| OCR Text |
Show j. Clin. N~uro-ophth.dmol. 1: 2b1~204. 1981. Ophthalmic and Central Nervous System Complications following Intracarotid BCNU (Carmustine) B. S. CRIMSON, M.D. M. S. MAHALEY. jR.. M.D., Ph.D. H. D. DUBEY, M.D. LYNN DUDKA, R.N. Abslr..cl Infusion of BCNU (Cmnustine) inlo Ihe intern",1 urotid utery is Ming invnlig"'ted loS '" method of incrusing lh~ dowge of this ch~mother",~utic "'gent 10 br",in tumon within the supply of this vessel. We teport .I l8-~",r-Qld white m.llie who developed both tunsitnt ",nd penNntnl ophlh.llimic compliulions refl«tins vueulu injury within the distribution of 1M ophtlulmic olrttry. F1oution of snulln .lIrtni.lll uthttfl'l up 1M inttrn.ll arotid .lind btyond the ophtluhnic olrtft')' prior to injection of dw1nothnlo~utic..gmts aw.y MIl' ",void such ocuw MqU.lllu u chronic ocul.llr isc:tM:mi.ll.llnd subsequmt ocullor n~lui.uotion. Introduction Intr..... neri..1 infusion of BCNU (C.. nnustine or 1,)~bis 12-chloroethyl)-I~nitrosourealis being investigated as a means of increasing the concentration of this chemotherapeutic agent to brain tumors while minimizing systemic side effects."~ Transient ipsilateral periocular pain, pcriorbitdl edema, dnd hyperemid ..nd chemosis of the conjunctiva commonly accompany intracarotid injKlion. Our case is noteworthy in that pennanent visual loss reflecting chronic ocular ischemia also developed. ColS~ Report This 28·year-old whIte nule underwent a craniotomy for a left frontal I.grade 11 .lIstrocyloma on Septem~r 2, 1976. followed 4 we-eks later with 6000 r.ds of cobalt therolipy delivered to the frontolil portion or the he..d over oIi '~w«k period. On April IS. 1980, .lI second CT..niotomy WoliS perfonned because of reC"t"nt difficulty with re.ding. spe.. king. writing. oIind the use of his right extremities. Th~ hom Ihe Dtp.lnmenl of Ophl.....lmoIOlY ..nd 1M Dov,~1Of"I of N~llnKutlery. University of Nonh C.. toI,n.. 5c"hooI of M~,· dne, Ch..ptl Hill. Non... Cuohn'" December 1981 tumor specimen dppeared more an.lpldstic than hiS previous surgiul biopsy. Postoperatively, he was neurologically nonnal. On July, I. 1980, selective catheriulion via the femoral artery <lnd angiography of the left internal carotid drtery demonstrated olin dVolisculu m<lss lesion in th~ left front.l lobe. Intr.llcuotid infusion of 500 mg (250 mg/M~) of BCNU over 45 minutes WoliS then perfonned with the Ulhetu tip lying within the cerviul portion of the internolil cuotid <lrtery. InfuSion WoliS .ccompa.nied by n..useoli, vomiting. left oculu pa.1O, .nd eryth~moli of the left eye .And forehe..d. Th~ pa.tient denied ..ny visuolil symptoms prior to BCNU therolipy but noted blurred vISion In the left eye immedi.tely following the Inlectlon. His p.lIin ..nd periorbit<l! edema resolved 24-48 hours .fter the Infusion, but his viSion remoliined mildly blurred. Four weeks following infusion, the p.lotient beg.m to experience recurrence of the penorbilat swelling .lind ocular pain. On hiS flTst neuro+ ophth.lmoiogicolil evaluation, 6 weeks after intracarotid BCNU, the best corrKted visudl acuity was 20/20 in the right eye <md 20/25 in the left eye. Mild left proptosis, moderat£' periorbital lid edema, and hyper£'mia and chemosis of th£' conjunctiva were observed (Fig. I). Th£' ('xtraoculdT movem£'nts on the left were modcrdtely limil£'d in .Ill fields of gue, and A- and B-scan orbit.al ultr<lsonogrJphy rev~oIiled moderdte enlargement of the rKti muscles oIind prolong<ltion of the periorbitolil.lnd retrobulbar r<lt pdltem. Goldmann perimetry uncovered hesi· I..nt responses to the st.ltic presentolillon of the !2e lest objKt in the central JO of the I~fl vlsu<ll field but otherwise W<lS nonn..1 bliolitcr.llly The ..nt~rior st'gments were unrem.lrk..lble In both eyes, oIind .. ppl.nation mtr.tOCl.tl.n prt'Ssures were II mm Hg in the TIght ~e oIind 9 mm Hg in the left eye. The fundus oIippe<lr~d benign in the oght eye, but diffu~ m.lculolir edem... disc edemoli oIind oIi single splin~ ter hemorrh.llge were present in the left eye (Fig. 2). At this time, the pdli~nt W.llS still neurologiCollly nonnolilotherwise. On evaluolition 10 wt't'ks .lifter Ihe intracarotid BCNU, he complained of progressively decreolising 26' fi~un' I. 5.. "",",J.s aft... 'nu....anC'.....1 SCl'U lCann~"'IC'1 Th prnorbllal pdpny and toRlunclrv.al ,nlf'Ct-' OS dod ..... ~ rlPtt"lv l'P'lid.... unlll IZ"",",0-$ aft.., ,nfu->n of Ihos clwrroo- IM'aprutlC' ~I ltlIO d... Irtr ,nl"~ ulOIod '11..1')' Fi&u~ l. 5.. Wffks follow'l\& Itft ,nltmal uror,d al"len,1 '";0'<:1'010 of BCNU O,ffu~ ..d..m, of th.. J>OSI....or pol.. ,"volvn Ih.. d,sc ,nd m,cul, Th.. I..mpor,l sm,lI 'l"I ..riolC' {"row' cross,ng tkC' d,sc m,rg,n al 'kt Z o'clock poslt,on and ,I~ Ihrff br,nchc.os liupplying lkt p,p,lIom.acul" bundl.. r,,!:l('In .. ppc.o'" no.m.1. vision in the left eye during the prior J weeks. during which time he had also experienced a grand mal seizure and had developed some confusion and speech difficulty. Brolin CT scan showed only some increased low density (edemd) in the left frontal dred. The ViSUdl acuity hold decreased to 20/100 in the left eye, Goldmann perimetry re~ vealed progressive visu,,1 field loss (a r("ldtive centr. al scotomA with mild peripheral depression of the superior isopters), "nd the edemA of the disc and retinol in the posterior pole WdS now accompdnied by sc..ltered f1.ame.shAped hemorrhages, soft exud. atrs, ..nd superficial retinoll folding. Ndrrowing dnd foc..l constnchon of A temporal peripapillolry utenole .and Its lhr« br.. nches supplying the ma~ culopdpill..ry bundle had developE'd (Fig. J). No further IOtr.aurolld BCNU w..s "dminislerC'd but the pdt,ent w"s begun .and contlOurs now on'prourbulOt' rnl'mothC'rapy or"Uy. RepeAt brAin IT O;C-.10 and oInJtIOKr.lphy oil 12 Wffks poslinfusion t .. h 1.11'."<1 He conlinued 10 complain of progressive visual loss 19 weeks afler intracArotid BCNU with ~,';'!-lll objects now completely disappe.Hing in the central portion of his left visual field. The viSUAl acuity remAined 20/100 in Ihe left eye, A large absolute cenlral scotoma Wol§ presenl (the V4e GoldmAnn trsl object w.as not visualized in the central 150 of the visual field) • .and chronic disc edema splinter hl'morrhAgrs .Ind cOlton wool l'xudalrs were still prt'S4!nl (Fig. 4). The choroid And pigment epithl'~ lium were nonnal to funduscopy ..nd no ocular neov.ascul....iz.alion was detected. The focal constnetlon and n..rrowmg of the sm..l1 temporal per~ Ipdplll.ary .Irtl'riolrs h..d prog~.sed. And fluorescein ..nglography reve.aled c.. pJllary perfusion de+ fects 10 the dlst..l supply of Ihese vessels (Fig. 5). Perifoveal npill.ary dll.aution W<lS Also seen but no rigurt ). T~n w....ks followIng BCNU ,nJ..Chon. D,sc: ..dem•. ~pl,nle. htmonhal!.c.os. CO"On wool ~"ud'lc.os. m,culn C'd..m. .nd su~,flC..1 rehn.l fold,ng .... prl"liC'nt, Th.. tempor.l pl"n. p.apdlary ~neriole I! o'clock] .nd ,l~ Ihre.. br.nch"li .ar" now nano...·ed .nd focally conslnet..d. fisure 4. N"wt~ Wffks foilOWll'lf Intr..c.olOtwl BCl\'U. Disc nl....... ~nd liphntn ~,conon wool spots. M>d dftp f'dnry reidUf ~n 'Iftn on fundus ~.pfty prior to Huoltio( l"In ~~ph)'. Crull"''', M.,h.IJey, Dubt·y, Dudk.. ,. I Ib I flsur" 5....nd 51t Nineteen weeks foU"wlng ,nt...·.. Meri..] BCNU, F1"ore).(tln .nS'OKr.m§ 15. I demonslr.ee c.p,U.ry non perfuSion n.. ~..lto thl' f"vl:,) In ,hr r"lllon supplied by the sm.1I tempor.1 penp.p,U",ry ","('noles Oil"lon of l .. p<II",nl·~ ..,t prnent In the penf~.l region utN ph.sn of the ",nlll~.",m 151t I ~h"w 'he' vrn"",J b..r-th..ptd p.lllt'm of up,U.. ry nonperfu~lOn Ibc.otwl'C'n "'rro~l ..dl.l(e'nt III Iht' uptlLary fr"" 10M of Iht' f~... subclinical p.lthology involving the retinal pigment epithelium or choroid was uncovered. The visual evok~ potential (flash and p.lttem) demonstrated delily~ I.te:ncy and decreased amplitude on the left. The: e:le:ctroretinograms were essentially normal bil.iter.illy. The p.ltie:nt's neurologic.l symptoms and sisns had improv~ by this time and evmhully cleared completely by 26 weeks postinIu> ion. AnotherCTscan 29 Wffks following intracarotid BCNU showtd no progression of the tumor, the poitie:nt continu~ to do well neurologically, but ViSUdl acuity in the left toye: hdd decredsed to counting fingers at 8 feet ,md was aSSOCiated with moderate loss of the peripheroll visu..! field. Early TlJbe: osis of the left iris WolS identified and gonioscopy rrveal~ accomp.inying euly neovascul.. riution of the entire peripheral anterior cholmber angle_ No peripheral anterior synrchia were obse:rv~ and gonioscopy was unrem.olrkable 10 the right eye. The applanoltion pressures weft' 12 mm Hg in the right eye: and 22 mm Hg in the: left e'ff!- The soft t'll:U' dates. splinter hemorrhages••nd retinoll ~ema had ~Ived but optic atrophy was now apparmt along Inlrolcolu'tiJ BCNU Figur\! 6. Tw~nty_n," .. WH'ks follow,nlo: Idl intrrn,,1 c"rulld ...lero,,1 ,"]('("1'0" of BCNU An arU of Nrly '~I,n,,1 n~oV"loCU· 1""UI,,'n It"p uJ:hl\ is "ss<x,at~d w'lh a v,lr«J"S h~m"trhal:~ [arly rubtos's of Iht iriS and n~ova~cularoutionof Ih.... nt~"or angl~s wtr~ pr~stnt ..Iltl~ time of Ih,~ pholo~r..ph with eddy retindl neovdsculdriulion inferiordlly dnd an associdled vitreous hemorrhdge (Fig, 6). Ophthdlmodyndmometry values were 75/35 in the right eye and 75/30 in the left eye. Cdrotid artery pulsations were equal 10 palpation bilaterally and no cervical bruits were hedrd on auscultation. Panretinal photocoagulation therapy in the left eye. was perfonned for his edTly oculdr neovdsculdrization and glaucoma. This patient has now been followed 9 months since intracarotid BCNU infusion and remains neurologically intdct except for the left eye, dlthough his seizure disorder has been more difficult to control. Discussion BCNU (Cannustine or 1,3-bis [2-chloroethyl]-Initrosourea) is a chemotherapeutic agent Iholt interfen~ s with DNA, RNA, and protein synthesis. Advantages of this alkylating dgl"nt in mana~ement of central nervous system nl"OpliiSid Me its lipophylic properties, electrical neutrollity, dnd rel.1tively sm.all moleculiir weight tholt ollIow reoldv penetriltion through th{' blood-brdin (olnd bl~ll,d~ retindl) barriers." If dcute retinoll toxicity hold ~'l'curred, his severe visual loss would h,lve been expected soon after intrd-drterial injection l,f BCNU. Therapeutic effects of BCNU on centroll nervous system neopldsid dre often presl"nt 4-5 weeks following injection. Th{' r{'tinJS of six rhesus monkeys 4-5 weeks followin~ n'ncentr.llions of intracMotid BCNU similar 10 Ihdt used in this patl('nt WNe normoll to li~ht microscopy.~ In (lur pilti{'nt signs of increJsed v,lsculJr penne., 1,,1'1'.' w,thin the di..tribulwn of the l'phthillmic artery occurred immediiltely, and this periorbital edema and coniunctival injection did not completely resolve for 12 weeks. Diffuse macular and disc edema was Visudlized during the fifth week dnd WdS accompanied by scattered flame-shaped hemorrhages, cotton wool exudates, and narrowing of retinal peripapillary arterioles at 10 weeks. In 19 weeks, fluorescein dngiographic evidence of retinal capilluy nonpl"rfusion was prl"sent within the distal supply of the tl"mporal peripapillary arterioles. By 29 weeks, early neovasculMiziition involving the posterior pole and anterior segment of the eye WdS identified. The constelliltion of ophthdlmologicdl symptoms and signs in our case reflects immediate vascular injury within the distribution of the ophthdlmic drt{'ry, with chronic ocular ischemia playing a major underlying role in his subsequent progressive ViSUd[ loss and ocular neovasculariution. The ocuIn blood supply may hdve been compromised by prolonged orbital edema or pdrtidl arterial thrombosis or occlusion. Vasculdr endothelial ddmdge following earlier radiation therapy to the left frontoll region may have been a filctor. Recurrent microembolizoltion to the eye remains iI possibility. In future patients. such permdnent oculdr sequdlde may be minimized by floilting smaller arterial catheters through the intrdCdvemous portion of the intemdl cilrotid drtery and beyond its first major branch, the ophthalmic artery. prior to infusion of chemotherdpeutic agents. However, the occurrence of an obvious encephalopathy, 10 weeks postBCNU infusion. strongly suggests that central nervous system toxicity will remain the limiting fdclor insofilr as dosdge with regiondl BCNU infusion is concerned. References I. Ydmada. K., et .II., Intra_arttna.1 BCNt; therapy in the lre.llmenl of metdstdlic bra.in tumor from lung c.Hcinoma. Cmcer,w: .!OOO-.!OO7, 1979. .!. A\·elldnosa.. A.M.. et dL Trea.tment of maligna.nt Cenlrol] ner....ous system gliomdS by intrJ-drttridl BCNU infUSion. Proc. Am. Cmcer Res. 20: 354, lQ7Q. .\. Wasstrmoln. T.H .. tt oiL Climedl eompuison of tht nitroS(lurt.ls. Cmcer 36: 1258-1268, 1975. ~. Crolfts. D.. levin. V.. and Nielsen, S., lntracdrolid BCNU (NSC-~()QQo.!I, A to"'icity study in six rhesus monl..eys. C.mcer TrE',lt. Rep. 60: 541-5~5. 1976. Acknowledgment This work WdS supported in p.art by Public Health Services Research Grant #RR-46 from the Gener.al CliniColl Reseolrch Center's brJnch of the Division of Research Rtsources. WritE' for reprints to: BS Grimson, M,D., University of North Cuolina. School of Medicine, 617 Clinic.al Sciences BUilding, ll9 H, Chdpel Hill, North Cuolind l7514. Joumdl of CHnicdl Neuro-ophlhdlmology |
