Neuroprotection

Therapeutic strategies aimed specifically at the protection or restoration of the optic nerve in eyes with glaucoma are beginning to show promise, but the clinical validation of candidate agents is likely to be a prolonged process, according to a series of presentations at the Glaucoma Day sessions at the XXX Congress of the ESCRS. “There is a considerable bulk of evidence that glaucoma is a neurodegenerative disease. The rationale for neural protection for glaucoma is supported by more than a dozen successful studies in glaucoma animal models, and yet none has been translated into clinical therapy,†Luca Rossetti University of Milan San Paolo Hospital, Milan, Italy. He noted that of nearly 74,000 agents with proven neuroprotectant effects, only eight have made it to the clinical trial stage. Of those, only brimonidine has shown real evidence of a clinically relevant effect, in the Low-Pressure Glaucoma Treatment Study (LOGTS), and that also requires further validation (Krupin et al. Am J Ophthalmol, 2011 ;151:671– 681). Conducting trials into the neuroprotective treatment of glaucoma has many special challenges, he said. Like other neurodegenerative diseases, glaucoma has a long slow course with an unpredictable rate of progression. In addition, randomised controlled trials would also have to compare treatment groups having similar IOP, to exclude that parameter as a confounding factor. Moreover, agents would have to have a fairly neutral effect on a patient’s quality of life to be acceptable to those who remain asymptomatic. The LOGTS study fulfilled the first of those two criteria. It showed that eyes with low-tension glaucoma that were treated with brimonidine had significantly less visual field loss than those receiving timolol, despite the IOP being very similar in the two treatment groups. However, the agent failed to meet the second criterion in that 40 per cent in the brimonidine group were lost to follow-up because of allergic reactions. In addition, further research will be needed to determine whether brimonidine has a neuroprotective effect or if other possible explanations may be more likely. For example, it might be that brimonidine has a neutral effect but timolol had a neurotoxic effect in eyes with normal tension glaucoma, he noted. “What is certain is that the considerable number of patients lost to follow-up limits the validity of this study. Moreover, it can be applied only for patients without an allergy to brimonidine. However, the LOGTS findings have been encouraging so we should not abandon the concept of neural protection strategy in glaucoma,†Dr Rossetti added. Cure may trump prevention In the case of glaucomatous damage to the optic nerve, an ounce of cure may be easier to prove or disprove than a pound of prevention, said Stefano Gandolfi, MD, University Eye Clinic, Parma, Italy. The unpredictable nature of glaucoma onset and progression means that proof of an agent’s protective effect in a randomised controlled trial would require patients to undergo lifelong treatment to prove its efficacy. In contrast, treatments that aim to restore the damaged neural tissue would tend to have as their endpoint a restoration of visual function within a specified time. Furthermore, the re-growth of axons in retinal ganglion cells may not be as impossible as conventional wisdom would suggest. One recent study, in particular, showed that damaged retinal ganglion cells from glaucomatous rat eyes can have a regenerative capacity, mediated, in part, by activated retinal glia (Lorber et al, Neurobiology of Disease 2102; 45:243-252). “When we're looking for the restoration of vision in previously blind areas as the clinical endpoint there is no need for complicated functional tests, the routine test of standard automated perimetry would be enough and we certainly could use a real-time approach and it's extremely aggressive, Dr Gandolfi added. Therefore, we should move, from the concept of neuro- “protectionâ€, into the world of neuro-“rescueâ€, he said. The preliminary results of a long-term trial on brimonidine vs laser trabeculoplasty (Gandolfi et al., Inv. Ophthal. Vis. Sci, ARVO abstract, 2004), on top of matching with the LoGTS outcomes, are tracing for brimonidine an interesting profile as a potential “neuro-rescuer†in responder patients. The neurovascular unit At present, IOP is the only modifiable risk factor for glaucoma to have the support of evidence from numerous randomised trials. There are also some potentially modifiable neurovascular risk factors said Leopold Schmetterer MD, Medical University of Vienna, Austria. “Associations between glaucoma and low perfusion pressure, migraine, vasospasm and autonomic dysfunction indicate that there is also a vascular factor involved, This corresponds well with the studies with Alzheimer's disease indicating the neurovascular unit could be a target,†he said. The neurovascular unit is what forms the interface between circulatory system and the nervous system. It is a complex of vascular endothelial cells, glial cells and neurons. There is evidence that vascular endothelial cell dysfunction throughout the body is common in patients with normal tension glaucoma, Dr Schmetterer said. Astrocytes in the neurovascular unit may also be a target for glaucoma therapy, since the star-shaped glial cells play a very important role in the signalling between the vascular cells and neurons. In particular, astrocytes mediate the increase of blood flow that usually occurs in response to neural activity in order to deliver oxygen and glucose and other nutrients to the active cell. With regard to neuroinflammation, the loss of the retinal nerve fibre layers and ganglion cells appears to result in the up-regulation of many inflammatory parameters, such as the levels of TNF receptors and colony stimulating factors. “If you want to have a successful neuroprotection strategy you’ve got to target neurodegeneration itself and at the same time you have to target neurovascular damage and neuroinflammation,†Dr Schmetterer added.Â