- •PROGRESS IN BRAIN RESEARCH
- •List of Contributors
- •Preface
- •Epidemiology of primary glaucoma: prevalence, incidence, and blinding effects
- •Introduction
- •Prevalence of glaucoma
- •PAC suspect
- •PACG
- •Incidence of glaucoma
- •Blinding effects of glaucoma
- •Abbreviations
- •Acknowledgment
- •References
- •Predictive models to estimate the risk of glaucoma development and progression
- •Risk assessment in ocular hypertension and glaucoma
- •Risk factors for glaucoma development
- •Intraocular pressure
- •Corneal thickness
- •Cup/disc ratio and pattern standard deviation
- •The need for predictive models
- •Predictive models for glaucoma development
- •Predictive models for glaucoma progression
- •Limitations of predictive models
- •References
- •Intraocular pressure and central corneal thickness
- •Main text
- •References
- •Angle-closure: risk factors, diagnosis and treatment
- •Introduction
- •Mechanism
- •Other causes of angle closure
- •Risk factors
- •Age and gender
- •Ethnicity
- •Ocular biometry
- •Genetics
- •Diagnosis
- •Acute primary angle closure
- •Angle assessment in angle closure
- •Gonioscopy technique
- •Ultrasound biomicroscopy (UBM)
- •Scanning peripheral anterior chamber depth analyzer (SPAC)
- •Management
- •Acute primary angle closure
- •Medical therapy
- •Argon laser peripheral iridoplasty (ALPI)
- •Laser peripheral iridotomy (PI)
- •Lens extraction
- •Monitoring for subsequent IOP rise in eyes with APAC
- •Fellow eye of APAC
- •Chronic primary angle-closure glaucoma (CACG)
- •Laser peripheral iridotomy
- •Laser iridoplasty
- •Medical therapy
- •Trabeculectomy
- •Lens extraction
- •Combined lens extraction and trabeculectomy surgery
- •Goniosynechialysis
- •Summary
- •List of abbreviations
- •References
- •Early diagnosis in glaucoma
- •Introduction
- •History and examination
- •Quantitative tests and the diagnostic process
- •Pretest probability
- •Test validity
- •Diagnostic test performance
- •Posttest probability
- •Combing test results
- •Selective tests of visual function
- •Early glaucoma diagnosis from quantitative test results
- •Progression to make a diagnosis
- •Conclusions
- •Abbreviations
- •References
- •Monitoring glaucoma progression
- •Introduction
- •Monitoring structural damage progression
- •Monitoring functional damage progression
- •Abbreviations
- •References
- •Standard automated perimetry and algorithms for monitoring glaucoma progression
- •Standard automated perimetry
- •Global indices
- •HFA: MD, SF, PSD, CPSD
- •Octopus indices: MD, SF, CLV
- •OCTOPUS seven-in-one report (Fig. 2)
- •SAP VF assessment: full-threshold strategy
- •SAP VF defects assessment: OHTS criteria
- •SAP VF defects assessment: AGIS criteria
- •SAP VF defects assessment: CIGTS
- •Fastpac
- •Swedish interactive threshold algorithm
- •SAP VF assessment: the glaucoma staging system
- •SAP: interocular asymmetries in OHTS
- •SAP, VF progression
- •SAP: the relationship to other functional and structural diagnostic tests in glaucoma
- •SAP, FDP-Matrix
- •SAP, SWAP, HPRP, FDT
- •SAP: the relationship between function and structure
- •SAP, confocal scanning laser ophthalmoscopy, SLP-VCC
- •SAP, optical coherence tomography
- •SAP and functional magnetic resonance imaging
- •References
- •Introduction
- •Retinal ganglion cells: anatomy and function
- •Is glaucoma damage selective for any subgroup of RGCs?
- •Segregation
- •Isolation
- •FDT: rationale and perimetric techniques
- •SWAP: rationale and perimetric techniques
- •FDT: clinical data
- •SWAP: clinical data
- •Clinical data comparing FDT and SWAP
- •Conclusions
- •References
- •Scanning laser polarimetry and confocal scanning laser ophthalmoscopy: technical notes on their use in glaucoma
- •The GDx scanning laser polarimeter
- •Serial analysis
- •Limits
- •The Heidelberg retinal tomograph
- •Limits
- •Conclusions
- •References
- •The role of OCT in glaucoma management
- •Introduction
- •How OCT works
- •How OCT is performed
- •Evaluation of RNFL thickness
- •Evaluation of optic disc
- •OCT in glaucoma management
- •New perspective
- •Abbreviations
- •References
- •Introduction
- •Technology
- •Visual stimulation
- •Reproducibility and habituation of RFonh
- •Retinal neural activity as assessed from the electroretinogram (ERG)
- •The Parvo (P)- and Magno (M)-cellular pathways
- •Physiology
- •Magnitude and time course of RFonh in humans
- •Varying the parameters of the stimulus on RFonh
- •Luminance versus chromatic modulation
- •Frequency
- •Effect of pattern stimulation
- •Neurovascular coupling in humans
- •Clinical application
- •RFonh in OHT and glaucoma patients
- •Discussion
- •FLDF and neurovascular coupling in humans
- •Comments on clinical application of FLDF in glaucoma
- •Conclusions and futures directions
- •Acknowledgements
- •References
- •Advances in neuroimaging of the visual pathways and their use in glaucoma
- •Introduction
- •Conventional MR imaging and the visual pathways
- •Diffusion MR imaging
- •Functional MR imaging
- •Proton MR spectroscopy
- •References
- •Primary open angle glaucoma: an overview on medical therapy
- •Introduction
- •When to treat
- •Whom to treat
- •Genetics
- •Race
- •Ocular and systemic abnormalities
- •Tonometry and pachymetry
- •How to treat
- •Beta-blockers
- •Prostaglandins
- •Alpha-agonists
- •Carbonic anhydrase inhibitors (CAIs)
- •Myotics
- •Fixed combinations
- •References
- •The treatment of normal-tension glaucoma
- •Introduction
- •Epidemiology
- •Clinical features
- •Optic disk
- •Central corneal thickness
- •Disease course
- •Risk factors
- •Intraocular pressure
- •Local vascular factors
- •Immune mechanisms
- •Differential diagnosis
- •Diagnostic evaluation
- •Therapy
- •IOP reduction
- •Systemic medications
- •Neuroprotection
- •Noncompliance
- •Genetics of NTG
- •Abbreviations
- •References
- •The management of exfoliative glaucoma
- •Introduction
- •Epidemiology
- •Ocular and systemic associations
- •Ocular associations
- •Systemic associations
- •Pathogenesis of exfoliation syndrome
- •Mechanisms of glaucoma development
- •Management
- •Medical therapy
- •Laser surgery
- •Operative surgery
- •Future treatment of exfoliation syndrome and exfoliative glaucoma
- •Treatment directed at exfoliation material
- •References
- •Laser therapies for glaucoma: new frontiers
- •Background
- •Laser iridotomy
- •Indications
- •Contraindications
- •Patient preparation
- •Technique
- •Nd:YAG laser iridectomy
- •Argon laser iridectomy
- •Complications
- •LASER trabeculoplasty
- •Treatment technique
- •Mechanism of action
- •Indications for treatment
- •Contraindications to treatment
- •Patient preparation and postoperative follow-up
- •Complications of the treatment
- •Selective laser trabeculoplasty
- •Results
- •LASER iridoplasty
- •Indications
- •Contraindications
- •Treatment technique
- •Complications
- •LASER cyclophotocoagulation
- •Introduction
- •Indications and contraindications
- •Patient preparation
- •Transpupillary cyclophotocoagulation
- •Endoscopic cyclophotocoagulation
- •Transscleral cyclophotocoagulation
- •Transscleral noncontact cyclophotocoagulation
- •Transscleral contact cyclophotocoagulation
- •Complications
- •Excimer laser trabeculotomy
- •References
- •Modulation of wound healing during and after glaucoma surgery
- •The process of wound healing
- •Using surgical and anatomical principles to modify therapy
- •Growth factors
- •Cellular proliferation and vascularization
- •Cell motility, matrix contraction and synthesis
- •Drug delivery
- •Future directions: total scarring control and tissue regeneration
- •Acknowledgments
- •References
- •Surgical alternative to trabeculectomy
- •Introduction
- •Deep sclerectomy
- •Viscocanalostomy
- •Conclusions
- •References
- •Modern aqueous shunt implantation: future challenges
- •Background
- •Current shunts and factors affecting their function
- •Shunt-related factors
- •Surface area
- •Plate material
- •Valved versus non-valved
- •Commercially available devices
- •Comparative studies
- •Patient and ocular factors
- •Severity of glaucoma damage
- •Tolerance of topical ocular hypotensive medications
- •Aqueous hyposecretion
- •Previous ocular surgery
- •Scleral thinning
- •Patient cooperation for and tolerance of potential slit-lamp interventions
- •Future challenges
- •Predictability
- •Cataract formation
- •The long-term effect on the cornea
- •References
- •Model systems for experimental studies: retinal ganglion cells in culture
- •Mixed RGCs in culture
- •Retinal explants
- •Glial cultures
- •RGC-5 cells
- •Differentiation of RGC-5 cells
- •RGC-5 cell neurites
- •Advantages and disadvantages of culture models
- •References
- •Rat models for glaucoma research
- •Rat models for glaucoma research
- •Use of animal models for POAG
- •Suitability of the rat for models of optic nerve damage in POAG
- •Methods for measuring IOP in rats
- •General considerations for measuring IOP in rats
- •Assessing optic nerve and retina damage
- •Experimental methods of producing elevated IOP
- •Laser treatment of limbal tissues
- •Episcleral vein cautery
- •Conclusions
- •Abbreviations
- •Acknowledgements
- •References
- •Mouse genetic models: an ideal system for understanding glaucomatous neurodegeneration and neuroprotection
- •Introduction
- •The mouse as a model system
- •Mice are suitable models for studying IOP elevation in glaucoma
- •Tools for glaucoma research
- •Accurate IOP measurements are fundamental to the study of glaucoma
- •The future of IOP assessment
- •Assessment of RGC function
- •Mouse models of glaucoma
- •Primary open-angle glaucoma
- •MYOC
- •OPTN
- •Strategies for developing new models of POAG
- •Developmental glaucoma
- •Pigmentary glaucoma
- •Experimentally induced models of glaucoma
- •Mouse models to characterize processes involved in glaucomatous neurodegeneration
- •Similar patterns of glaucomatous damage occur in humans and mice
- •The lamina cribrosa is an important site of early glaucomatous damage
- •An insult occurs to the axons of RGCs within the lamina in glaucoma
- •What is the nature of the insult at the lamina?
- •Other changes occur in the retina in glaucoma
- •PERG and complement
- •Using mouse models to develop neuroprotective strategies
- •Somal protection
- •Axonal protection
- •Erythropoietin administration
- •Radiation-based treatment
- •References
- •Clinical trials in neuroprotection
- •Introduction
- •Methods of clinical studies
- •Issues in the design and conduct of clinical trials
- •Clinical trials of neuroprotection
- •Clinical trials of neuroprotection in ophthalmology
- •Endpoints
- •Neuroprotection and glaucoma
- •Conclusions
- •Abbreviations
- •References
- •Pathogenesis of ganglion ‘‘cell death’’ in glaucoma and neuroprotection: focus on ganglion cell axonal mitochondria
- •Introduction
- •Retinal ganglion cells and mitochondria
- •Possible causes for ganglion cell death in glaucoma
- •Mitochondrial functions and apoptosis
- •Mitochondrial function enhancement and the attenuation of ganglion cell death
- •Creatine
- •Nicotinamide
- •Epigallocatechin gallate
- •Conclusion
- •References
- •Astrocytes in glaucomatous optic neuropathy
- •Introduction
- •Quiescent astrocytes
- •Reactive astrocytes in glaucoma
- •Signal transduction in glaucomatous astrocytes
- •Protein tyrosine kinases (PTKs)
- •Serine/threonine protein mitogen-activated kinases (MAPKs)
- •G protein-coupled receptors
- •Ras superfamily of small G proteins
- •Astrocyte migration in the glaucomatous optic nerve head
- •Cell adhesion of ONH astrocytes
- •Connective tissue changes in the glaucomatous optic nerve head
- •Extracellular matrix synthesis by ONH astrocytes
- •Extracellular matrix degradation by reactive astrocytes
- •Oxidative stress in ONH astrocytes
- •Conclusions
- •Acknowledgments
- •References
- •Glaucoma as a neuropathy amenable to neuroprotection and immune manipulation
- •Glaucoma as a neurodegenerative disease
- •Oxidative stress and free radicals
- •Excessive glutamate, increased calcium levels, and excitotoxicity
- •Deprivation of neurotrophins and growth factors
- •Abnormal accumulation of proteins
- •Pharmacological neuroprotection for glaucoma
- •Protection of the retinal ganglion cells involves the immune system
- •Searching for an antigen for potential glaucoma therapy
- •Concluding remarks
- •References
- •Oxidative stress and glaucoma: injury in the anterior segment of the eye
- •Introduction
- •Oxidative stress
- •Trabecular meshwork
- •IOP increase and free radicals
- •Glaucomatous cascade
- •Nitric oxide and endothelins
- •Extracellular matrix
- •Metalloproteinases
- •Other factors of interest
- •Therapeutic and preventive substances of interest in glaucoma
- •Ginkgo biloba extract
- •Green tea
- •Ginseng
- •Memantine and its derivates
- •Conclusions
- •Abbreviations
- •References
- •Conclusions on neuroprotective treatment targets in glaucoma
- •Acknowledgments
- •References
- •Involvement of the Bcl2 gene family in the signaling and control of retinal ganglion cell death
- •Introduction
- •Intrinsic apoptosis vs. extrinsic apoptosis
- •The Bcl2 family of proteins
- •The requirement of BAX for RGC soma death
- •BH3-only proteins and the early signaling of ganglion cell apoptosis
- •Conclusion
- •Abbreviations
- •Acknowledgments
- •References
- •Assessment of neuroprotection in the retina with DARC
- •Introduction
- •DARC
- •Introducing the DARC technique
- •Annexin 5-labeled apoptosis and ophthalmoloscopy
- •Detection of RGC apoptosis in glaucoma-related animal models with DARC
- •Assessment of glutamate modulation with DARC
- •Glutamate at synaptic endings
- •Glutamate excitotoxicity in glaucoma
- •Assessment of coenzyme Q10 in glaucoma-related models with DARC
- •Summary
- •Abbreviations
- •Acknowledgment
- •References
- •Potential roles of (endo)cannabinoids in the treatment of glaucoma: from intraocular pressure control to neuroprotection
- •Introduction
- •The endocannabinoid system in the eye
- •The IOP-lowering effects of endocannabinoids
- •Endocannabinoids and neuroprotection
- •Conclusions
- •References
- •Glaucoma of the brain: a disease model for the study of transsynaptic neural degeneration
- •Retinal ganglion cells, retino-geniculate neurons
- •Lateral geniculate nucleus
- •Mechanisms of RGC injury in glaucoma
- •Transsynaptic degeneration of the lateral geniculate nucleus in glaucoma
- •Neural degeneration in magno-, parvo-, and koniocellular LGN layers
- •Visual cortex in glaucoma
- •Neuropathology of glaucoma in the visual pathways in the human brain
- •Mechanisms of glaucoma damage in the central visual pathways
- •Implications of central visual system injury in glaucoma
- •Conclusion
- •Acknowledgments
- •References
- •Clinical relevance of optic neuropathy
- •Is there a remodeling of retinal circuitry?
- •Behavioral consequences of glaucoma
- •Glaucoma as a neurodegenerative disease versus neuroplasticity and adaptive changes
- •Future directions
- •Acknowledgment
- •References
- •Targeting excitotoxic/free radical signaling pathways for therapeutic intervention in glaucoma
- •Introduction
- •Channel properties of NMDA receptors correlated with excitotoxicity
- •Downstream signaling cascades after overactivation of NMDA receptors
- •Relevance of excitotoxicity to glaucoma
- •Therapeutic approaches to prevent RGC death by targeting the pathways involved in NMDA excitotoxicity
- •Drugs targeting NMDA receptors
- •Kinetics of NMDA receptor antagonists
- •Memantine
- •NitroMemantines
- •Drugs targeting downstream signaling molecules in NMDA-induced cell death pathways
- •p38 MAPK inhibitors
- •Averting caspase-mediated neurodegeneration
- •Abbreviations
- •Acknowledgments
- •References
- •Stem cells for neuroprotection in glaucoma
- •Introduction
- •Glaucoma as a model of neurodegenerative disease
- •Why use stem cells for neuroprotective therapy?
- •Stem cell sources
- •Neuroprotection by transplanted stem cells
- •Endogenous stem cells
- •Key challenges
- •Conclusion
- •Abbreviations
- •Acknowledgments
- •References
- •The relationship between neurotrophic factors and CaMKII in the death and survival of retinal ganglion cells
- •Introduction
- •Glaucoma and the RGCs
- •Are other retinal cells affected in glaucoma?
- •Retinal ischemia related glaucoma
- •Excitotoxicity and the retina
- •Signal transduction
- •NMDA receptor antagonists and CaMKII
- •Caspase-3 activation in NMDA-induced retinal cell death and its inhibition by m-AIP
- •BDNF and neuroprotection of RGCs
- •Summary and conclusions
- •Abbreviations
- •Acknowledgments
- •References
- •Evidence of the neuroprotective role of citicoline in glaucoma patients
- •Introduction
- •Patients: selection and recruitment criteria
- •Pharmacological treatment protocol
- •Methodology of visual function evaluation: electrophysiological examinations
- •PERG recordings
- •VEP recordings
- •Statistic evaluation of electrophysiological results
- •Electrophysiological (PERG and VEP) responses in OAG patients after the second period of evaluation
- •Effects of citicoline on retinal function in glaucoma patients: neurophysiological implications
- •Effects of citicoline on neural conduction along the visual pathways in glaucoma patients: neurophysiological implications
- •Possibility of neuroprotective role of citicoline in glaucoma patients
- •Conclusive remarks
- •Abbreviations
- •References
- •Neuroprotection: VEGF, IL-6, and clusterin: the dark side of the moon
- •Neuroprotection: VEGF-A, a shared growth factor
- •VEGF-A isoforms
- •VEGF-A receptors
- •Angiogenesis, mitogenesis, and endothelial survival
- •Neurotrophic and neuroprotective effect
- •Intravitreal VEGF inhibition therapy and neuroretina toxicity
- •Neuroprotection: clusterin, a multifunctional protein
- •Clusterin/ApoJ: a debated physiological role
- •Clusterin and diseases
- •Clusterin and the nervous system
- •Neuroprotection: IL-6, VEGF, clusterin, and glaucoma
- •Rational basis for the development of coenzyme Q10 as a neurotherapeutic agent for retinal protection
- •Introduction
- •Ischemia model
- •Neuroprotective effect of Coenzyme Q10 against cell loss yielded by transient ischemia in the RGC layer
- •Retinal ischemia and glutamate
- •Coenzyme Q10 minimizes glutamate increase induced by ischemia/reperfusion
- •Summary
- •Acknowledgment
- •References
- •17beta-Estradiol prevents retinal ganglion cell loss induced by acute rise of intraocular pressure in rat
- •Methods
- •Morphometric analysis
- •Microdialysis
- •Drug application
- •Statistical analysis
- •Results
- •17beta-Estradiol pretreatment minimizes RGC loss
- •Discussion
- •Acknowledgment
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glaucoma. Keltner et al. (1993) developed a VF classification system for the Optic Neuritis Treatment Trial that also has been used in the Ocular Hypertension Treatment Study (OHTS).
SAP VF assessment: full-threshold strategy
Deciding which perimetric program to apply requires knowledge of both the pathology concerned and the characteristics of the various programs available. One can nonetheless affirm that the majority of ocular and neuro-ophthalmo- logical diseases affecting the VF can be studied analyzing the central VF with a 301 fixed grid of points set at 61 or at a variable density, using a III white target stimulus (program 30/2 or 24/2 Humphrey, G1/G2 or 30/2 Octopus) (Anderson and Patella, 1999).
The FT is the most suitable strategy to evaluate VF in glaucoma patients, except in certain cases (the elderly, patients who are particularly fatigued, etc.) when fast threshold strategies (Humphrey Fastpac, Octopus tendency-oriented perimetry [TOP] strategies) could be better.
In some cases with very advanced perimetric damage in which only a small area of residual central functionality remains, or in patients suffering from macular pathologies, the examination pattern can be focused on the central 101 field, with specific programs (10/2 and Macula for Humphrey and M1 or M2 for Octopus) and/or using a V target stimulus in the case of low-vision patients.
Before carrying out the examination, it is important to explain to the patient what automated perimetry is, how it is carried out, and its importance in diagnosing and/or treating the pathology with which the patient is affected. Indeed, the patient’s informed awareness is fundamental in order to obtain reliable and clinically useful results. It must not be forgotten that SAP is a subjective, psychophysical method in which collaboration between the patient and the person carrying out the examination is essential and the importance of the learning effect should also be taken into consideration (Kulze et al., 1990; Marra and Flammer, 1991) (Fig. 3).
In other words, the patient must ‘‘learn’’ to carry out an automated perimetry exam, and it is therefore always advisable to repeat the test if the results are in doubt or not consistent with the clinical situation. It is also necessary to consider the psychological behavior of the patient undergoing perimetry. In most cases, the patient is suffering from glaucoma and is aware of the chronic nature of the disease and the way it develops. Consequently, the VF examination often causes anxiety in that it represents the moment of verifying effective ocular conditions and progression of the disease. It is therefore up to the person carrying out the exam to reassure the patient and warn him that certain light stimuli may not be seen but that this does not necessarily mean having pathological implications.
Particular care must also be taken in the correct insertion of the data. As is known, the single perimetric exam results are compared with a normative database that takes into account the age of the patient. Therefore, an erroneous date of birth can lead to comparison with the wrong age group and the possibility of diagnosing nonexistent perimetric defects or masking real defects.
The pupil diameter influences the quantity of light reaching the retina and consequently its adaptation. It is therefore advisable to carry out and repeat a perimetric examination under the same pupil diameter conditions. Furthermore, normal perimetric data are gathered from subjects with nondilated pupils. Consequently, it is best to carry out an automated perimetry in physiological conditions, monitoring successive examinations for the constancy of the pupil diameter in order to ensure a correct comparison of the results obtained (Park and Youn, 1994).
Another important aspect is the use of optical corrections. For refractive defects of up to 1 spherical and/or cylindrical diopter, it is advisable not to use corrective lenses because the support of these can lead to artifacts that can compromise a correct clinical and statistical interpretation of the results (Zalta, 1989). In cases in which an additional optical correction is required, it is absolutely necessary to use lenses with metallic frames to avoid false ‘‘annular’’ scotomata due to the lens frame (Fig. 4). Anatomical anomalies such
83
Fig. 3. Learning effect: Note the improvement in differential light sensitivity on the fourth visual field.
84
Fig. 4. Artifact due to corrective lens.
as congenital or acquired ptosis, facial asymmetries, and prominent noses should always be noted in the exam report, because they may cause perimetric artifacts.
As mentioned above, SAP results represented a primary outcome in most of the clinical trials and population-based studies on glaucoma and ocular hypertension. Each trial adopted different criteria to define a glaucomatous VF defect (Heijl et al., 2008).
SAP VF defects assessment: OHTS criteria
In the OHTS, a reliable VF was considered to be abnormal if GHT and/or corrected CPSD global index results were outside normal limits (Po0.01 and Po0.05, respectively).
Borderline GHT results were not included as an abnormal field. These results were an indication that the results were suspicious but not clearly abnormal.
An OHTS VF was classified as reliable if none of the reliability indices (false-positive errors, falsenegative errors, or fixation losses) exceeded the 33% limit.
In OHTS, glaucomatous VF damage was defined as follows: two consecutively abnormal SAP test results, with at least one of the two abnormal tests being within the 6-month interval (Gordon and Kass, 1999).
Only few studies suggested the possibility that the VF index MD would be more likely than PSD to capture a generalized depression of sensitivity that may be a prominent feature of early glaucoma cases. The OHTS showed that PSD, but not MD, is a predictor of glaucoma development among ocular hypertensive subjects. PSD may be important for identification of early glaucoma cases. PSD was found to be a good predictor of the development of OAG in the EGPS (Miglior et al., 2007).
However, an average loss of 27.3% of retinal ganglion cells is necessary for the corrected PSD index of standard achromatic perimetry to fall below the 95% normal confidence limits (Kerrigan– Baumrind et al., 2000).
In another study, using SAP-SITA PSD at 95% specificity, the average percentage loss of rim area of the patients with glaucoma identified as
