Neuroprotective effects of bone marrow Sca-1+ cells against age-related retinal degeneration in OPTN E50K mice.

Glaucoma is characterized by retinal ganglion cell (RGC) death, the underlying mechanisms of which are still largely unknown. An E50K mutation in the Optineurin (OPTN) gene is a leading cause of normal-tension glaucoma (NTG), which directly affects RGCs in the absence of high intraocular pressure and causes severe glaucomatous symptoms in patients. Bone marrow (BM) stem cells have been demonstrated to play a key role in regenerating damaged tissue during ageing and disease through their trophic effects and homing capability. Here, we separated BM stem cells into Sca-1+ and Sca-1- cells and transplanted them into lethally irradiated aged OPTN E50K mice to generate Sca-1+ and Sca-1- chimaeras, respectively. After 3 months of BM repopulation, we investigated whether Sca-1+ cells maximized the regenerative effects in the retinas of NTG model mice with the OPTN E50K mutation. We found that the OPTN E50K mutation aggravated age-related deficiency of neurotrophic factors in both retinas and BM during NTG development, leading to retinal degeneration and BM dysfunction. Sca-1+ cells from young healthy mice had greater paracrine trophic effects than Sca-1- cells and Sca-1+ cells from young OPTN E50K mice. In addition, Sca-1+ chimaeras demonstrated better visual functions than Sca-1- chimaeras and untreated OPTN E50K mice. More Sca-1+ cells than Sca-1- cells were recruited to repair damaged retinas and reverse visual impairment in NTG resulting from high expression levels of neurotrophic factors. These findings indicated that the Sca-1+ cells from young, healthy mice may have exhibited an enhanced ability to repair retinal degeneration in NTG because of their excellent neurotrophic capability.

Ginkgo Biloba Extract in Ophthalmic and Systemic Disease, With a Focus on Normal-Tension Glaucoma.

Glaucoma is a neurodegenerative eye disease that results in retinal ganglion cell loss and ultimately loss of vision. Elevated intraocular pressure (IOP) is the most common known risk factor for retinal ganglion cell damage and visual field loss, and the only modifiable risk factor proven to reduce the development and progression of glaucoma. This has greatly influenced our approach and assessment in terms of diagnosis and treatment. However, as many as ≥50% of patients with progressive vision loss from primary open angle glaucoma without IOP elevation (≤22 mm Hg) have been reported in the United States and Canada; 90% in Japan and 80% in Korea. Extensive research is currently underway to identify the etiology of risk factors for glaucoma other than or in addition to elevated IOP (so-called "normal-tension" glaucoma; NTG) and use this knowledge to expand available treatment options. Currently, Food and Drug Administration-approved medications for glaucoma exclusively target elevated IOP, suggesting the need for additional approaches to treatment options beyond the current scope as the definition of glaucoma changes to encompass cellular and molecular mechanisms. This review focuses on alternative medical approaches, specifically Ginkgo Biloba extract, as a potential treatment option for normal-tension glaucoma.

[The Keyrole of Multiomics in the Predictive, Preventive and Personalised Medical Approach towards Glaucoma Management]. / Die Schlüsselrolle der Multiomics in Prädiktion, Prävention und personalisierter Behandlung vom Glaukom.

Glaucoma is the second leading cause of blindness, with altogether about 70 million patients registered worldwide. These facts prompt us to reconsider currently applied concepts in overall glaucoma management. Innovative strategies of predictive, preventive and personalised medicine (PPPM) are expected to considerably improve disease prevention and personalised treatment. The comprehensive PPPM measures include the application of individualised patient profiles, "phenotyping", molecular characterisation of the pre-lesions and disease stages, innovative screening programs, patient stratification, early and predictive diagnosis, targeted prevention, and the creation of personalised treatment algorithms. The main stakeholders are glaucoma-dedicated researchers, ophthalmologists, general practitioners, groups at risk, specialised medical units, affected patients and their family members, insurances, policy makers, and the diagnostic and pharmaceutical industries. Potential beneficiaries include these groups as well as society as a whole, due to financial savings in the healthcare expected.

Comparison of Changes in Macular Ganglion Cell-Inner Plexiform Layer Thickness Between Medically and Surgically Treated Eyes With Advanced Glaucoma.

PURPOSE: To compare changes in the macular ganglion cell layer and inner plexiform layer (mGCIPL) thickness over 5 years between surgically treated eyes (STE) and medically treated eyes (MTE) with advanced glaucoma. DESIGN: Retrospective, comparative case series. METHODS: Eighty-six patients comprising 43 with open-angle glaucoma (OAG) with trabeculectomy and 43 with medically treated OAG. The mGCIPL thickness was measured more than 5 times during follow-up by optical coherence tomography. Main outcome measure was differences in mGCIPL thickness thinning rate between the groups. RESULTS: The mean age at study initiation was 62.5 ± 9.2 years in STE and 62.7 ± 9.5 years in MTE. The mean deviations (MD), according to the Humphrey Field Analyzer central program 30-2, and the mGCIPL thickness in each sector showed no significant differences at initial measurement. The averaged intraocular pressure (IOP) throughout follow-up was 10.5 ± 2.0 mm Hg in STE and 10.8 ± 0.8 mm Hg in MTE (P = .429; Mann-Whitney U test). There was no significant difference in the MD changes over 5 years between the 2 groups (P = .405; Mann-Whitney U test). Changes in the mGCIPL thickness over 5 years in MTE were significantly greater than that in STE in all sectors (all 6 sectors P < .0001, Mann-Whitney U test). The IOP fluctuation over 5 years in STE was significantly less than that in MTE (P < .0001, Mann-Whitney U test). CONCLUSIONS: The structure of the mGCIPL was better preserved in STE than in MTE, even when the IOPs during follow-up were similar.

Management of Blood Pressure in Patients with Glaucoma.

PURPOSE OF REVIEW: Ocular perfusion pressure (OPP) is defined as the difference between BP and intraocular pressure (IOP). With low BP comes low OPP and resultant ischemic damage to the optic nerve, leading to glaucoma progression. The purpose of this article is to review the literature on BP as it relates to glaucoma and to create a forum of discussion between ophthalmologists and internal medicine specialists. RECENT FINDINGS: Both high and low BP has been linked glaucoma. Low BP is particularly associated with glaucoma progression in normal-tension glaucoma (NTG) patients. Patients who have low nighttime BP readings are at highest risk of progression of their glaucoma. Internal medicine specialists and ophthalmologists should consider the relationship between BP and glaucoma when treating patients with concomitant disease. Too-low nighttime BP should be avoided. Ambulatory blood pressure monitoring is a useful tool to identify patients at greatest risk for progression.

Normal tension glaucoma management: a survey of contemporary practice.

OBJECTIVE: The aim of this study was to investigate contemporary practice patterns with respect to normal tension glaucoma (NTG) management and to determine whether the 2 largest NTG trials have influenced ophthalmologists' clinical practice. METHODS: A survey questionnaire was sent to ophthalmologists via the American Glaucoma Society, the Canadian Glaucoma Society, and the Canadian Ophthalmological Society. The questionnaire was designed to investigate ophthalmologists' usual practice with respect to NTG and the extent to which practice has been influenced by the Collaborative Normal Tension Glaucoma Study (CNTGS) and the Low pressure Glaucoma Treatment Study (LoGTS). RESULTS: In total, 419 ophthalmologists completed the survey. Of these, 264 respondents were glaucoma subspecialists. The survey showed that 95% and 64% of ophthalmologists were familiar with the CNTGS and the LoGTS, respectively. Of the respondents, 70% indicated that they would initiate treatment in mild-to-moderate NTG without waiting for documented disease progression. Of the respondents, 61% of the total surveyed and 50% of the glaucoma subspecialists felt that the LoGTS results had no impact on their usual clinical practice. The first-choice topical drug for NTG was a prostaglandin analogue (88% of respondents) or brimonidine (10% of respondents). CONCLUSIONS: Most ophthalmologists treat NTG more aggressively than recommended by the CTNGS protocol. Most ophthalmologists felt that the LoGTS results had no impact on their normal clinical practice. The prostaglandin analogues are, by far, the most popular choice of drug for contemporary management of NTG.

Impact of intraocular pressure reduction on visual field progression in normal-tension glaucoma followed up over 15 years.

PURPOSE: To investigate the impact of surgical or medical reduction of intraocular pressure (IOP) on progressive normal-tension glaucoma followed up over 15 years. METHODS: Sixty eyes of 60 patients were divided into 3 intervention groups: group 1 (trabeculectomy, n = 17); group 2 (IOP reduction rate ≥15% with prostaglandin analogs, n = 24); and group 3 (IOP reduction rate <15% with prostaglandin analogs, n = 19). The preintervention and postintervention mean deviation (MD) slopes and IOP were compared. Factors associated with the rate of visual field progression were identified by multiple regression analysis. RESULTS: The mean follow-up was 19.8 years. In group 1, the preintervention and postintervention IOPs were 14.7 ± 1.3 and 9.1 ± 2.0 mmHg, respectively (P < .001, 38% reduction). The MD slope decreased significantly after trabeculectomy (-0.86 ± 0.51 versus -0.19 ± 0.20 dB/y; P < .001). In group 2, the preintervention and postintervention IOPs were 14.7 ± 1.5 and 11.7 ± 1.2 mmHg, respectively (P < 0.001, 20% reduction), with significant differences in the MD slope (-0.52 ± 0.37 versus -0.31 ± 0.30 dB/y; P = .019). In group 3, the preintervention and postintervention IOPs were 14.4 ± 1.8 and 13.2 ± 1.6 mmHg, respectively (P < 0.001, 8% reduction), with no differences in the MD slope (-0.40 ± 0.27 versus -0.50 ± 0.65 dB/y; P > .05). Multiple regression analysis showed that the average IOP, IOP reduction rate, and preintervention MD slope were related to the extent of the postintervention reduction in the MD slope. The difference in the preintervention and postintervention MD slopes significantly correlated with the rate of IOP reduction (r = 0.559, P < .001). CONCLUSIONS: A pressure-dependent maintenance effect of the visual field was confirmed in progressive normal-tension glaucoma.

The effects of selective laser trabeculoplasty and travoprost on circadian intraocular pressure fluctuations: A randomized clinical trial.

BACKGROUND: To compare the effect of selective laser trabeculoplasty (SLT) and travoprost on 24-hour IOP fluctuations in primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG). METHODS: Sixty eyes were included. Sixteen and 14 eyes of POAG patients were randomized to receive 360° SLT or 0.004% travoprost, respectively. Fourteen and 16 eyes of NTG patients were randomized to receive either SLT or travoprost, respectively. The 24-hour IOP data were collected before treatment and 6 to 8 weeks after treatment. IOP was measured at 2 hours intervals in the sitting position during daytime (9 AM to 7 PM) and in the supine position during nighttime (9 PM to 7 AM). Main outcome measure was the percentage of eyes that achieved posttreatment 24-hour IOP fluctuations <3 mm Hg. Success in fluctuation reduction was defined as at least a 50% reduction in these fluctuations. RESULTS: Fifty-eight eyes were analyzed. Overall, eyes in the SLT and the travoprost groups achieved a significant reduction in IOP compared with the baseline IOP values (-3.7 mm Hg [P = 0.002] vs -4.1 mm Hg [P < 0.001], respectively). There was no significant difference in IOP reduction in both groups according to type of glaucoma. During the diurnal period, 100% of POAG eyes in the travoprost group achieved posttreatment IOP fluctuations <3 mm Hg, and 87% of eyes in the SLT group achieved the same level of fluctuations (P < 0.001). Ninety-six percent of NTG eyes in the travoprost group, and 82% of eyes in the SLT group had IOP fluctuations <3 mm Hg (P = 0.01). Success in fluctuation reduction was 75% and 92% for the SLT and travoprost groups, respectively (P = 0.005). The effect of travoprost on IOP reduction in POAG and NTG patients was significant both during the daytime and the nighttime, while the SLT's effect was significant only during the nighttime. CONCLUSIONS: Both travoprost and SLT can significantly reduce the IOP in patients with POAG and NTG. Based on habitual positions, travoprost better controls IOP fluctuations than SLT, especially during the daytime.

[Phenomenology and Clinical Relevance of the Flammer Syndrome]. / Phänomenologie und klinische Bedeutung des Flammer-Syndroms.

The Flammer syndrome (FS) describes the phenotype of people with a predisposition for an altered reaction of the blood vessels to stimuli like coldness, emotional stress or high altitude. Frequent symptoms are: cold hands and/or feet, low blood pressure, prolonged sleep onset time, reduced feeling of thirst, increased sensitivity to odour, pain, vibration and certain drugs. SF subjects are often ambitious and successful but also perfectionistic and sometimes brooding. Frequent signs are: altered gene expression, prolonged blood flow cessation in nailfold capillaroscopy after cold provocation, reduced autoregulation of ocular blood flow, and reduced vasodilation after stimulation with flickering light. Retinal venous pressure is on the average higher and retinal astrocytes are more often activated. FS occurs more often in females than in males, in thin than in obese subjects, in young than in old people, in graduates than in blue collar workers, in subjects with indoor than outdoor jobs. Associated diseases are: normal tension glaucoma, occlusion of ocular vessels, retinitis pigmentosa, multiple sclerosis, tinnitus or even sudden hearing loss.

Frequency of unplanned interventions in patients attending for a presumed routine glaucoma follow-up appointment.

OBJECTIVE: To determine the frequency of patient visits in which an unplanned treatment modification was required in chronic patients attending a glaucoma clinic for routine follow-up and to identify the treatment interventions most commonly employed. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: A total of 630 previously stable patients attending a glaucoma clinic for routine follow-up. METHODS: This was a single-centre survey of all eligible patients returning to an academic glaucoma clinic. Data regarding whether patients' visit remained routine or required intervention, which clinical parameter had changed, and any alterations in treatment regimens were studied. RESULTS: The percentage of patients found to require a change in management was 20.79% (131 of 630 patients); 16.9% were found to have a cause for change because of glaucoma, and the remaining 4% required intervention because of a nonglaucomatous condition. The most common parameter that changed treatment was intraocular pressure (43.87%), followed by visual fields (21.29%). The frequency of abnormal parameters varied within each subtype of glaucoma. The frequency of treatment changes among those with primary open-angle glaucoma was 22.58% compared with 16.5% of glaucoma suspects, 14% of ocular hypertensives, 32% of pseudoexfoliative glaucoma, and 50% of normal tension glaucoma patients. The most common intervention (32.84%) was a change in antiglaucoma medications. The next most frequent interventions were laser procedures (21.90%) and surgery (16.06%). CONCLUSIONS: This study suggests that a significant minority of patients attending a glaucoma clinic for a routine appointment require treatment modification.

Normal-tension glaucoma: an update.

Normal-tension glaucoma (NTG) is a progressive optic neuropathy with intraocular pressure (IOP) within the statistically normal range (≤21 mmHg). The prevalence of NTG varies widely among different population studies, being the most prevalent open-angle glaucoma subtype in some reports. The etiology of NTG possibly is multifactorial and still not well defined. Alternative treatments have been proposed based on pathogenesis details. However, in clinical practice, adequate reduction of IOP remains the keystone of managing patients with NTG. We review the pathogenesis of NTG and the available therapies for this optic neuropathy.

Normal-tension glaucoma: an update / Glaucoma de pressão normal: atualização

ABSTRACT Normal-tension glaucoma (NTG) is a progressive optic neuropathy with intraocular pressure (IOP) within the statistically normal range (≤21 mmHg). The prevalence of NTG varies widely among different population studies, being the most prevalent open-angle glaucoma subtype in some reports. The etiology of NTG possibly is multifactorial and still not well defined. Alternative treatments have been proposed based on pathogenesis details. However, in clinical practice, adequate reduction of IOP remains the keystone of managing patients with NTG. We review the pathogenesis of NTG and the available therapies for this optic neuropathy.

RESUMO O glaucoma de pressão normal (GPN) é uma neuropatia óptica progressiva que cursa com a pressão intraocular (PIO) dentro da faixa de normalidade (≤21 mmHg). A prevalência do glaucoma de pressão normal varia entre os estudos populacionais, sendo em alguns o principal subtipo de glaucoma primário de ângulo aberto. A etiologia do glaucoma de pressão normal possivelmente é multifatorial e ainda não foi totalmente esclarecida. Tratamentos alternativos baseados nos diferentes detalhes da patogenia foram recentemente propostos. Entretanto, na prática clínica, a redução adequada da pressão intraocular continua sendo a base do tratamento do glaucoma de pressão normal. O objetivo deste artigo é revisar a patogênese do glaucoma de pressão normal e as formas de terapia disponíveis.

Advance in the pathogenesis and treatment of normal-tension glaucoma.

Normal-tension glaucoma (NTG) is a multifactorial disease where mechanical stresses and vascular alterations to the optic nerve head probably represent the key pathogenic moments. Although intraocular pressure (IOP) plays a crucial role in the retinal ganglion cell loss, the IOP reduction does not necessarily reduces the disease progression. Therefore, several IOP-independent factors such as glutamate toxicity, oxidative stress, autoimmunity, and vascular dysregulation have been considered in the pathogenesis of NTG. Numerous evidences documented an impairment of the ocular blood flow, involved both in the onset and progression of the disease. The IOP reduction remains the main strategy to reduce the damage progression in NTG. Recently, new treatment strategies have been proposed to improve the control of the disease. Neuroprotection is a rapidly expanding area of research, which represents a promising tool. In the present review, we summarize the recent scientific advancements in the pathogenesis and treatment of NTG.

[Current aspects on the management of normal tension glaucoma]. / Aktuelle Aspekte zum Management des Normaldruckglaukoms.

In a considerable proportion of glaucoma patients (25-50 %) the intraocular pressure (IOP) is not elevated higher than 22 mmHg at first diagnosis and during subsequent follow-up controls. Although the IOP level remains in the low range < 22 mmHg, progression of glaucoma can still occur. A multitude of different factors are assumed to be involved in glaucoma progression, such as very low nocturnal diastolic blood pressure values, a low mean ocular perfusion pressure, extensive fluctuations in perfusion (e.g. in cases of vascular dysregulation), an increased vulnerability of the optic nerve support structures, an increased translaminar pressure gradient and various underlying systemic diseases. The most important evidence-based aspect of treatment in normal tension glaucoma is pharmaceutical or surgical reduction of the IOP by 30 % or more in comparison to the initial pressure level. Vascular and neuroprotective concepts of treatment for normal tension glaucoma have been strongly advocated and the object of experimental and clinical studies. As yet a clear clinical benefit has not been proven by large prospective randomized studies.

New directions in the treatment of normal tension glaucoma.

Glaucoma is a progressive optic neuropathy that causes characteristic changes of the optic nerve and visual field in relation to intraocular pressure (IOP). It is now known that glaucoma can occur at statistically normal IOPs and prevalence studies have shown that normal tension glaucoma (NTG) is more common than previously thought. While IOP is believed to be the predominant risk factor in primary open angle glaucoma (POAG), IOP-independent risk factors, such as vascular dysregulation, are believed to play an important part in the pathogenesis of NTG. Though certain distinguishing phenotypic features of NTG have been reported, such as an increased frequency of disc hemorrhages, acquired pits of the optic nerve and characteristic patterns of disc cupping and visual field loss, there is much overlap of the clinical findings in NTG with POAG, suggesting that NTG is likely part of a continuum of open angle glaucomas. However, IOP modification is still the mainstay of treatment in NTG. As in traditional POAG, reduction of IOP can be achieved with the use of medications, laser trabeculoplasty or surgery. Studies now show that the choice of medication may also be important in determining the outcomes of these patients. Though it is likely that future treatment of NTG will involve modification of both IOP and IOP-independent risk factors, current efforts to develop IOP-independent neuroprotective treatments have not yet proven to be effective in humans.

Control of outflow resistance by soluble adenylyl cyclase.

Abstract Glaucoma is a leading cause of blindness in the United States affecting as many as 2.2 million Americans. All current glaucoma treatment strategies aim to reduce intraocular pressure, even in patients with normal tension glaucoma. Typically, this is accomplished by reducing the rate of aqueous flow by limiting aqueous production or enhancing drainage using drugs and surgery. Whereas these strategies are effective in diminishing vision loss, some patients continue to lose vision and many discontinue use of their medications because of undesirable side effects. Drugs known to be effective in altering conventional outflow have for the most part been abandoned from modern clinical practice due to undesirable side effects. Identification of new drugs that could enhance conventional outflow, would offer additional options in the treatment of glaucoma and ocular hypertension. To this end, our laboratory has recently uncovered a novel pathway for regulation of conventional outflow by the ciliary body. This pathway is dependent on soluble adenylyl cyclase, an enzyme that catalyzes the generation of cyclic adenosine 3',5' monophosphate (cAMP) in response to bicarbonate.