Characterizing ethambutol-induced optic neuropathy with a 3D computer-automated threshold Amsler grid test REFERENCES. 484 Letters to the Editor

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1 CEO Letters to the Editor Tking the dvnced stge of the disese with systemic metstses into considertion, pllitive surgery to preserve vision in the only eye ws performed. The lterl mid-fcil pproch included osteotomy of the lterl oritl wll nd the zygom. Upon opening the periorit, the rown tumour infiltrting the muscle ws visile. The optic nerve nd its nutritive vessels were completely preserved. The lterl rectus tendon ws then severed through liml incision. After sutotl removl of the metstsis nd the rectus superior muscle, stright position of the eye ws restored using 1-mm silicone tue. Through two urr holes, this tue ws fixed to the lterl oritl wll. The tue ws then threded through the empty pulley, tht is, the hole in Tenon s cpsule, which remined fter the lterl rectus muscle ws removed. The tue ws sutured to the former insertion site of the lterl rectus muscle (Fig. 3). In this wy the gloe ws positioned in n duction of pproximtely 5. After surgery, chemosis rpidly disppered nd visul cuity recovered up to.63 within 2 weeks. The visul field ws not impired. Upgze ws reduced to 15, duction to 5 ; nd dduction ws possile up to 1. The histopthologicl findings verified the dignosis of mlignnt melnom, which correltes to the primry tumour. Systemic metstses of choroidl melnom predominntly pper in the liver. Lung, one, skin nd lymph nodes re often involved, mostly in ptients with liver metstses. Our ptient lso hd liver, lung nd lymph node metstses efore the oritl metstsis. Metsttic melnom of the orit, in contrst to recurrence of melnom in the ipsilterl orit due to extrsclerl seeding of the tumour, develops in the terminl stges of the disese. The life expectncy of the ptient is short, nd therefore tretment should e pllitive. 2 Rdiotherpy is n ccepted tretment for introculr tumours. 4,5 In literture, rdiotherpy is descried s tretment for similr cses with ilterl choroidl melnom. 6 In our ptient, we decided to decompress the optic nerve y removing the tumour. A xenotrnsplnt ws used to reposition the eye. We pplied method similr to the one descried y Kolling for tretment of 6th nerve plsy, 7 nd comprle to the recently descried periostel nchor of the medil rectus for tretment of 3rd nerve plsy. 8 Hummelsheim trnsposition ws discussed s n lterntive. This would, however, hve included significnt risk of ischemi in our cse, owing to the interruption of nterior ciliry vessels of three neighouring rectus muscles. Heidrun Schf MD, 1 Philipp Streckein DDS, 1 Sestin Schmidt MD, 2 Hns-Peter Howldt MD PhD 1 nd Michel Gräf MD PhD 2 Deprtments of 1 Orl nd Mxillofcil Plstic Surgery nd 2 Ophthlmology, University of Giessen Mrurg GmH, Cmpus Giessen, Germny Received 21 Jnury 8; ccepted 17 April 8. Figure 3. Digrm showing silicon tue, which ws fixed to the lterl oritl wll, then directed through the empty pulley in Tenon s cpsule nd sutured to the former insertion site of the lterl rectus muscle. REFERENCES 1. Singh AD, Tophm A. Incidence of uvel melnom in the United Sttes: Ophthlmology 3; 11: Zogrfos L, Ducrey N, Beti D et l. Metsttic melnom in the eye nd orit. Ophthlmology 3; 11: Shields JA, Shields CL, Shkin EP, Koetz LE. Metstsis of choroidl melnom to the contrlterl choroid, orit, nd eyelid. Br J Ophthlmol 1988; 72: Bell DJ, Wilson MW. Choroidl melnom: nturl history nd mngement options. Cncer Control 4; 11: Dwson E, Sgoo MS, Meht JS, Comer R, Hungerford J, Lee J. Strismus in dults with uvel melnom following episclerl plque rchytherpy. J Apos 7; 11: Furut M, Shields CL, Uysl Y, Shields JA. Bilterl primry choroidl melnom treted with ilterl plque rdiotherpy: report of three cses. Eur J Ophthlmol 6; 16: Kolling GH. [Therpy of ducens nerve prlysis.] Ophthlmologe 1; 98: Sxen R, Sinh A, Shrm P, Pthk H, Menon V, Sethi H. Precrunculr periostel nchor of medil rectus, new technique in the mngement of complete externl third nerve plsy. Orit (Amsterdm, Netherlnds) 6; 25: 5 8. Chrcterizing ethmutol-induced optic neuropthy with 3D computer-utomted threshold Amsler grid test Ethmutol is commonly used in tretment ginst tuerculosis nd Mycocterium vium complex infections. Optic nerve toxicity is mong the more serious dverse effects ssocited with ethmutol use nd occurs in 6% of ptients tking the drug. 1,2 8 The Authors Journl compiltion 8 Royl Austrlin nd New Zelnd College of Ophthlmologists

2 CEO 17 Letters to the Editor 485 Figure 1. Colour fundus photogrphs showed very sutle temporl pllor OU with mild reduction of fires in the ppillomculr undle region OU, () right nd () left eyes, respectively. OU, oth eyes. Ethmutol-induced optic neuropthy mnifests s decresed visul cuity, diminished colour vision nd contrst sensitivity, nd centrl scotom. 3 As oculr toxicity is dose- nd durtion-dependent, prompt recognition of declining visul function nd erly cesstion of ethmutol therpy is importnt in preventing further progression of vision loss. 2 Current stndrd methods for monitoring ethmutol use include visul cuity ssessment, visul field testing, funduscopy, nd most sensitive, colour vision testing. However, these tests my not detect erly, sutle chnges in vision nd remin non-specific. The pthophysiology of ethmutol-induced optic neuropthy is uncler. One possile explntion for vision loss is tht ethmutol cheltes copper in the retinl gnglion cells nd their fires in the optic nerve. This decreses the levels of copper ville for cytochrome C-oxidse in the electron trnsfer chin, leding to mitochondril insufficiency nd impired xonl trnsport in the optic nerve. 4,5 Ppillomculr undle fires re prticulrly ffected in ethmutol-induced optic neuropthy. 6 We pplied 3D computer-utomted threshold Amsler grid testing (3D-CTAG), 7,8 to guge visul function in ptient with ethmutol-induced optic neuropthy. A 71-yer-old womn reported colour defects nd decresed visul cuity 2 months fter inititing ethmutol tretment for Mycocterium vium infection. The ptient hd een tking ethmutol t dose of 1 mg/dy (24 mg/kg/dy) for 2 months when she first noticed diminished green colour perception nd difficulty reding. The symptoms progressively worsened, up to the ptient s first clinic visit. The ptient hd no prior ophthlmologic illness nd hd 6/6 corrected vision oth eyes (OU) efore eginning ethmutol. On exmintion, the ptient hd est corrected visul cuity of 6/6 right eye (OD) nd 6/ left eye (OS). The ptient hd decresed colour vision ilterlly, scoring 4.5/8 OD nd 5/8 OS on Ishihr pseudoisochromtic colour pltes. The ptient descried sense of decresed rightness OD compred with OS. Pupils were equl, round nd rective to light with no fferent pupillry defects. Slit-lmp exmintion ws unremrkle. Funduscopy reveled shrply delineted optic discs with sutle temporl pllor OU (Fig. 1). Visul fields were ssessed y Humphrey Visul Field 3 2 (SITA Fst) test (fovel sensitivity of 33d; Fig. 2), tngent screen t three feet nd stndrd Amsler grid. All showed norml visul fields Conflict or commercil interest: Drs Fink nd Sdun my hve proprietry interest s ptents on the 3D computer-utomted threshold Amsler grid test technology used in this study re issued. Dr Kim, Dr Fhimi, Dr Nzemi nd Dr Nguyen hve no proprietry interest. OU. The ptient ws recommended for ssessment vi 3D-CTAG. USC IRB pprovl ws otined. Alredy successfully used in severl clinicl pilot studies, 9,1 3D-CTAG displys grid upon lck computer screen t series of user-defined gryscle (i.e. contrst) levels. While mintining their gze on centrl fixtion mrker, ptients trce scotoms directly on the touch screen for ech contrst level. The contrst levels nd the ngulr resolution (i.e. sptil frequency) of the grid cn e defined for ech testing session. The sme cthode ry tue monitor ws exclusively used for ll testing with n unchnged rightness/luminnce setting. To ensure stility, the monitor ws turned on t lest 3 min prior to the testing sessions. The ptient ws presented with grid lines.5 prt s opposed to the 1 spcing of stndrd Amsler grid, t five progressively higher levels of contrst (%, 4%, 6%, %, 1%). Ech eye ws tested seprtely. The results of ech tested level were recorded nd fterwrds displyed s 3D depiction of the centrl hill-of-vision (i.e. 25 rdilly from fixtion), oth s topogrphicl contour rings nd 3D wire digrms. Ares of % contrst sensitivity corresponded to the inility of the ptient to recognize n Amsler grid t 1% contrst difference, nd res of 1% contrst sensitivity to the ility to recognize it t the lowest preset contrst, tht is, the drkest grid. 9,1 3D-CTAG with.5 grid spcing reveled reltive scotoms tht hd een missed oth y stndrd visul field testing methods nd 3D-CTAG with 1 grid spcing: Figure 3 shows visul field defects predominntly in the centrl nd temporl regions, ilterlly. The 3D depictions of visul field loss demonstrte step-like pttern with incresing scotom re s grid contrst pproches zero. The ethmutol ws discontinued, nd the ptient s condition ws ressessed two months lter. The ptient hd mild improvement in colour vision, scoring 5/8 OD nd 6/8 OS on pseudoisochromtic colour pltes. Visul cuity improved to 6/18 OD nd 6/12 OS. A yer fter the initil dignosis, the ptient showed excellent recovery of visul function with norml colour vision nd visul cuity of 6/7.5 OU. This recovery of function my spek more to retinl nerve fire lyer dysfunction rther thn n solute loss. Using 3D-CTAG, we were le to distinguish visul field deficits consistent with ethmutol-induced optic neuropthy. Due to its greter sensitivity 3D-CTAG my revel smll depressions, which re vrints of norml (i.e. lesser specificity). However, 3D-CTAG conducted t.5 grid spcing detected lrge-scle field defects not found on Humphrey Fisul Field 3-2 test, tngent screen perimetry, nd conventionl Amsler grid. This selective impirment of higher sptil frequency function suggests tht currently used lower frequency tests my not e sensitive enough to detect ethmutol toxicity. 8 The Authors Journl compiltion 8 Royl Austrlin nd New Zelnd College of Ophthlmologists

3 CEO Letters to the Editor Figure 2. Norml Humphrey Visul Field 3-2 (SITA Fst) test t fovel sensitivity of 33d for () right nd () left eyes, respectively. The pttern of ethmutol toxicity of ilterl visul cuity loss nd diminished colour nd contrst sensitivity, long with its predominnt involvement of the ppillomculr undle, strongly support metolic etiology ssocited with mitochondril dysfunction. 6 As in other mitochondril optic neuropthies, the ppillomculr undle is preferentilly sensitive in ethmutol toxicity. It is composed of smller prvocellulr xons tht fire more frequently yet hve fewer mitochondri. 6 These P cells detect chnge t higher sptil frequencies. Tht the scotoms were detected only t higher sptil frequency of.5 versus 1 grid spcing is consistent with P cell dysfunction. In our ptient, 3D-CTAG identified pttern of visul field loss consistent with ethmutol-induced optic neuropthy tht ws not detected using stndrd visul field tests. 3D-CTAG my e useful complement to stndrd exmintion methods for erly detection, ccurte evlution nd monitoring of ethmutol toxicity. Further studies re needed for vlidting 3D-CTAG s screening tool. Jnet K Kim MD, 1 Ali Fhimi MD, 1 Wolfgng Fink PhD, 2,1 Pul P Nzemi MD, 1 Dieuthu Nguyen MD, 1 nd Alfredo A Sdun MD PhD 1 1 Doheny Eye Institute nd Keck School of Medicine t the University of Southern Cliforni, Los Angeles, nd 2 Visul nd Autonomous Explortion Systems Reserch Lortory, Division of Physics, Mthemtics nd Astronomy, Cliforni Institute of Technology, Psden, Cliforni, USA Received 11 Jnury 8; ccepted 28 My 8. 8 The Authors Journl compiltion 8 Royl Austrlin nd New Zelnd College of Ophthlmologists

4 Letters to the Editor 487 Contrst sensitivity/[%] X/[deg] Y/[deg] Contrst sensitivity/[%] X/[deg] Y/[deg] Figure 3. 3D computer-utomted threshold Amsler grid testing results. At lower levels of contrst, Amsler grid lines pper finter on lck ckground, llowing unmsking of sutle field defects. This tests for high contrst sensitivity. At 1% contrst, Amsler grid lines re white on lck ckground nd test for low contrst sensitivity. The red regions represent the grid res visile to the ptient, plotted over the x/y (i.e. horizontl/verticl) plne of the visul field. This resemles terrestril contour mp with contour rings, where higher ltitudes indicte etter contrst sensitivity nd the vlleys demonstrte depressed contrst sensitivity. The stepwise slopes represent stges of impired contrst sensitivity, which ecome worse towrds the temporl visul field of () right nd () left eyes, respectively. REFERENCES 1. Brron GJ, Tepper L, Iovine G. Oculr toxicity from ethmutol. Am J Ophthlmol 1974; 77: Leiold JE. The oculr toxicity of ethmutol nd its reltion to dose. Ann NY Acd Sci 1966; 135: Frunfelder FW, Sdun AA, Wood T. Updte on ethmutol optic neuropthy. Expert Opin Drug Sf 6; 5: Kozk FS, Inderlied CB, Hsu HY, Heller KB, Sdun AA. The role of copper on ethmutol s ntimicroil ction nd implictions for ethmutol-induced optic neuropthy. Dign Microiol Infect Dis 1998; 3: Sdun AA. Metolic optic neuropthies. Semin Ophthlmol 2; 17: Crelli V, Ross-Cisneros FN, Sdun AA. Mitochondril dysfunction s cuse of optic neuropthies. Prog Retin Eye Res 4; 23: The Authors Journl compiltion 8 Royl Austrlin nd New Zelnd College of Ophthlmologists

5 488 Letters to the Editor 7. Fink W, Sdun AA. Novel 3D Computerized Threshold Amsler Grid Test, Perimetry Updte 2/3. Proceedings of the XVth Interntionl Perimetric Society Meeting in Strtford Upon Avon, Englnd, June, 2. Amsterdm/New York: Kugler Pulictions v, 2, pp Fink W, Sdun AA. Three-dimensionl computer-utomted threshold Amsler Grid Test. J Biomed Opt 4; 9: Nzemi PP, Fink W, Lim JI, Sdun AA. Scotoms of ge-relted mculr degenertion detected nd chrcterized y mens of novel three-dimensionl computer-utomted visul field test. Retin 5; 25: Nzemi PP, Fink W, Sdun AA, Frncis B, Minckler D. Erly detection of glucom y mens of novel 3-D computerutomted visul field test. Br J Ophthlmol 7; 91, doi: /jo Bilterl nterior optic neuropthy ssocited with use of terinfine Terinfine is n ntifungl drug used to tret onychomycosis of toenil nd fingernil. Severl side-effects hve een ssocited with its use, including systemic lupus erythemtosis, 1 generlized pustulr psorisis 2 nd development of green vision. 3 To our knowledge, optic neuropthy hs not een previously recognized. Herein we report ptient who developed ilterl optic disc swelling during orl terinfine therpy for onychomycosis. The 43-yer-old mn hd noticed decresed vision of the right eye (OD) 2 months fter strting terinfine hydrochloride (Lmisil, Novrtis, Istnul, Turkey). Two weeks lter, the vision of the left eye (OS) ws lso ffected. He hd neither significnt hedche nor other neurologicl symptoms. The ptient ws using only terinfine HCl on high dose (5 mg/dy insted of 25 mg) for onychomychosis s systemic mediction. There ws no history of ingestion of toxins like lcohol or tocco. The visul cuities (VA) of the OD nd OS were.8 nd 1, respectively, on the Snellen chrt. He could detect eight figures OD nd 12 figures OS from 12 Ishir colour pltes y the OD. Fundus exmintion reveled ilterl low-grde disc oedem: Frisen scle stge 1 for OD (Fig. 1) nd for the OS (Fig. 1). Lumr puncture (LP) ws plnned, ut the ptient refused the procedure. One month fter first dmission, the ptient presented with VA of.3 in oth eyes (OU). The pupillry light reflexes were wek in OU, ut colour vision ws 6/6. The right optic disc ws slightly ple (Frisen stge 2; Fig. 1C) nd the left one ws oedemtous with splinter hemorrhge on the superior pole (Frisen stge 4; Fig. 1D). The visul fields y Humphrey Visul Field Anlyzer of OU were concentriclly constricted (Fig. 2). The fundus fluorescein ngiogrphy of OU ws norml except for the lekge eyond the optic disc mrgins. His lood pressure ws norml. Intrcrnil pressure ws not elevted which ws mesured s 1 mm H 2O during the LP. The MRI, MRA nd MRV were ll within norml limits. The results of spinl fluid nd serum iochemistry were not significnt. The chest X-ry, serum ACE, vitmin B 12 levels, PPD, sputum nd smer were within norml limits. The lyme, Brtonell nd virl serologies in serum were ll norml. The titres of the utontiodies specific for lupus, scleroderm, polymyositis, dermtomyositis nd Wegener s grnulomtosis were not signifying n utoimmune pthology. The only systemic mediction, terinfine which ws found out to e used t reltively high dose ws stopped nd the ptient ws followed for 8 dys. He ws dischrged with VA of.5 in OU. Five dys lter, the vision ws.8 OU. Right optic disc oedem hd resolved nd the temporl side of left optic disc ws slightly oedemtous. One month lter, the VA ws gin.8 OU nd the orders of oth optic nerves were regulr with slight pllor of the left optic disc (Fig. 1e,f for OD nd OS respectively) nd the visul fields of OU were still concentriclly constricted. Severl drugs including miodrone 4 nd perhexilene mlete 5 my cuse toxic optic neuropthies with disc oedem. 4 In cses with ilterl optic disc oedem nd slight VA nd visul field chnges, it is importnt to exclude incresed intrcrnil pressure y LP. Our ptient did not report ny hedche nd he hd norml intrcrnil pressure, cererospinl fluid iochemistry nd norml serologicl mrkers. His colour vision ws not ffected mrkedly. In toxic optic neuropthies, s the ppillomculr undle is preferentilly ffected, usully centrl visul field defects re reported though some exceptions. 6 A possiility of retinl toxicity with mild disc oedem my lso e expected ccording to these oservtions. Optic disc oedem my cuse generlized constriction of the visul field s in our ptient. Norml MRI, lck of pin nd the slow progression of the visul loss were not in fvour of demyelinting optic neuropthy. When we nlyse Hill s criteri 7 for cuslity of drug effect in this cse, we oserve temporl reltion nd cliniclly resonle response on withdrwl (de-chllenge) of terinfine. However, with just one oserved cse, the strength, consistency nd Figure 1. At presenttion ilterl low-grde disc oedem ws oserved: Frisen scle stge 1 for right eye () nd for the left eye (). One month fter first dmission slightly ple right optic disc (Frisen stge 2) (c) nd oedemtous left one with splinter hemorrhge on the superior pole (Frisen stge 4) (d). One month fter dischrge from hospitl the orders of oth optic nerves were regulr with slight pllor of the left optic disc (e: right eye; f: left eye). 8 The Authors Journl compiltion 8 Royl Austrlin nd New Zelnd College of Ophthlmologists