These clinical findings inspired a series of laboratory studies on mice and rabbits,16–23 where alkali burn of the cornea was used as a model. Not only did the expected cornea damage occur but also rapid subclinical injury to the retina16–23(Fig. 3). With TUNEL stain, substantial apoptosis of the ganglion cells (the hallmark of glaucoma) was demonstrated within 24 to 72 hours. In addition, the depletion of the number of optic nerve axons was recorded after 3 months. These studies helped to understand the importance of inflammation, and its rapid onset, in this glaucomatous neurodegeneration.
Thus, insult to the cornea can result in a very rapid and widespread damage to the retina (Figs. 3 and 4). In chemical burns, the retina injury does not result from a direct pH affect—alkali is effectively buffered at the iris–lens level, as measured with pH probes.16,19 Rather, the inflammatory cytokine tumor necrosis factor alpha (TNF-α) is generated in the anterior segment and rapidly (within hours) diffuses posteriorly to cause the ganglion cell apoptosis16–21—presumably capable of resulting in later glaucoma. TNF-α was shown to cause permanent changes in the immune function of the retina, termed “permanent neuroglia remodeling,” which continued to cause neuronal degeneration even long after the noxious stimuli were removed and the TNF-α production in the anterior segment had subsided. This immunological shift was demonstrated to occur not only in burns but also after ocular hypertension and cornea surgical trauma, indicating the role of inflammation and TNF-α in long-term retinal health.22,23
How do we know that TNF-α is a mediator in the process of ganglion cell apoptosis? We showed that infliximab (antibody to TNF-α), infused over 60 minutes starting 15 minutes after the burn, had a strong protective effect against the apoptosis16–19 (Fig. 4) and ameliorated the process of neuroglia remodeling.23 These findings may open new prophylactic treatment possibilities.26
Thus (in animals), the TNF-α can promptly destroy a substantial portion of the retinal ganglion cells. Is that enough to cause functional loss in patients? It likely is, because it is already well-established that in humans and primates, a 20% to 40% ganglion cell loss results in visual field defects.24,25
These results from the laboratory, combined with clinical experience, prompted a reevaluation of the treatment of our patients with chemical burns.26 It is well known that penetrating keratoplasty (PK) after severe burns have a virtually hopeless visual prognosis,27 whereas KPros usually do well surgically.7,28 Late glaucoma is the problem. Therefore, because the above-cited experience from animals points to a very rapid (hours or days) destruction of ganglion cells after a burn, it seems logical to start strong antiinflammatory prophylaxis in patients promptly after the accident.26,30 Both corticosteroids and antibodies to TNF-α show rapid and effective neuroprotection of ganglion cells in animals,19 but biologics are well documented to be considerably safer in long-term treatment (eg, in rheumatology) and are used successfully in uveitis.29 A modified treatment paradigm for patients with chemical burn might start promptly in the emergency department (in addition to standard treatment such as lavage, etc.) with the local administration of triamcinolone (Kenalog), injected sub-Tenon or subconjunctivally. The initial choice of a corticosteroid allows a tuberculosis test to be performed, and the results returned before considering biologics—which presently can take 24 hours. When tuberculosis has been proven absent in the patient, a biologic such as adalimumab (Humira) subcutaneously, or infliximab (Remicade) intravenously, might be a logical drug for long-term continuation.30 Doses, routes of administration, duration of treatment, and the effect of recently introduced new cytokine inhibitors are presently under investigation.
If a major ocular trauma such as a chemical burn to the cornea can have immediate dire consequences for the retinal ganglion cells—with expected glaucomatous optic neuropathy as a consequence—is there a need of prophylactic treatment even after standard corneal surgery such as PK, where glaucoma is also very common postoperatively?31–34 Close to 200,000 PKs are presently being performed annually worldwide, and a reduction of the incidence of postoperative glaucoma could result in a major improvement of ocular public health. To investigate this question further in the laboratory, mice were implanted with miniature corneal grafts or with miniature KPros into their previously untouched, normal corneas.18 As was suspected, also such a penetrating surgery triggers rapid upregulation of TNF-α in the retina, as well as ganglion cell apoptosis, although of less magnitude than in the alkali burn model used earlier (Fig. 5). Even a short penetrating injury in a mouse cornea can release potentially injurious levels of inflammatory cytokines.35 The fact that glaucoma is such a long-term problem postoperatively after PK and after KPro, in patients, speaks for likely future routine local administration of a powerful antiinflammatory drug (steroid or biologic) at the end of any surgical procedure—similar to what is recommended after chemical burns. The route of local administration can be subconjunctival, sub-Tenon or, less likely, intravitreal. Postoperative antiinflammatory drops to the surface of the eye, or released from a subconjunctival drug-eluting device,20 or from a contact lens (Ciolino, unpublished), may have some effect also at the retinal level, but the necessary dosing is not yet known, nor the tradeoffs regarding complications from the steroids.
The clinical literature correlated with the laboratory studies cited in this brief review seems to indicate the existence of a rapid, inflammatory, IOP-independent pathway to glaucoma—susceptible to effective inhibition by antibodies (Fig. 7). TNF-α has already been shown experimentally to be a mediator between high IOP and ganglion cell apoptosis.38,39 However, in our animal experiments, ganglion cell attrition was clearly triggered by the postburn inflammation, not by the IOP—the latter remaining in a harmless range within 1 to 3 days after the exposure (depending on the animal) when severe damage to the ganglion cells had already occurred19 (Fig. 6). In addition, autoimmune inflammation has lately been shown to affect the optic nerve and result in neuropathy.40 Thus, arguments for an IOP-independent pathway to glaucoma can be formulated as follows:
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