MOSBY
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`

`

`Chapter
`
`108
`
`Drug Toxicity of the Posterior Segment
`Robert A. Mittra
`William F. Mieler
`
`A variety of systemic medications can generate retinal toxicity.
`Fortunately, in the majority of cases the loss of visual function
`is minirnal or re,·er ible following discontinu:nion of the inciting
`drug. Ne\'ertheless, permanent or progressive visual loss may
`occur in some instances. \Ve present only those medications
`known to produce a well-described anomaly and ha,·e omitted
`those that have not been deflnith·ely proven to cause retinal
`.1bnormalities. The medications are grouped according to the
`type of retinal toxicity they produce (Box IO -1 ).
`
`DISRUPTION OF THE RETINA AND RETINAL
`PIGMENT EPITHELIUM
`Phenothiazines
`Thioridazine
`Blurred vi!tion, dy hromato~ia (reddish or brownish diM:'oloration
`of vision), and nyct.1lopia chilr:-icterize ~C1.1te- toxicit)' ,,•ith thiori•
`da.zine. 1 In the earl iest Mriges the fundus oppearance may be
`nonnnl or di>pby only mild gr:,nulnr piginent Slipphng (Fig. 10 -1).
`An intermediate stilge is charil terized by circumscribed nmn·
`mular areas of retinal pigment epithelia l (RPE) le»s from the
`posterior pole 10 the rnidperiphery2 (Fig. 10 -2A). Fluore>cein
`angiography (FA) ,e\'eals disrupti n of the choriocapillari
`in
`these zones of pigment rarefaction (Fig. I08-2B). In lote stoges
`of thi ridilz.ine toxi ity, \\'ide-spread areas of depigmentotion
`;,1lt rnating with hyperpigrncnted plaques, vas ular :att m1ation,
`and optic atrophy are ,een1 (Fig. 108-3).
`Retinal rnxi ity from thioridazine i:, dependent more on the
`tot3I d.1ily dose th3n on the 01rnuk1.ti\'e amo\1nt of drug received."'
`\Vith higher daily doses, toxi ity can occur rapidly, e,·en within
`the lfSt 2 weeks oftheropy. 5 Toxi i<y is rare at dosages Jes, thon
`00 mg/day. Nonetheless, a ~ w c,ses have been r ported with
`lower doses given o,·er se,·er::il years.6--IO As a result, many now
`sugge>< thot any palient taking thioridazine, regordless of lhe doily
`dose, be monitored. for the de\'elopment of visu:11 .symptoms or
`fundus ch:mges.
`In the initinl !ttage!t of toxi ity, \'i!;u3I field te!tting can reveal
`rnild constriction, p.,'1ra cntral cotomas, or ring scotoma . Elec·
`troretinogrnphy (ERG) is either normal or show, decreased
`oscillotory potentiols. In the later stages. bo1h the rod ond cone
`functions of the ERG, as well as the electro-oculography (E G),
`are markedlyabnom,al. 11 If the dmg i stopped earl)', ERG testing
`
`itllpro\'es over the first year.'2 Histologic studies demonstrate
`that atrophy and disorgnnizntion of photoreceptor outer
`segments occur prirn:lrily, with 3 econdary lo of the RPE 3nd
`choriocapi ll a ris. 1
`The e3rly fundus changes asso iated with thioridazine often
`progress despite discontinuation of ther3py.2 lt is ,1ndear whether
`this degene rat ion represents continued toxicity of the dmg or a
`delayed expansion of chorioretinol s.arring to areas of subdini ,11,
`pre-existing cbmagc.12 Visu3) function, in contra t to fundus
`appearance, usually impro\'eS over the first year after a toxic
`rc;:iction; this undoubtedly would not oc ur if thforidaz.inc
`auscd persistent toxicity.
`The mechanism of thioridazine-mediated toxicity remains
`unknown. Mony phenothiazines bind melanin granules of 1he RPE
`and uveal tissue, but not 3)1 comrno1,ly instigate retinal toxi•
`ily. ll ,s The compound NP-207 (piperidyl<hlorophenothiazine
`hydrochloride) has a remarkably similar chemical stmcture to
`thiorida2ine, including the same piperidyl :,ide chain. i: P•207
`wa~ never marketed be au.!te of the pronoun ed pigment.ary
`retinopathy that developed during earl y clinical trials. It> This
`piperidyl side ch:1in i~ not present in other phenothiaz.ines ~uch
`.a~ hlorprom:1zine, whi h exhibit mu h le:ios retin:11 toxi ity.
`Experimental studies demonstrate that phenothiazines both alter
`enZ)'ITie kinetics and inhibit oxidati,·e phosphorylation with
`M1b:ioequent nbnornialities in rhodopsin :iornthesis. 11 1" Other
`studies postulate that phenothiazine toxicity is due to the drug's
`effect on the dopamine receptor~ in the retina. Further study
`is nece sary to determine whether these observed effect:, are
`in\'oked in the pathogenesis of thioridazine toxicity.
`A re\'ie,v of the daily and cumulati\"e drug do:,,age is essential
`in po1ien1, taking 1hioridazine. Baseline fundu photograph)' and
`possibly ERG testing may be helpful if future toxicity develops.
`Given the many antipsy(hotic medications a\"ailable today, con(cid:173)
`!tiderotion of 3ltemati\'e .igenb rn..1y be discussed ""ith the patient's
`psychiatrist. At the earliest sign of toxicity, thioridazine shou ld
`be di:iocontinued.
`
`Chlorpromazine
`Chlorpromazine i a piperazine similar to thioridazine but la ks
`the piperidyl ,ide hain mentioned obove. The compound binds
`.strongly to melanin and can cause hyperpigmentation in the skin,
`conjun liva, cornea, Jen,, ond retino'°"2' (Fig. 108-4). Other ocufar
`
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`

`

`1840
`
`Medical Retina
`Section 7 Other Diseases
`
`Box 108-1 Patterns of reunal tox,c,ty
`
`Disruption of the retina and retinal pigment
`epithelium
`Phonothia,inas
`Quinine sutate
`ThlOridaZ1ne
`Clofami1no
`Ollorp,omame
`Deleroxanw,e
`Cl..-oqu,nedeovatr;es
`Corticosteroid preparat,ons
`Olloroqooe
`Qsplalll and BCN\J (canrustlf18)
`Hydroxychloroqwne
`
`Vascular damage
`Ou1n1nestJfaJ.0
`
`Am1nogycos,de - (cid:173)
`Qsplalll and BCNU (canrustlf18)
`1n1erleron
`Etgo, alkaloids
`Talc
`Phenjtpropanolam,ne
`Oral contraceptives
`Cystoid macular edema
`Ep,nephrne
`Latanoprost
`NN::ot,ruc acid
`Retinal folds
`Sulfa antibc>llcs
`Hydrochloroll-.azide
`Aoolazolarnldo
`Tnamtemne
`Ethoxyzolamde
`Metronodazole
`Ctblhafldono
`Crystalline retinopathy
`Tamoxilen
`Talc
`CsnlhaxMthone
`trofutaotoin
`Methoxyflurane
`Uveltls
`Rifabum
`Odolow
`Miscellaneous
`D,goxin
`Methanol
`
`effects in lu le oculogyri
`risis, miosis, ond blurred \'i:.ion caused
`by par,i)ysi of accommodation. Usual doses range from 40 to
`75 mg/day, but dosages up to 800 mg/day are not uncommon.
`Retinal toxi ity from hlorpromnzine i!io mre. \Vhen massive
`doses are given (e.g. 2400 mg/day for 12 month ), p igmentory
`changes may occur in the retina with auenu.uion of retina.I \·essels
`and opti nerve pall r21 (Fig. 10 -"). Simibr to thioridazine,
`the de\'elopment and extent of toxicity are more closely related
`to dai ly dosage than total amount of drug taken.
`
`Fig. 108-1 Early th4onda211e toxic,ty. Phot0graph shows mid granuw
`p,gmool shppl,ng ol lhe temporal macular reg,on.
`
`Chloroquine derivatives
`Chlo roq ui ne
`bloroql1ine w:;i:. first usf:d as 30 antim;:1larial dn1g in \ Vorld \Var
`II. Currend>· it is prescribed for treatment of :m1ebiasb, rheuma·
`lupus erythematosus, and for prophylaxb
`toid arthriti~. ~ys.temi
`again:.l malari::1. Retinal toxicity with degeneration of the RPE
`and neurosen~ory retina 35- a resu lt of long·term daily use of
`chloroquine has been well described.ZS 12 However, 111ost cases
`of retinopathy ha,·e de,·eloped when a higher th,n currently
`recommended (3 mg/kg/day using lean body weight) dose was
`used. l1 A daily dose exceeding 250 mg with a total cumulath·e
`dose bet ween l 00 and 300 g is customarily needed to produce
`toxicity.M One study howe-cl a I 9% incidence of chloroquine
`retinopathy in patients taking a mean daily do e of 32 mg."
`Com•ersely, with strict adherence to a low dose per diem, the
`is
`l'l'linim.il e\'en when
`incidence of reti11al abnormalities
`cumulative do es rea h o,·er I 000 g.'4>
`A paracentral scotoma may be t he earlies\ manifesta t ion of
`retinal toxicity and an precede the de\"e lopment of any ophthal(cid:173)
`moscopic or ERG abnom1ality.11 ubtle macular pigment stippling
`wit h a loss of the fo,·eal light renex (Fig. IO -6) usually appears
`on fondu c:xami,ution before t he d \'e loprncnt of a da i
`bull 's-eye maculop3.thy, in whic h a ring of depigment3.tion sur(cid:173)
`rounded by an area of hyperpigmen\ation is seen centered on
`the fovea (Fig. 10 -7). Visual acuity decrca s when the RP£
`abnormalities im·ol\'e the center of t he fovea. The peripheral
`retina can display pigment mottling, which may, in severe cases,
`dt:"\lelop into the appear:ince of primary t3pctoretinal degenera(cid:173)
`tion with narrowed retinal vessels, optic disc pallor, ::ind e\'entual
`b lindness [Fig. I OS-SJ.
`Aftf.:'r the cessation of chloroq,1ine treatment, c:irly subtle
`macular changes can revert to nonl'lal. Alt hough for advanced
`cases may progress despite discont inuation of the drug, most
`p.1tients remain stable wit h long-tem, follow-up."'i..39 hloroquinc,
`
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`

`

`Chapter 108
`Drug Toxicity of the Posterior Segment 1
`
`184i.....J
`
`Fig. 108-2 Intermediate tl'oondazlne toXJOty. Photograph (A) and lw<esceon anglog,:am (Bl show central and periphetal numnua, pogmentary changes
`wrth cooaspond1ng atrophy of lhe chonocaplllans.
`
`Fig. 108-3 End-stage tnoridazlne loXJOty. Photograph (A) and !kJomsceol angiogram (8) show dilfuso pigmootary and cho<iocapillans atrophy. optic
`atrophy, and vas<:uar attenuat10<1.
`
`lowly excret d from the body. h has bt..-en
`however, is \'ery
`detected in the plas ma, red blood cell , ,nd urine of patients S
`years after t heir last known ingestion. 40 This prolonged presence
`may 3Ccount for th rare cases of <leb.yed Oil et of c hloroquine
`retinopathy seen up to 7 years or longer after discontinuation.~ 1·"'2
`Fluorescein angiography can be helpful in the early demon(cid:173)
`stration of pigment abnormalities in the macula (s e Figs IO •6
`and 10 -7). The re is minimal evidence of damage to the chorio(cid:173)
`capillaris on FA in the areas of pigment disturbance. The ERG
`and E C may be abnorma l early, although the E G is some(cid:173)
`times supernormal initially."'3 H istopathologic sections de monstrate
`loss of RPE pigmentation with an accumu latio n of pigment(cid:173)
`bcten cells in the oute r retina l layer ~ with damage and reduc(cid:173)
`ti on of photoreceptors."'"' Electron microscopic studies re\'ea l
`more widespread damage to the retina, especia lly the ganglion
`cell laycr."'5
`
`The mechanism of chloroqoine•mediated retina l toxicity i
`unkn own. Like the phenothiazines, chloroq uine is bound by
`me lanin and concentrated in the RPE and uvea l t issues."'t.
`ible explanatio11s: ind ud
`in hibition of rit ical enzyme :lnd
`Po
`inte rference w ith the meta bolic funct ion of the RPE and
`photoreceptors."' 1·" 1
`
`Hydroxychloroquine
`Given the incidence of toxicity with chloroquine, most rheumatolo(cid:173)
`gists prefer hyd r xych loroqui nc fo r the treatment of rhcum:l•
`to id arthrit is and systemic lupus erythematosus. Although it can
`produce a retinopathy identical to chloroquine. its occurrence
`nly a fow case of toxicity have bt:-en well docu·
`is rare. ◄ SI
`mented, involving decreased \'isual acu it y, paracentral scot oma,
`and a bull' -eye maculopathy (Figs 10 -9 and 108-10).""
`Many of these patients recci\'ect abo,·e the recommended daily
`
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`

`

`1842
`
`Medical Retina
`Section 7 Other Diseases
`
`tlwy an n'IOnitor their \'isoal fun tion at homr. Recent dat;;i
`ugge.st that multifocJI electroretinographic evaluation may detect
`toxicity at its earliest stages_68-7l
`TI,e Amcri on Acodemy of Ophthalmology guidelines for
`creening inclL1de a baseline examination performed ac the com(cid:173)
`mencement of therapy. 11 Screening exams during the first fh·e
`years of ther.ipy an be perfomied during routine ophthalmic
`exa mination (interval to be detem1ined by age of the patient).
`If the dosage used is higher than 6.5 mg/kg/day for hyd roxr•
`ch loroq11ine (3 mg/kg/day for chloroquine), the J)'ltient is obese,
`has ren.1 \ or liver dysfunction, has concomitant m:-icul:lr di ease
`or is more than 60 years of age, screening should be performed
`at least annually. After five years of th er:ipy,.:. reening should be(cid:173)
`performed at least af'lnu:illy. 7◄ If ocuhir toxicity occurs/5 78 and
`is recognized at an early stage, efforts should be made to
`commi1nican.1 this d ire t ly to the prescribing physician :.o that
`altern::nive can be discussed with the patient. Ji1 a lmo t all
`cases, cessation of the drug should be suggested.
`
`Quinine sulfate
`Quinine sulfate was first used for the treatment of malaria in
`World W,r II , but it urrent lr is prescribed for the management
`of nocturnal muscle crJmps or "restless leg yndrome. H 11,e
`recommended daily dose is less than 2 g. Signs of systemic
`to, icity occur with d es greater than 4 g, and the fatal oral dose
`is g. Ocubr toxicity with quinine de\·elops after an overdose,
`either by accidental ingest ion or by attempted abortion o r sui(cid:173)
`cide. Rarely, chroni
`ingestion at low levels can result in ocular
`t oxicity as ,,•ell. 79 \\rith an o,•erdo e, a ynd ro1ne known as
`ciudronism is rapidly produ ed, onsisting of n:n1S(l'a, \'Omiting,
`headache, tremor, and sometimes hypotension and lo s of con(cid:173)
`s iou~ness. \Vhen patients awake they often are completely
`b lind and h:we dilated, unrea ti ve pupils.1!11 In the acu te stages
`of toxicity, fundus examination re\"eals mild venous dilation
`with minimal retina l edema and normal arterial caliber. The FA
`
`Fig. 108-4 Typocal ci'jc,rpromaz,ne-,nduced aoteno, stelate lens
`opac1hes.
`
`dosage of 6.5 mg/kg/day, but the classic fundus findings ha\'e
`been reported at lower doses a.s well. 5s..t,O
`e,·eral authors ha\•e questioned the utility of screening given
`the low yield, high co>t, and the difficu lty in diagnosing the
`01,dition early e nough to prevent d:-image. M tt◄ Ne\'Crtheless,
`toxicity does occur, and if retinal and function:-il changes are
`detected early, severe visual impairment can be avertecf,6>.t,t, Use
`of t.1tic perirnetry t hrough the vertical meridian with a red te.st
`object may be the best met hod to detect an early para e ntral
`scotomaY These hanges usually occur before visible relinal
`:1bnormalities and therefore should be perfonned on follow-up
`examinations. The red Amsler grid is also u~ful in de tecting an
`early para entral scoto1na and rnay be ~ub tituted for
`t.ltic(cid:173)
`perimetry.67 In addition, the grid can be gh·en to patients !!.O that
`
`Fig. 108-5 Oilo,p,omaz,ne toxiaty. Phologrnph (A) and ikJo<esoe1n ang,ogram (B) show granular p,gment changes less sew,re thM those seen wrth
`lh"'1dame.
`
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`

`

`Chapter 108
`Drug Toxicity of the Posterior Segment 1
`
`1843=-:J
`
`Fig. 108-6 Early chloroquine Iox10ty. Photog,aph (A) and lluo<escein angiog:am (B) show oorty poofovool p,gmenta,y changes. From Mielet WF.
`Focal po,nts. Amencan Academy of Ophlhamology, Dec 1997.
`
`Fig. 108· 7 Advanced cltlroqune toxiaty. Later phologaph (A) and !kJofescoin ang<>gram (8) from It.) poliOOI il F,g. !07 -6 show matkad prograssion
`Wllh advanced W1despread p,gmanta,y change$. From M- WF. Focal points. Amencan Academy of Ophlharmology, Dec 1997.
`
`dispbys minimal abnormalities. ERG testing shows an a ute
`slowing of the a-wa\'e with increased depth, loss of oscillatory
`potentials, and a decreased b-wave. EOG and visual e\·oked
`potential (VEP) iesting ore also abnormal.
`Over the next few days \'isual acuity returns. but the patient
`is left with a small central island of vision. There is a progres•
`iH• auenuation of the retinal arterioles with the de\•elopment
`of optic disc pallor on"r the next few weeks to mo11ths (Fig.
`IO .) I). Early im·est igators believed the mechanism of qt1inine
`toxicit)r to be va:s ular in origin. This wa based primarily on
`the fundus appearance se\'eral weeks after ingestion, which
`showed marked arteriolar attent1ation and optic disc pallor.-...:11i
`More recent experimental and clini al studie ha\'e demon·
`
`Mrnted minimal im·oh·ement of the retinal ,·a.sculature in the
`early stages of quinine toxicity.~
`Furthermore, ERG and
`histologic :studies show that the site of toxicity is likely the
`retinal ganglion, bipolar, and photoreceptor cells.~·"'2 The ex.act
`mechanism of quinine toxicity is unidentified, but some han:•
`suggested that it may act as an acetykholine antagonist and
`dismpt cholinergic transmis~ion in the retina.SJ
`
`Clofazimine
`Clofozimine is a red phenazine d)·e that h::is been used to tre::it
`dapsone ~resistant leprosy, psoriasis, pyoderma gangrenosum,
`discoid lupus, and more recently, ;\ifycobac1eri11m cwiwtr•complex
`infections in AlDS patients. \ Vith trea tment 0\'er se\·ernl month:,,
`
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`

`

`1844
`
`Medical Retina
`Section 7 Other Diseases
`
`antivir;;il 2' 13'-dideoxyinosine.11o The ases were 3.s.sociated \\ith
`ERG and EOG changes. The re1inal 1oxicity stabilized after
`discontinuation of the medi 3tion.
`
`Deferoxamine
`lntra,·enous (IV) and subcut,meous (SQ) admini,,tration of defer(cid:173)
`oxamine has been usOO to treat patients who require repeated
`blood transfusion.; and subsequently de,·e lop omplications of
`iron overload. High-dose JV and Q therapy ha produ e<I visual
`los,, nyctalopi,1, peripheral and central field loss, and re<luce<I
`ERG amplitudes and EOG ratios." Fundi can be nom,al initially,
`or there may be a foint graying of the ma ula."' Pigmenta,;•
`ch.·mges in lhe m3cula and periphery d('velop within a fow weeks
`ond are particularly highlighted by Ouorescein angiography (Fig.
`IO - I 3) ."" Mo ular hange, an resemble vitielliform marnlopa(cid:173)
`thy.91 Ret.urn of visual funct ion occurs with ess3tion of therapy.
`Deferoxamine chel:nes many metals other than iron, and il is
`possible that the n,ecfomism of toxicity may im•oh'e the removal
`of opper from the RPE." Histopmhologic hongesoccurprimarily
`in the RPE and include loss of micro,,illi from ,he apica l
`surface, patchy depigmentotion, va uolation of the ytoplasm,
`swelling and al ifkation of mitoch ndria, and disorganization
`of the pla-.>ma membrane.eii
`
`Corticosteroid preparations
`The vehicles of several common corticosteroid preparntionl,
`ha\'e been shown to cau-!t-e retinal ne rosis when inad\'ertently
`injected into the eye•'·"' (Fig. 10 - 14) . The corticosteroid,
`themselves prob.ibl)' have a minimal toxic effect on the retina.1.)5
`Celestone Soluspan, with its ,·ehicle benwlkonium chloride,
`and Depo-Medrol, with myri tyl gamma-picolinium chloride,
`caused the most extensi\'e rNinal dan'lage in an eXJ'4:rimental
`study comparing several depot steroids.% If one of the e :igents
`is inadvertently injected, immediate surgical removal should be
`in tituted.
`
`Cisplatin and BCNU {carmustine)
`Cisplatin nnrl 8 N
`are used for the tre:ument of m:1lign:1nt
`gliomas .and metnst.atic brea t c.ancer. 1l'lree different types of
`retinal toxicity have been reported with these agents. One type
`of change consists of .a pigmentary retinop.athy of che n'l:1cub
`with markedly decreased visual acuity and frequently abnormal
`electrophysiologic testing. This pigmentary change has been
`reporte<l :ifter ad.ministratio1l of combined intraarterial i.spbtin
`and B NU and with cisplatin alone for malignant glioma.q,_-..i
`These findings probably are the result of platinum toxicity of
`the retin.a. cv r bilat 1'"31 \'isual lo s was reported :1fter intra•
`\'enous cisplatin in a patient that receh·ed four times the inte1'lded
`dose for treatment of lymphoma.c,q Later histology showed a
`plitting of the outer plexiform layer.
`A second type of retinopathy has been described and consists
`of cotton-wool spots, intraret inal hemorrhages. macular exudate,
`and optk neuropathy with d i
`sw lling. This was reported in
`the setting of high-dose chemotherapy with cisplatin, cyclophos•
`phamide, carmustine, and autologous bone marrow transplan(cid:173)
`tation for metastatic breast cancer. 100 The third type of change
`
`Fig. 108-8 Chloroquine relnopathy. Photogaph shows bone-spicule
`pgnonta,y ct..-gos Iha! can ~ ,n advanced cases. Tho appear"'°"
`,s ,.,,...., to end-stage ret,n,tis pigmentosa.
`
`Fig. 108-9 1-iyd<o,oychloroquile to>oClty. Pholograph displays pigmenta,y
`changes in the central macula.
`
`lofazimine rystals moy a umulate in the cornea. l\\'O ca es o
`bull's-eye maculopothy with pigmen<ory retinopothy (Fig. 108- 12)
`ho,·e been reported in AIDS patients with doses of 200 to
`300 mg/day (total dose, 40 10 4 g) ... ~' Visu, I 3 ui1 y wa,
`mildly affected. wi1h reduced >eotopi , photopi , ond flicker
`ERG ampliwdes. Cessation of treatment m:i)· result in the
`le, ranee of the orneal depo,its but does not oppear to affect
`th retinop31hy.
`
`DOI
`A midperipherol pigmentary retinopathy has be n noted in
`three children with Al DS receiving high dose therapy with the
`
`Novartis Exhibit 2295.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Chapter 108
`Drug Toxicity of the Posterior Segment 1
`
`1840
`
`cause profound , 1isu.JI loss and ext ensi\'e fundus pigmen tary
`abnormalities. tru: Fluorescein angiography reveals RPE window
`defects and ERG and YEP testing shows marked impairme nt of
`retim1I function. Visual ncui ty may im pro\'e slowly over e\'er.31
`months.
`
`VASCULAR DAMAGE
`
`ee Oi)ruption or the retina and ret inal pigment epitheliu m,
`p. 1839.
`
`Cisplatin and BCNU (carmustine)
`See Di~ru ption of the retina and retinal pigme nt epithelium ,
`p. I 39.
`
`A har.ic-teristi rC'tinop. .. uhy c nsi.stin.g f rnall, white, gli.:,tening
`crystals concentrated in the end arterioles of the posterior pole hos
`been described in int rn,'enous (IV) drng abusers10'-"" (Fig. I 08- 1 SJ.
`The,e addicts cru h orol medications such as met hylphenidote
`I and then crc,re an
`hydrochloride (Ritalin) or methadone H
`aqueous sus~nsion by adding w,ner and heati ng the mixture.
`The solution is subsequ ntly drawn up into a syringe, with
`occ1sional 3tlempts at: filtering the mi.xture with cotton fiberS,
`gatrz.e, or
`iga reu.e filters. The~e oral medi ations ontain tal
`(hydrous magnesium silicate) a
`inert fi ll r mat ria l; ofter IV
`administration, talc particles embolize to the pulmonary vascu(cid:173)
`lature, where the larger parli !es .:1re trn pped. After re~3 ted
`injc-ctions over months to ye;,1rs, col bter3( va.sc-\llature dc-,·elops,
`.:1llowing the particles to enter the :,1•stemic
`ir ulation ,md
`emlx>lize to other organs, including the eye. Even before shun,
`de-velopment 1 particles small r th.in 7 µm can tra\'erse thc(cid:173)
`pulmom,ry capillary bed and e nter the retinal cir u lati n. 106
`On e • large number of tal porti les lodge in the ,moll orte·
`rioles of lhe retinal vasc-ulatore, a ch:,racte rist ic pict1.1re of an
`pilbry nonperfusion,
`ischemic retinopathy begins to develop.
`
`Fig. 108-11 Ou,nine toXJC1ty. Photograph Illustrates lhe charactensllc
`oplK: nerve head ~ r with diffuse artenolar at1enuatKX1 approximalely
`2 months aner lngest100.
`
`in\'olves a vn ular retinopathy or opti neuropathy, whi h an
`include arterial occlu ion, vasculiti , and papillitis. This h..1s been
`seen in approximately 65% of patients receiving intraan eria l
`BCNU olone or ombined with cispbtin for molignont gliomo."'
`The ~ fond us change are associ:ned with ~ profound vi.su.il lo s
`that begins alx>ut 6 weeks after the start of therapy. Other
`ulo:r effe ts may in lude orbital pain, heinosis, se ondary
`gl::iucoma, int rna l ophthalmoplegia, and caverno,1s .sim• syn(cid:173)
`drome. Inje tion of medication 31JO,·e the ophthalmic artery can
`still re~ult in t xicity. 1m The ,•i uol lo s u~uull y is progres~ive,
`and no treatment i known .
`
`Potassium iodate
`,·erdose of pot:,ssium iodate, an iodized .SJlt used for iodine
`supplementation in area.s endemi for goiter, has been hown to
`
`Novartis Exhibit 2295.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`1846
`
`Medical Retina
`Section 7 Other Diseases
`
`Fig. 108-12 Clofaiirrwle loXJCdy. Photograph (A) and !klor8SC<l01 angiogram (Bl show modemle macua, pogmentary chang8s in a bull's-eye pattern.
`
`Fig. 108-13 Deferoxam,ne 1ox,c,1y. Pholograph (A) and !uoresce,n 8J'l(JIOQram (BJ show a diffuse p,gmenta,y ret,nopathy wilh macutar and re1onal
`edema.
`
`microaneurysm formation, cotton-wool spots, and \"enous loops.
`can all be seen. 107 Jn severe cases optic disc and peripheral neo•
`V3SC\lbriZ-3ti n ::rnd vitr ou hemorrhage can develop 108, 109 (Fig.
`IO r 16). An experimental model of calc retinopathy in monkeys.
`has demonstrated with light and electron microscopic tech•
`\lbr ;1bnormalities induced are very similar
`niques that the va
`to other ischemic retinopathies seen in humans, such as skkle
`cell and hypertensh·e retinopathy. 116 112
`nee tJlc r tinopathy is di:ignosed, an :-ittempt at educating
`the patient a.s to the cause of the disorder is indicated. Treatment
`of neovascularization and vitreous hemorrhage s.hot1ld be under•
`taken using bser photocoagulation ~rnd pars pbn:1 vitrectomy if
`
`necess3f)' in a manner simibr to that used for sickle cell or
`proliferath"e diabetic retinopathy.
`
`Oral contraceptives
`Oral contraceptives have been implicated in some cases of central
`retinal vein occlusion, retin;1l and cilioretinal artery ob tru tion,
`and retinal edema occurring in young women. 11l--l lilTue .synthetic
`e.strogen and progesterone contained in contracepth·e pills are
`thought to ad,·ersely effect coagubtion factor
`:ind induce a
`hypercoagulable state leading to thromboembolic complications.
`Most of the studies reporting ocular complications are from the
`1960s and 1970s, when dw estrogen concencrations used in .. the
`
`Novartis Exhibit 2295.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Chapter 108
`Drug Toxicity of the Posterior Segment 1
`
`184i.....J
`
`beading (Fig. I 08-17). 125 Fluorescein angiography re\'eals se,•ere
`vascular nonperfu.sion in the acute tages. Visu:il los is profound,
`and late mbeosis iridis, neo\"asailar glaucoma, pigmentar)' retinopa•
`thy, and optic atrophy 3re common. lnt ra-,·it real injection of
`smJller doses thought to be safe for the eye ( I 00 t o 400 µg) can
`.still cause toxicity with less severe fundus changes. 12:3 IZ!i TI1e major
`presen•ati ves found in injectable ge ntam icin (methylpa raben,
`propylpar3ben, sodium bisulfhe, and edetate disodium) likel)'
`play ;:m additive ro le in its ocular toxicity.
`A number of factors appear to affect the exte nt of toxicity
`observed with imilar do es of these medications. Peyman found
`that retina l toxicity could be enh:inced with an intr'a•vitreal
`inje tion directed al t he posterior pole with the be\'el of the
`needle pointed toward the retina, anrl Zach;1ry and Fol'Ster demon•
`.str-ated that an increased rate of injection during intraocular
`administration could also increase the retinal ta.xkity observed. 1~· 129
`ne investigator stated that eyes that ha\·e undergone a pre\'ious
`pars pbn::i. vitrectomy are at grea ter risk for genta micin toxicity,
`but an experimental model has shown no difference between
`eyes that had cataract exti.tction J!one compJred with those thJt
`undenvent lensect omy and vitrectomy.12t.,l 30 Finally, increased
`ocular pigmen tat ion protects the rabbit retina from am ino(cid:173)
`glyco.side toxicity and may explain some of the wide variability
`een with intraocular exposure in humans. m ,,,z
`Althoug h clinical ami noglycoside toxicity appears lo afre l the
`re t inal vascu latu re primarily, pathologi
`tudie have revealed
`tha t gentatnicin in small doses cau es the formation of abnormal
`lame-liar lysosomal inclusions in the RPE, and larger doses cause
`increa ing ::imount of retinal r1ecro is, fir t of the oute r the11
`inner segm~nts. 111-. i i,; H isrologicall y, vessel
`losu re ap~ars l O
`result from gra nulocytic plugging.
`Preventio n of ~uninoglycoside toxi ity c-an be a c-omplished
`by .ibandoning the use of lhese medi at ions as routine p rophyl(cid:173)
`axis follo wing intraocular surgery. eli minating them from intr.l(cid:173)
`ocular infusion fluid~ used in \' itrectomy and catarac t surgery,
`and using altern3tive medicmions fi r the tre~nment of bacteri al
`endophth3hn itis. An irnal stu dies hi\\'e- demonstr:ited that
`thinned sdera alone- without perforation can result in marked ly
`devated intraoc-ular gentJmi in leveb after :iub onj uctivol
`inj ection. 111 If inad \•e rt ent intraoeu lJr inj~tion doe,:, OCC\1 r,
`i mm ed i □ te pars pl:ma vit rectomy with posterior segment lavage
`should ~ performed.ns. 139 Sin e there i soine eviden e that
`gravity play, a role in t he pr dil ction of gentamicin-induced
`toxicity for t he- macu la, the patient should be placed upright as
`won as possible after surgery.1"°
`
`Interferon
`Interferon-a is used to treat K3posi's :i.ar ma, hemongiomas f
`infa ncy, chronic hepat iti
`, mel::inom:1, r n::il C('II carcinoma, in
`c hemotherapy protocol
`for leukemia, lymphoma and heman(cid:173)
`giomatosis, and experimentally ~ r the treatment o
`h roidal
`neov;.1scul:lr membr::ine, _ Interferon th rapy has been a sociated
`with the de,·e lopment of multiple o tton-wool ,:,pots a ociated
`with retinal hemorrhages'" '" (Fig. 10 -I ). Opti dis edema,
`branch arterfal and vcnoos occlusion, cen tral retinal venous
`obstrnction and CME have been reported with the more severe
`
`Fig , 108-14 lnlraocular corticoslerood in)OCl!On. Pholograph shows rod·
`s1age relnOpalhy, with sclerobc vessels and diffuse p,gmeolaly changes,
`aJtor an inadvertent 11traocular l1jeclJOn of cortJcosterood.
`
`Fig. 108-15 Talc mtInopathy. Characlerishc pernoveal yellow•whIle
`gllslenng c,ystals.
`
`pill '" were mu h higher. More r en1. prospecti\'~ M:udies haw~
`foiled to show 3n increased incidence of ocular cornpl i ations
`with the drug. 1JO, m
`
`Aminoglycoside antibiotics
`Retinal toxicity from aminogly oside antibioti s has been reported
`a ter inad\·ertent intr ocular injecti n of rn:J.s:..i\'e doses, introvit(cid:173)
`real injection for bacterial endophthalmitis, prophylactic intrmitre□l
`injection after pars pl