Translational neuroprotection research in glaucoma: a review of definitions and principles

Review

Translational neuroprotection research inglaucoma: a review of definitions and principlesRobert J Casson DPhil FRANZCO,1 Glyn Chidlow DPhil,1 Andreas Ebneter MD,1 John PM Wood DPhil,1

Jonathan Crowston MD PhD2 and Ivan Goldberg FRANZCO3

1South Australian Institute of Ophthalmology, Hanson Institute and Adelaide University, Adelaide, South Australia, 2Centre for EyeResearch Australia, University of Melbourne and The Royal Victorian Eye and Ear hospital, Melbourne, Victoria, and 3Eye Associates,Glaucoma Services, Sydney Eye Hospital, University of Sydney, Sydney, New South Wales, Australia[Correction added after online publication 27 April 2011]

ABSTRACT

The maintenance of vision, through prevention andattenuation of neuronal injury in glaucoma, forms thebasis of current clinical practice. Currently, the reduc-tion of intraocular pressure is the only proven methodto achieve these goals. Although this strategy enjoysconsiderable success, some patients progress to blind-ness; hence, additional management options are highlydesirable. Several terms describing treatment modali-ties of neuronal diseases with potential applicability toglaucoma are used in the literature, including neuropro-tection, neurorecovery, neurorescue and neuroregeneration.These phenomena have not been defined within acoherent framework. Here, we suggest a set of defini-tions, postulates and principles to form a foundation forthe successful translation of novel glaucoma therapiesfrom the laboratory to the clinic.

Key words: glaucoma, glaucoma medical therapy,glaucoma medication.

PRINCIPLES OF NEUROPROTECTION IN GLAUCOMA

Protection of neurons from experimental insult iseasy; protection of neurons in the clinic has provedmore difficult. The first technique to protect neuronsagainst ischaemic injury was ‘human refrigeration’,developed by the neurosurgeon Temple Fay in the1930s1 Eighty years on, hypothermia remains one ofthe few clinically successful methods to protectneurons against ischaemic injury.

Pharmacological protection of neurons was devel-oped by researchers in the 1980s, with particularfocus on stroke and excitotoxic injury.2,3 As a logicalextension, ‘neuroprotection’ was applied to chronicneurodegenerative diseases.4,5 In 1994, Schumer andPodos suggested that glaucoma should be consideredas a neurodegenerative disease possibly amenable totherapies other than intraocular pressure (IOP)reduction,6 and that developments in the neuro-logical field may translate to glaucoma.6 Despitethousands of publications describing protection ofneurons in the laboratory, this translation for humanbenefit has failed frustratingly.

Attempts to translate the results of experimentalglaucoma research from the laboratory to the clinicremain in their infancy. To date, only two long-termstudies assessing the effect of non-IOP-related phar-macological therapy on the outcome of human glau-coma have been undertaken. The Memantine Studyassessed the affect of the anti-excitotoxic oral agent,memantine, on progression of glaucoma. The resultsremain unpublished, but a report to shareholdersindicated that there was no difference in primaryoutcome between treated and control groups.Recently, the results from the Low-pressure Glau-coma Treatment Study have been reported.7 This wasa randomized, double-masked multicentre trial. The‘main outcome measure was field progression ineither eye, defined as the same 3 or more pointswith a negative slope �-1 dB/year at P < 5%, on 3consecutive tests, assessed by pointwise linearregression.’ The IOPs in both groups were similar.By this definition, 9.1% of those on brimonidine

� Correspondence: Professor Robert J Casson, South Australian Institute of Ophthalmology, Level 8, East Wing, Royal Adelaide Hospital, Adelaide, SA

5000, Australia. Email: [email protected]

Received 19 December 2010; accepted 17 February 2011.

Clinical and Experimental Ophthalmology 2011; ••: ••–•• doi: 10.1111/j.1442-9071.2011.02563.x

© 2011 The AuthorsClinical and Experimental Ophthalmology © 2011 Royal Australian and New Zealand College of Ophthalmologists

progressed compared with 39.2% on timolol (P =0.001; log–rank test). A considerable proportion ofthose randomized to the brimonidine group stoppedtreatment because of allergy, but the effect sizeremains impressive and highly significant. Theexplanation for the results remains unclear, but anon-IOP-related neuroprotective effect of brimoni-dine is a strong possibility.

A decade ago, Wheeler et al.8 proposed four criteriafor ‘assessing the likely therapeutic utility in humanglaucoma of drugs that have demonstrated neuropro-tective activity in animal models: 1) A specific recep-tor target must be in the retina/optic nerve; 2)Activation of the target must trigger pathways thatenhance a neuron’s resistance to stress/injury and/orsuppresses toxic insults; 3) The drug must reach theretina/vitreous at pharmacologic doses; and 4) Theneuroprotective activity should be demonstrated inclinical trials.’ As these criteria remain valid, itwould seem timely to expand on this logical frame-work so that the translation of nerve protection fromthe laboratory to the clinic might be optimized.

To prevent or attenuate neuronal injury in glau-coma is the basis of current clinical practice.Although this strategy is broadly successful, a sig-nificant number of glaucoma patients still lose visionand additional treatment strategies are needed. Newtreatment strategies are likely to be adjunctive tocurrent methods to reduce IOP medically andsurgically. The place of new treatment methodsin current treatment algorithms would dependon their relative risk/benefit profiles. If a new treat-ment proved particularly efficacious and safe then itis likely its use would become routine clinicalpractice.

Several terms describing the treatment of neuronaldiseases are used haphazardly in the literature,including neuroprotection, neurorecovery, neurores-cue and neuroregeneration. These phenomena havenot been defined within a cohesive framework. Wesuggest a set of definitions for these concepts andpostulates relating to neuronal function and the aeti-ology of glaucoma. Following the postulates, weoffer a set of clinically pragmatic principles for neu-roprotection in glaucoma and discuss current knowl-edge surrounding these principles. Necessarily, theprinciples are limited by current poor understandingof disease pathogenesis and await refinement.

DEFINITIONS

Glaucoma is a term describing group of ocular disor-ders with multi-factorial aetiology united by a clini-cally characteristic intraocular pressure-associatedoptic neuropathy.

Neurodegeneration is the ongoing loss of neuronalstructure and function.

Neuroprotection is the relative preservation of neu-ronal structure and/or function.

Neurorecovery is the complete or partial restorationof a living, non-functioning or poorly functioningneuron to structural and functional health.

Neurorescue is the combination of neurorecoveryand neuroprotection.

Neuroregeneration is the generation of new neuronsand their axons, in part or whole.

Notes on the definitions

Neuroprotection is a ‘relative preservation’: it can onlybe understood in the light of an actual or threatenedneuronal insult. Hence, one can always ask, ‘neuro-protection against what?’. It can be applied to allpresent or future neuronal insults, including neuro-degenerative diseases. An insult in the past that hasceased and has no prospect of recurring is not ame-nable to neuroprotection. If the past or ongoinginsult resulted in unhealthy but living neurons,further deterioration could be limited by a neuro-protectant, and health could be restored by aneurorecoverant. If the past insult resulted in deadneurons, then only neuroregeneration would bepossible. Hence, the definitions are based on thetiming of treatment in relation to the disease processand on a tripartite state of neuronal well-being.

Structural integrity refers to the neuron in itsentirety or in part. Hence, loss of axons in the nervefibre layer without knowledge of the structure oftheir corresponding somata is considered evidence ofloss of structural integrity. Similarly, functionalintegrity may be lost completely or in part. Underthis definition, both the prevention and reduction ofloss of neuronal structure and/or function is consid-ered as neuroprotection. Hence, reducing body tem-perature prior to cardiac surgery is neuroprotective.9

In the case of an ongoing insult (a neurodegenera-tive insult) the relative preservation of neuronalintegrity implies a reduction in any rate of loss overtime. Provided that neuronal structural or functionalintegrity can be quantified, neurodegeneration andneuroprotection can be expressed as a mathematicalfunction of time (t). We have N = f(t), where N rep-resents the measured structural or functional integ-rity (Fig. 1). Neurodegeneration and neuroprotectionare functions of time (t) in the sense that for anyvalue of t, there is a unique value for N, which, in theabsence of neurorecovery or neuroregeneration, iseither static (zero gradient) or decreasing (negativegradient).

Although we may be ignorant of the shape of the‘curve’ described by f(t), mathematically, the slope ofthe line at (t) is expressed as dN/dt, such that inneurodegeneration dN/dt < 0 and in neuroprotec-tion dN/dt � 0. For a given individual, if the balance

2 Casson et al.


of forces favours neurodegeneration at (t1) andneuroprotection at t2, then dN/dt at t2 > dN/dt at t1.Similarly, if a group of individuals have receivedsuccessful neuroprotective treatment for a neurode-generative disease then the average rate of decline inneuronal integrity will be less than in the controlgroup (Fig. 1).

In neurorecovery, a measurable structural or func-tional neuronal marker is partially or fully restoredfrom a ‘sick’ state to a ‘healthy’ state. Conceivably,neurorecovery can occur over a short time frame suchthat it is not necessarily a function of time anddepends only on the effectiveness of the neurorecov-ery strategy. This implies it is an easier phenomenonto demonstrate clinically. If neurorecovery is occur-ring in an individual at time (t1) then, in the absenceof neurodegeneration, dN/dt at t1 > 0 (Fig. 2). Resto-ration of blood flow or oxygen to acutely ischaemic/hypoxic retina with rapid recovery of visual functionis an example of neurorecovery.

Neurorecovery during the course of a neurodegen-erative disease does not confirm neuronal structuralor functional integrity improvement in the long term.A treatment (a neurorecoverant) could improve

neuron function briefly, but then accelerate the rateof neuron loss, so that in the long term the averagerate of neuronal decline was greater in those receiv-ing the neurorecoverant.

Furthermore, at any given time some neuronsare likely to be recovering whereas some will bedegenerating: the measured quantity, N, will dependon the balance of restorative and degenerativeprocesses. Similarly, a neuroprotectant may protectone type of degenerating neuron but not another.

In glaucoma management, the current treatmentstrategy is focused on neuroprotection using the onlyknown strategy: IOP reduction. Under this definitionsystem, IOP reduction is a bone fide clinical neuropro-tectant in glaucoma. This could be referred to as anindirect neuroprotectant in the sense that the treat-ment does not act directly on retinal ganglion cells(RGCs), and could be distinguished from a directneuroprotectant, which did act directly on RGCs.Similarly, if improved blood flow to the optic nervewas convincingly shown to reduce the rate of neuro-degeneration, it too would be an indirect clinicalneuroprotectant. Any risk factor that could be elimi-nated or attenuated that reduced the rate of progres-sion would be a bone fide neuroprotectant.

N

t

A

B

O

t0

t1

x

a

Figure 1. Graphical representation of neuroprotection. They-axis, N, is some measurable variable of neuronal structural orfunctional integrity. The x-axis, t, is time. The dashed line at t0

represents the onset of neuroprotection. The line segment OBrepresents the mean reduction in N during the natural course ofa neurodegenerative disease. The line segment OA representsthe mean reduction in N in the presence of a neuroprotectant.The rate of change in N is given by dN/dt (the slope of the linesegments). In neuroprotection the slope is always less negativethan in neurodegeneration, but is never >0. The treatment effect,x, at time, t1, is a function of the neuroprotective ‘lift’ describedby the angle, a, and time, t; x is the difference in means betweenthe treated and control group, and is a function of the differencein the rates of change between the groups.

N

t

A

B

O

t0

t1

x

Figure 2. Graphical representation of neurorecovery. They-axis, N, is some variable of neuronal structural or functionalintegrity that is capable of measurable neurorecovery. The x-axis,t, is time. The dashed line at t0 represents the onset ofneurorecovery. The time interval t1–t0 could be extremely short.The line segment OB represents the mean reduction in N duringthe natural course of a neurodegenerative disease, but over timet1–t0 is negligible. The line segment OA represents the meanincrease in N in the presence of a neurorecoverant. The slope ofOA is positive. Because the time interval can be negligible, thetreatment effect, x, is a function of the neurorecoverant strengthbut not necessarily of time.

Glaucoma: Translational Neuroprotection 3


POSTULATES

1 Neurons are structurally and functionallydivided into three primary compartments: soma,axon and dendrites.

2 All neuronal compartments must be functioningnormally to maintain normal function.

3 Changes to neuronal structure and function willhave clinical correlates.

PRINCIPLES

Primarily affected neurons mustbe treated

All neurons affected by the disease process requiredirect therapeutic attention. Omission of treatment ofa primarily affected neuron either through ignoranceor inability results in incomplete treatment. Second-arily affected neurons would not necessarily requiretreatment if primary neurons were protectedcompletely. In glaucoma the primarily affectedneurons are the RGCs. Other retinal cell types seemunaffected in glaucoma, but perhaps owing to therelative scarcity of tissue, there has been little pub-lished on retinal pathology in human glaucoma.There is evidence of orthograde trans-synapticdegeneration in the visual pathway in human glau-coma (from a single post-mortem report),10 andunconfirmed evidence of photoreceptor abnormalityin human glaucoma.11 Based on current evidence,RGCs are the only neurons that need primarytargeting.

All neuronal compartments that areprimarily affected must be treated

Even though the pathogenesis of glaucoma remainspoorly understood, an adherence to this second pos-tulate is necessary for successful clinical outcomes.The convergence of clinical and experimental evi-dence indicates that the primary site of injury inglaucoma is the optic nerve head (ONH). Thirty yearsago, Quigley et al. provided evidence of axonal trans-port obstruction at the ONH in primates and arguedthat patterns of axonal loss reflected sectoral ana-tomical differences in the lamina cribrosa.12,13

Although recent evidence indicates that the earliestobservable pathology in experimental glaucoma mayoccur at the distal RGC axon (closer to its synapse),14

the primary site of injury remains the ONH.In an elegant set of experiments, Howell et al.

recently provided convincing evidence that the siteof injury in the DBA/2J mouse glaucoma model wasat the ONH.15 Although the RGC axons may not be

the initial tissue element damaged at the ONH, interms of the neuronal compartment, human glau-coma seems to be primarily an axonopathy. The axonand soma exhibit different death pathways afteraxonal transection and in experimental glaucoma:16,17

the somal death is apoptotic and caspase-dependent,whereas the axon degenerates via caspase-independent pathways.16,17 Recent data implicateNmnat2 as a key regulator of axonal survival.18 Anyprotection of RGC bodies while ignoring axons isimplicitly futile clinically. Whether RGC bodies arealso primarily involved in some forms of humanglaucoma requires further study.

All relevant upstream death pathwaysmust be addressed

Cell death is complex and incompletely understood.Even at what point a cell is actually ‘dead’ is unclear.Assuming a complete understanding of cellulardeath pathways and an ability to manipulate them atthe molecular level, could RGC death in glaucoma beindefinitely postponed despite ongoing or repeatedinsult at the ONH? For some insults such as anaxonal compressive injury, it may be possible toprolong cell survival by direct provision of essential‘survival factors’ to the axon and soma. If the cellularcompartments remained functionally connected,then normal function may persist even if the primarycompression continued. This treatment could work ifall upstream death pathway triggers had beenaddressed. However, triggers such as ischaemia willactivate multiple death pathways.19 Although a treat-ment that inhibits the molecular pathways of neuro-degeneration is highly desirable, on its own, it isunlikely to provide clinically significant neuropro-tection with ongoing multiple insults.

Development of a ‘universal direct neuropro-tectant’ is unlikely. More likely is the situationwhere glaucoma patients are managed with a cock-tail of neuroprotective strategies that addresses themechanisms of injury pertinent to each individual,direct and indirect, and ideally matched to their indi-vidualized risk factors and neuronal death pathwaytriggers.

To be useful, neuroprotection requiresmeasurable clinical outcomes

Lack of measurable clinical outcomes has been astumbling block in the translation of neuroprotec-tion from the lab to the clinic. Neuroprotection isrelatively easy to measure in the laboratory because(i) disease models have relatively short time frames;and (ii) animals can be killed and neurons examinedby histological or molecular biological techniques.

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This contrasts with human chronic glaucoma wheretime frames are much longer and neuronal loss ordysfunction must be detected in vivo.

Clinical measurement of RGC structural integrityis confined to assessment of the intraocular RGCaxon, either at the ONH or within the retinal nervefibre layer. The structure of RGC somata and den-drites are not clinically detectable yet, and neuroim-aging techniques of the visual pathway, althoughreported to be abnormal in glaucoma,20,21 are notroutine. This is not necessarily problematic, pro-vided that measurements can be made over practi-cable time frames. Perhaps the most difficult obstacleto overcome in the clinical translation of neuropro-tection is the ability to demonstrate neuroprotectionmeaningfully in a chronic disease.

In terms of IOP reduction, neuroprotection inglaucoma has been demonstrated convincingly, andis the foundation of clinical practice. Perhaps the bestevidence comes from the Early Manifest GlaucomaTreatment Study (EMGTS).22 The design and resultsof this study provide insights about measuring neu-roprotection clinically.

The EMGTS randomized 255 subjects with earlyglaucoma either to treatment or no treatment. Treat-ment consisted of 360 degree Argon laser trabeculo-plasty and topical betaxolol, and resulted in asignificantly lower mean IOP than untreatedpatients. The null hypothesis was that treatment didnot alter disease progression after 4-year minimumfollow up, where progression was defined by pre-specified changes to automated perimetry or opticdisc changes on flicker chronoscopy. The outcomewas binary: at the 4-year minimum follow up, foreach patient either there was progression or therewas not.

At this time point, the EMGTS investigatorsapplied a simple c2-test of proportions and obtaineda P-value of 0.007, providing convincing evidence ofneuroprotection. This methodology is consistentwith the notion of neuroprotection reducing therate (incidence) of defined neuronal loss and/ordysfunction. Could the time frame of this study havebeen shorter? From a survival analysis interpretationof the data, the incidence of progression in eachgroup diverged quite early. Given the same samplesize, a significant difference (P < 0.05) wouldhave been obtained after approximately 18-monthminimum follow up. Additionally, shorter timeframes would have been possible if the neuroprotec-tive ‘lift’ provided by IOP reduction had beengreater.

Neurorecovery in glaucoma has received lessattention than neuroprotection, but it is appealingnot only because of its therapeutic potential butbecause it is a phenomenon that could be demon-strated over a short time frame. Neurorecovery relies

on the notion that some RGCs are sick but not irre-versibly dying. Although intuitive, evidence for sickRGCs is scant. Weber et al. demonstrated changes tothe RGC dendritic tree with associated functionaldeficits in relatively small numbers of primates withexperimental glaucoma.23,24 Unlike visual field lossassociated with optic nerve compression, glaucoma-tous field loss is permanent. Although an apparentmild recovery of visual fields may be observed inglaucoma patients, it is difficult to know whetherthis represents genuine neuronal recovery or is ameasurement artefact. It is generally assumed to bethe latter. However, there is intriguing circumstantialevidence for sick RGCs in human glaucoma fromseveral studies reporting an improvement in contrastsensitivity after treatment of glaucoma patients withseveral methods.25–27

Contrast sensitivity is an easy-to-measure psycho-physical parameter with a strong correlation withvision-related quality of life in glaucoma patients.28

The physiological substrate of contrast sensitivityinvolves the centre-surround receptive fields ofthe RGCs. It is not routinely measured in clinicalglaucoma practice, but is affected by glaucoma.29–31

Several studies have demonstrated an improvementin contrast sensitivity after short-term treatment ofglaucoma.25–27 Gandolfi et al. showed that contrastsensitivity improved after reduction of IOP follow-ing trabeculectomy.27 In a double-blind, randomizedstudy, Bose et al. reported improvement in contrastsensitivity in patients with normal tension glau-coma and in normal controls over 2 h after oralnimodipine.25 In a randomized study comparingtimolol with brimonidine, Evans et al. found that bri-monidine significantly improved contrast sensitivityin glaucoma patients.26

Although the pathophysiological substrate ofthese results is unclear, perhaps a portion of theRGCs in these glaucoma patients were functioningsuboptimally prior to treatment (‘sick’ RGCs) andthat after treatment their function increased, with acorresponding improvement in contrast sensitivity. Ifwe accept this notion, these studies provide evidencethat the three treatments (IOP reduction, brimo-nidine and nimodipine) are neurorecoverants.Whether they provide neuroprotection is a separatematter requiring a different longer-term studymethod, which assesses rates of change. The onlyknown neuroprotectant in glaucoma (IOP reduction)also happens to be a neurorecoverant; hence, there isevidence that IOP reduction is a ‘neurorescuant’.

Measurement of neuroprotection can be con-founded by clinical independence of neuronal structure andfunction. That neuronal structure and function aretightly related is intuitive. This forms the basisfor the pathophysiological interpretation of clinicalfindings. However, in practice, the relationship



between structure and function in glaucoma iscomplex.32 This owes partly to the different scales ofmeasurement for structure and function and theeffect of retinal eccentricity on the relationship.32

RGC density on a decibel (logarithmic) scale has alinear relationship with retinal sensitivity on adecibel scale for a given eccentricity.1,2

Retinal ganglion cell densities cannot be measuredclinically, and studies in patients with glaucomaand ocular hypertension have shown that visualfield changes can occur independently of structuralchanges to the retinal nerve fibre layer or optic disc.3

This does not mean necessarily that there is a genuinedissociation between structure and function, but thatour current measurement techniques find an appa-rent dissociation. Alternatively, possibly functionalchanges do occur without structural changes. There-fore, detection of clinical neuroprotection requiresboth structural and functional endpoints to optimizemeasurement of differential rates of neurodegenera-tion in treated and control groups.

The time course for effective clinicalneuroprotection must parallel that ofthe disease process

This follows from the definition of neuroprotection.In a neurological disease with a short time frame,such as stroke, neuroprotection needs to be appliedfor a short time. But in a chronic, incurable diseasesuch as glaucoma, neuroprotection must be appliedfrom diagnosis to death. The demonstration of clini-cal neuroprotection becomes increasingly difficult asthe chronicity of the disease increases and the rate ofneurodegeneration decreases.

The minimum time interval in which neuropro-tection could be demonstrated convincingly is theminimum time interval in which a definite rate ofneurodegeneration could be measured for any givendisease. This minimum time interval requires com-plete neuroprotection: no further structural or func-tional loss occurs after the onset of neuroprotection,a situation that is unlikely in practice. More likelyis where a treatment is partially neuroprotective.Here, the minimum time interval required to dem-onstrate a neuroprotective effect is the minimumtime required to measure a difference in the rates ofstructural or functional loss (Fig. 1).

Hence, a strategy to optimize a clinical study ofglaucoma neuroprotection would be to select adisease variant with a shorter time frame or to selectpatients who are rapidly progressing. For example,clinical neuroprotection of the optic neuropathy asso-ciated with acute angle closure is potentially easier todemonstrate than clinical neuroprotection of chronicglaucoma (albeit that the optic neuropathy from acuteangle closure may not be strictly glaucomatous).

Advances in statistical techniques are also likelyto improve the efficiency of clinical trials. Adoptionof a Bayesian approach to clinical trials would beadvantageous.3 Although the frequentist approach tostatistics is still mainstream, trials using a Bayesianapproach are becoming more common. Advantagesinclude stopping the trial at any point and changingrecruitment patterns based on incoming evidence.The disadvantage is that a certain ‘prior probability’must be chosen to obtain the posterior probability.Frequentists view this as an unacceptable flaw, butclinical practice is essentially Bayesian, and it makessense that clinical trials should be too.

Optimal treatment requires anunderstanding of the disease aetiologyat the individual level

Glaucoma is not a single entity. This fact causessome confusion when treatment modalities, includ-ing neuroprotection are discussed. The clinicalprinciple that arises from the definition of glaucoma(it has multifactorial aetiology) is that treatmentstrategies are ideally individualized. Currently,there is a relative lack of individualized treatmentbecause only one treatment strategy is available:reduction of IOP. The mechanism of the elevatedIOP may be directly targeted in some cases, andalthough the method of IOP reduction is tailored tothe individual patient, the mechanism of the glau-comatous optic neuropathy on an individualizedbasis is not targeted.

Large-scale, population-based epidemiologicalstudies have identified a number of risk factors forprimary open-angle glaucoma (POAG): increasingage, IOP levels, low perfusion pressure, familyhistory, myopia and ethnicity. Other risk factors havebeen inconsistently reported. Female gender, vasos-pasm, migraine and autonomic dysregulation havebeen reported as risk factors for ‘normal tension’glaucoma. Unknown risk factors almost certainlycoexist. The sum total of these risk factors, a mix ofgene/environment interactions combine in a multi-tude of patterns to ‘cause’ POAG in any given indi-vidual (Fig. 3).

Different clinical phenotypes of the glaucomatousONH in POAG may indicate different modes of cau-sation,33 but our ability to determine the pathogen-esis of glaucomatous optic neuropathy in a givenindividual remains rudimentary. An indirect neuro-protectant (such as IOP reduction) may be moreeffective in some individuals than others. Forexample, we would expect that if the IOP in a patientwith pigment dispersion was always maintained atless than 16 mmHg, then the patient would be pro-tected against pigment dispersion glaucoma, but notfrom the development of normal tension glaucoma.

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The variable nature of glaucoma pathogenesisposes considerable problems for the assessment ofnew treatments. For example, a study assessing theeffect of an agent that improves ONH blood flow inpatients with POAG could miss a genuine treat-ment effect if a significant proportion of thoseenrolled did not have insufficient blood flow as animportant part of the pathogenesis. The ability toidentify pathophysiology in individual POAGpatients is not an easy task and awaits understand-ing of genetics and new measurement techniques,which allow the testing of hypotheses regardingPOAG causation.

REFERENCES

1. Henderson AR, Temple Fay MD. Unconformable cru-sader and harbinger of human refrigeration, 1895–1963. J Neurosurg 1963; 20: 627–34.

2. Gill R, Foster AC, Woodruff GN. Systemic administra-tion of MK-801 protects against ischemia-induced hip-pocampal neurodegeneration in the gerbil. J Neurosci1987; 7: 3343–9.

3. McDonald JW, Roeser NF, Silverstein FS, JohnstonMV. Quantitative assessment of neuroprotectionagainst NMDA-induced brain injury. Exp Neurol 1989;106: 289–96.

4. Cooper JM, Schapira AH. Mitochondrial dysfunctionin neurodegeneration. J Bioenerg Biomembr 1997; 29:175–83.

5. Lange KW, Youdim MB, Riederer P. Neurotoxicity andneuroprotection in Parkinson’s disease. J Neural TransmSuppl 1992; 38: 27–44.

6. Schumer RA, Podos SM. The nerve of glaucoma! ArchOphthalmol 1994; 112: 37–44.

7. Krupin T, Liebmann JM, Greenfield DS, Ritch R, Gar-diner S. A randomized trial of brimonidine versustimolol in preserving visual function: results from thelow-pressure glaucoma treatment study. Am J Glaucoma2011; 151(4): 671–81.

8. Wheeler LA, Gil DW, WoldeMussie E. Role of alpha-2adrenergic receptors in neuroprotection and glaucoma.Surv Ophthalmol 2001; 45 (Suppl. 3): S290–4; discussionS295–6.

9. Grocott HP, Yoshitani K. Neuroprotection duringcardiac surgery. J Anesth 2007; 21: 367–77.

10. Gupta N, Ang LC, Noël de Tilly L, Bidaisee L, YücelYH. Human glaucoma and neural degeneration inintracranial optic nerve, lateral geniculate nucleus, andvisual cortex. Br J Ophthalmol 2006; 90: 674–8.

11. Nork TM, Ver Hoeve JN, Poulsen GL et al. Swellingand loss of photoreceptors in chronic human andexperimental glaucomas. Arch Ophthalmol 2000; 118:235–45.

12. Quigley HA, Addicks EM. Chronic experimental glau-coma in primates. I. Production of elevated intraocularpressure by anterior chamber injection of autologousghost red blood cells. Invest Ophthalmol Vis Sci 1980; 19:126–36.

13. Quigley HA, Guy J, Anderson DR. Blockade of rapidaxonal transport. Effect of intraocular pressure eleva-tion in primate optic nerve. Arch Ophthalmol 1979; 97:525–31.

14. Crish SD, Sappington RM, Inman DM, Horner PJ,Calkins DJ. Distal axonopathy with structural persis-tence in glaucomatous neurodegeneration. Proc NatlAcad Sci USA 2010; 107: 5196–201.

15. Howell GR, Libby RT, Jakobs TC et al. Axons ofretinal ganglion cells are insulted in the optic nerveearly in DBA/2J glaucoma. J Cell Biol 2007; 179: 1523–37.

16. Raff MC, Whitmore AV, Finn JT. Axonal self-destruction and neurodegeneration. Science 2002; 296:868–71.

17. Whitmore AV, Libby RT, John SW. Glaucoma: think-ing in new ways-a role for autonomous axonal self-destruction and other compartmentalised processes?Prog Retin Eye Res 2005; 24: 639–62.

18. Gilley J, Coleman MP. Endogenous Nmnat2 is anessential survival factor for maintenance of healthyaxons. PLoS Biol 2010; 8: e1000300.

19. Osborne NN, Casson RJ, Wood JP, Chidlow G,Graham M, Melena J. Retinal ischemia: mechanisms ofdamage and potential therapeutic strategies. Prog RetinEye Res 2004; 23: 91–147.

20. Gupta N, Greenberg G, de Tilly LN, Gray B, Pole-midiotis M, Yücel YH. Atrophy of the lateral geni-culate nucleus in human glaucoma detected bymagnetic resonance imaging. Br J Ophthalmol 2009;93: 56–60.

other

perfusionpressure

age

IOP

Figure 3. Theoretical example of a glaucoma ‘causation’. Glau-comatous optic neuropathy is likely to be multifactorial with anamalgamation of factors in variable proportions, such that eachpatient’s ‘causation pie chart’ will be unique. IOP, intraocularpressure.



21. Lagreze WA, Gaggl M, Weigel M et al. Retrobulbaroptic nerve diameter measured by high-speed mag-netic resonance imaging as a biomarker for axonal lossin glaucomatous optic atrophy. Invest Ophthalmol Vis Sci2009; 50: 4223–8.

22. Heijl A, Leske MC, Bengtsson B, Hyman L, BengtssonB, Hussein M, Early Manifest Glaucoma Trial Group.Reduction of intraocular pressure and glaucoma pro-gression: results from the Early Manifest GlaucomaTrial. Arch Ophthalmol 2002; 120: 1268–79.

23. Weber AJ, Harman CD. Structure-function relations ofparasol cells in the normal and glaucomatous primateretina. Invest Ophthalmol Vis Sci 2005; 46: 3197–207.

24. Weber AJ, Kaufman PL, Hubbard WC. Morphology ofsingle ganglion cells in the glaucomatous primateretina. Invest Ophthalmol Vis Sci 1998; 39: 2304–20.

25. Bose S, Piltz JR, Breton ME. Nimodipine, a centrallyactive calcium antagonist, exerts a beneficial effect oncontrast sensitivity in patients with normal-tensionglaucoma and in control subjects. Ophthalmology 1995;102: 1236–41.

26. Evans DW, Hosking SL, Gherghel D, Bartlett JD.Contrast sensitivity improves after brimonidinetherapy in primary open angle glaucoma: a case forneuroprotection. Br J Ophthalmol 2003; 87: 1463–5.

27. Gandolfi SA, Cimino L, Sangermani C, Ungaro N,Mora P, Tardini MG. Improvement of spatial contrast

sensitivity threshold after surgical reduction ofintraocular pressure in unilateral high-tensionglaucoma. Invest Ophthalmol Vis Sci 2005; 46: 197–201.

28. Nelson P, Aspinall P, Papasouliotis O, Worton B,O’Brien C. Quality of life in glaucoma and its rela-tionship with visual function. J Glaucoma 2003; 12:139–50.

29. Arden G. Measuring contrast sensitivity with gratings:a new simple technique for the early diagnosis ofretinal and neurological disease. J Am Optom Assoc 1979;50: 35–9.

30. Arden GB, Jacobson JJ. A simple grating test for con-trast sensitivity: preliminary results indicate value inscreening for glaucoma. Invest Ophthalmol Vis Sci 1978;17: 23–32.

31. Atkin A, Bodis-Wollner I, Wolkstein M, Moss A,Podos SM. Abnormalities of central contrast sensitiv-ity in glaucoma. Am J Ophthalmol 1979; 88: 205–11.

32. Artes PH, Chauhan BC. Longitudinal changes in thevisual field and optic disc in glaucoma. Prog Retin EyeRes 2005; 24: 333–54.

33. Drance SM. What can we learn from the disc appear-ance about the risk factors in glaucoma? Can J Ophthal-mol 2008; 43: 322–7.

8 Casson et al.


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Translational neuroprotection research in glaucoma: a review of definitions and principles