Vision restoration in glaucoma: Nihilism and optimism at the crossroads.

Advances in modern medicine have paved the way for optimism when it comes to treatment/cure of ailments previously considered irremediable. A classic example of this is the sister disease of glaucoma we know as cataract. Until recently, individuals suffering from cataract slowly progressed toward irreversible loss of vision, but now, a simple surgical procedure restores almost hundred percent of the vision without complications. Is such a treatment possible for glaucoma? This intriguing question perplexes a majority of ophthalmologists. This is because glaucoma is an intricate form of progressive optic neuropathy characterized by the retinal ganglion cell (RGC) death due to which the ensuing loss of vision is generally considered to be irreversible (reversal of neurodegenerative processes has not been achieved yet). There are many reasons underlying this, most importantly late diagnosis of the condition and nonavailability of effective treatment modalities. At the outset, the response to the prospect of vision restoration in glaucoma seems to be a frank “No” at least from the contemporary standpoint. Some practitioners may be a bit optimistic to consider effective treatment possible in early cases.[12] However, what proportion of such early cases do we see in glaucoma clinics? The truth is obviously disheartening because by the time an individual is diagnosed with glaucoma, a lot of damage has already ensued (almost half a million RGCs are already dead). The extent of vision restoration (if any) with the currently available treatment modalities is so small that the improvement is not even felt by the patient and can only be detected by sensitive techniques. In addition, the so achieved minimal vision restoration is lost within a short span of time.[3] This has given rise to pessimism but the prospect may not be as nihilistic. The issue, nevertheless, needs to be understood and put in proper context. The source of contention is the consideration that if many previously incurable diseases can effectively be treated by modern medicine, what is the great difficulty about lowering slightly high intraocular pressure (IOP)? The answer to this over-optimistic deduction is that glaucoma is a multifarious disease involving IOP, blood flow to optic nerve head, and neurodegenerative processes in various permutations. Other factors include intracranial pressure, lateral geniculate nuclei and many other brain structures, various systemic parameters, ageing, inflammation, psychological stress, oxidative stress, mitochondria, genetics, and numerous other factors. Furthermore, there are many normotensive glaucoma cases and a substantial number of cases progress to vision loss even after controlling the IOP.[4]

As of now, there is very little we can do to realize the dream of vision restoration in clinical settings. The first milestone that needs to be crossed is the early/predictive diagnosis. There is, at present, no way to predict the onset of glaucoma except for identifying some high-risk individuals with known family history. Early RGC loss can be identified by pattern electroretinography; an expensive and labor intensive modality. Molecular biology and genomic approaches may hold promise for identifying the whole genome, proteome, and epigenome signatures that may serve as diagnostic, predictive, and prognostic markers for glaucoma. We have already reviewed the molecular biology, diagnostic aspects, and genetic counseling protocols in primary congenital glaucoma.[5] The second part of the issue emphasizes that very little can be done to rescue or restore vision. Therefore, novel therapies that address glaucoma beyond IOP need to be identified to develop effective strategies. In this regard, new theories and hypotheses have been proposed which aim at explaining and understanding glaucoma beyond ocular hypertension. The use of neurotrophic factors, antioxidants, anti-inflammatory interventions has recently been employed.[4] Gene therapy and stem-cell treatments have also shown promise in preliminary studies.[67] Corrective approaches to gene defects and understanding of relevant pathophysiology are important. For this, functional genomic studies are inevitable. For example, the expression of full-length unmodified human CYP1B1 (implicated in various forms of glaucoma) protein did not meet any success until recently we reported a dedicated protocol for that.[8] The third important issue is long-term sustenance of the vision improvement. For this, a proper understanding of the disease etiology and progression is pertinent. Molecular approaches aimed at understanding the etiomechanisms and identifying important interventions are likely to promote sustained vision restoration. A detailed review of these aspects can be found in one of our recent articles.[9] In addition, long-term follow-up studies are important to know which treatments have long-lasting effects.

Although the above arguments seed some hope, the reality is not that encouraging in the present context. There is, however, a quantum of solace that vision loss in early glaucoma is reversible even in adults.[12] If glaucoma is visualized as a malady of the nervous system, then some optimism is foreseeable because of neuroplasticity which makes the brain able to adapt to changes by various mechanisms.[210] It may, therefore, be concluded that vision restoration in glaucoma is a long-sought goal but a tough nut to crack. Although there is a lot of pessimism prevailing right now, the situation is not entirely hopeless. Yet, there is very little we can do right now, but the possibilities are immense. Molecular biology, genetics, biochemistry, pharmacology, and alternate therapeutic methods have to be accommodative of each other and have to work in synergy to tackle this “sneak thief future memories.” The controversy of vision restoration in glaucoma is an area where “No” does not really mean “No” and “Yes” means something less than “Yes.”