Hope for patients with progressiveglaucoma may lie, in essence,

within, according to Joseph Caprioli,M.D., Stark Professor of Ophthalmologyand Chief of the Glaucoma Division atthe Jules Stein Eye Institute. “Loweringintraocular pressure by medication orsurgery fails to help many patients andprobably doesn’t address underlyingmechanisms of optic nerve damage.Enhancing endogenous self-defensemechanisms to directly safeguard theoptic nerve would be a more com-prehensive way to manage glaucoma.Our focus now is on neuroprotectivestrategies as a means of sustainingthe optic nerve that have significantclinical potential,” he says.

In PrincipleManipulating and mitigating

destructive physiologic processes — viacalcium channel blockade, glutamateblockade, antioxidants, nitric oxide

synthase inhibition, anti-apoptotic path-ways, cellular regeneration, and partic-ularly stress protein induction — areapproaches that engage much ongoingresearch, including Dr. Caprioli’s. Hebelieves the concept of rousing thebody’s own protective mechanisms towithstand disease is quite realistic.Citing Nietzsche’s axiom, “What doesnot destroy me makes me stronger,”Dr. Caprioli explains, “Sublethal stres-sors actually boost the body’s ownhealing mechanisms, which are amongthe fundamental processes that occurin all living cells. The genetic code forthe stress proteins, for instance, is high-ly homologous between bacteria andhumans. Investigations of variousagents and mechanisms that stimulateendogenous protection are promising,and species specificity is unlikely to bea problem.” (Figure 1)

Precedents and PossibilitiesOne precedent for this approach that

exploits endogenous neuroprotectionclinically, says Dr. Caprioli, is the anti-ulcer agent geranylgeranylace-tone (GGA) being used success-fully for patients in Japan. “An oral regi-men of GGA protects the gastric mucosawithout affecting gastric acid or pepsinsecretion. It has also been effective andnontoxic for other organ systems, includ-ing the liver, lung, kidney, and heart,and has been shown to penetrate thecentral nervous system,” he notes.“Recently, our own studies in an animalmodel confirmed GGA to be neuropro-tective in the eye as well: pretreatmentwith GGA induced heat shock protein(HSP72) expression, thereby protectingretinal ganglion cells from glaucoma

Figure 1: Schematic of thepotential pathways for

neuroprotection of retinalganglion cells against

glaucomatous damage.

Jules Stein Eye InstituteU C L A

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September 2003Volume 12, Number 3

Self-Defense Against Glaucoma?

ClinicalUpdate

Our web site address ishttp://www.jsei.org

Physician’s Direct Referral Line:

(310) 794-9770

IOP-dependent and IOP-independent factorsIOP-dependent and IOP-independent factors

excitotoxicity abnormalglial -neuronal

interactions

neurotrophinstarvation

defectiveendogenousprotection

autoimmunemechanisms

glutamate

TNF-NO[Ca ++]

proteases

p53 activation

Bax / Bcl-X

apoptosisnecrosis

HeatShockProtein

nucleases

Figure 2

damage.” Furthermore, says Dr.Caprioli, there were no signs of sideeffects or toxicity after repeat GGAadministration, a significant factor if itis to be used for ongoing treatmentin glaucoma patients. (Figure 2)

Another neuroprotective agent,the glutamate blocker Memantine,may be even closer to application ina clinical setting. “Memantine hasproven beneficial for patients withAlzheimer’s disease,” Dr. Capriolistates. “Currently, Jules Stein EyeInstitute is participating in a multi-cen-ter clinical trial using Memantine as anadjunct to intraocular pressure con-trol, assessing its effectiveness in opticnerve neuroprotection and its poten-tial for patients with glaucoma.”

Next QuestionsDemonstrating the efficacy of

heat shock protein induction andother neuroprotective mechanismsbrings treatment possibilities closer,but many issues of clinical feasibili-ty — dosage, timing, tolerance —remain to be investigated further.Dr. Caprioli notes that, in laborato-ry studies, increased production ofneuroprotective stress proteins isfairly transient, peaking at 12 hoursafter challenge and falling againafter 24 to 36 hours. How, then,can stress protein induction beused to treat a chronic diseaseoccurring over years? He says,

“Perhaps some sort of pulsed treat-ment — repeated induction of thestress proteins — would be thekey. The usefulness of GGA inulcer patients proves that this gen-eral approach does work for achronic disease. I would hope thatwhatever neuroprotective stimulantwe develop could be used once aday or once a week, which is theway many drugs work.”

Other “Home” Remedies?In addition to the potential of

medication therapies, Dr. Capriolibelieves that there may be other,non-drug means for enhancingendogenous protection, such ashyperthermia. “Interestingly, medicalhistory before antibiotics records a‘fever treatment’ using toxins tocause high fever for a brief time tohelp some patients with tuberculosisand other diseases. Induction ofstress protein may explain theobserved benefits of that approach,”he says. Similarly, recent oncologyliterature reports that patients receiv-ing bone marrow transplants whobecame septic and developed highfever had a lower recurrence rate oftheir cancers than those patients whonever developed fever. “Perhaps rais-ing body temperature, even throughintense exercise or taking a saunaperiodically, could someday be usedto enhance neuroprotection enough

to defend against glaucoma andother neurodegenerations,” he notes.

Dr. Caprioli and his colleagues atthe Institute have also been pursuingand are about to publish findingsabout whether caloric restriction pro-vides enough subtle stress on thebody, without harming health, toprotect against certain diseasesincluding ocular disorders. Barringunforeseen roadblocks, he antici-pates clinical trials within a few yearsto study these non-drug approachesas well as medical means of self-acti-vating neuroprotection.

In PracticeDeveloping a neuroprotective

approach to glaucoma, says Dr.Caprioli, would be particularly bene-ficial for those patients with so-callednormal tension glaucoma, in whomnerve damage progresses despitetreatments to lower intraocular pres-sure. “Since glaucoma is probably aspectrum of diseases, having in com-mon a characteristic optic nervedamage associated with a characteris-tic course of visual loss, I favor theendogenous protective approachmost. It is likely to be effective fordifferent mechanisms of damage, andwe won’t need to know the exactmechanism for it to work,” he notes.Decreasing the cell’s susceptibility todamage and death across a widerange of insults would be a realadvantage and has much broaderpotential than current therapies.”

PUBLICATIONS:Park KH, Cozier, F, Ong OC, Caprioli J: Inductionof heat shock protein 72 protects retinal gan-glion cells in a rat glaucoma model. InvestOphthalmol Vis Sci 2001; 42:1522-30.

Ishii Y, Kwong JKM, Caprioli J: Retinal GanglionCell Protection with Geranylgeranylacetone, aHeat Shock Protein Inducer, in a Rat GlaucomaModel. Invest Ophthalmol Vis Sci 2003; 44:1982-92.

2 JSEI Clinical Update September 2003

GLAUCOMA (continued from page 1)

Figure 2: Flat mounts of retinalganglion cells (RGCs) in a ratmodel of glaucoma. Top left,control. Top right, the decreasednumber of RGCs after exposureto elevated IOP for 8 weeks.Bottom left, the protective effectof adding GGA: the RGC countsare similar to controls, GGA hav-ing blocked the glaucomatousdamage. Bottom right, shows theeffect of quercetin (Q), whichabolishes the protective effects ofstress (heat-shock) proteins.

Vehicle Elevated IOP + Vehicle

Elevated IOP + GGA Elevated IOP + GGA + Q

3

Glaucoma Photography LaboratoryThe Glaucoma Photography

Laboratory provides a series of spe-cialized photographs to assist in themanagement of new and follow-upglaucoma patients. Heidelberg reti-nal tomography (HRT II), usingconfocal laser light, measures struc-tural parameters of the optic nerveand provides more information onthe nerve fiber layer. The NerveFiber Analyzer (GDx Access VCC)uses polarized light in place of dila-tion to measure the thickness of thenerve fiber layer and is particularlyuseful in diagnosing new glaucoma.Optical coherence tomography(OCT Stratus) uses measurements ofreflected light to measure the nervefiber layer as well as to measuremacular holes as a staging proce-dure for surgical repair, and detect-ing cystoid macular. An ophthalmicfundus camera photographs theoptic nerve in stereo.

Director: Joseph Caprioli, M.D.Information and Referral(310) 794-9442

Ocular Motility Clinical LaboratoryThe Ocular Motility Clinical

Laboratory records and quantita-tively analyzes eye movementabnormalities resulting from ocularand neurological disorders, such asocular myasthenia gravis. Fourtypes of tests are performed.Electro-oculography (placing elec-trodes around the eye) evaluatesnerve muscle palsies and lost orslipped eye muscles. The Hessscreen test evaluates patterns of

strabismus in patients who are ableto perceive diplopia. Magnetic scle-ral search coil techniques are uti-lized in clinical research studies formaximum resolution of vertical aswell as horizontal eye movements.Video recording of eye and eyelidmovement is also performed.

Director: Joseph L. Demer, M.D., Ph.D.Information and Referral(310) 206-6354

Ophthalmic Photography LaboratoryThe Ophthalmic Photography

Laboratory provides a wide array ofclinical examination techniques toaid in the diagnosis and manage-ment of complex eye conditions.Patient care services in the laborato-ry include photographic documen-tation of anterior segment diseases;photographs of ocular motility torecord abnormalities of eye move-ment; fundus photography; anddiagnostic testing using fluoresceinand indocyanine green angiogra-phy, which record the dynamics ofblood flow in the eye. The labora-tory also supports the research andteaching activities of the Jules SteinEye Institute by preparing andduplicating graphic materials forpresentation and publication.

Director: Steven D. Schwartz, M.D.Information and Referral(310) 825-6398

Ophthalmic UltrasonographyLaboratory

The Ophthalmic Ultrasonogra-phy Laboratory performs clinical

examinations that are useful indiagnosing ocular and orbital eyediseases and performing intracocu-lar lens calculation for cataractsurgery. Standardized A-scan ultra-sonography is useful in tissue dif-ferentiation and is employed todiagnose ocular and orbital tumors.Biometry and lens calculationexaminations are performed todetermine the power of the lensimplant for cataract patients. B-scanultrasonography provides tumorand foreign body location and con-tour information. Ultrasound biomi-croscopy provides detailed, high-resolution views of the anterior seg-ment of the eye and is a criticaltool for the evaluation of ocularpathology, including choroidalmelanoma and involvement of lens,iris and ciliary body. Optical coher-ence tomography (OCT 3) uses themost advanced technology to imagea cross-section of the retinal con-tour and is especially helpful invisualizing retinal lesions that affectthe retinal cyto-architecture and vit-reoretinal interface.

Director: Marc O. Yoshizumi, M.D.Information and Referral(310) 825-9483

Ophthalmology Diagnostic Laboratory The Ophthalmology Diagnostic

Laboratory offers four quantitativetests, including measurement ofvision acuity and field of vision.The potential acuity meter (PAM)and the laser interferometer mea-sure potential vision acuity, usuallypreparatory to cataract surgery, for

3September 2003 JSEI Clinical Update

(continued on page 4)

The Ophthalmology Clinical Laboratories at the Jules Stein Eye Instituteprovide precise measurements, photographs, and quantitative studies ofthe eye and the visual system. Services include fluorescein angiography,glaucoma testing, ocular motility testing, ophthalmic photography, ultra-sonography, visual field testing and visual physiology. Laboratory ser-vices are available to referring ophthalmologists in the community.

Ophthalmology Clinical Laboratories

patients with complicating eye dis-eases such as macular degenera-tion. The Goldmann perimeter usesmanual perimetry to measure thefield of vision (including peripheralvision). This is particularly usefulfor patients such as those with reti-nal degenerations who cannot per-form automated perimetry. Theendothelial cell counter uses ahigh-powered microscope andvideo camera to photograph theinner layer of the cornea and mea-sure corneal thickness.

Director: Joseph Caprioli, M.D.Information and Referral(310) 825-5798

Visual Field LaboratoryThe Visual Field Laboratory

performs visual field examinationsthat determine the sensitivity ofcentral and peripheral vision.Examinations are conducted withHumphrey automated perimetryequipment. Testing detects visualfield deficits associated with glau-

coma, retinal disorders, andneuro-ophthalmic conditions.Utilizing pinpoints of light that areprojected around a perimetrybowl, the test evaluates differentareas of the field of vision. Testresults are computerized and com-pared to a range of normal valuesby age group. Patterns of dimin-ished fields of vision are related tospecific eye diseases. Perimetrytesting is employed for diagnosticpurposes and to monitor visualfield sensitivity over time, espe-cially for glaucoma patients. Bothstandard and shortwave-lengthautomated techniques are avail-able in addition to frequency-dou-bling perimetry (FDT) and motiondetection perimetry.

Director: Joseph Caprioli, M.D.Information and Referral(310) 794-9442

Visual Physiology LaboratoryThe Visual Physiology

Laboratory evaluates the function

of the retina and visual pathwaysto confirm a specific diagnosis orrule out alternative diagnostic pos-sibilities. Electrophysiological tests,including the full-field elec-troretinogram (ERG) and multi-focal electroretinograms (MERG),electro-oculogram (EOG), and visu-ally evoked cortical response(VECR), record electrical signalsgenerated from different layers ofthe visual system. Psychophysicaltests require the participation ofthe patient in specific tasks to eval-uate visual function. The VisualPhysiology Laboratory performscolor discrimination testing, con-trast sensitivity testing and thresh-old dark adaptometry. In manycases, both electrophysiologicaland psychophysical tests are per-formed together in order to obtaina specific diagnosis.

Directors: John R. Heckenlively, M.D.and Steven Nusinowitz, Ph.D.Information and Referral(310) 825-5798

4 JSEI Clinical Update September 2003

CLINICAL LABORATORY SERVICES (continued from page 3)

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