The Pathophysiology and Treatment of Glaucoma

Weinreb, Robert N.; Aung, Tin; Medeiros, Felipe A.

doi:10.1001/jama.2014.3192

Cited by 2,975 publications

(2,802 citation statements)

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“…retinal ischemia/reperfusion injury | cell apoptosis A cute glaucoma is a significant cause of permanent vision loss and irreversible blindness worldwide (1). It is most common among people of Asian descent, in part due to their having a more crowded anterior chamber (2,3).…”

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confidence: 99%

Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1β production in acute glaucoma

Chi

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Acute glaucoma is a sight-threatening condition characterized by a sudden and substantial rise in intraocular pressure (IOP) and consequent retinal ganglion cell (RGC) death. Angle closure glaucoma, a common cause of glaucoma in Asia that affects tens of millions of people worldwide, often presents acutely with loss of vision, pain, and high IOP. Even when medical and surgical treatment is available, acute angle closure glaucoma can cause permanent and irreversible loss of vision. Toll-like receptor 4 (TLR4) signaling has been previously implicated in the pathogenesis of IOP-induced RGC death, although the underlying mechanisms are largely unknown. In the present study, we used an acute IOP elevation/glaucoma model to investigate the underlying mechanism of RGC death. We found that TLR4 leads to increased caspase-8 expression; this elevation increases IL-1β expression and RGC death via a caspase-1-dependent pathway involving Nod-like receptor family, pyrin domain containing 1 (NLRP1)/NLRP3 inflammasomes and a caspase-1-independent pathway. We show that inhibition of caspase-8 activation significantly attenuates RGC death by down-regulating the activation of NLRP1 and NLRP3, thus demonstrating the pivotal role of caspase-8 in the TLR4-mediated activation of inflammasomes. These findings demonstrate collectively a critical role of caspase-8 in transducing TLR4-mediated IL-1β production and RGC death and highlight signal transduction in a caspase-1-dependent NLRP1/NLRP3 inflammasome pathway and a caspase-1-independent pathway in acute glaucoma. These results provide new insight into the pathogenesis of glaucoma and point to a treatment strategy.retinal ischemia/reperfusion injury | cell apoptosis A cute glaucoma is a significant cause of permanent vision loss and irreversible blindness worldwide (1). It is most common among people of Asian descent, in part due to their having a more crowded anterior chamber (2, 3). With a rapid increase in intraocular pressure (IOP) to levels exceeding retinal perfusion pressure, there is resulting retinal ischemia and retinal ganglion cell (RGC) death. Individuals with angle closure glaucoma are much more likely to lose vision and become blind than those with primary open-angle glaucoma (4). The precise mechanisms by which elevated IOP leads to RGC death are not well understood. Accumulating evidence suggests that overactivated microglia have pivotal roles in triggering neurotoxicity in the CNS, including retinal inflammatory responses (5, 6), by producing proinflammatory factors such as IL-1β. IL-1β production is tightly controlled as part of the innate immune response in the CNS (7).Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are two key pattern recognition receptors (PRRs) in the initiation of the innate immune response (8-10). TLR4 has been shown to have a central role in retinal and CNS ischemia/reperfusion (I/R) injuries (11-13). Neuronal death following ischemic injury activates intense inflammation, which triggers TLR4 signaling. It has been demonstrated that ...

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confidence: 99%

Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1β production in acute glaucoma

Chi

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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255

222

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“…2014; Weinreb et al. 2014). Common barriers to instilling eyedrops include low self‐efficacy, forgetfulness and difficulty with drop administration and medication schedules (Kashiwagi & Furuya 2014; Newman‐Casey et al.…”

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confidence: 99%

Additive effects and safety of fixed combination therapy with 1% brinzolamide and 0.5% timolol versus 1% dorzolamide and 0.5% timolol in prostaglandin‐treated glaucoma patients

Aihara

Adachi

Matsuo

et al. 2017

Acta Ophthalmologica

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PurposeTo compare the additive effects and safety of 1% brinzolamide/0.5% timolol fixed combination (BTFC) versus the low‐dose regimen of 1% dorzolamide/0.5% timolol fixed combination (DTFC) in patients with open‐angle glaucoma and ocular hypertension (OAG/OH) following treatment with prostaglandin analogues (PGAs).MethodsA prospective, randomized, double‐masked, multicentre, parallel‐group and active‐controlled study included 201 Japanese OAG/OH patients who had been treated with PGA. Efficacy was assessed as the change in intra‐ocular pressure (IOP) from baseline after weeks 4 and 8. Safety was assessed with adverse event rates, ocular discomfort score, blur scale, blood pressure and heart rates, best‐corrected visual acuity (BCVA) and slit lamp examinations.ResultsIntra‐ocular pressure (IOP) change from baseline at 9 AM/11 AM pooled over the 8 weeks was −3.3/−3.3 mmHg in the BTFC group and −2.9/−3.4 mmHg in the DTFC group, demonstrating non‐inferiority of BTFC to DTFC. Ocular irritation was frequently seen in DTFC group. Although blurred vision was frequently seen in BTFC group, it was transient and blurring became the equivalent 3 min after instillation between two groups. No noteworthy issue was observed in other safety outcome.ConclusionNon‐inferiority of BTFC to DTFC in IOP reduction was demonstrated after adding onto PGA therapy in Japanese OAG/OH patients. Although the score of blurred vision was transiently higher in BTFC than DTFC, treatment difference decreased and disappeared with time. Thus, BTFC can be considered as a safe and effective agent for glaucoma treatment.

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“…The typical presentation is associated with conjunctival injection, yet the extent of autonomic symptoms and periorbital swelling, as well as the self-limiting character of the pain episodes and absent visual impairment, would be very unusual. 2 Magnetic resonance imaging of the head revealed a mucocele with inflammatory changes (Figure 2) and a slim gadoliniumcontrasted boundary as the underlying cause. Nasal endoscopy showed the bulging mucocele.…”

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confidence: 99%