Ischemic Optic Neuropathy

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Ischemic optic neuropathy

Geetha Athappilly Victoria S Pelak Naresh Mandava andJeffrey L Bennett

Department of Neurology and Department of Ophthalmology Rocky Mountain Lions Eye InstituteUniversity of Colorado at Denver and Health Sciences Center Denver CO USA

Ischemic optic neuropathy is the most frequent cause of vision loss in middle age Clinical andlaboratory research studies have begun to clarify the natural history clinical presentationdiagnostic criteria and pathogenesis of various ischemic nerve injuries As a result physicians areacquiring new tools to aid in the diagnosis and potential treatment of ischemic nerve injury Theaim of this review is to examine recent data on anterior and posterior ischemic optic neuropathyand to provide a framework for physicians to manage and counsel affected individuals [NeurolRes 2008 30 794ndash800]

Keywords Ischemic optic neuropathy non-arteritic anterior ischemic optic neuropathyposterior ischemic optic neuropathy arteritic ischemic optic neuropathy giant cell arteritis

INTRODUCTIONIschemic optic neuropathy results from a critical loss ofblood flow to retinal ganglion cell axons and surround-ing glial tissue Ischemic optic neuropathy is typicallyclassified by the funduscopic appearance of the opticnerve head and the underlying pathophysiology Whenclassified by the appearance of the optic disk it istermed either anterior or posterior ischemic opticneuropathy In anterior ischemic optic neuropathyoptic nerve head edema is present while in posteriorischemic optic neuropathy the optic disc appearsnormal and only the portions behind the nerve headnamely the intraorbital intracanalicular or intracranialportions are involved

While the causes of ischemic optic neuropathy areprotean the underlying mechanisms resulting in celldeath are likely to be identical to those governingischemic injury to other regions of the central nervoussystem Therefore improved understanding of ischemicoptic neuropathy will impact significantly on themanagement of stroke patients In this review we willdiscuss the varied clinical presentations of ischemicoptic neuropathy and attempt to establish a frameworkfor future scientific and clinical investigations

ANTERIOR ISCHEMIC OPTIC NEUROPATHYAnterior ischemic optic neuropathy (AION) is animportant cause of vision loss in patients older than50 years of age Symptoms are characterized byrelatively acute vision loss occurring over hours todays The vision loss is typically painless and unilateralin cases of non-arteritic AION whereas patients witharteritic AION usually report associated head or eye

pain On examination an afferent papillary defect ispresent unless there is relatively symmetric bilateralinvolvement The optic nerve edema is frequentlysectoral and is present for several weeks After resolu-tion of the disk edema the nerve appears pale Thevisual field characteristically shows optic nerve-relateddefects such as altitudinal arcuate and centrocecalscotomas It is important to determine whether thecause of AION is arteritic or non-arteritic becausetreatment of arteritic ischemic optic neuropathy shouldbegin immediately to prevent further vision loss in theaffected and unaffected eye

Giant cell arteritisThe most common disorder associated with arteritic

AION is giant cell arteritis (GCA) Although vision loss inGCA may occur due to posterior ischemic optic neuro-pathy retinal artery occlusion or choroidal ischemiaAION is the most common event Both ischemic opticneuropathy and choroidal ischemia result from occlusionof the short posterior ciliary arteries leading to loss ofblood flow to the optic nerve head and choroids-outerretina In GCA there is an inflammatory responseinvolving large and medium arteries The classic histolo-gic picture is focal and segmental granulomatousinflammation at the junction of the intima and media ofthe arterial wall The classic histologic presentation ispresent in y50 of cases the remainder demonstrating amixed inflammatory infiltrate of mononuclear cells with-out giant cell formation1 In rare instances the conditionmay be limited to a small-vessel vasculitis surrounding anormal temporal artery Vascular inflammation in GCAcauses secondary stenosis of the vascular lumen withocclusion ultimately arising from either luminal occlusionor in situ thrombosis

GCA typically affects older adults and is rarely seen inpatients younger than 50 years In a recent 50 year

Correspondence and reprint requests to Jeffrey Bennett MD PhD4200 E Ninth Ave Box B-182 Denver CO 80262 USA[jeffreybennettuchscedu]

794 Neurological Research 2008 Volume 30 October 2008 W S Maney amp Son Ltd101179174313208X319107

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epidemiologic analysis of GCA cases from OlmstedCounty MN USA the average incidence was 188cases per 100000 persons at 50 years of age and older2It is twice as common in women and the frequency ofcases increases at higher latitudes3 There are periodicclustering of cases suggesting an infectious origin23however epidemiologic studies investigating the asso-ciation of GCA with various infectious agents have beeninconsistent4ndash6 Recently prokaryotic gene fragmentswere isolated from GCA lesions and immunoglobulinfrom GCA patients was shown to recognize thetranslational products of these clones7 This sensitivemolecular biologic approach provides initial tantalizingevidence for an infectious etiology in GCA In contrastan alternative autoimmune hypotheses has been sug-gested based on the presentation of arterial wall antigenfollowing vascular injury8 In this model maturationand antigen presentation by adventitial dendritic cellsresults in local type I cytokine production infiltration ofmononuclear cells the formation of multinucleatedgiant cells internal elastic lamina breakdown andluminal occlusion Interestingly HLA haplotypesDRB104 and DRB101 are increased among indivi-duals with polymyalgia rheumatica GCA and rheuma-toid arthritis910

GCA is a systemic disease process and patientstypically present with symptoms other than visualcomplaints headache scalp tenderness jaw claudica-tion polymyalgia rheumatica (PMR) fever nightsweats fatigue and weight loss11 While headache isthe most common symptoms such as neck painanorexia and jaw claudication are more specific12 Insome instances local findings such as induration of thetemporal region and nodularity or cord-like firmness ofthe temporal artery can be noted Cerebrovasculardisease occurs in 3ndash4 of GCA patients Histopatho-logy indicates that the predominate cause is vasculitisinvolving the extradural portions of the carotid andvertebral arteries concurrent intracranial vasculitis israre13 In y20 of patients with arteritic AION theremay not be any systemic complaints

Vision loss occurs from arteritic ION is usually severeand acuity is often worse than 2020014 Some patientsexperience dimming or amaurosis fugax (transient visualloss) in the weeks preceding the optic neuropathy andthese event have a strong correlation with irreversiblevision loss15 Therefore it is imperative that patientsover the age of 55 years complaining of transientmonocular vision loss be evaluated for GCA Onexamination the optic nerve demonstrates pallid swel-ling Other findings include cotton wool spots andperipapillary pallor from choroidal ischemia (Figure 1)Additional visual symptoms and signs in GCA patientsinclude diplopia ophthalmoplegia hallucinosis uveitisand hypotony1116

If there is clinical suspicion for arteritic AIONlaboratory studies should include an erythrocyte sedi-mentation rate (ESR) C-reactive protein (CRP) andplatelet count1217 An ESR should not be ordered aloneas it is not a very sensitive or specific When combinedwith an elevated platelet count the ESR becomes a

better predictor of GCA but the improvement ismarginal thrombocytosis does improve the predictivepower of an elevated CRP17 An elevated ESR and CRPhave the greatest specificity for the detection of giantcell arteritis y9712 In contrast to non-arteriticischemic optic neuropathy fluorescein angiography inpatients with arteritic AION reveals a significant delayin choroidal filling (Figure 2)1819

A definite diagnosis must be made with temporalartery biopsy It is recommended that a biopsy beperformed in all cases of suspected arteritic AIONsince treatment requires high dose steroids for aprolonged period of time Approximately 5 oftemporal artery biopsies may be falsely negativeReasons include inadequate arterial sampling limitedhistopathologic analysis and partial treatment there-fore a negative biopsy does not rule out the presenceof GCA In instances of strong clinical suspicionbilateral or sequential biopsies can be performedIn recent studies however the concordance ratebetween arteries was found to be 989 Thereforeit is unlikely that a diagnosis will be made if theoriginal sample and histopathology were adequate20Immediate treatment with high dose corticosteroids isrecommended before performing the biopsy howeverthe biopsy must be performed within 7ndash15 daysfollowing the initiation of therapy because treatmentdecreases the amount of granulomatous inflam-mation in the biopsy specimen quickly Histopa-thologic staining of the internal elastic lamina mayyield additional sensitivity by demonstrating featuresof non-artherosclerotic arterial wall disruption

As mentioned previously treatment of GCA requireshigh dose corticosteroids Initial treatment may beginwith intravenous methylprednisolone (1000 mgday) ororal prednisone (60 mgday) In a small cohort of GCApatients with visual symptoms the use of intravenousmethylprednisolone reduced the incidence of fellow

Figure 1 Acute pallid disc edema in a patient with arteriticischemic optic neuropathy from giant cell arteritis

Ischemic optic neuropathy G Athappilly et al

Neurological Research 2008 Volume 30 October 795

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eye involvement and produced a mildly higher inci-dence of visual recovery in the affected eye whencompared to oral prednisone21 These benefits havenot been confirmed in another cohort14 A smallrandomized study has suggested that the use ofearly intravenous methylprednisolone produces ahigher frequency of sustained remission among GCApatients22 but similar results were not observed in alarger randomized trial comparing oral and intravenoussteroids23 In general therapy with high dose oralsteroids is necessary for several weeks and is thenfollowed by a slow taper and maintenance dosing tomaintain low ESR and CRP24 The main goal oftreatment is to prevent involvement of the fellow eyeand other systemic vascular complications such asstroke or myocardial infarction Once vision lossensues recovery is rare14 and y30 of patients willcontinue to suffer visual decline despite the use of highdose intravenous methylprednisolone25 In cases ofsteroid resistant GCA anecdotal success has beenreported with the use of heparin26 and tumor necrosisfactor-alpha (TNF-a) inhibition27 Heparin may limitischemic injury by inhibiting intravascular thrombosisand TNF-a inhibition may directly abrogate the type Icytokine-mediated pro-inflammatory response in thevessel wall Interestingly in two recent trials infliximaba TNF-a inhibitor demonstrated no benefit in maintain-ing glucocorticoid-induced remission in GCA orPMR2829 Additional studies will be needed to measurethe utility of biologic agents and heparin in improvingvisual outcome and inducing disease remission insteroid sensitive and resistant disease

Non-arteritic ischemic optic neuropathyOf the two types of anterior ischemic optic neuro-

pathy non-arteritic AION (NAION) is more commonthan arteritic AION accounting for close to 95 ofION The exact etiology of the ischemic injury remainsunknown but current evidence favors occlusion of thesmall blood vessels supplying the optic nerve headdirect branches of the posterior ciliary arteries and theanastomotic arterial circle of ZinnndashHaller30

Fluorescein angiography demonstrates diminished diskfilling and delays in the posterior ciliary arterycirculation3132 but histopathologic demonstration ofsmall vessel vascular occlusion is lacking NAION isobserved in the setting of an optic nerve with a smallcup-to-disk ratio termed the lsquodisk at riskrsquo It is thoughtthat the small disk creates physical crowding thatcompromises the arterial microcirculation but theexact relationship remains uncertain

NAION occurs most commonly in patients aged 55ndash65 years with an incidence of y16000000 There isno gender predilection but the disorder tends to occurin a higher frequency in the white population NAIONhas been associated with nocturnal hypotension33obstructive sleep apnea34 vasculopathic systemic dis-eases3536 and prothrombotic factors37 In the ischemicoptic neuropathy decompression trial (IONDT) 60 ofpatients had known cerebrovascular risk factors hyper-tension diabetes hypercholesterolemia and tobaccouse38 These risk factors may become increasinglyprevalent in younger individuals39 Interestingly thereis no increased incidence of cerebrovascular andcoronary artery disease among NAION patients sug-gesting that the physical crowding imposed by the lsquolsquodiskat riskrsquorsquo contributes significantly to the risk equation

Prothrombotic risk factors associated with NAIONinclude protein C S and antithrombin III deficienciesantiphospholipid antibodies factor V Leiden mutationpolymorphisms in platelet glycoproteins and hyperho-mocysteinemia3740ndash43 Despite the frequency of casereports the prevalence of these abnormalities inNAION patients is likely to be low36 For that reasonroutine screening is indicated only in younger indivi-duals without vasculopathic risk factors or in cases offamilial NAION44 In at-risk individuals medicalprocedures that increase intraocular pressure or resultin significant blood loss or hypotension may precipitateNAION Medications such as interferon alpha andsildenafil have been reported to precipitateNAION4546 Phosphodiesterase inhibitors such assildenafil are thought to increase the risk of ischemicoptic neuropathy by causing systemic hypotension but

Figure 2 Fluorescein angiography demonstrating delayed and patchy choroidal filling in a patient with giant cell arteritis The time afterinjection is noted in the upper left corner of each panel


796 Neurological Research 2008 Volume 30 October

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additional mechanisms such as venous dilation andsecondary vascular congestion may contribute to theequation

Vision loss due to NAION is often less severe thanarteritic AION with the majority of affected individualshaving a visual acuity better than 2020038 The risk ofrecurrence in the affected eye is only 647 but the riskof fellow eye involvement is 147 after 5 years48 Onexamination the optic nerve typically has minimal tono pallor The edema can be diffuse or segmental withprominence of the surface microvasculature andhemorrhages are present in 70 of cases (Figure 3)After resolution of the disk edema there is oftennarrowing of the arterioles in the peripapillary region

Unlike arteritic AION NAION is rarely bilateraloccurring in less than 20 of cases

There are no proven therapies for the treatmentof NAION Multiple medical therapies have beenconsidered including corticosteroids brimonidinelevodopa anticoagulation diphenylhydantoin and nor-epinephrine (Table 1)49ndash53 Levodopa may improverecent-onset NAION but the data are limited due tothe limited design of the study50 Steroids have neverdemonstrated benefit in improving visual outcome butmay hasten the recovery of disc edema54 Proceduressuch as hyperbaric oxygen and optic nerve sheathdecompression have also demonstrated no benefit in thetreatment of NAION5556 In fact many patients in theIONDT had a decrease in visual acuity after undergoingoptic nerve sheath fenestration suggesting that thisprocedure may be harmful Memantine a NMDAantagonist has shown neuroprotective properties in arabbit model of ischemic optic neuropathy57 but clinicaldata are lacking

Owing to the prominent role of disk architecturein NAION agents that antagonize vascular permeabilitymay improve visual outcome in NAION Agents suchas vascular endothelial growth factor (VEGF) inhibitorsmay prove useful in reducing ischemic injury bylimiting secondary vascular edema Indeed VEGFinhibition has shown benefit in reducing ischemicvolume in a murine stroke model58 To this end wehave been able to demonstrate a rapid reductionin disk edema and visual recovery in a NAIONpatient treated with intravitreal bevacizumab59 Withthese exciting preliminary results phase I clinicalstudies with intravitreal ranibizumab are currentlyunderway

Prophylaxis to prevent fellow eye involvement inNAION has also led to similar disappointment In asmall cohort of NAION patients aspirin therapyreduced the 2 year incidence of NAION in the fellow

Figure 3 Acute hemorrhagic disk edema in a patient with non-arteritic anterior ischemic optic neuropathy

Table 1 Therapeutic agents-modalities used in the treatment or prophylaxis of NAION

Agent Analysis Conclusion Reference no

Acute therapy

Aspirin Retrospective No change in outcome 49

Diphenylhydantoin Retrospective n57 Central visual field improvement 53

Levodopa Retrospective n537 (18 treated) Acuity improved at 6 monthsno visual field change

50

Brimonidine Retrospective n536 no change in visual outcome at 3 months 52

Corticosteroids Retrospective n5591 (237 treated) steroids given(2 weeks after onset decreased the time torecovery of disk edema

54

Optic nerve sheathdecompression

Prospective n5258 (127 treated)no change in visual outcome

55

Hyperbaric oxygen Prospective n547 (20 treated)no change in visual acuity or field

56

Prophylaxis

Aspirin Retrospective n5431 (153 treated)2 year cumulative probability of NAION in fellow eye7 in aspirin group and 15 in untreated group5 year cumulative probability17 in aspirin group and 20 in untreated group

60



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eye but by 5 years there was no observable benefit60In the IONDT a retrospective analysis of aspirin usedemonstrated no beneficial effect on visual outcome48Owing to its benefit in the prevention of cerebrovas-cular disease and the high prevalence of atheroscleroticrisk factors among patients with NAION aspirinprophylaxis is commonly prescribed in this disorder

POSTERIOR ISCHEMIC OPTIC NEUROPATHYPosterior ischemic optic neuropathy (PION) is far lesscommon than anterior ischemic optic neuropathyPION occurs when there is acute ischemic injury tothe portion behind the optic nerve head The retrobulbaroptic nerve is supplied by the pial plexus from theophthalmic artery and by branches from the internalcarotid anterior cerebral and anterior communicatingarteries As with AION PION can be due to arteriticnon-arteritic and post-surgical causes6162 As withAION the affected patient population typically hasvasculopathic risk factors such as hypertension diabetesand hypercholesterolemia

Hemodynamic compromise resulting in PION occursin three main settings systemic hypotension blood lossor anemia Blood loss leading to a PION can occur witheither surgery or trauma (Figure 4)63ndash65 In perioperativePION many patients had associated anemia hypoten-sion or both when the event occurred Systemichypotension causing PION has been observed inpatients with chronic renal failure on dialysis but themost common mechanism is anterior ischemic injury66Following blood loss or hypotension vision loss mayoccur immediately or up to 3 weeks later possibly dueto delayed activation of the renin-angiotensin andadrenergic pathways67 Rapid restoration of the anemiaand intravascular volume in these patients may lead toan improvement in vision68

PION is typically painless except for associatedheadache when due to arteritic disease Vision loss isusually severe with over 50 of patients having CFvision or worse62 Central field loss is common

Funduscopic examination is initially unremarkablebut disk pallor typically ensues within 6ndash8 weeks62As with AION neuroimaging should be carried out torule out other causes such as compressive or infiltrativedisease Recovery of the visual loss is highly variableand generally poor Treatment depends on the under-lying etiology In cases of arteritic PION high dosecorticosteroid therapy should be instituted rapidly toprevent involvement of the fellow eye Interestingly in aretrospective cohort Hayreh observed some therapeuticbenefit to steroid therapy in non-arteritic non-surgicalcases of PION62 The mechanism of this benefit isuncertain

CONCLUSIONAs in the cerebrovascular disease optimal clinicaloutcome in ischemic optic neuropathy is dependenton prompt recognition and the rapid institution ofappropriate therapy Lack of familiarity may result ininappropriate testing significant treatment delay andincreased risk of fellow eye involvement While wecurrently lack definitive treatment to reverse or amelio-rate anterior or posterior ischemic optic neuropathyour increased understanding of ischemic nerve injurycombined with our expanding armamentarium oftherapeutic agents is allowing us to intervene at multiplestages in disease pathogenesis In the near future weexpect to see several agents approved for the treatmentand prevention of arteritic and non-arteritic ischemicoptic neuropathy

ACKNOWLEDGEMENTJ L Bennett is supported by Public Health Service Grants (grantnos NS32623 and EY014573) and a grant from the National MultipleSclerosis Society (grant no RG3908)

REFERENCES1 Lie JT Illustrated histopathologic classification criteria for selected

vasculitis syndromes American College of RheumatologySubcommittee on Classification of Vasculitis Arthritis Rheum1990 33 1074ndash1087

2 Salvarani C Crowson CS OrsquoFallon WM et al Reappraisal of theepidemiology of giant cell arteritis in Olmsted County Minnesotaover a fifty-year period Arthritis Rheum 2004 51 264ndash268

3 Salvarani C Gabriel SE OrsquoFallon WM et al The incidence ofgiant cell arteritis in Olmsted County Minnesota Apparentfluctuations in a cyclic pattern Ann Intern Med 1995 123 192ndash194

4 Elling P Olsson AT Elling H Synchronous variations of theincidence of temporal arteritis and polymyalgia rheumatica indifferent regions of Denmark association with epidemics ofMycoplasma pneumoniae infection J Rheumatol 1996 23 112ndash119

5 Narvaez J Clavaguera MT Nolla-Sole JM et al Lack of associationbetween infection and onset of polymyalgia rheumatica JRheumatol 2000 27 953ndash957

6 Elling H Olsson AT Elling P Human parvovirus and giant cellarteritis A selective arteritic impact Clin Exp Rheumatol 2000 18S12ndash14

7 Gordon LK Goldman M Sandusky H et al Identification ofcandidate microbial sequences from inflammatory lesion of giantcell arteritis Clin Immunol 2004 111 286ndash296

8 Ma-Krupa W Jeon MS Spoerl S et al Activation of arterial walldendritic cells and breakdown of self-tolerance in giant cellarteritis J Exp Med 2004 199 173ndash183

Figure 4 Pale atrophic disk from posterior ischemic nerve injurydue to trauma



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9 Haworth S Ridgeway J Stewart I et al Polymyalgia rheumatica isassociated with both HLA-DRB10401 and DRB10404 Br JRheumatol 1996 35 632ndash635

10 Weyand CM Hunder NN Hicok KC et al HLA-DRB1 alleles inpolymyalgia rheumatica giant cell arteritis and rheumatoidarthritis Arthritis Rheum 1994 37 514ndash520

11 Keltner JL Giant-cell arteritis Signs and symptomsOphthalmology 1982 89 1101ndash1110

12 Hayreh SS Podhajsky PA Raman R et al Giant cell arteritisValidity and reliability of various diagnostic criteria Am JOphthalmol 1997 123 285ndash296

13 Salvarani C Giannini C Miller DV et al Giant cell arteritisInvolvement of intracranial arteries Arthritis Rheum 2006 55985ndash989

14 Hayreh SS Zimmerman B Kardon RH Visual improvement withcorticosteroid therapy in giant cell arteritis Report of a large studyand review of literature Acta Ophthalmol Scand 2002 80 355ndash367

15 Gonzalez-Gay MA Garcia-Porrua C Llorca J et al Visualmanifestations of giant cell arteritis Trends and clinical spectrumin 161 patients Medicine (Baltimore) 2000 79 283ndash292

16 Bandini F Benedetti L Ceppa P et al Uveitis as a presenting signof giant cell arteritis J Neuroophthalmol 2005 25 247ndash248

17 Costello F Zimmerman MB Podhajsky PA et al Role ofthrombocytosis in diagnosis of giant cell arteritis and differentia-tion of arteritic from non-arteritic anterior ischemic optic neuro-pathy Eur J Ophthalmol 2004 14 245ndash257

18 Mack HG OrsquoDay J Currie JN Delayed choroidal perfusion ingiant cell arteritis J Clin Neuroophthalmol 1991 11 221ndash227

19 Siatkowski RM Gass JD Glaser JS et al Fluorescein angiographyin the diagnosis of giant cell arteritis Am J Ophthalmol 1993 11557ndash63

20 Danesh-Meyer HV Savino PJ Eagle RC Jr et al Low diagnosticyield with second biopsies in suspected giant cell arteritis JNeuroophthalmol 2000 20 213ndash215

21 Liu GT Glaser JS Schatz NJ et al Visual morbidity in giant cellarteritis Clinical characteristics and prognosis for visionOphthalmology 1994 101 1779ndash1785

22 Mazlumzadeh M Hunder GG Easley KA et al Treatment of giantcell arteritis using induction therapy with high-dose glucocorti-coids A double-blind placebo-controlled randomized prospec-tive clinical trial Arthritis Rheum 2006 54 3310ndash3318

23 Chevalet P Barrier JH Pottier P et al A randomized multicentercontrolled trial using intravenous pulses of methylprednisolone inthe initial treatment of simple forms of giant cell arteritis A oneyear followup study of 164 patients J Rheumatol 2000 27 1484ndash1491

24 Hayreh SS Zimmerman B Management of giant cell arteritis Our27-year clinical study New light on old controversiesOphthalmologica 2003 217 239ndash259

25 Danesh-Meyer H Savino PJ Gamble GG Poor prognosis of visualoutcome after visual loss from giant cell arteritis Ophthalmology2005 112 1098ndash1103

26 Buono LM Foroozan R de Virgiliis M et al Heparin therapy ingiant cell arteritis Br J Ophthalmol 2004 88 298ndash301

27 Torrente SV Guerri RC Perez-Garcia C et al Amaurosis inpatients with giant cell arteritis Treatment with anti-tumournecrosis factor-alpha Intern Med J 2007 37 280ndash281

28 Hoffman GS Cid MC Rendt-Zagar KE et al Infliximab formaintenance of glucocorticosteroid-induced remission of giantcell arteritis A randomized trial Ann Intern Med 2007 146 621ndash630

29 Salvarani C Macchioni P Manzini C et al Infliximab plusprednisone or placebo plus prednisone for the initial treatment ofpolymyalgia rheumatica A randomized trial Ann Intern Med2007 146 631ndash639

30 Hayreh SS The blood supply of the optic nerve head and theevaluation of it ndash myth and reality Prog Retin Eye Res 2001 20563ndash593

31 Arnold AC Hepler RS Fluorescein angiography in acutenonarteritic anterior ischemic optic neuropathy Am JOphthalmol 1994 117 222ndash230

32 Hayreh SS Anterior ischemic optic neuropathy Arch Neurol1981 38 675ndash678

33 Hayreh SS Podhajsky P Zimmerman MB Role of nocturnalarterial hypotension in optic nerve head ischemic disordersOphthalmologica 1999 213 76ndash96

34 Mojon DS Hedges TR 3rd Ehrenberg B et al Associationbetween sleep apnea syndrome and nonarteritic anterior ischemicoptic neuropathy Arch Ophthalmol 2002 120 601ndash605

35 Jacobson DM Vierkant RA Belongia EA Nonarteritic anteriorischemic optic neuropathy A case-control study of potential riskfactors Arch Ophthalmol 1997 115 1403ndash1407

36 Salomon O Huna-Baron R Kurtz S et al Analysis of prothrom-botic and vascular risk factors in patients with nonarteritic anteriorischemic optic neuropathy Ophthalmology 1999 106 739ndash742

37 Salomon O Rosenberg N Steinberg DM et al Nonarteriticanterior ischemic optic neuropathy is associated with a specificplatelet polymorphism located on the glycoprotein Ibalpha geneOphthalmology 2004 111 184ndash188

38 The Ischemic Optic Neuropathy Decompression Trial ResearchGroup Characteristics of patients with nonarteritic anteriorischemic optic neuropathy eligible for the Ischemic OpticNeuropathy Decompression Trial Arch Ophthalmol 1996 1141366ndash1374

39 Deramo VA Sergott RC Augsburger JJ et al Ischemic opticneuropathy as the first manifestation of elevated cholesterol levelsin young patients Ophthalmology 2003 110 1041ndash1046

40 Weger M Stanger O Deutschmann H et alHyperhomocyst(e)inaemia but not MTHFR C677T mutation as arisk factor for non-arteritic ischaemic optic neuropathy Br JOphthalmol 2001 85 803ndash806

41 Palmowski-Wolfe AM Denninger E Geisel J et alAntiphospholipid antibodies in ocular arterial and venous occlu-sive disease Ophthalmologica 2007 221 41ndash46

42 Bertram B Remky A Arend O et al Protein C protein S andantithrombin III in acute ocular occlusive diseases Ger JOphthalmol 1995 4 332ndash335

43 Srinivasan S Fern A Watson WH et al Reversal of nonarteriticanterior ischemic optic neuropathy associated with coexistingprimary antiphospholipid syndrome and Factor V Leiden mutationAm J Ophthalmol 2001 131 671ndash673

44 Lee AG Prothrombotic and vascular risk factors in nonarteriticanterior ischemic optic neuropathy Ophthalmology 1999 1062231

45 Chan J Bilateral non-arteritic ischemic optic neuropathy asso-ciated with pegylated interferon for chronic hepatitis C Eye 200710 1038

46 Pomeranz HD Smith KH Hart WM Jr et al Sildenafil-associatednonarteritic anterior ischemic optic neuropathy Ophthalmology2002 109 584ndash587

47 Hayreh SS Podhajsky PA Zimmerman B Ipsilateral recurrence ofnonarteritic anterior ischemic optic neuropathy Am J Ophthalmol2001 132 734ndash742

48 Newman NJ Scherer R Langenberg P et al The fellow eye inNAION Report from the ischemic optic neuropathy decompres-sion trial follow-up study Am J Ophthalmol 2002 134 317ndash328

49 Botelho PJ Johnson LN Arnold AC The effect of aspirin on thevisual outcome of nonarteritic anterior ischemic optic neuropathyAm J Ophthalmol 1996 121 450ndash451

50 Johnson LN Guy ME Krohel GB et al Levodopa may improvevision loss in recent-onset nonarteritic anterior ischemic opticneuropathy Ophthalmology 2000 107 521ndash526

51 Kollarits CR McCarthy RW Corrie WS et al Norepinephrinetherapy of ischemic optic neuropathy J Clin Neuroophthalmol1981 1 283ndash288

52 Wilhelm B Ludtke H Wilhelm H Efficacy and tolerability of 02brimonidine tartrate for the treatment of acute non-arteriticanterior ischemic optic neuropathy (NAION) A 3-month dou-ble-masked randomised placebo-controlled trial Graefes ArchClin Exp Ophthalmol 2006 244 551ndash558

53 Keltner JL Becker B Gay AJ et al Effect of diphenylhydantoin inischemic optic neuritis Trans Am Ophthalmol Soc 1972 70 113ndash130

54 Hayreh SS Zimmerman MB Optic disc edema in non-arteriticanterior ischemic optic neuropathy Graefes Arch Clin ExpOphthalmol 2007 245 1107ndash1121



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55 The Ischemic Optic Neuropathy Decompression Trial ResearchGroup Optic nerve decompression surgery for nonarteriticanterior ischemic optic neuropathy (NAION) is not effective andmay be harmful JAMA 1995 273 625ndash632

56 Arnold AC Hepler RS Lieber M et al Hyperbaric oxygen therapyfor nonarteritic anterior ischemic optic neuropathy Am JOphthalmol 1996 122 535ndash541

57 Kim TW Kim DM Park KH et al Neuroprotective effect ofmemantine in a rabbit model of optic nerve ischemia Korean JOphthalmol 2002 16 1ndash7

58 van Bruggen N Thibodeaux H Palmer JT et al VEGF antagonismreduces edema formation and tissue damage after ischemiareperfusioninjury in the mouse brain J Clin Invest 1999 104 1613ndash1620

59 Bennet JL Thomas S Olson JL et al Treatment of nonarteriticanterior ischemic optic neuropathy with intravitreal bevacizumabJ Neuroophthalmol 2007 27 238ndash240

60 Beck RW Hayreh SS Podhajsky PA et al Aspirin therapy innonarteritic anterior ischemic optic neuropathy Am J Ophthalmol1997 123 212ndash217

61 Sadda SR Nee M Miller NR et al Clinical spectrum of posteriorischemic optic neuropathy Am J Ophthalmol 2001 132 743ndash750

62 Hayreh SS Posterior ischaemic optic neuropathy Clinical featurespathogenesis and management Eye 2004 18 1188ndash1206

63 Chang SH Miller NR The incidence of vision loss due toperioperative ischemic optic neuropathy associated with spinesurgery The Johns Hopkins Hospital Experience Spine 2005 301299ndash1302

64 Myers MA Hamilton SR Bogosian AJ et al Visual loss as acomplication of spine surgery A review of 37 cases Spine 199722 1325ndash1329

65 Shaked G Gavriel A Roy-Shapira A Anterior ischemic opticneuropathy after hemorrhagic shock J Trauma 1998 44 923ndash925

66 Buono LM Foroozan R Savino PJ et al Posterior ischemic opticneuropathy after hemodialysis Ophthalmology 2003 110 1216ndash1218

67 Hayreh SS Anterior ischemic optic neuropathy VIII Clinicalfeatures and pathogenesis of post-hemorrhagic amaurosisOphthalmology 1987 94 1488ndash1502

68 Winkelmayer WC Eigner M Berger O et al Optic neuropathy inuremia An interdisciplinary emergency Am J Kidney Dis 200137 E23



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ited

epidemiologic analysis of GCA cases from OlmstedCounty MN USA the average incidence was 188cases per 100000 persons at 50 years of age and older2It is twice as common in women and the frequency ofcases increases at higher latitudes3 There are periodicclustering of cases suggesting an infectious origin23however epidemiologic studies investigating the asso-ciation of GCA with various infectious agents have beeninconsistent4ndash6 Recently prokaryotic gene fragmentswere isolated from GCA lesions and immunoglobulinfrom GCA patients was shown to recognize thetranslational products of these clones7 This sensitivemolecular biologic approach provides initial tantalizingevidence for an infectious etiology in GCA In contrastan alternative autoimmune hypotheses has been sug-gested based on the presentation of arterial wall antigenfollowing vascular injury8 In this model maturationand antigen presentation by adventitial dendritic cellsresults in local type I cytokine production infiltration ofmononuclear cells the formation of multinucleatedgiant cells internal elastic lamina breakdown andluminal occlusion Interestingly HLA haplotypesDRB104 and DRB101 are increased among indivi-duals with polymyalgia rheumatica GCA and rheuma-toid arthritis910

GCA is a systemic disease process and patientstypically present with symptoms other than visualcomplaints headache scalp tenderness jaw claudica-tion polymyalgia rheumatica (PMR) fever nightsweats fatigue and weight loss11 While headache isthe most common symptoms such as neck painanorexia and jaw claudication are more specific12 Insome instances local findings such as induration of thetemporal region and nodularity or cord-like firmness ofthe temporal artery can be noted Cerebrovasculardisease occurs in 3ndash4 of GCA patients Histopatho-logy indicates that the predominate cause is vasculitisinvolving the extradural portions of the carotid andvertebral arteries concurrent intracranial vasculitis israre13 In y20 of patients with arteritic AION theremay not be any systemic complaints

Vision loss occurs from arteritic ION is usually severeand acuity is often worse than 2020014 Some patientsexperience dimming or amaurosis fugax (transient visualloss) in the weeks preceding the optic neuropathy andthese event have a strong correlation with irreversiblevision loss15 Therefore it is imperative that patientsover the age of 55 years complaining of transientmonocular vision loss be evaluated for GCA Onexamination the optic nerve demonstrates pallid swel-ling Other findings include cotton wool spots andperipapillary pallor from choroidal ischemia (Figure 1)Additional visual symptoms and signs in GCA patientsinclude diplopia ophthalmoplegia hallucinosis uveitisand hypotony1116

If there is clinical suspicion for arteritic AIONlaboratory studies should include an erythrocyte sedi-mentation rate (ESR) C-reactive protein (CRP) andplatelet count1217 An ESR should not be ordered aloneas it is not a very sensitive or specific When combinedwith an elevated platelet count the ESR becomes a

better predictor of GCA but the improvement ismarginal thrombocytosis does improve the predictivepower of an elevated CRP17 An elevated ESR and CRPhave the greatest specificity for the detection of giantcell arteritis y9712 In contrast to non-arteriticischemic optic neuropathy fluorescein angiography inpatients with arteritic AION reveals a significant delayin choroidal filling (Figure 2)1819

A definite diagnosis must be made with temporalartery biopsy It is recommended that a biopsy beperformed in all cases of suspected arteritic AIONsince treatment requires high dose steroids for aprolonged period of time Approximately 5 oftemporal artery biopsies may be falsely negativeReasons include inadequate arterial sampling limitedhistopathologic analysis and partial treatment there-fore a negative biopsy does not rule out the presenceof GCA In instances of strong clinical suspicionbilateral or sequential biopsies can be performedIn recent studies however the concordance ratebetween arteries was found to be 989 Thereforeit is unlikely that a diagnosis will be made if theoriginal sample and histopathology were adequate20Immediate treatment with high dose corticosteroids isrecommended before performing the biopsy howeverthe biopsy must be performed within 7ndash15 daysfollowing the initiation of therapy because treatmentdecreases the amount of granulomatous inflam-mation in the biopsy specimen quickly Histopa-thologic staining of the internal elastic lamina mayyield additional sensitivity by demonstrating featuresof non-artherosclerotic arterial wall disruption

As mentioned previously treatment of GCA requireshigh dose corticosteroids Initial treatment may beginwith intravenous methylprednisolone (1000 mgday) ororal prednisone (60 mgday) In a small cohort of GCApatients with visual symptoms the use of intravenousmethylprednisolone reduced the incidence of fellow

Figure 1 Acute pallid disc edema in a patient with arteriticischemic optic neuropathy from giant cell arteritis



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Ischemic Optic Neuropathy

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