glaucoma: a prospective, nonrandomized pilot study. Arch Ophthalmol 2003;121:957–960.

23.Gracner T. Intraocular pressure response to selective laser trabeculoplasty in the treatment of primary open angle glaucoma. Ophthalmologica 2001;215:267–270.

24.Damji KF, Bovell AM, Hodge WG, Rock W, Shah K, Buhrmann R, Pan YI. Selective laser trabeculoplasty versus argon laser trabeculoplasty: results from a 1-year randomized clinical trial. Br J Ophthalmol 2006;90(12):1490–1494.

25.Martinez-de la Casa JM, Garcia-Feijoo J, Castillo A, et al. Selective vs. argon laser trabeculoplasty: hypotensive efficacy, anterior chamber inflammation, and postoperative pain. Eye 2004;18(5):498–502.