Cyclodialysis, i.e., separation of the ciliary body from scleral spur, allowing free communication between anterior chamber and SCS, was the first surgical intervention for glaucoma that increases AH outflow via the uveoscleral pathway. Classic transscleral cyclodialysis ab externo was first described by Leopold Heine in 1905. When successfully performed, cyclodialysis reduces IOP not only by enhancing drainage of AH via the SCS and choroid but also by reducing AH production because restriction of blood supply to the ciliary body causes atrophy (“ciliary shutdown”) [78, 79]. The ab externo cyclodialysis procedure has been abandoned in clinical practice, however, due to an unacceptably high rate of complications (e.g., severe intra- and postoperative bleeding from the scleral vessels, profound postoperative hypotony), the failure of the cyclodialysis cleft to remain open over time (mainly due to scarring), and the advent of trabecular filtration surgery.

In cyclodialysis ab interno procedures, the integrity of the conjunctiva is spared and space-retaining substances with an extended duration are used in an attempt to keep the cyclodialysis cleft open and prevent scarring [80]. A variety of such space-retaining substances have been investigated, but finding substances that stay in place long enough and prevent scarring has been a challenge. Portney treated five eyes with severe, intractable, secondary angle-closure glaucoma with a cyclodialysis procedure that utilized a T-shaped silicone elastomer implantation [81]. The technique was unsuccessful, largely because of an inflammatory reaction and fibrous scar formation that surrounded the implant and obliterated the cyclodialysis cleft. The use of hylan gel as a space retainer was pioneered by Wirt and Draeger, working with Bill, in the cynomolgus monkey model [82] (cited by Klemm et al. [80]). Subsequently, working with Klemm and Balazs, Wirt and Draeger investigated two modified forms of hylan gel with different molecular weights (8,000 kDa and 25,000 kDA) as space retainers in 12 nonglaucomatous eyes of six owl monkeys that underwent cyclodialysis ab interno [80]. Postoperatively, IOP was effectively reduced from the preoperative level. Histological evaluation of enucleated eyes on postoperative days 140, 155, and 210 revealed no tissue reactions or inflammation, and with one exception the cyclodialysis cleft remained widely open for several months.

Jordan et al. reported cyclodialysis ab interno in a series of 20 patients (28 treated eyes) with intractable glaucoma [79]. The viscoelastic substance Healon (1 % sodium hyaluronate with a viscosity of 300,000 mPas and a molecular weight of 4.0 million daltons) was the space retainer left in the SCS at the end of surgery; the substance is usually resorbed within a few days after surgery. The mean baseline IOP was 34.3 mmHg despite maximum therapy, and a mean of 4.4 previous interventions had been performed. Absolute success was defined as lowering IOP to <21 mmHg without further medication or intervention and qualified success as lowering IOP to <21 mmHg with topical medication or further surgery. The mean follow-up was 122 days. Postoperatively, the mean IOP was 14.6 mmHg. After a mean of 60 days, 21 eyes (75 %) required further surgical intervention due to return of uncontrolled IOP. Qualified success was achieved in four eyes (14.3 %), with mean follow-up of 384 days (range 3–573 days), and absolute success in three eyes (10.7 %), with mean follow-up of 203 days (range 20–322 days). The greatest success was observed in phakic eyes, followed by pseudophakic and aphakic eyes. Patients experienced no postoperative hypotony, localized infection or endophthalmitis, or loss of vision. The authors concluded that although they did not demonstrate the functional efficacy of cyclodialysis ab interno, the procedure was easy to perform and offered atraumatic access to the SCS drainage route with a low rate of side effects. They further suggested that other viscoelastic substances with a higher viscosity and molecular weight or the use of slowly resorbable elastic implants might more effectively prevent closure of the cyclodialysis cleft—ideally, for approximately 3 months so that wound healing is completed.

Several attempts have been made to increase AH drainage through the uveoscleral pathway with novel surgical techniques, abandoning the cyclodialysis approach but further pursuing the use of space-retaining substances or devices to keep the pathway open long term. Some of these approaches are reviewed below.

A method reported by Ozdamar et al. employed implantation of a modified (trimmed for size) Krupin eye valve with a disk (typically used for episcleral fixation) into the SCS to increase uveoscleral outflow [83] in four painful-blind eyes of four patients with neovascular glaucoma complicating diabetic retinopathy (n = 3) and chronic angle-closure glaucoma (n = 1). The anterior tube part of the implanted device courses from the anterior chamber through the long scleral tunnel to drain AH into the SCS. The mean preoperative IOP in patients on two antiglaucoma medications was 58.5 mmHg (range 45–65 mmHg). Postoperatively, mean IOP was reduced to 14.2 mmHg at 1 week, 13.5 mmHg at 1 month, 15 mmHg at 3 months, and 17 mmHg (range 12–24 mmHg) at the last follow-up (timing not stated). “Successful control of IOP” (not specifically defined in the report, but ranging from 12 to 19 mmHg) at the last examination was achieved in 3 of 4 patients (i.e., 75 %). Postoperative hypotony occurred in only one patient in whom the procedure caused choroidal detachment; there were no serious cases of postoperative bleeding or infection, and none of the eyes had developed tube erosion or suprachoroidal hemorrhage as of the last follow-up.

Yablonski has reported a novel approach to trabeculectomy that utilizes an internal tube shunt for suprachoroidal drainage [84]. In a pilot study in 23 eyes in 23 patients with OAG, only 3 of whom had a history of incisional glaucoma surgery, a deep sclerectomy was performed under a scleral flap, producing an intrascleral lake. A small silicone tube was then placed between the intrascleral lake and the SCS, with a trabeculectomy stoma and a peripheral iridectomy allowing easy flow of AH into the tube. After a mean follow-up of 324 days, the mean postoperative IOP had dropped to 13.8 mmHg from a preoperative value of 25.4 mmHg, and patients were using a mean of 1.1 medications for IOP control compared with 3.0 preoperatively. The size of the surgically created bleb was substantially smaller in these eyes than in 45 control eyes that underwent conventional trabeculectomy, and postoperative outflow facility was significantly increased only in the control eyes. Eighteen of the 23 eyes required laser lysis of the scleral nylon sutures or postoperative 5-fluorouracil to control IOP. Yablonski attributed the success of this trabeculectomy with internal tube shunt procedure mostly to increased access of the AH to the SCS, where the protein colloid osmotic pressure of uveal blood results in AH absorption.

Other techniques utilizing a silicone tube to shunt AH from the anterior chamber to the SCS have been reported by several other investigative teams [85–87]. Jordan et al. reported their study of an ab externo procedure conducted in 31 eyes of 31 patients with uncontrollable refractory glaucoma (i.e., a mean baseline IOP of 44.3 mmHg despite maximum therapy, including a mean of 3.5 previous surgical interventions) [86]. The silicone tube was fed through the anterior chamber and connected intrasclerally to the SCS via a deep posterior scleral flap. Mean IOP was reduced to 13 mmHg in 70 % of all eyes at 30 weeks after surgery. Success, defined as lowering IOP to <21 mmHg without further medication or intervention, was achieved in 60 % of eyes at 52 weeks postoperatively and in 40 % at 76 weeks. There were no serious complications, no severe postoperative hypotony or suprachoroidal bleeding, and no localized or general inflammation related to the implant. However, anterior chamber lavage was required in two patients because of intracameral bleeding, and dislocated tubes had to be removed from two patients because of corneal endothelial contact. The mean functional survival of the shunt was 56 weeks, with an initial peak of failure after only 4 weeks and a second peak after 1 year. Scarring in the SCS was the rate-limiting factor in long-term success, with connective tissue formation (fibroblast reaction) observed under ultrasound biomicroscopy at the posterior lumen of the tube in failed eyes.

Palamar et al. reported their retrospective study of an ab externo procedure similar to that used by Jordan et al. but using a modified silicone implant with no valve implanted into the SCS [87]. They treated 15 eyes in 14 patients with intractable glaucoma (7 eyes with OAG, 4 with glaucoma secondary to trauma, 4 with juvenile glaucoma) who were receiving two or more antiglaucoma medications and who had undergone at least one prior failed glaucoma surgery. The mean follow-up time was 17.1 months (range 10–28 months). The mean baseline IOP in the 15 eyes was 33 mmHg. A 30 % postoperative decrease in IOP was achieved in 66.7 % of eyes. Functional success, defined as lowering IOP to ≤21 mmHg both with and without medication at 6 months after surgery, was 93.3 %; total success, defined as lowering IOP to ≤21 mmHg without medication at 6 months after surgery, was 13.3 %. The mean number of antiglaucoma medications dropped from a mean of 3.8 (range 2–5) before surgery to a mean of 2.2 (range 0–4) after surgery. Only minor complications were seen, with the occurrence of shallow choroidal detachment in all eyes considered to be proof of uveoscleral drainage of AH.

Unal et al. also used an ab externo procedure similar to that of Jordan et al. to implant a silicone tube with the anterior end in the anterior chamber and the posterior end in the SCS in 24 glaucomatous eyes in 24 patients unresponsive to maximal medical treatment (including seven with earlier trabeculectomy). The glaucoma diagnoses in these eyes included POAG (n = 5), neovascular (n = 6), uveitic (n = 5), secondary to vitreoretinal surgery with silicone injection (n = 2), pseudoexfoliative (n = 2), congenital (n = 2), traumatic (n = 1), and juvenile (n = 1). The mean preoperative IOP was 32.8 mmHg (range 24–50 mmHg). Patients were followed for a mean of 24.4 weeks (range 4–78 weeks) after surgery. Mean postoperative IOPs were significantly reduced from preoperative baseline: 8.5, 12.9, 17.0, 15.3, 18.3, and 15.1 mmHg, respectively, for 1 day, 1 week, and 1, 3, 6, and 12 months after surgery. Failure was defined as a postoperative IOP >21 or <5 mmHg after 3 months, complete success was defined as eyes not failed and not on supplemental medical therapy, and qualified success as eyes not failed with or without supplemental medical therapy. The complete success rate was 95.8 % at 1 week after surgery, 79.2 % at 1 and 3 months, and 63.3 % at 6 and 12 months. Qualified success was achieved in 95.8 % at 1 week and 87.5 % at 1, 3, 6, and 12 months. The success rate was significantly higher in eyes without earlier trabeculectomy. The surgery failed in seven eyes, with three requiring reoperation for glaucoma. Complications included early hypotony in six eyes, fibrin reaction in the anterior chamber in three eyes, and intracameral bleeding in two eyes, with one requiring anterior chamber lavage. No postoperative infection or choroidal or retinal detachment was observed. The authors concluded that their SCS implantation procedure effectively reduced IOP with a lower rate of serious complications than frequently occurs with trabeculectomy and could be a preferred initial surgery—particularly in cases without previous trabeculectomy.

Gold has been used as a biocompatible material for the development of another type of shunt connecting the anterior chamber with the SCS. Based on a design concept developed in 2001 by Gabriel Simon, the SOLX Gold Shunt (GMS; SOLX Ltd, Boston, MA) is a micro-device marketed in Canada and select European countries but not yet approved for use in the USA. This shunt is a nonvalved flat-plate, rectangular (2.3 mm W × 5.2 mm L × 44 μm thick) drainage device made of 24-karat medical-grade gold. Two plates are welded together, with two rounded projections on the distal end for anchoring the device in the SCS and with a gently curved proximal end that projects into the anterior chamber. A grid of holes in the anterior and posterior ends allows AH to flow into and out of the device, respectively. The device is implanted using an ab externo technique.

The first peer-reviewed publication on the gold shunt [88] reported a pilot study in 38 patients with advanced glaucoma (66 % with primary open-angle glaucoma (POAG)) and uncontrolled IOP, more than half of whom had a history of a failed glaucoma surgery or drainage device. After surgery, patients were followed for a mean of 11.7 months. The mean preoperative IOP in these patients was 27.6 mmHg. Surgical success was defined as IOP <22 and >5 mmHg with or without medication at the last follow-up; complete success was defined as achievement of the same mmHg criteria but without medication. Implantation of the device resulted in a statistically significant mean IOP decrease from baseline of 9 mmHg (mean = 18.2 mmHg), with a surgical success rate of 79 % and a complete success rate of 13.2 %. The most frequent complication was mild to moderate hyphema (eight patients; 21 %), with shunt exposure, synechia formation, and exudative inferior retinal detachment reported in one patient each. The authors concluded that the device and procedure were safe and effective and could be an alternative to trabeculectomy.

A series of publications from Italian investigators have further elucidated the efficacy and safety of the gold micro shunt. In 2010, Mastropasqua et al. [89] reported their in vivo analysis of conjunctival features observed using confocal laser-scanning microscopy following implantation of the gold micro shunt in 14 eyes of 14 patients with uncontrolled POAG who had a history of multiple failed incisional surgeries. After implantation of the gold shunt, eyes were examined at follow-up times ranging from 3 to 20 months (mean = 15.4 months). Based on the degree of IOP control achieved and on evidence of surgical success, the patients were divided into two analysis groups. Group 1 (n = 8) comprised patients with successful implantation, defined as a 1/3 reduction from their preoperative IOP with or without medications. Group 2 (n = 6) comprised patients with failed implantations, defined as less than 1/3 reduction in IOP with maximal tolerated medical therapy. The mean postoperative IOP was significantly higher in patients with failed implantations than in those with success (32.3 mmHg vs. 14 mmHg, respectively) despite similar preoperative IOP in the two groups. The main outcome measures were the mean density and area of conjunctival mean microcysts. The results showed that successful gold shunt implantation significantly increased conjunctival microcyst density and surface area at the site of device insertion (five- to sixfold higher in Group 1 than in Group 2). The authors considered this finding to be evidence of AH percolation through the scleral layers and then the conjunctiva, leading them to conclude that uveoscleral outflow of AH is enhanced by this device.

The following year, another publication that included authors from the same team as the 2010 report described evaluation of the gold micro shunt in a 2-year study of 55 eyes of 55 patients with refractory glaucoma despite maximal medical treatment [90]. The patients had previously undergone a mean of 1.9 (range 1–5) surgical interventions for glaucoma. Prior to gold shunt implantation, the patients’ mean IOP was 30.8 mmHg (range 22–58 mmHg). At 2 years, 37 eyes (67.3 %) were deemed a qualified success and 3 eyes (5.5 %) a complete success. In eyes that achieved success, mean IOP had dropped from a preoperative mean of 27.6 mmHg to 13.7 ± 2.98 mmHg; the mean number of medications decreased from 2.5 preoperatively to 1.4 ± 0.7 postoperatively. Twenty-one of the 55 patients experienced mild to moderate postoperative adverse events, with mild or moderate hyphema the most common. The authors determined that development of a thin membrane that obstructed the anterior holes of the shunt in 12 patients from the failure group (66.7 % of failures) was the most important factor contributing to lack of efficacy.

In 2012, an investigative team including authors from the previous two publications coming out of Italy [91] reported histological features of failed GMS implantations in an interventional case series study of 5 eyes in 5 patients who had received the gold micro shunt for refractory POAG. When the shunts were removed, 4 of 5 were found to have been correctly placed into the anterior chamber and SCS, so mislocation did not appear to be the main issue responsible for the poor efficacy. Examination of the failed shunts revealed connective tissue filling all the inner spaces of the device, creating a thick fibrotic capsule surrounding both ends of the shunt that impeded AH flow through the shunt.

The gold micro shunt, although composed of a biologically inert material, has some of the same problems with fibrotic obstruction as the silicone shunts used to improve uveoscleral outflow. However, an advantage is the ability of the surgeon to successively open the device after implant by applying a laser to the fenestrations in its anterior chamber component, allowing in vivo postoperative adjustment of the outflow [92]. Because the shunt is not resorbable, a disadvantage compared with the silicone shunts is the presence of a permanent implant in the AC and SCS, with risk of erosion or exposure of the device.

Another novel and experimental procedure for improving uveoscleral outflow of AH is ab interno implantation of a fenestrated micro-stent composed of a biocompatible polyamide material—the CyPass Micro-Stent (Transcend Medical, Menlo Park, CA)—into the supraciliary space [93–97]. Because CyPass implantation is ab interno, conjunctiva sparing without surgical trauma to the sclera, it has the additional advantage of minimizing tissue inflammation and subsequent fibrosis. The ab interno surgical approach involves no scleral penetration and also leaves the trabecular meshwork intact. Using a special manual applier, the CyPass Micro-Stent is placed in the supraciliary space below the scleral spur at the iris root, either through a clear corneal incision or through the primary phacoemulsification incision when combined with cataract removal. CyPass stent is approved in the EU and under FDA investigation in the USA.

Ianchulev et al. [93] first reported on 81 glaucomatous (OAG) eyes that underwent cataract surgery (phacoemulsification) followed by CyPass implantation. At 6 months after surgery, the mean IOP had decreased to 16 mmHg from a preoperative mean value of 22.9 mmHg. The procedure was well tolerated, with postoperative complications of shallow anterior chamber and transient hyphema in one patient each. The following year, Craven et al. reported on safety outcomes of 121 eyes that underwent phacoemulsification and CyPass implantation [97]. The adverse events following the procedure were transient hyphema (n = 8), persistent inflammation (n = 1), branch retinal vein occlusion (n = 1), and diabetic macular edema exacerbation (n = 1).