Are intracranial pressure fluctuations important in glaucoma?

Glaucoma is one of the leading causes of irreversible blindness. Primary open-angle glaucoma (POAG), the most common type, is a progressive optic neuropathy with characteristic structural changes in the optic nerve head and functional changes in the visual field. Mechanical and vascular theories for the pathogenesis of glaucomatous optic neuropathy have been proposed. Elevated intraocular pressure (IOP) is a strong risk factor, although a subset of POAG patients has normal IOP and is designated normal tension glaucoma (NTG). Clearly, factors other than IOP are likely to be involved in retinal ganglion cell death in glaucoma. An intriguing finding of recent studies is that intracranial pressure (ICP) is lower in patients with POAG and NTG when compared with nonglaucomatous control subjects. It has been suggested that the relationship between IOP and ICP may play a fundamental role in the development of glaucoma. A decreased ICP could result in an increased trans-lamina cribrosa pressure difference (IOP minus ICP) and lead to glaucomatous damage. In the present paper, we raise the question of whether ICP fluctuations also may be important in glaucoma. The effect of ICP fluctuation might be comparable to that of IOP fluctuation, which has been recognized as an independent risk factor for glaucoma progression.     

New insights into blindness; mechanical fatigue of optic nerve head in glaucomatous optic neuropathy

A common cause of blindness worldwide is glaucoma. It is characterized by visual field loss which is caused by optic nerve damage leading to glaucomatous optic neuropathy (GON). Modelling of GON development may be helpful for designing strategies to decelerate the rate of GON progression and prevent GON development at early stages. Attempts to complete the modelling of GON development continue. In this paper, it was speculated that the modelling could be more completed through a biomechanical point of view. GON may result from the mechanical fatigue effects of radial tensile stress (TS), caused by intra-ocular pressure (IOP), on the optic nerve head (ONH). The mechanical fatigue rate is influenced by patient’s age, the maximum and minimum magnitude of IOP, the amplitude of IOP and TS fluctuations, the ONH geometry, scleral thickness and biomechanical properties of the sclera, particularly the peripapillary part, and the axial length of the globe. Based on this model, more efficient strategies can be developed to augment the ONH and decelerate the progression of glaucomatous optic nerve damage, and even screen high-risk individuals at early stages.     

Role of cerebrospinal fluid in glaucoma: Pressure and beyond

Glaucoma is the second leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is characterized by optic disc cupping and visual field impairment. Though the elevated intraocular pressure (IOP) is thought to be the major risk factor for POAG, about 50% of the POAG patients have normal IOP, called ‘normal-tension’ glaucoma. Besides, many POAG patients still experience visual field loss and/or optic disc cupping even though the IOP has been well controlled. The mechanisms underlying the pathogenesis of POAG remain unclear. Extensive studies have shed lights on the mechanisms that may be involved in the etiopathology and/or the optic neuropathic manifestations of POAG. In this article, we noticed that the changes in the cerebrospinal fluid, particularly that existing in the subarachnoid space of the optic nerve, appear to be actively involved in the pathogenesis of POAG.     

Development of a Platform for Studying 3D Astrocyte Mechanobiology: Compression of Astrocytes in Collagen Gels

Glaucoma is a common optic neuropathy characterized by retinal ganglion cell death. Elevated intraocular pressure (IOP), a key risk factor for glaucoma, leads to significant biomechanical deformation of optic nerve head (ONH) cells and tissues. ONH astrocytes respond to this deformation by transforming to a reactive, proliferative phenotype, which has been implicated in the progression of glaucomatous vision loss. However, little is known about the mechanisms of this transformation. In this study, we developed a 3D collagen gel culture system to mimic features of ONH deformation due to elevated IOP. Compressive loading of astrocyte-seeded collagen gels led to cell alignment perpendicular to the direction of strain, and increased astrocyte activation, as assayed by GFAP, vimentin, and s100β levels, as well as MMP activity. This proof-of-concept study shows that this system has potential for studying mechanisms of astrocyte mechanobiology as related to the pathogenesis of glaucoma. Further work is needed to establish the possible interplay of mechanical stimulation, matrix properties, and hypoxia on the observed response of astrocytes.     

Therapeutic potentials of aspirin in glaucomatous optic neuropathy

Glaucoma is a common blinding disease worldwide. Although traditionally considered as a disease of elevated intraocular pressure, it is now clear that glaucoma is primarily a distinctive optic neuropathy with many proposed pathogenic mechanisms. Impaired blood flow resulting in ischemia has been proposed to be involved in the retinal ganglion cell loss seen in glaucoma. Aspirin might improve optic nerve head perfusion by stabilizing microcirculatory flow. Evidence also indicates that apoptosis may be the final common pathway for ganglion cell death in glaucoma. Aspirin has been shown to exhibit neuroprotective properties. Prostaglandins play an important role in the regulation of intraocular pressure. Aspirin is well known to inhibit cyclooxygenase mediated prostaglandin synthesis. The NSAID-inhibition of PGs synthesis up-regulates the concentration prostaglandin receptors in retinovascular tissues. Based on the body of evidence implicating ocular blood flow disturbances, apoptotic cell death, and also the role of prostaglandins in the pathogenesis of glaucoma we hypothesize that aspirin could be potentially useful drugs in the treatment of glaucoma. Hypothetical pathophysiologic mechanisms explaining potential beneficial effects of aspirin on glaucomatous optic neuropathy include: increasing optic nerve blood flow, preventing retinal ganglion cell death through neuroprotective mechanisms, and upregulating prostaglandin receptors.     

Effects of Scleral Stiffness Properties on Optic Nerve Head Biomechanics

The biomechanical environment within the optic nerve head, important in glaucoma, depends strongly on scleral biomechanical properties. Here we use a range of measured nonlinear scleral stress–strain relationships in a finite element (FE) model of the eye to compute the biomechanical environment in the optic nerve head at three levels of intraocular pressure (IOP). Three stress–strain relationships consistent with the 5th, 50th and 95th percentiles of measured human scleral stiffness were selected from a pool of 30 scleral samples taken from 10 eyes and implemented in a generic FE model of the eye using a hyperelastic five-parameter Mooney-Rivlin material model. Computed strains within optic nerve head tissues depended strongly on scleral properties, with most of this difference occurring between the compliant and median scenarios. Also, the magnitudes of strains were found to be substantial even at normal IOP (up to 5.25% in the lamina cribrosa at 15 mmHg), being larger than previously reported values even at normal levels of IOP. We conclude that scleras that are “weak”, but still within the physiologic range, will result in appreciably increased optic nerve head strains and could represent a risk factor for glaucomatous optic neuropathy. Estimations of the deformation at the optic nerve head region, particularly at elevated IOP, should take into account the nonlinear nature of scleral stiffness.     

猫视乳头三维模型重建及有限元分析

BACKGROUND: Glaucoma is a kind of eye disease that can cause irreversible blindness which is characterized by visual field loss. Clinical research shows that the optic nerve head has changed before the visual field loss. The morphological changes of the optic nerve head have become the key to determine the early diagnosis of glaucoma and disease development. So it has important significance for us to study the morphological changes of the tissues of optic nerve head under the high intraocular pressure.     

Scleral edge, not optic disc or retina, is the primary site of injury in chronic glaucoma

In chronic glaucoma, there is a gradual painless loss of vision, early manifestation of arcuate field defect and typical atrophy of the optic disc known as 'cupping'. Chronic glaucoma is classified into high-tension glaucoma (HTG) and normal-tension glaucoma (NTG). Although both types manifest with the same typical visual field defect and cupping of the optic disc, high-tension glaucoma has elevated intraocular pressure whereas in normal-tension glaucoma the intraocular pressure (IOP) is within the normal range (10-21 mmHg). There are several theories about the pathogenesis of chronic glaucoma ranging from high intraocular pressure directly damaging the optic disc to programmed death(apoptosis) of the ganglion cells of the retina. But none of them satisfactorily explain the manifestation of the early arcuate field defect which is a pathognomonic feature of both types of chronic glaucoma. This article focuses on two main issues. First, how and why the arcuate field defects are produced in the early stages of glaucoma and secondly to find out the common ground in the pathogenesis of both high and normal tension glaucoma. The early arcuate field defects are an important lead in discovering the pathogenesis of glaucoma, therefore if any factor or site which could not possibly produce initial sharply defined arcuate field defects was ruled out. This article presents an unconventional approach to the pathogenesis of glaucoma. Instead of looking for various factors causing glaucoma, emphasis was placed on determining the primary site of injury which could produce the initial arcuate field defects. Keeping the arcuate visual field defects in mind, the primary site of injury appears to be at the scleral edge and not the optic disc or the retina in chronic glaucoma. The border tissue which separates the sclera and choroid from the nerve fibers would atrophy due to chronic ischemia as a result of high intraocular pressure in HTG, whereas due to poor systemic circulation in NTG. In both types of chronic glaucoma, the ciliary circulation supplying the prelaminar and border tissue is compromised. As a result of atrophy of the border tissue, the optic disc sinks as a whole beginning temporally due to its tilted position and causing nerve fibers to stretch, kink, and cut at the scleral edge. This process of optic disc sinking would accelerate due to loss of nerve fibers which also provides anchorage to the optic disc. This cycle would continue until all the nerve fibers are cut at the scleral edge and the optic disc is destroyed.     

Soluble amyloid beta oligomers may contribute to apoptosis of retinal ganglion cells in glaucoma

Glaucoma is one of the leading causes of visual impairment and blindness. It is characterized by excavation of optic nerve head and visual field loss. Even though the pathogenesis of glaucoma remains unclear, it is generally accepted that elevated intraocular pressure is the major risk factor. No matter what the specific initiators are, retinal ganglion cells are believed to die via apoptosis eventually. It is known that glaucoma correlates strongly with Alzheimer's disease and the two diseases share many similarities in pathogenic mechanisms. Recent studies have indicated that amyloid beta peptide, which is implicated in the progression of Alzheimer's disease, may be also responsible for retinal ganglion cells death in glaucoma. Amyloid beta exists in different forms, including monomers, oligomers and fibrils, and among these, as demonstrated by extensive evidences, soluble amyloid beta oligomers rather than insoluble amyloid beta fibrils induced apoptosis of neurons in Alzheimer's disease. Here we propose that soluble amyloid beta oligomers may play an important role in activation of apoptotic cascades in retinal ganglion cells in glaucoma.     

Estrogen deficiency accelerates aging of the optic nerve

The aim of this study was to provide a comprehensive review on hormone-based pathophysiology of aging of the optic nerve and glaucoma, including a literature review and expert opinions. Glaucoma, a group of intraocular pressure-related optic neuropathies, is characterized by the slow progressive neurodegeneration of retinal ganglion cells and their axons, resulting in irreversible visual sensitivity loss and blindness. Increasing evidence suggests that glaucoma represents the accelerated aging of the optic nerve and is a neurodegenerative disease of the central nervous system. This review highlights the high burden of glaucoma in older women and the importance of understanding the hormone-related pathophysiology of optic nerve aging and glaucoma in women. Strong epidemiological, clinical, and experimental evidence supports the proposed hypothesis that early loss of estrogen leads to premature aging and increased susceptibility of the optic nerve to glaucomatous damage. Future investigations into the hormone-related mechanisms of aging and glaucoma will support the development of novel sex-specific preventive and therapeutic strategies in glaucoma.     

Correlated or not: Glaucoma prevalence and modern industrialization

The higher prevalence of primary angle-closure glaucoma (PACG) among Eskimos, Chinese and Mongolians has long been acknowledged, while primary open-angle glaucoma (POAG) is common in blacks and Caucasians. However, in recent years, the incidence of Chinese POAG has increased to a level similar to that of Western countries, and the urban prevalence is higher than the rural one. Is this a coincidental result, or is it a consequence of modern industrialization? The etiology of glaucoma is believed to be due to both genetic and environmental factors. Genetics plays an important role in the growth of the eye, as demonstrated in ethnic variations in glaucoma prevalence and family studies. At the same time, changes in environmental factors have resulted in countries experiencing one of the most rapid epidemiological transitions in history. For the modern human eye to adapt to a more close-up working environment, and with more education requiring close reading, there have been some changes in the eye structure, including a deepening of the anterior chamber, an increase in myopia, a decrease of hyperopia, etc. The changes in these factors were closely associated with the pathogenesis of glaucoma. And of these factors, myopia may have been the most important contributor. Myopia, as an independent risk factor, may increase susceptibility to glaucomatous damage of the optic nerve in myopic eyes. Myopic eyes are more sensitive to intraocular pressure (IOP) (even normal IOP)-induced stress for the thinner lamina cribrosa and larger scleral canal than emmetropic eyes. Axial myopia has longer axial length of the eye and deeper anterior chamber than the normal eye, leading to a less chance to develop angle-closure glaucoma. Due to the increase in myopia among the younger generation in the process of industrialization and urbanization, we hypothesize that the prevalence of glaucoma is correlated with these changes, and that POAG could become more common in Eskimos, Chinese and other Asian descendants in the future.     

The translaminar pressure gradient in sustained zero gravity,idiopathic intracranial hypertension,and glaucoma

Papilledema has long been associated with elevated intracranial pressure. Classically, tumors, idiopathic intracranial hypertension, and obstructive hydrocephalus have led to an increase in intracranial pressure causing optic nerve head edema and observable optic nerve swelling. Recent reports describe astronauts returning from prolonged space flight on the International Space Station with papilledema (Mader et al., 2011) [1]. Papilledema has not been observed in shorter duration space flight. Other recent work has shown that the difference in intraocular pressure (IOP) and cerebrospinal fluid pressure (CSFp) may be very important in the pathogenesis of diseases of the optic nerve, especially glaucoma (Berdahl and Allingham, 2009; Berdahl, Allingham, et al., 2008; Berdahl et al., 2008; Ren et al., 2009; Ren et al., 2011) [2], [3], [4], [5], [6]. The difference in IOP and CSFp across the lamina cribrosa is known as the translaminar pressure difference (TLPD).We hypothesize that in zero gravity, CSF no longer pools in the caudal spinal column as it does in the upright position on earth. Instead, CSF diffuses throughout the subarachnoid space resulting in a moderate but persistently elevated cranial CSF pressure, including the region just posterior to the lamina cribrosa known as the optic nerve subarachnoid space (ONSAS). This small but chronically elevated CSFp could lead to papilledema when CSFp is greater than the IOP. If the TLPD is the cause of optic nerve head edema in astronauts subjected to prolonged zero gravity, raising IOP and/or orbital pressure may treat this condition and protect astronauts in future space travels from the effect of zero gravity on the optic nerve head. Additionally, the same TLPD concept may offer a deeper understanding of the pathogenesis and treatment options of idiopathic intracranial hypertension (IIH), glaucoma and other diseases of the optic nerve head.     

Clinical features, molecular genetics, and pathophysiology of dominant optic atrophy.

Inherited optic neuropathies are a significant cause of childhood and adult blindness and dominant optic atrophy (DOA) is the most common form of autosomally inherited (non-glaucomatous) optic neuropathy. Patients with DOA present with an insidious onset of bilateral visual loss and they characteristically have temporal optic nerve pallor, centrocaecal visual field scotoma, and a colour vision deficit, which is frequently blue-yellow. Evidence from histological and electrophysiological studies suggests that the pathology is confined to the retinal ganglion cell. A gene for dominant optic atrophy (OPA1) has been mapped to chromosome 3q28-qter, and studies are under way to refine the genetic interval in which the gene lies, to map the region physically, and hence to clone the gene. A second locus for dominant optic atrophy has recently been shown to map to chromosome 18q12.2-12.3 near the Kidd blood group locus. The cloning of genes for dominant optic atrophy will provide important insights into the pathophysiology of the retinal ganglion cell in health and disease. These insights may prove to be of great value in the understanding of other primary ganglion cell diseases, such as the mitochondrially inherited Leber's hereditary optic neuropathy and other diseases associated with ganglion cell loss, such as glaucoma.     

Is low dose of Estrogen beneficial for prevention of glaucoma?

Glaucoma, as characterized by accelerated retinal ganglion cell (RGC) death and cupping of optic nerve head (ONH), is one of the leading causes of blindness worldwide. Elevated intraocular pressure (IOP) is generally considered as a major risk factor in the pathogenesis of glaucoma. Previous studies showed that glaucoma caused decrease in collagen and elastin density in several ocular tissues, such as lamina cribrosa, peripapillary sclera and cornea, and resulted in reduced elasticity and compliance of these tissues. It is known that estrogen has protective effects against glaucoma, yet the underlying mechanism still remains obscure. Prior researches have provided evidences showing that the estrogen receptors (ERs) express in a variety of the ocular tissues. Estrogen activates the synthesis of collagen fiber and improves the compliance of these tissues. This leads to a reasonable postulation that increased estrogen may result in a higher content of the collagen fibers and enhanced flexibility of the whole eye, which would therefore decrease IOP. Particularly, the increase in the amounts of collagen fibers at lamina cribrosa improves its compliance, which in turn relieves its compression on RGC axons. Therefore, even at the same IOP level, the softening of cribriform foramina yields a more flexible environment for the RGCs to survive. We therefore hypothesize that estrogen at proper dosage can be considered as a potential therapy for glaucoma since it is able to prevent the eye from glaucomatous damage and lower IOP, especially for those menopausal women with glaucoma.     

免疫系统在青光眼发病机制中的作用

青光眼曾被认为是一种病因单纯疾病，近些年研究表明，是由多原因导致的视神经永久性损伤和视野丢失的一类疾病。而免疫系统在青光眼的视网膜视神经损害中所起的作用应该是双重的。一方面自身免疫机制引起视神经损伤可以由自身抗体直接导致，也可以间接模拟对敏感抗原的自身免疫反应所引起，另一方面，免疫系统监督和调节可以对应激作出反应，从而起到一定保护作用。了解免疫系统在青光眼发病机制中的作用对于预防及治疗青光眼有着重要的意义。     

A family with X-linked optic atrophy linked to the OPA2 locus Xp11.4-Xp11.2

Autosomal dominant optic atrophy (ADOA) is the most common inherited optic atrophy. Clinical features of ADOA include a slowly progressive bilateral loss of visual acuity, constriction of peripheral visual fields, central scotomas, and color vision abnormalities. Although ADOA is the most commonly inherited optic atrophy, autosomal recessive, X-linked, mitochondrial, and sporadic forms have also been reported. Four families with X-linked optic atrophy (XLOA) were previously described. One family was subsequently linked to Xp11.4-Xp11.2 (OPA2). This investigation studied one multi-generation family with an apparently X-linked form of optic atrophy and compared their clinical characteristics with those of the previously described families, and determined whether this family was linked to the same genetic locus. Fifteen individuals in a three-generation Idaho family underwent complete eye examination, color vision testing, automated perimetry, and fundus photography. Polymorphic markers were used to genotype each individual and to determine linkage. Visual acuities ranged from 20/30 to 20/100. All affected subjects had significant optic nerve pallor. Obligate female carriers were clinically unaffected. Preliminary linkage analysis (LOD score = 1.8) revealed that the disease gene localized to the OPA2 locus on Xp11.4-Xp11.2. Four forms of inherited optic neuropathy, ADOA, autosomal recessive optic atrophy (Costeff Syndrome), Leber hereditary optic neuropathy, and Charcot-Marie-Tooth disease with optic atrophy, are associated with mitochondrial dysfunction. Future identification of the XLOA gene will reveal whether this form of optic atrophy is also associated with a mitochondrial defect. Identification of the XLOA gene will advance our understanding of the inherited optic neuropathies and perhaps suggest treatments for these diseases. An improved understanding of inherited optic neuropathies may in turn advance our understanding of acquired optic nerve diseases, such as glaucoma and ischemic optic neuropathy.     

An hypothesis on pressure transmission from anterior chamber to optic nerve

Few studies have characterized how pressure in the anterior chamber (AC) of the eye is transmitted via the vitreous to the vitreous–ganglion cell interface. We are aware of only one study that simultaneously measured the pressures in the AC and vitreous humor; and of only one study that simultaneously measured the pressures in the AC and the suprachoroidal space (SCS). The pressure in the AC is defined as the intraocular pressure (IOP), which when elevated beyond statistically normal limits is a recognized risk factor for glaucoma, a malady best described as an optic neuropathy with degeneration and eventual death of the retinal ganglion cells (GC’s) and highly characteristic changes in the optic nerve head (ONH). Most investigators currently believe that the prevalent risk factor for GC apoptosis is ocular hypertension, but no one has demonstrated how an increase in IOP in the AC is transmitted to the GC’s. In patients with primary open angle glaucoma, the pressure in the AC increases due to an increase in the resistance of the trabecular meshwork (TM) outflow pathway. We questioned how such increased pressure in the AC would be transmitted to the GC to produce the changes in the ONH seen in glaucoma. Based on our preliminary data and purview of the literature, we hypothesize that a pressure increase originating in the AC is likely transmitted via both the SCS and the vitreous, with transmission via the former pathway probably most efficient in affecting the GC. Independently of the mechanism that produces GC apoptosis, the ones that are first affected, as repeatedly shown by visual field tests, are the most peripheral ones; i.e., those whose axons are the most external as they form the ONH and enter the lamina cribrosa. There are no published reports explaining this peculiarity. The dogma is that the pressure transmitted via the vitreous is higher at the periphery because it is transmitted across a shorter distance, since the vitreous acts as a buffer that absorbs part of the pressure being transmitted. We propose that IOP is not only transmitted via the vitreous but also via the SCS. Increases in IOP could be efficiently applied via the SCS to the most external axons of the ONH as they leave the eye. Our hypothesis can also explain low-tension glaucoma in which the most peripheral GC’s are also affected first, because pressure is transmitted without decay due to a reduced uveoscleral (UVS) flow.     

The translaminar pressure gradient in sustained zero gravity,idiopathic intracranial hypertension,and glaucoma

Papilledema has long been associated with elevated intracranial pressure. Classically, tumors, idiopathic intracranial hypertension, and obstructive hydrocephalus have led to an increase in intracranial pressure causing optic nerve head edema and observable optic nerve swelling. Recent reports describe astronauts returning from prolonged space flight on the International Space Station with papilledema (Mader et al., 2011) [1]. Papilledema has not been observed in shorter duration space flight. Other recent work has shown that the difference in intraocular pressure (IOP) and cerebrospinal fluid pressure (CSFp) may be very important in the pathogenesis of diseases of the optic nerve, especially glaucoma (Berdahl and Allingham, 2009; Berdahl, Allingham, et al., 2008; Berdahl et al., 2008; Ren et al., 2009; Ren et al., 2011) , , ,  and . The difference in IOP and CSFp across the lamina cribrosa is known as the translaminar pressure difference (TLPD).