Redefining glaucoma

  The past decade has seen great strides made in the management of glaucoma. From the refinement of optical coherence tomography (OCT) imaging of the optic disc and retinal nerve fibre layer (RNFL) to the development of preservative-free prostaglandin analogs and the introduction of minimally invasive glaucoma surgery (MIGS), glaucoma treatment has changed for the better. However, we still have a long way to go. Several promising drug classes have not lived up to the hype they had generated, and all the new medications recently released on to the market have been variations or combinations of older molecules. Neuroprotection has not yet entered the general clinics and stem cell therapy is still in the realm of science fiction. So where will glaucoma management find itself 10 years from now? Diagnostics “Although major advances have been made in OCT imaging, there are still a lot of issues to work out. Image quality remains a problem, particularly the signal-to-noise ratio in advanced disease,” explained Hans Lemij MD, PhD, of The Rotterdam Eye Hospital, The Netherlands. Because the thin tissue of interest left over in advanced disease is more difficult to detect, the signals tend to get obscured by the noise inherent to the current technology. “As such, the monitoring of advanced glaucomatous damage is in need of something else, something more precise, because measurement variability becomes too large, both in imaging and in functional testing,” observed Dr Lemij. Would that be more advanced OCT, or another modality entirely? “I don’t know. I’ve been thinking about it for years now, but I haven’t come up with the answer, nor do I know of anyone else who has.” He is, however, actively investigating. “It turns out that with advanced glaucomatous damage, the RNFL tissue not only thins, but it also becomes more transparent,” he said, describing the decreased attenuation coefficient that characterises the tissue. Dr Lemij’s team has developed a new algorithm that combines the tissue’s transparency measurements with those of the tissue’s thickness, allowing the technology to highlight the characteristic wedge-shaped defects seen in glaucoma. “This might shed more light on the pathogenesis of the disease.” What about the future of diagnostics? “I doubt anything will replace OCT in the near future,” predicts Dr Lemij. “It’s here to stay for at least 10 more years, especially for early and intermediate disease. A possible advance in follow-up might be found in visual field testing with other stimuli, other backgrounds or other algorithms,” he added. Neuroprotection “Maintaining low intraocular pressure (IOP) is still the best neuroprotective strategy that we’ve come up with, but unfortunately it’s impossible in some patients and insufficient in others,” says Francesca Cordeiro MD, PhD, UCL and Imperial College London, UK. “Both retinal ganglion cell loss and optic nerve atrophy can independently occur with IOP at normal levels.” How might this be prevented? “Pharmacologic goals are to counteract oxidative stress and prevent apoptosis,” said Dr Cordeiro. There are medications known to do this, but whether this applies to the loss encountered in glaucoma remains to be seen. Neuroprotection has not made the same type of headway into the day-to-day clinics as IOP-lowering strategies. This might have something to do with the difficulty of study design. Early trials were too complex, too long and too expensive, with too many patients and vague endpoints, explained Dr Cordeiro. “But we have learned that neuroprotection research should start with a proof-of-concept study in order to obtain data within a reasonable time frame. This can be done by studying patients with rapidly progressing disease. For example, pseudoexfoliative glaucoma can progress by 1.6 decibels per year. If the endpoint is a 50 per cent reduction in that progression as compared to historical controls, then 50 to 60 patients followed over 12 months are all we would need for a proof-of-concept trial,” she added. This is a great advantage over the 10 years previously thought to be necessary for a study into neuroprotection, she stressed. As for actual molecules of interest, these include neurotrophic factors, NMDA receptor antagonists, anti-apoptotic agents, and antioxidants. Medical Therapeutics “I expect new pharmacologic advances will make breakthroughs within five years. Injectable anterior chamber depots with slow release of prostaglandins are being evaluated by several companies. These would provide slow release over a three-month period, despite containing the same tiny amount of medication as is contained in a single drop of traditional topical treatment,” says Dr Lemij. These are currently being tested in patients and might counter the well-known problems of local irritation and variable medical compliance in glaucoma. Ingeborg Stalmans MD, PhD, of University Hospitals Leuven (UZ Leuven), Belgium, is equally enthusiastic about this modality. “Fortunately, we haven’t yet seen any of the theoretical problems that one might expect from a foreign body in the anterior chamber, such as inflammation, endothelial damage or injury to the trabecular meshwork. Goniophotographic monitoring in the study settings has not shown any damage to the angle, and the injection needle, custom-designed for the anterior chamber, makes the administration quite safe,” she told EuroTimes. Dr Lemij is also confident that further advances will be made to develop preservative-free topical medications. “Considering the growing literature about how counterproductive preservatives can be, pharmaceutical companies have certainly taken notice. They’ll find ways of storing and administering these new preservative-free medications. The only drawback will be the price tag,” he noted. Dr Stalmans reminds us, however, that not all topical medications can be manufactured without preservatives. “Molecules like carbonic anhydrase inhibitors are unstable as solutions when formulated at a physiological pH. If they are manufactured as a suspension, a more neutral pH can be maintained, improving comfort over more acidic formulations, but suspensions must contain preservatives to remain stable. It’s a delicate balance between the irritation of a low pH and the stability of a preserved suspension.” Surgical Therapeutics Once medical treatment has been maximised and further lowering of the IOP is necessary, what’s next? Dr Lemij is very hopeful when it comes to the advances in surgical treatment of glaucoma. MIGS (also referred to as microinvasive glaucoma surgery), which includes various types of micro-stents that bypass the trabecular meshwork, can cause a 20-30 per cent decrease in IOP. They can be implanted independently or concurrently with cataract surgery. The implants are currently considered by many to be an acceptable option prior to trabeculectomy or glaucoma tube, since these can still be performed if the MIGS implant fails. “What I’ve seen so far are cleverly made shunts and tubes. They are all very sophisticated in design and manufacturing, made of either titanium-based alloys or collagen. There are several caveats, however. Follow-up is still quite short at this point, around three years. They occasionally scar down and grow over. Further, they are quite costly,” said Dr Lemij. Dr Lemij finds them to be useful primarily for moderate decreases in IOP, but for more dramatic and long-lasting IOP control, the more traditional procedures like glaucoma tube implantation or trabeculectomy are more appropriate. “Ideally, MIGS procedures would be less invasive and as efficacious as the traditional techniques. All the studies have shown that they have a good safety profile, but their efficacy is clearly inferior to the gold standard of trabeculectomy,” notes Dr Stalmans. Most of the MIGS were studied in trials which compared cataract surgery alone against cataract surgery plus MIGS implantation. “Both procedures decrease the IOP, but the difference with or without MIGS is not very large. It’s in the realm of approximately 1.0mmHg, albeit with fewer IOP-lowering medications. Now, one can claim that every millimetre of mercury counts, but how much is 1.0mm really worth in financial terms? The implants cost between €500 and €1,000 apiece!” Some Exceptions There may be some exceptions, however. “The available one-year data from an ongoing phase IV trial suggest that the XEN® implant from Allergan seems to generate a more significant decrease in IOP,” says Dr Stalmans. The transcleral XEN® gel implant is a minimally invasive ab interno glaucoma device that creates a fistula between anterior chamber and subconjunctival space. But why might there be a difference between the various MIGS implants? “Each MIGS implant shunts aqueous to a specific intraocular or periocular space. Some target Schlemm’s canal, while others drain to the suprachoroidal space. The XEN® drains subconjunctivally. Maybe this is the ideal location to which to drain aqueous: there’s plenty of space and very low resistance, as we have known for a long time with trabs and glaucoma tubes,” explained Dr Stalmans. What might be a problem with Schlemm’s canal or the suprachoroidal space? Dr Stalmans emphasised that there are currently no data to explain the differences in effect between the various implants, but that the following hypothesis might be sound: “In patients with glaucoma, the trabeculum has not been properly working for years. This can lead to a collapse of Schlemm’s canal. If you plug in a stent, why would it reopen? Moreover, scarring is an issue for all types of glaucoma surgery. Despite it’s off-label status for ocular use in Europe, mitomycine C is widely used for glaucoma surgery because of its reported beneficial effects on surgical outcome.” Clearly, we can’t inject mitomycin C into the eye. It can, however, be used under the conjunctiva. To Tube or to Trab? There are big differences of preference and opinion regarding surgical treatment. “In patients with primary glaucoma, I still prefer to first perform trabeculectomy and keep drainage tubes as an option of last resort. I’m not fond of the tube-first strategy, as I feel like one option, the trabeculectomy, has been passed over,” Dr Stalmans explained. “Various trials show that in the long run, large glaucoma tubes like the Baerveldt perform better than trabeculectomy, in terms of complication rates, notably in the early postoperative phase, although trabs show somewhat lower IOPs,” counters Dr Lemij. “We almost completely abandoned trabeculectomies many years ago, primarily due to the early postoperative complications. We currently perform about 95 per cent glaucoma tubes and only about five per cent trabeculectomies.” The jury is clearly still out on this question. Key opinion leaders’ research interests often point the way to the future. “Are glaucoma tubes’ anterior chamber tubes harmful to the corneal endothelium? The reports have been mixed, so we’re running a trial to investigate that question,” said Dr Lemij. Dr Cordeiro is interested in initiating a pan-European trial that compares the optic neuroprotective effects of several different molecules in a systemic fashion. And Dr Stalmans will continue her investigations into the ideal combination of drugs to decrease the fibrotic reactions which can complicate a perfectly good glaucoma procedure. Hans Lemij: h.lemij@oogziekenhuis.nl Francesca Cordeiro: m.cordeiro@ucl.ac.uk Ingeborg Stalmans: ingeborg.stalmans@mac.com