Ischaemia in the Zinn-Haller circle and glaucomatous optic neuropathy in macaque monkeys.

1.7 MB·English

by  Hiraoka, Mari

Laboratory science
Ischaemia in the Zinn–Haller circle and glaucomatous
optic neuropathy in macaque monkeys
Mari Hiraoka,1 Kenichi Inoue,2 Taihei Ninomiya,2 Masahiko Takada2
1DivisionofBrainDevelopment ABSTRACT By contrast, angiography showed segmental filling
andNeuroregeneration,Tokyo Aims To elucidate the morphological features of optic that is supplied by an end artery.8 9 Furthermore,
MetropolitanInstituteof neuropathy in an ischaemic model of glaucoma in surgical intervention in the lateral SPCA induced
MedicalScience,Setagaya-ku,
macaque monkeys. interruption of fast axonal transport and
Tokyo,Japan
2SystemsNeuroscience Methods The regional degenerative process was a segmental filling defect in the focal blood
Section,PrimateResearch investigated by experimentally occluding the paraoptic supply.10 11 To determine whether damage to the
Institute,KyotoUniversity, branchesofthelateralshortposteriorciliaryartery,that circle of Haller and Zinn causes a segmental insult
Inuyama,Aichi,Japan
is,thecircleofHallerandZinn,in11eyes.Morphological depending on end-arterial supply or diffuse deteri-
Correspondenceto changes in nerve fibres in the lamina cribrosa were orationduetocompensatory coverage,thepresent
DrMariHiraoka,EyeResearch evaluated by histopathology, immunocytochemistry and study used moderate mechanical occlusion of the
Division,CentralEyeInfirmary, angiography,andthefindingswerecomparedwiththose paraoptic branch of the lateral SPCA to induce
1-24-15Nukui-kitamachi, observed in an aged macaque with spontaneous progressive ischaemic neuropathy. Because glau-
Koganei,Tokyo184-0015,
glaucomatous optic neuropathy. comatousneuropathyisslowlyprogressiveandthe
Japan;
[email protected] Results Retinal ganglion cell axons were grouped in durationofexperimentalobservationinthepresent
bundles and traversed through pores in columns of the study was limited to the period necessary for
Accepted8November2011 laminacribrosa.Theprocessesofastrocytesextendedto development of advanced glaucoma, the experi-
PublishedOnlineFirst the bundles, and capillaries branched in surrounding mental findings were compared with observations
4January2012
connective tissue from the circular arterioles. ofslowlyprogressivevisualimpairmentinanaged
Experimental ischaemia induced time-dependent anoxic monkey to reveal the long-term characteristics of
deterioration of phosphorylated fibres in the temporal glaucomatous neuropathy.
arcuate zone, accompanied by glial proliferation. A
monkey with spontaneous visual impairment had nerve
MATERIALS AND METHODS
fibrelossandgliosiswithcollagenousproliferationinthe
We studied 11 pairs of monkey eyes from adult
temporal hemisphere, suggesting glaucomatous Japanese macaques (Macaca fuscata) weighing
neuropathy. 5e9kg provided by neurophysiologists. All experi-
Conclusions Circulatory interference in the circle of
ments were performed according to the Institu-
Haller and Zinn caused time-dependent deterioration in
tional Guidelines for Animal Handling and
the area where anoxic segmental degeneration is
Experimentation of the Tokyo Metropolitan Insti-
associated with pathogenesis of open-angle glaucoma.
tuteofMedicalScience.Intheexperiment,11eyes
underwent cauterisation and 11 eyes served as
control. Surgical exploration of the junction of
INTRODUCTION optic nerve stalk and sclera was done by superior-
Theperipapillaryartery,alsoknownasthecircleof temporal orbitotomy under intravenous anaes-
HallerandZinn,isthevesselthatprovidesmostof thesia. The paraoptic lateral SPCA was identified
thebloodsupplytothelaminacribrosa(LC)region with twoorthree branches onthesurfacecurving
oftheopticnerve.Over100millionretinalganglion into a junctional cave. Cauterisation was done
cell (RGC) axons group together into approxi- using a 2mm diameter bipolar disc electrode with
mately 1 million axon fascicles,1 which form 2mA of current placed on the bent junction
bundles of various sizes and traverse through the (schematic view in figure 3A, stereoscopic view in
laminar pores to the neurons of the lateral genicu- figure3B).Theprocedurewascarefullydesignedto
latenucleus(LGN).Atallpoints,thebiomechanical produce incomplete blockage of vessels and avoid
propertiesofthislongpathwayaresubjecttonerve necrosis of theunderlying nerve. Toallow progres-
damage. Mechanical injury to the axon causes sive observation, interval to pathological examina-
astrocyte reactivation and subsequent remodelling tion after cauterisation varied from 2 to 56days.
of the extracellular matrix (ECM) in the LC.2 3 Pre- and postoperative fundus photographs and
Furthermore,vascularnutritionintheaxonisvital. imagesfromfluoresceinangiographywereanalysed
ThecircleofHallerandZinncomprisescompleteor infiveeyes.Intraocularpressurewasnotmeasured
incomplete anastomoses around the optic nerve due to the lack of appropriate instruments. The
between the medial and lateral short posterior animals were killed and exsanguinated under deep
ciliary arteries (SPCAs), which form a dense capil- anaesthesia. The posterior halves were sliced into
laryplexusaroundtheopticnerve.However,there 6mm thick sections for paraffin processing and
is controversy regarding the distributary variation 14mm thick sections for cryopreservation. The
Thispaperisfreelyavailable andcharacteristicsoftheseanastomoses.Corrosion anterior trabecular meshwork and LGN were also
onlineundertheBMJJournals
cast studies in humans and primates revealed examined for spontaneous neuropathy. One of the
unlockedscheme,seehttp://
bjo.bmj.com/site/about/ a circular anastomosis, which allows circulatory followingmethodsofstainingwaschosenforeach
unlocked.xhtml compensationtocircumventsegmentaldeficits.4e7 purpose: Gomori’s aldehyde-fuchsin, Elastica van
BrJOphthalmol2012;96:597e603.doi:10.1136/bjophthalmol-2011-300831 597
Laboratory science
Gieson, silvereLuxol fast blue and Nissle. For immunohisto- interaction in columnar spaces. The tracer (concentration of
chemistry, a primary antibodydeither phosphorylated mono- 30mM/3mlofsaline)wasinjectedintothetemporalretrobulbar
clonal mouse antibody (SMI-31; Sternberger Monoclonal Inc., space and examined 3days later.
Lutherville, Maryland, USA) or non-phosphorylated neurofila- An aged monkey that had been kept for 25years at our
ment (SMI-32), neurofilament-H (NF-H; Biomol International, Institute had developed impaired visual task performance
LP, Plymouth Meeting, Pennsylvania, USA) for both NFs, or without other neurological disability. His eyes were examined
monoclonal rabbitanti-glialfibrillaryacidicprotein(anti-GFAP; for evidence of advanced glaucomatous neuropathy, using
Sigma-Aldrich Inc, St. Louis, Missouri, USA)dwas applied to fundus photography andpathological analysis. Specimens were
paraffin-embedded sections. The procedure was performed as observedandphotographedvialightandconfocallaserscanning
previously reported12 except for substrate chromogen staining (Nikon C1TE-2000, Japan)microscopy.
with 3,3’-diaminobenzidine-nickel chloride (DABni; Sigma-
Aldrich Inc). Secondary antibodies of rhodamine-conjugated RESULTS
anti-mouse immunoglobulin G (IgG) for SMI-31 and Alexa The RGC axons formed axon fascicles with contiguous axons,
Fluor-conjugatedanti-rabbitIgGforGFAPwereusedfordouble with an almost 1e10 correspondence. These fascicles were
labelling. Specificity of staining was confirmed by omitting the groupedintobundlesenvelopedbytheepineurium.Thenumber
primary antibody. A membrane-permeable tracer (Cell Tracker offibrescontainedinabundledifferedbyretinalquadrant,that
CMRA, Molecular Probes Inc, Eugene, Oregon, USA) was used is, there were fewer in the temporal quadrant and more in the
to investigate blood flow in capillary and glial cell-capillary inferior quadrant (figure 1A). These bundles were arrayed
Figure 1 (A) Immunostaining of
neurofilaments (NF-H; DABni).Figures
are recomposed inthecircle bycut
endsoftheretina.Themagnifiedretina
in thenasal (N;a), inferior(I; b),
temporal (T; c)and superior(S; d)
quadrants isshown. Axons ofthe
retinal ganglion cells aregrouped at
theiroriginandformbundlesenveloped
bytheepineurium.Thebundlediameter
differs byquadrant: T (c)<S (d)<N
(a)<I(b). (B) Thedifference between
phosphorylated(a;SMI-31,DABni)and
non-phosphorylated (b;SMI-32)
neurofilaments inlaminacribrosa is
unremarkableinthetemporalquadrant,
except forthe innermost small bundles
nearthecentralvessel.Thearterioleof
the circleof HallerandZinnpenetrates
inside (seen asacircle attheright-
central border). Thescattered dots in
the columns indicate glial cells (a).
598 BrJOphthalmol2012;96:597e603.doi:10.1136/bjophthalmol-2011-300831
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centripetally towards the optic nerve head (ONH) along the and distributed as capillaries in the intercolumnar spaces
surfaceinthenerve fibre layer.Bundlediameter wasconsistent (figure 2Ba,b). Fluorescent tracer injected in the connective
intheprelaminartolaminarregion.Themacaquemonkeysused tissue of the subarachnoid space surrounding the optic nerve
in this study, the number of bundles was approximately 800. wasfoundinthecapillariesandseptumofintercolumnarspaces
The distribution of phosphorylated (as determined by SMI-31 (figure 2C). These uptakes represent the lack of blood-brain-
staining) and non-phosphorylated (as determined by SMI-32 barrier characteristics and non-specific permeability in the prel-
staining) axonal bundles did not clearly differ in the temporal aminar region. In addition, astrocytes containing fluorescent
optic nerve in the LC, except in the innermost small bundles particles were observed on bundles and near capillaries (figure
temporal tothe centralvessel (figure1B). 2D), which suggests that the fixation of astrocyte processes to
The bundles were intercalated among spaces containing unmyelinated fibres functions as metabolic bridges between
capillaries, astrocytes and ECMs in columns (figure 2Aa). The capillariesandbundles.Ischaemiaofthecirclewouldaffectthe
astrocytes formed perpendicular lamellae and their processes nervesincluded inthis complex relationship.
were distributed around the bundles with connections to Experimental cauterisation of the paraoptic branches of the
contiguousprocesses(figure2Ab).Arteriolesinthebordertissue lateralSPCAcausedtime-dependentchangesinnervesintheLC.
of Elschnig penetrated the septum of the optic nerve sheath At 1week and earlier, eyes (n¼4) showed swelling in bundles
Figure 2 (A) SilvereLuxol fast blue
staining ofthefrontal section ofthe
optic nerve inthelamina cribrosa. (a)
Each bundle (brown) issurrounded by
a column inthe laminacribrosa septa.
(b)High-magnificationviewofthesepta
shows neurofilaments (black),
numerous astrocytes with processes,
oligodendrocytes(ovalyellowish-brown
cells withnuclei) andextracellular
connective tissue (light blue)
circumferentially enveloping the bundle
(brown). (B)Elastica vanGieson
staining oftheextracellular matrix of
the temporal border withthe
subarachnoid space oftheoptic nerve.
(a) Arterioles are visibleinthe
surrounding connective tissue(*). A
capillary (white arrowhead) isvisible
and elastic(red) connective tissue
(black arrows) isdistributed inthe
column. (b) Magnified viewofthesite
ofpenetration ofanarteriole (*) and
capillary (white arrowhead) into
columnar spaces(white arrow).
Bundles are stained brown. (C)
Membrane-permeable, thiol-binding
traceruptake(reddots)intothecolumn
(white arrows) via vessels(white
arrowheads). (D) High-magnification
view ofcapillary (white arrowheads)
andastrocytesonandadjacenttonerve
bundles withtracer uptake (red spots,
white arrows.) Thephase-differential
configuration (b) shows the orientation
ofcapillary andnerve bundles.
BrJOphthalmol2012;96:597e603.doi:10.1136/bjophthalmol-2011-300831 599
Laboratory science
and microhaemorrhage in the LC. At three weeks (n¼3), we image).Focalischaemiacausedthedecreasedimmunoactivityon
observed bundles of phosphorylated fibres with decreased phosphorylated nerve bundles (stained by SMI-31, DABni) in
immunoactivity (on SMI31 staining) in the temporal bundle thetemporalhalf,exceptfortheinnermostrownearthecentral
(figure 3C). Double immunostaining by SMI-31 and GFAP vessel (figure 4B). A sagittal view showed a clear difference
revealedthatthephosphorylatedbundlesweresmaller(compare between phosphorylated (SMI-31, figure 4Ca) and non-phos-
with figure 2Ba) and that glial proliferation into the widened phorylated (SMI-32, figure 4Cb) bundles in the temporal half.
columnswasalmostentirelyconfinedtothetemporalquadrant Moreover, glial proliferation was clearly more extensive in the
(figure3D).Afundusphotographshowedadarkshadowinthe temporalthaninthenasalhalf(GFAP,figure4Cc).Thediameter
temporal peripapillary subretina and focal round discolouration of the temporal bundles decreased, resulting in wider columnar
(figure 3E). Fluorescein angiography revealed a filling defect in spaces, accompanied by glial proliferation (figure 4D). Acute
the temporal peripapillary margin (figure 3F) and focal disco- (2days)deteriorationoftheNFswasmorediffuse,probablydue
louration of scar formation due to recurrent branch occlusion tofocaloedemaoftheoperatedsite,butitwasdecreased5days
(white arrowin figure3C). later(datanotshown).Thesefindingsindicatethatischaemiain
These features were more obvious at five weeks (n¼5). Post- the paraoptic temporal SPCA causes progressive damage to
operative(figure4Ab)fundusphotographrevealeddevelopment temporal segmental optic nerve fibres. We conclude that this
of arcuate superior and inferior discolourations, whereas the time-dependent deterioration corresponds to the progression of
papillomacular region was preserved (figure 4Aa; preoperative an arcuate visualfielddefect inglaucoma.
Figure 3 (A) Schematic view of
retrobulbar structure andthevessel
targeted forcauterisation (red;two
branchesaredrawn)withabipolardisc
electrode (blackstickwithcord) and
cautery point (blackarrow). (B)
Stereoscopic viewofthe junction
between the optic nerve andsclera
shows the two branches ofthe
paraoptic lateral shortposterior ciliary
artery (blackarrows) andthecave of
the siteofscleral penetration (white
arrows). (C) Deteriorationoftemporal
segmental phosphorylated axons
(immunostained bySMI-31; DABni)in
asagittalsectionatthreepostoperative
weeks. Anartery penetrates the optic
nervefromthebordertissueofElschnig
atthe level ofthe pre-laminacribrosa
(black arrow).Focal retinal
discolouration(whitearrowsinEandF)
indicates a lesion caused bysubretinal
scarring ofthe recurrent artery(white
arrow). (D) Doublestaining ofglial
fibrillaryacidicprotein(Alexa488)with
SMI-31 (Rhodamine555)inthe frontal
section. Marked glial proliferation from
thecircumferentialrowispresentinthe
temporal quadrant. (E) A fundus
photograph shows the darkhaloof
a temporal discmargin(black
arrowheads) withfocal subretinal
atrophy (white arrow). (F)Fluorescein
angiography shows afilling defect in
the temporal discmargin(black
arrowheads) anda focal scar (white
arrow)correspondingtothefocalretinal
lesioninC.Themaculaisnormal(black
arrows).D,down;IOM,inferioroblique
muscle; IRM, inferiorrectus muscle;
LRM, lateral rectus muscle;MRM,
medial rectus muscle; N, nasal; NRM,
nucleusraphemagnus;M,theregionof
macula;ON,opticnerve;SOM,superior
oblique muscle; SRM,superior rectus
muscle, T, temporal; U, up.
600 BrJOphthalmol2012;96:597e603.doi:10.1136/bjophthalmol-2011-300831
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Figure 4 (A) Fundusphotographs (a)
before and(b) 5weeks after surgery.
After surgery, distinctsubretinal
arcuate discolouration ispresent inthe
superior and inferiortemporal arcuate
zone (white arrows) anda marginal
dark haloaround the disc(black
arrowheads) anda normalmacula
(black arrow) areseen(b). Retinal
vascularity isunchanged. (B)
Immunostaining ofphosphorylated
neurofilaments inafrontal section.
Diffuse deterioration ofSMI-31-positive
axons (DABni)is evidentinthe
temporal (T) arcuate zone, withthe
exception ofarow intheinnermost
marginal bundles. (C)Immunostaining
(DABni) ofsagittal sections reveals
acleardifferenceinphosphorylated(a)
and non-phosphorylated (b)
neurofilament reactivity.Thenumberof
SMI-31-positive bundles decreased in
the optical nerve head andlamina
cribrosa inthetemporal division (black
arrow), inclear contrastto thenasal
half (Ca). SMI-32-positiveprofiles in
temporal bundles (blackarrow) cannot
be distinguished fromthosein nasal
bundles inONH (Cb). Expression of
gliosis byglial fibrillary acidic protein
increased inthetemporal half (black
arrow) (Cc). (D) Doublestaining by
SMI-31withglialfibrillaryacidicprotein
ofa frontal section demonstrates the
markedly decreaseddiameter of
phosphorylated bundles (Rhodamine
555),with widenedcolumns andglial
proliferation (Alexa 488),inthe
temporal arcuate zone.
As mentioned above, we examined an aged monkey with axons from the retinal periphery were preserved. The temporal
slowly progressive visual impairment. He had no history of opticatrophyevidentinthephotographinfigure5issimilarto
glaucomatous attack or pain, according to the records of the thepathology inhumansand confirmsa diagnosis of advanced
supervising veterinarian. An eye examination showed temporal open-angle glaucoma. The observation period in the present
pallorwithexcavation(figure5C).Theanglewaswideopen,the experiment was short; thus, the unexpected observation of
corneawasclear,andtherewasnoobstructionofthetrabecular glaucomatous changesdalthough the exact duration of optic
meshwork (figure 5B). The LGN showed clear zonal organisa- atrophywasnotestimateddishighlyinformativeinelucidating
tion, without focal cell loss (figure 5A). The bundles of the the pathological progression ofthis disease.
temporalhalfoftheopticdiscwerecompletelyoccupiedbyglial
proliferation (GFAP) (figure 5D); however, bundles in the nasal DISCUSSION
half retained a clearly circumferential configuration with well- The branches of the SPCA supply blood to the region of the
definedcolumnarspaces(figure5Ea).TheLCwasthinnerinthe ONH. There is a controversy as to whether the circle of Heller
temporalhalf(binfigure5Ea)andlaminarporeswereirregularly and Zinn is a complete or incomplete collateral circle between
deformed by ingrowth of collagenous tissues (figure 5Eb). The thelateralandmedialparaopticposteriorciliaryarteries.4589It
retinalfibrelayeroftheONHwasnotatrophic,suggestingthat isgenerallyacceptedthat,innervefibredefectsinglaucoma,the
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Figure 5 Spontaneous glaucomatous
opticneuropathy.(A)Nisslestainingof
lateral geniculate nucleusreveals
a normal, layered configuration. (B)
Sagittal histology ofwide-open uveo-
corneal angle andnormal trabecular
meshwork stained withGomori’s
aldehyde-fuchsin. (C) Fundus
photograph shows the optic discwith
temporal pallor andexcavation and
a darkhalo around thetemporal
subretina, demonstrating a nerve fibre
layer defect. Themacula isnormal
(black arrow).(D) Double labelling of
SMI-31(green)andglialfibrillaryacidic
protein(red).Markedgliosiswithafew
bundles can be seeninthetemporal
half. (E) Sagittal sectionofoptic nerve
head and laminacribrosa stained with
Gomori’s aldehyde-fuchsin. (a) Nerve
bundles arealmost completely absent
andreplacedbyglialproliferationinthe
temporal half ofabroad region from
pre- topost-lamina cribrosa (Ea),
despite a normallateral geniculate
nucleus configuration. By contrast,
demarcated bundles areoriented
normally inthe nasalhalf. Superficial
nervebundlesinthetemporalhalfofthe
disc head arenot atrophic(white
arrow),presumablyduetothepresence
ofnervesfromtheperipheralretina.(b)
High-magnification viewofthe boxed
area in(a) reveals thedetails ofglial
proliferation (blackarrow) andmassive
collagenous tissue (green) ingrowth
(white arrow)with elastictissue
remnants ofatrophied vessel wall
(purple, white arrow).
lesionsiteisinthediscandvascularinsufficiencyinONHplays tion between capillaries andbundles via astrocytes. Our results
an important role in pathogenesis. To induce a moderate clearly showed that capillaries in intercolumnar spaces are
ischaemia,mechanicalocclusionismoreeffectivethaninjection directly supplied by circumferential arterioles (figure 2Da). In
of vasoconstrictive drugs6 or temporal posterior ciliary artery addition, the tracer in capillaries is transmitted to bundles via
cut-off.10 In the present study, we cauterised the branches of astrocyteprocesses,demonstratingthatcapillariesintheLCare
lateral SPCAthat were on the surface of entry points into the fluid-permeable, without bloodebrain barrier properties (figure
sclera.ThebranchofthemedialSPCAwasnottargetedandthe 2Db).Thisiscrucialifcauterisationistobeeffectiveininducing
possibility ofthe results beingaffected isconsidered. selective ischaemia intheoptic nerve inLC.
The tracing study revealed that capillaries in intercolumnar Glaucoma is a slowly degenerative and irreversible optic
spaces are directly supplied by circumferential arterioles neuropathy. We attempted to study the progression of this
(figure 2Da). The paraoptic branches pierced the sclero-optic disease by modelling the glaucoma process in macaque eyes,
junctionandcoursedthroughthebordertissueofElschnigatthe using an experimental ischaemic intervention in the LC. Our
level of the prelaminar cribrosa.13 The lack of bloodebrain findingsshowthatmechanicalobstructionofcirculationinthe
barrier properties in capillaries,14 as well as the uptake of circle of Haller and Zinn causes segmental anoxia in the
horseradish peroxidase into the lamina via the blood stream,15 temporal arcuate region and progressive deterioration corre-
demonstrated non-specific permeability from the arterioles to spondingtothatseeninglaucoma.Althoughacompletearterial
the columns. The use of a membrane-permeable, thiol-reactive circle,formedbyboththemedialandlateralSPCAs,ispresentin
tracer that can be transported through the gap junction or more than 75% of humans,5 our intervention was selectively
capillary endothelium and is retained for an extended period of appliedtothetemporalbranches.Inindividualswithacomplete
time in the cell body is ideal for investigating the flow connec- circle, ischaemia would affect whole bundles. Nevertheless, the
602 BrJOphthalmol2012;96:597e603.doi:10.1136/bjophthalmol-2011-300831
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experimental results show that segmental ischaemic reactivity damage in glaucoma, which suggests that therapy with anti-
wasrestrictedtothetemporal arcuateregion andshedlighton ischaemic and/or vasodilative topical and/or systemic drugs
the end-arterial features ofSPCAswith sectorial bloodsupply. could increase the clinical effectiveness of existing treatment
The correlation of markers of axonal injury with the phos- regimens.
phorylation pattern in NFs after ischaemic intervention is
crucial in characterising the extent of damage. SMI-31-labelled AcknowledgementsWethankTeikoKuroda,MichikoImanishiandHirokoUeda
phosphorylated NFs and SMI-32-labelled non-phosphorylated fortheirexcellenttechnicalassistanceinpreparingthehistologyspecimens.We
NFsareusedasmarkers,astheirconcurrentactivationconfirms alsothankDrHaruoOkado,directorofthedivision,forhishelpinconductingthe
experiments.
progressive deterioration.16 We applied this method to non-
myelinated axonsofthe opticnerveinthe LCandthe findings FundingThisworkissupportedbytheTokyoMetropolitanInstituteResearchProject
forMedicalSciences.
were useful in understanding ischaemic changes. The subset of
axons positively labelled for both NFs is normal in the optic CompetinginterestsNone.
nerveofcontroleyes(figure1Ba,b);however,ischaemiaresulted ContributorsMH:fullresponsibilityforthiswork.KI:responsibleforanimal
in a decrease in phosphorylated NFs and an increase in non- experimentaldesign,acquisitionofdataandhistologicalprocedures.TN:responsible
phosphorylated NFs (figure 4C). The observation period was forbrainpathologywithopticnervedegeneration,itsanalysisandinterpretationof
data.MT:finalapprovaloftheversiontobepublished.
limited in our study; however, the results suggest that func-
tional changes related to the duration of ischaemia and the ProvenanceandpeerreviewNotcommissioned;externallypeerreviewed.
different response of the NFs precede glial proliferation in
injuredaxons.Inanadvancedstageofdegeneration,theabsence
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