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BRAIN

A JOURNALOFNEUROLOG Y

LETTERTOTHE EDITOR

Microcysts inthe innernuclear layerfrom opticatrophy arecaused byretrograde trans-synaptic degenerationcombined withvitreous tractionon theretinal surface

Brandon J.Lujan

1 and JonathanC. Horton 2

1 WestCoastRetina MedicalGroup, SanFrancisco, CA,94107, USA

2 Neuro-OphthalmologyService, Universityof California,San Francisco,Department ofOphthalmology, SanFrancisco, CA,94143, USA

Correspondence to:Jonathan C.Horton MD,PhD,

Beckman VisionCentre, Universityof California,

San Francisco,10 KoretWay,

San Francisco,

CA 94143-0730

E-mail: hortonj@vision.ucsf.edu

Sir, ithas beenreported thatmicrocysts frommacular oedema occur in4.7% ofpatients withmultiple sclerosis(Gelfand et al.,

2012). Itis nowevident thatthese microcystsdo notrepresent

oedema, noris theiroccurrence aspecific featureof demyelinating disease, becausethey havebeen identifiedin patientswith Leber's hereditary opticneuropathy, Kjer'sdominant opticatrophy, and optic glioma(Abegg et al., 2012;Barboni et al., 2013).However, their preciseaetiology hasremained amystery. As pointedout byAbegg et al. (2012),the classicalocular path- ology literatureprovides aclue tothe formationof microcysts. Van Buren(1963) describedretrograde trans-synapticdegener-

ation ofthe innernuclear layerin histologicalsections ofthe retina afterlesions ofthe opticnerve orchiasm, causing'cystic degeneration' thatresembles the'microcysts' nowbeing imagedwith opticalcoherence tomography.Gills andWadsworth (1967)found a15-60% reductionin cellpopulation inthe innernuclear

layer innine patientswith longstandingblindness fromcompres- sive ortraumatic lesionsof theoptic nerve.In atleast threecases, microcycsts werepresent inthe innernuclear layer(Fig. 1).In two patients withmore recentblindness, cellloss wasnot observed. Presumably, sufficienttime hadnot elapsedfor trans-synaptic degeneration tooccur. Gills andWadsworth (1967)also reportedcell lossin theinner nuclear layerin patientswith opticatrophy frommultiple sclerosis.

Figure 1(A) Histologicalsection ofthe retinashowing cystsin theinner nuclearlayer followingretrograde trans-synapticdegeneration

from atumour ofthe opticnerve. Reproducedfrom Gillsand Wadsworth(1967) withpermission fromJames P.Gills. (B) Imageobtained

by opticalcoherence tomographyfrom apatient withoptic atrophy,showing cystsin theinner nuclearlayer. IPL= innerplexiform layer;

INL =inner nuclearlayer; OPL= outerplexiform layer;HFL =Henle fibrelayer; ONL= outernuclear layer.doi:10.1093/brain/awt154Brain 2013:136; 1-4

|e260

Advance Accesspublication July 19,2013

?The Author(2013). Publishedby OxfordUniversity Presson behalfof theGuarantors ofBrain. All rightsreserved.

For Permissions,p leaseemail:journals.permissions@oup.com by guest on May 8, 2016http://brain.oxfordjournals.org/Downloaded from They concludedthat 'Theloss ofcells inthe innernuclear layerin eyes ofpatients withadvanced multiplesclerosis iscompatible with trans-synapticdegeneration ofthe innernuclear layer'. Gelfandet al. (2012)have succeededadmirably atimaging trans-synaptic degenerationin livingpatients byusing opticalco- herence tomography.Not surprisingly,they foundthat patients

with microcystswere older,with longerdisease durationand worse disability.Such individualsare likelyto havemore severe

trans-synaptic degeneration.The microcystsshould notbe treated with steroidsor angiogenesisblockers, becausethey donot signify macular oedema. It hasbeen controversialwhether retrogradetrans-synaptic de- generation occursin thevisual system.The disputehas been settled byevidence thatthe retinalnerve fibrelayer becomes

Figure 2(AandB) Opticalcoherence tomographyscans throughthe opticnerve andfovea ineach eyeof a49-year-old femalewith

dominant opticatrophy showingvitreous insertion(arrows). Nasally,but nottemporally, vitreoustraction hasthickened theinner nuclear

layer andproduced microcysts.Note severeattenuation ofthe ganglioncell andnerve fibrelayer. (CandD) Ringof microcystsbetween

3-8

visualized inen facereconstructions of512 ?128 macularcubes achievedusing CirrusHD-OCT advancedvisualization software

(version 6.0)with a68 mm RPE-basedcontour passingthrough theinner nuclearlayer. Thegreen linescorrespond tothe orientationof the

scans shownabove. (EandF)20mm internallimiting membranebased slabshowing aring ofhyper-reflectivity wherethe retinalsurface is

perpendicular toincident light,presumably fromvitreous traction.Red ovalmarks theinsertion ofthe posteriorhyaloid membrane,

determined frominspection ofserial cross-sections.In E, thevertical yellowline correspondsto theorientation ofFig. 3,with two

prominent bloodvessels denotedas 1and 2. e260|Brain 2013:136; 1-4Letter tothe Editor by guest on May 8, 2016http://brain.oxfordjournals.org/Downloaded from atrophic afterdamage tothe visualcortex (Jindahraet al., 2009). Shifting forwardone synapse,there isno reasonwhy theinner nuclear layershould notbecome atrophicafter damageto gan- glion cells.A recentobservation bySigler et al. (2013)provides the mostdirect evidencethat microcystsof theinner nuclearlayer are dueto retrogradetrans-synaptic degeneration.In eightpa- tients thenerve fibreand ganglioncell layerswere damagedby surgical removalof anepi-retinal membrane.A monthpostopera- tively nomicrocysts werepresent inthe innernuclear layer. However, microcystsappeared ata meanof 3.3months following surgery, andcontinued toincrease insize forup to18 months. This observationsuggests thatwith thepassage oftime, progres- sive trans-synapticdegeneration inthe innernuclear layerleads to the formationof microcysts. Barboniet al. (2013)denied thatmicrocysts aredue totrans- synaptic degeneration,because theydevelop inonly aminority of patients, whereastrans-synaptic degenerationoccurs inall patients given sufficienttime. Asan alternativemechanism, theyproposed a combinedeffect fromoptic atrophyand vitreoustraction. According totheir idea,loss ofthe nervefibre andganglion cell layers allowsthe vitreousto tugdirectly onthe innernuclear layer, resulting inschisis. Here wepresent imagingdata thatsupport theirproposal that traction onthe retinais necessaryfor theoccurrence ofmicro- cysts. However,we suggestthat trans-synapticdegeneration is also important.A 49-year-oldfemale withdominant opticatro- phy hada 5-yearhistory ofblurred visionand dychromatopsia. The visualacuity was20/30 ineach eyeand therewere bilateral central scotomas.Fundus examinationwas normalexcept for marked temporalpallor ofboth opticdiscs. Anangiogram showed nofluorescein leakage,but opticalcoherence tomog- raphy revealedextensive microcystsin theinner nuclearlayer of botheyes (Fig.2A andB). Anen facereconstruction showed thatthe microcystswere distributedin aC-shaped ring that wasincomplete temporally(Fig. 2Cand D).Abegg et al. (2012) illustrateda similardistribution ofmicrocysts, although they didnot commentupon it.Gelfand (personalcommunication) has alsoconfirmed thatin theircohort, microcystswere more extensive onthe nasalcompared withthe temporalside ofthe fovea. In ourpatient, themicrocysts wereconcentrated atan eccen- tricity between3-8 in themacula. Theposterior hyaloidmembrane insertedinto thering ofmicrocysts atan eccentricityof?6 . Opticalcoherence tomographyrevealed azone ofbright signal inan en facereconstruction atthe levelof thevitreo-retinal interface, correspondingto thering ofmicrocysts (Fig.2E andF). In cross-sectionthe retinawas tentedupwards bythe posterior hyaloid membrane,causing flatteningof theretinal surface,rela- tive thickeningof theinner nuclearlayer, andthe developmentof microcysts (Fig.3). Intemporal retina,where microcystswere absent, theretina wasnot elevatedby theposterior hyaloidmem- brane (Fig.2A andB). Why doesvitreous tractioncombined withtrans-synaptic degeneration producemicrocysts? Innormal subjects,the inner nuclear layeris thickestand mostdensely populatedin aring from 3-8 . Hence,following trans-synapticdegeneration, this zone ofthe innernuclear layersuffers themost pronounced reduction intissue volume.We proposethat collapseof the inner nuclearlayer isprevented byinwards andlateral traction exerted bythe intactor partiallydetached posteriorhyaloid membrane. Thismembrane insertsinto theinternal limiting membrane ofthe retina,which isformed bythe footplatesof Mu¨llercells.These cellsserve asa scaffoldfor thelayers ofthe retina. Tractionexerted bythe vitreousbody counteractsthe loss of volumecaused bytrans-synaptic cellulardegeneration. The volume formerlyoccupied bycells thathave degeneratedmust be replacedby something.Hence, fluid-filledmicrocysts beginto form inthe innernuclear layer.Of course,the lostbipolar cells were oncepresent diffuselywithin theinner nuclearlayer, but intercellular adhesionbetween thesurviving neuronspromotes the developmentof cysticclefts. Inpatients withrelatively mild volume loss,weak vitreoustraction, orstrong intercellularadhe- sion, microcystsdo notoccur. Theyalso donot occurin patients with opticneuropathies thatspare themacula. Several questionsremain. Whyare nocysts presentbetween the fovea and3 , orat eccentricitiesbeyond 8 ? Theinner nuclear layer isthinner inthese regions,so volumeloss isless. Inaddition, retinal elevationis maximalwhere theposterior hyaloidmembrane inserts, anddissipates withincreasing distancefrom thesite of vitreous-retinal contact.Why isthe ringof cystsincomplete tem- porally? Althoughthe vitreousinserts intothe retinatemporally, it exerts lesstraction alongthe temporalraphe, judgingfrom the lack oftissue elevation(Fig. 2Aand B).Why docysts occur from epi-retinalmembrane peeling,even afterthe vitreoushas

Figure 3Optical tomographycoherence scanof theright eye,corresponding tothe yellowline inFig. 2Ewith bloodvessels marked1 and

2, showingtenting ofthe innernuclear layerfrom vitreoustraction (arrows).The thicknessof theinner nuclearlayer isincreased by40% in

the zonewhere itis elevatedby traction,giving riseto ?30microcysts.

Letter tothe EditorBrain 2013:136; 1-4|e260

by guest on May 8, 2016http://brain.oxfordjournals.org/Downloaded from been removed(Sigler et al., 2013)?This questionis difficultto answer, butresidual epi-retinalmembrane andscarring maybe responsible. Barboniet al. (2013)are correctthat microcystsin theinner nuclear layerof themacula revealedby opticalcoherence tomog- raphy aresimply aconsequence oflong standingoptic atrophy. Therefore, thisimaging technologymay notadvance ourunder- standing ofthe biologyof multiplesclerosis asmuch ashoped.

Acknowledgements

Technical supportwas providedby ValerieL. Wu.

Funding

This workwas supportedby grantsEY10217 (J.C.H.),EY017269 (B.J.L.), andEY02162 (BeckmanVision Center)from theNational

Eye Institute.

References

Abegg M,Zinkernagel M,Wolf S.Microcystic maculardegeneration from opticneuropathy. Brain2012; 135:e225. Barboni P,Carelli V,Savini G,Carbonelli M,La MorgiaC, SadunAA. Microcystic maculardegeneration fromoptic neuropathy:not inflam- matory, nottrans-synaptic degeneration.Brain 2013.Advance Access published onFebruary 8,2013. Gelfand JM,N olanR,SchwartzDM, GravesJ, GreenAJ. Microcystic macular oedemain multiple sclerosisisassociatedwith diseasesever- ity. Brain2012; 135:1786-93. Gills JP,Wadsworth JA.Retrograde transsynapticdegeneration ofthe inner nuclearlayer ofthe retina.Invest OphthalmolVis Sci1967; 6:

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Jindahra P,Petrie A,Plant GT.Retrograde trans-synapticretinal ganglion cell lossidentified byoptical coherencetomography. Brain2009; 132:

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Sigler EJ,Randolph JC,Charles S.Delayed onsetinner nuclearlayer cystic changes followinginternal limitingmembrane removalfor epimacular membrane. GraefesArch ClinExp Ophthalmol2013. AdvanceAccess published onJanuary 10,2013. Van BurenJM. Trans-synapticretrograde degenerationin thevisual system ofprimates. JN eurolNeurosurg Psychiatry1963;26:402-9. e260|Brain 2013:136; 1-4Letter tothe Editor by guest on May 8, 2016http://brain.oxfordjournals.org/Downloaded fromquotesdbs_dbs25.pdfusesText_31

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