Acquired pits of the optic nerve. Increased prevalence in patients with low-tension glaucoma

The authors studied 232 glaucoma patients in an attempt to shed light on the implications of the pit-like localized cupping of the optic nerve often referred to as an "acquired pit of the optic nerve" (APON) both in low-tension glaucoma and in glaucoma associated with elevated intraocular pressure (IOP). Twenty (74%) of the 27 patients with low-tension glaucoma had APONs, whereas 31 (15%) of the 232 patients with elevated pressure did (P less than 0.001). Overall, there was no difference between the degree of field loss in patients with APONs and in those without. We suggest that APONs may signal an abnormal susceptibility of the optic nerve to the damaging effects of IOP.     

Glaucoma without ocular hypertension. A clinical study

One hundred eighty-four glaucomatous eyes (125 patients) with visual field defects of Stage I and II in the central visual field were examined with the Octopus perimeter 201, Program 31 or 33, and were divided into 3 groups according to maximum intraocular pressures: (1) low-tension glaucoma (21 mm Hg), (2) glaucoma simplex (22-29 mm Hg), (3) glaucoma simplex (30-39 mm Hg). In these three groups of glaucomatous eyes the cupping of the optic disk, vision and blood pressure were examined and a further check for cardiovascular risk factors was carried out by the internist. All three groups proved to have an equally high incidence of cardiac insufficiency, abnormal EKG changes and diabetes. However, a low systolic blood pressure was found to be the risk factor more often in patients with low-tension glaucoma than with glaucoma simplex. Furthermore, intraocular pressures in the low-tension glaucoma group were higher than those in the normal population. The occurrence of cupping of the optic disk, which is not present with purely vascular optic nerve diseases, and the location of visual field defects in low-tension glaucoma, which is similar to that in glaucoma simplex but different from vascular diseases, as well as the increased diurnal tension variations of diurnal tension curves compared to the normal population are all factors which indicate that low-tension glaucoma is not a purely vascular optic nerve disease, and that pressure-lowering therapy is necessary.(ABSTRACT TRUNCATED AT 250 WORDS)     

Optic disk and visual field correlations in primary open-angle and low-tension glaucoma

If the amount of visual field loss is less than expected from the amount of optic disk cupping in low-tension glaucoma compared with primary open-angle glaucoma, it might imply a difference between the two conditions in the type of optic nerve lesion produced. To test this hypothesis, three observers independently examined, in a masked fashion, optic disk stereoscopic photographs of 127 eyes with primary open-angle glaucoma and 71 eyes with low-tension glaucoma. For each stereoscopic photograph the observer predicted whether the visual field loss would be mild, moderate, or severe. The visual field were then classified, according to the number of sectors defective on the Goldmann perimeter chart, as having mild (1 to 15 sectors), moderate (16 to 30 sectors), or severe (more than 30 sectors) visual field loss. For no observer did the frequency of underpredictions or overpredictions in the two conditions differ significantly. The results of this study, thus, did not support the theory that the optic disk damage in primary open-angle glaucoma differs from that in low-tension glaucoma.     

Investigations into a vascular etiology for low-tension glaucoma

Increased intraocular pressure is accepted as a primary etiologic factor for the atrophy of the optic nerve head and visual field defects of high-tension glaucoma. Other factors must be present to explain these findings in low-tension glaucoma. One of the current theories is that low-tension glaucoma is the result of decreased optic nerve perfusion on the basis of vascular disease or other factors such as altered blood viscosity. This study compared the non-invasive vascular profiles, coagulation tests, and rheological profiles of 46 consecutive cases of low-tension glaucoma with 69 similarly unselected cases of high-tension glaucoma and 47 age-matched controls. Despite the multifactorial approach and the use of previously validated objective tests, no significant group differences were detected with any of the above investigations. If vascular disease is important in the etiology of low-tension glaucoma, then it must be localized or vasospastic since this study does not support the concept of a generalized vascular etiology, either of an atheromatous or hyperviscous nature, for the genesis of low-tension glaucoma.     

Fluorescein angiography in chronic simple and low-tension glaucoma.

Fluorescein angiograms were performed on a group of low-tension glaucoma and chronic simple glaucoma patients with similar extent of visual field loss, under standardised conditions, to see whether differences attributable to chronic intraocular pressure elevation could be detected. There was no evidence for difference in circulation times between these two groups. There was no evidence that hypoperfusion of the peripapillary choroid contributed to optic nerve hypoperfusion. Low-tension glaucoma patients demonstrated focal sector hypoperfusion of the optic nerve in every case, while the chronic simple glaucoma patients demonstrated a wide range of optic nerve fluorescence, suggesting both focal and diffuse optic nerve head hypoperfusion. It was concluded that, while focal hypoperfusion of the optic nerve may reflect susceptible vasculature at the nerve head with or without intraocular pressure elevation, diffuse hypoperfusion suggested that prolonged intraocular pressure elevation may simultaneously affect the whole of the optic nerve head. This could be a direct effect on blood vessels or a mechanical effect with secondary vascular changes.     

Measurement of peripapillary retinal nerve fiber layer volume in glaucoma

PURPOSE: To measure peripapillary retinal nerve fiber layer volume in normal subjects and patients with ocular hypertension, primary open-angle glaucoma, and low-tension glaucoma. METHODS: Sixty-five subjects were classified into four groups of normal subjects and subjects with ocular hypertension, primary open-angle glaucoma, and low-tension glaucoma on the basis of intraocular pressure measurements, visual field loss, and optic disk appearance. Groups were matched for sex, age, and optic disk area. Peripapillary retinal nerve fiber layer volume measurements were made with a modification of software version 1.11 of the Heidelberg Retina Tomograph confocal scanning laser ophthalmoscope. Retinal nerve fiber layer volume measurements were taken at 0.1-mm increments from the disk margin for a global 360-degree assessment and at four predefined segments using two different reference planes. Statistical analysis was carried out using analysis of variance with Bonferroni correction. RESULTS: Retinal nerve fiber layer volume measurements showed a gradation from normal to ocular hypertension and from ocular hypertension to glaucoma groups. Mean group measurements showed statistically significant differences (P <.05) in peripapillary retinal nerve fiber layer volume for most segmental measures between the groups. Measurements with the default reference plane in the 0.0-mm to 0.1-mm and 0.1-mm to 0.2-mm increments for the superotemporal segment showed the greatest differences between groups (P <.00005). CONCLUSION: Peripapillary retinal nerve fiber layer volume measurements differ between groups of normal subjects and patients with ocular hypertension, primary open-angle glaucoma, and low-tension glaucoma. This measure offers a further method of assessment of retinal nerve fiber layer in patients with glaucoma and glaucoma suspects.     

Central corneal thickness in low-tension glaucoma

BACKGROUND: It is possible that the intraocular pressure (IOP) is underestimated in eyes whose central cornea is thinner than normal. The objective of this study was to determine and establish the significance of central corneal thickness in patients with low-tension (normal-tension) glaucoma compared with those with chronic open-angle glaucoma (COAG) or ocular hypertension and healthy eyes. METHODS: The study was carried out from February 1998 to May 1999. Central corneal thickness was measured by ultrasonic pachymetry and IOP was measured by Goldmann applanation tonometry in 25 patients with low-tension glaucoma (untreated IOP less than 21 mm Hg with evidence of optic nerve head damage and corresponding visual field loss on automated perimetry), 80 patients with COAG (untreated IOP 21 mm Hg or greater with evidence of optic nerve head damage and corresponding visual field loss on automated perimetry), 16 patients with ocular hypertension (untreated IOP 21 mm Hg or greater, with normal optic nerve head and no history of glaucoma or elevated IOP, and normal visual field on automated perimetry) and 50 control subjects (untreated IOP less than 21 mm Hg with normal optic nerve head and no history of glaucoma or elevated IOP). Analysis with Pearson's product-moment correlation was performed to determine the correlation of IOP and central corneal thickness, and one-way analysis of variance was used to compare corneal thickness between groups. RESULTS: The central cornea was significantly thinner in the low-tension glaucoma group (mean 513.2 mu [standard deviation (SD) 26.1 mu]) than in the COAG group (mean 548.2 mu [SD 35.0 mu]) and the control group (mean 556.7 mu [SD 35.9 mu]) (p < 0.001). No significant difference in corneal thickness was found between the COAG and control groups. The ocular hypertension group had significantly thicker corneas (mean 597.5 mu [SD 23.6 mu]) than the three other groups (p < 0.001). INTERPRETATION: Patients with low-tension glaucoma may have thinner corneas than patients with COAG and healthy subjects. This results in underestimation of their IOP. Corneal thickness should be taken into account when managing these patients to avoid undertreatment.     

Difference of optic disc topography between a low-tension group and a high-tension group in normal-tension glaucoma patients

PURPOSE: Glaucomatous visual field loss and optic disc damage differ by intraocular pressure (IOP) levels. In this study, we compared the optic disc topography in the high-tension group and the low-tension group in normal-tension glaucoma (NTG). METHOD: We selected NTG patients with mean deviation (MD) > or = -10.00 dB and the highest recorded IOP of < 14 mmHg or > or = 17 mmHg without glaucoma treatment. We classified NTG eyes into the following two groups: 1) a low-tension group with the highest recorded IOP of < 14 mmHg, 2) a high-tension group with the highest recorded IOP of > or = 17 mmHg. The optic disc parameters in the low-tension group eyes were compared with those in the high-tension group eyes using a Heidelberg Retina Tomograph. RESULTS: Nineteen eyes of nineteen patients were selected for each group. The cup/disc area ratio in the global sector, and the rim volume in the nasal sector of the low-tension group had deteriorated more than in the high-tension group. CONCLUSIONS: The disc topography is different between the low-tension group and the high-tension group in the nasal sector, suggesting that different pathogenetic mechanisms exist in the optic disc damage in NTG.     

Comparison of visual field defects in the low-tension glaucomas with those in the high-tension glaucomas

We compared the visual fields of 79 eyes (48 patients) with low-tension glaucoma (intraocular pressure less than 21 mm Hg) to the visual fields of 106 eyes (74 patients) with high-tension glaucoma (intraocular pressure greater than 30 mm Hg). Both groups had similar amounts of total field loss as determined by computerized threshold perimetry. Scotomas in the low-tension group had a steeper slope (P less than .001), were significantly closer to fixation (P less than .001), and had greater depth (P less than .001) than those in the high-tension group. These findings suggested that more than one causative factor is important in the production of optic nerve damage in glaucoma.     

Induction of HLA-DR expression in human lamina cribrosa astrocytes by cytokines and simulated ischemia

PURPOSE: Recent evidence strongly suggests that activated immunity occurs during the neurodegenerative process of glaucomatous optic neuropathy. Although activation of lamina cribrosa astrocytes has been identified in glaucomatous optic nerve head, their role on the activated immune responses seen in glaucoma patients is unknown. Here, the authors aimed to study the potential role of lamina cribrosa astrocytes as a component of activated immune responses seen in glaucoma patients. METHODS: Expression of HLA-DR in optic nerve head astrocytes was studied using immunohistochemistry in postmortem eyes of patients with glaucoma and normal donors. Serum cytokine levels of patients with glaucoma and control subjects were measured using enzyme-linked, immunosorbent assay. In addition, in vitro experiments were performed using astrocyte cultures derived from human optic nerve head or fetal human brain. The cultured astrocytes were incubated under selected stress conditions such as exposure to cytokines, IFN-gamma and IL-10, or simulated ischemia for up to 48 hours. The expression of HLA-DR was studied in these cells using flow cytometry and immunocytochemistry. RESULTS: Immunohistochemistry demonstrated an upregulation of the HLA-DR expression in the optic nerve head astrocytes in glaucoma. In addition, serum levels of IL-10 was higher in the patients with normal pressure glaucoma compared to age-matched control subjects (P: = 0.001). Regarding in vitro experiments, unlike brain astrocytes, the percentage of cells expressing HLA-DR was approximately 3 times higher in the cultures of optic nerve head astrocytes exposed to simulated ischemia compared to cultures incubated under normal conditions (P: = 0.09). Incubation with IFN-gamma induced HLA-DR expression in brain and lamina cribrosa astrocytes, up to 25-fold, (P < 0.001) either in the absence or presence of simulated ischemia. Induction of HLA-DR expression by IL-10 was approximately 6 times higher in lamina cribrosa astrocytes incubated under simulated ischemia compared to that incubated under normal condition (P: = 0.004) and was not prominent in brain astrocytes. CONCLUSIONS: These findings suggest that optic nerve head astrocytes function as antigen-presenting cells and that their immunogenic capacity is more sensitive to ischemia than brain astrocytes. Taken together, these findings provide novel evidence that regulation of immunogenic capacity of optic nerve head astrocytes by cytokines or ischemic stress may have a role during the neurodegeneration process in patients with glaucoma.     

The case for autoimmunity in glaucoma

Although the majority of patients with glaucoma have elevated intraocular pressure as the presumed etiology for their resultant neuropathy, it is well known that approximately 25% of patients with glaucoma have intraocular pressure within the normal range for their race. These patients may have conditions that facilitate non-pressure related stress to the retina and optic nerve that might directly contribute to their glaucomatous neuropathy and include chronic or intermittent ischemia (i.e atherosclerosis, heart disease, vasospasm, migraine, sleep apnea), altered scleral/optic nerve head morphology that predisposes to glaucomatous stress (i.e myopia); genetic mutations that predispose to glaucoma damage at normal IOP (OPA-1,optineurin, myocilin) and evidence of aberrant immunity that suggests that their glaucoma might be a form of an autoimmune neuropathy (i.e. presumed autoimmune glaucoma). This review provides a critical assessment of the potential role for autoimmunity as an initiating or exacerbating etiology in some patients with glaucoma.     

Arterial narrowing as a predictive factor in glaucoma

Purpose: To evaluate whether retinal arteriolar widths change in normal patients and in different glaucoma types. We measured the arteriolar width at the merge in the optic nerve (MD), at the edge of the optic nerve (ED) and at the peripapillary area (1 disc diameter distance) (disc distance D). HRT software 1.11, Interactive Means program was used.One hundred forty three eyes of seventy-two patients divided in four subgroups normal, low-tension glaucoma (LTG), primary open angle glaucoma (POAG) and ocular hypertensive (OH). No statistically significant was found in each studied group. The normal patients showed no changes in the retinal arteriolar width compared with all the glaucoma groups.     

Oculo-oscillodynamography findings in glaucoma without hypertension

Oculo-oscillodynamography after Ulrich was performed in 27 patients suffering from glaucoma without hypertension (so-called low-tension glaucoma). Patients who had severe systemic disease or were receiving systemic medication which might influence IOP, and patients with narrow angle and an IOP higher than 22 mm Hg were excluded. In 85% of the patients a severe decrease in systolic ciliary perfusion pressure was found, whereas the systolic retinal and diastolic ocular perfusion pressures were significantly lower in almost 30% of the cases. Glaucoma without hypertension appears to be caused by the vascular change at the disk.     

Is there a role for the immune system in glaucomatous optic neuropathy?

Glaucoma and immunity are not traditionally perceived as being causally related. Recently, however, compelling observations have provided insight into a potential role for the immune system in the development of glaucomatous optic neuropathy. In this article, it is proposed that the role of the immune system in glaucoma is two-fold. In some patients, there is evidence that an autoimmune mechanism may be responsible for eliciting damage to the optic nerve, resulting in glaucomatous injury. Autoimmune damage to the optic nerve may occur directly by autoantibodies, or indirectly by way of a "mimicked" autoimmune response to a sensitizing antigen which, in turn, injuries retinal ganglion cells. We suggest that autoimmune-mediated glaucoma injury occurs most often, but not exclusively, in patients in whom the intraocular pressure has never been found to be elevated. A second role of the immune system in glaucoma is likely one of surveillance, in which signal pathways of the immune system regulate cell death in response to conditions that stress retinal neurons in glaucoma. These might include mechanical stress from high intraocular pressure, ischemia, excessive excitatory amino acids, or toxic products resulting from excessive nitric oxide synthase production in either neurons or glial fibers that surround the optic nerve as it exits the eye. In these cases, we propose that the immune system acts as an "arbiter" to help determine whether a neuronal cell will ultimately survive, or succumb to, those stressors that are perceived as injurious. It is conceivable that such surveillance and cell death regulation by the immune system is important in determining the fate of retinal neurons in both the more common "high-pressure" forms of glaucoma, such as primary open-angle glaucoma, and in cases in which the intraocular pressure appears within normal range.     

Optic neuropathies of different etiology and normal tension glaucoma: the point of differential diagnosis

62 patients (109 eyes) with glaucoma-like optic nerve head cupping and normal IOP indices (Po not more than 21 mm Hg) were examined to find the etiology of optic nerve changes. Regarding corneal biomechanics new-onset primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG) were diagnosed in 27% and 3% of examined patients respectively. In 59% of patients optic neuropathy (ON) of different etiology was found to be the cause of glaucoma-like optic nerve changes including compression ON due to lesion of intracranial portion of optic nerve and chiasma in 6% of cases. In 11% physiologic large optic nerve head cupping with normal visual functions and absence of nerve fiber structural changes was found.     

Primary open angle glaucoma and low tension glaucoma--pathogenesis and mechanism of optic nerve damage]

The etiology, pathogenesis and mechanism of optic nerve damage in primary open angle glaucoma (POAG) and low tension glaucoma (LTG) were investigated by experimental glaucoma in monkey and by follow-up studies of many patients over 15 years, by pathohistological and immunohistochemical analysis. 1) LTG was proved to be a real glaucoma, showing pressure-dependent optic nerve damage. The pathological entity was a primary weakness of the lamina cribrosa (LC), and therefore even normal pressure could deform the LC. Due to backward distortion of LC the channels were disarranged and twisted, inducing mechanical optic nerve damage. There was no active vascular damage or vascular constriction at the site of the optic nerve damage. The filling defects of the advanced glaucomatous optic disc were not the cause of optic nerve damage, but the result of regressive vascular change after axon bundle loss. Splinter hemorrhage of the optic disc might be the result of the same process. 2) The weakness of LC might be induced by the abnormal metabolism of the extracellular matrix of the LC. 3) To arrest the progressive optic nerve damage in LTG, the intraocular pressure (IOP) should be maintained under 12, or ideally, 10 mmHg. 4) The optic nerve damage in POAG was not only pressure-dependent, but also dependent on the weakness of the LC, as in the case of LTG. In the early stage the IOP should be under 19 mmHg, in the advanced stage under 14 mmHg in order to arrest progression for over 15 years. 5) In advanced experimental glaucoma of monkeys, the LC showed reduction of elastin, fragmentation of collagen, and change of proteoglycans. 6) As in the LC, the trabecular meshwork also showed abnormal metabolism and abnormal deposits on the extracellular matrix in POAG, and LTG as well. 7) POAG and LTG might belong to the same family in which common abnormal metabolism of LC and trabecular meshwork induce various clinical features.     

Double-blind study in the treatment of normal tension glaucoma with naftidrofuryl

Naftidrofuryl is an antiserotonin S2-specific agent, with the three following effects: (1) peripheral vasodilatation, (2) antiaggregation and (3) increase in cellular metabolic. These effects could be interesting in the management of the optic nerve ischemia of glaucomatous patients and especially of those with normal tension glaucoma. The administration of 2 x 200 mg/day of naftidrofuryl during 6 weeks to 12 patients with normal tension glaucoma has shown an improvement of the visual acuity and the visual field compared with a 6-week period of placebo administration, with a double-blind study method. It suggested that naftidrofuryl might be administered as a useful complement to conventional hypotensive therapy, since it acts positively on the glaucomatous optic nerve damage.     

An autosomal dominant form of low-tension glaucoma

A condition causing glaucomatous optic atrophy and visual field loss at normal or borderline intraocular pressure affected eight members of a family of consecutive generations. The disease was detectable in early adulthood and progressed slowly throughout life. The pattern of inheritance is autosomal dominant. One affected individual died of a myocardial infarction, and his eyes were obtained post mortem. Light and electron microscopic examination demonstrated glaucomatous optic atrophy with loss of ganglion cells. The trabecular meshwork, choroidal and optic nerve vasculature, retinal pigment epithelium, and photoreceptors were normal in appearance. We believe this family has an autosomal dominant genetic condition that is a distinct type of low-tension glaucoma.     

Quantitative analysis of visual field and optic disk in glaucoma: retinal nerve fiber bundle-associated analysis

 Background: A study was performed to evaluate whether visual field analysis using a perimetric nerve fiber bundle map gives information additional to global visual field indices and cumulative defect curves for early glaucoma diagnosis. Methods: One hundred and four control subjects, 124 patients with ocular hypertension (OHT), 97 patients with high-tension glaucoma without visual field defects (preHTG) and 91 patients with open-angle glaucoma with visual field defects [30 low-tension glaucoma (LTG), 61 high-tension glaucoma (HTG)] were included in this study. Correlation analyses were performed between (a) global visual field indices and total neuroretinal rim (NRR) area; (b) local mean values of four visual field areas and the NRR area of the corresponding four optic disk sectors; and (c) local mean values of 10 perimetric nerve fiber bundles (PNFB1–10) according to Weber and Ulrich (1991) and the four optic disk sectors. The correlations were adjusted for global mean defect and total NRR. Results: There were no significant correlations between NRR area and visual field in control subjects or in patients with OHT or preHTG for all three analyses. Significant correlations were found between the global visual field indices and the total NRR area for LTG and HTG. Significant correlations between local mean defects and NRR area of corresponding optic disk sectors were found only in LTG for the superior and inferior visual field area and the PNFB covering these areas. Conclusion: The method used for visual field analysis and sectorization of the optic disk does not give additional information on visual field defects in patients with normal global visual field indices and a normal cumulative defect curve. The nerve fiber bundle-related visual field analysis allows the topographical determination and quantification of glaucomatous damage. Received: 4 February 1999 Revised: 20 September 1999 Accepted: 4 October 1999     

Optic nerve oxygenation

The oxygen tension of the optic nerve is regulated by the intraocular pressure and systemic blood pressure, the resistance in the blood vessels and oxygen consumption of the tissue. The oxygen tension is autoregulated and moderate changes in intraocular pressure or blood pressure do not affect the optic nerve oxygen tension. If the intraocular pressure is increased above 40 mmHg or the ocular perfusion pressure decreased below 50 mmHg the autoregulation is overwhelmed and the optic nerve becomes hypoxic. A disturbance in oxidative metabolism in the cytochromes of the optic nerve can be seen at similar levels of perfusion pressure. The levels of perfusion pressure that lead to optic nerve hypoxia in the laboratory correspond remarkably well to the levels that increase the risk of glaucomatous optic nerve atrophy in human glaucoma patients. The risk for progressive optic nerve atrophy in human glaucoma patients is six times higher at a perfusion pressure of 30 mmHg, which corresponds to a level where the optic nerve is hypoxic in experimental animals, as compared to perfusion pressure levels above 50 mmHg where the optic nerve is normoxic. Medical intervention can affect optic nerve oxygen tension. Lowering the intraocular pressure tends to increase the optic nerve oxygen tension, even though this effect may be masked by the autoregulation when the optic nerve oxygen tension and perfusion pressure is in the normal range. Carbonic anhydrase inhibitors increase the optic nerve oxygen tension through a mechanism of vasodilatation and lowering of the intraocular pressure. Carbonic anhydrase inhibition reduces the removal of CO2 from the tissue and the CO2 accumulation induces vasodilatation resulting in increased blood flow and improved oxygen supply. This effect is inhibited by the cyclo-oxygenase inhibitor, indomethacin, which indicates that prostaglandin metabolism plays a role. Laboratory studies suggest that carbonic anhydrase inhibitors might be useful for medical treatment of optic nerve and retinal ischemia, potentially in diseases such as glaucoma and diabetic retinopathy. However, clinical trials and needed to test this hypotheses.