Changes in the retinal-nerve-fiber layer due to ethambutol toxic optic neuropathy

Transcription

1 VOL. 34 NO. 1 PHILIPPINE JOURNAL OF Ophthlmology JANUARY CASE REPORT JUNE 2009 Christopher Npoleon G. Delos Reyes, MD 1 John Michel L. Dquiog, MD 1 Milgros H. Arroyo, MD, MPH 1, 2 Sidney Y. Cheng, MD 1 Heriberto G. Gubll, MD 1 Richrd C. Kho, MD 1, 2 1 Deprtment of Ophthlmology The Medicl City Psig City, Philippines Chnges in the retinl-nerve-fiber lyer due to ethmbutol toxic optic neuropthy 2 Deprtment of Ophthlmology nd Visul Sciences Sentro Oftlmologico Jose Rizl University of the Philippines Philippine Generl Hospitl Mnil, Philippines ABSTRACT Objective To describe chnges in the retinl-nerve-fiber lyer (RNFL) in ptients dignosed with ethmbutol toxic optic neuropthy (ETON) using opticl coherence tomogrphy (OCT). Methods Ophthlmologicl exmintions were performed in 3 ptients dignosed with ETON. Visul cuity (VA), contrst sensitivity, color vision testing, slitlmp exmintion, pplntion tonometry, dilted funduscopic exmintion, fundus nd disc photogrphy, utomted perimetry, nd OCT were performed. Results Three ptients with ETON hd VA rnging from 20/150 to counting fingers (CF). They were unble to resolve contrst sensitivity nd discriminte colors. Two ptients with VA of CF in both eyes hd RNFL thinning of 48.8% nd 49.5%. A third ptient 3 with VA of 20/150 in both eyes showed RNFL thickening of 14.10%. Correspondence to Christopher Npoleon G. Delos Reyes, MD Deprtment of Ophthlmology The Medicl City Ortigs Avenue, Psig City Metro Mnil, Philippines Telephone : ext E-mil : dcky_boy@yhoo.com Conclusion The results suggest tht OCT my be useful ncillry procedure in erly detection nd monitoring of ophthlmologicl chnges due to ETON. Keywords: Ethmbutol toxic optic neuropthy, Retinl-nerve-fiber lyer, Opticl coherence tomogrphy, Tuberculosis The uthors hve no proprietry or finncil interest in ny product used or cited in this study PHILIPP J OPHTHALMOL 2009; 34(1): PHILIPP J OPHTHALMOL VOL 34 NO. 1 JANUARY - JUNE

2 SINCE its introduction in 1961, ethmbutol (EMB) hs often been ssocited with EMB toxic optic neuropthy (ETON). 1-7 ETON is estimted to hve n incidence of 1 to 5% mong EMB users, even t the recommended dose of 15 mg/kg/bw. 1, 3, 8-9 The incidence in the Philippines cn be clculted t 6,000 per yer bsed on 134,000 cses under directly observed therpy short-course (DOTS) 4, therpy. In ETON, bilterl, insidious, nd ner symmetric loss of visul cuity is the rule. The fundus commonly shows no remrkble findings. Optic nerves re initilly norml but my grdully trophy. The more common visulfield mnifesttion is centrl or cecocentorl scotom. Less commonly, bitemporl defects or peripherl constriction my develop. Involvement of the centrl fibers of the optic nerve leds to loss of red or green color vision. It hs been reported tht mjor blue-green vision errors occur s n erly sign of ethmbutol-induced optic neuropthy in ptients with norml cuity nd no visul 1, 13, 16, 21 symptoms. Using opticl coherence tomogrphy (OCT,) Zoumln et l. 12 showed significnt thinning in the retinl-nervefiber lyer (RNFL) in 3 ptients with ethmbutol-induced optic neuropthy. Chronic visul loss ws ssocited with greter RNFL thinning. They noted predominnt involvement of the RNFL in the temporl qudrnt with men loss of 72% of the nerve-fiber lyer. In this study we described 3 ptients with ETON nd finding of chnges in RNFL thickness. METHODS Three ptients who were treted with qudruple nti- Koch s therpy (including EMB within the therpeutic mximl sfe dosge of 15mg/kg/dy) were included in this study. Slitlmp biomicroscopy, pplntion tonometry, nd dilted funduscopic exmintion by indirect ophthlmoscopy were done. None of the ptients hd ny significnt ctrcts or nterior-segment chnges to preclude exmintion of the posterior pole. None hd glucom, other retinl pthologies, or cliniclly detected optic-nerve bnormlities. Best-corrected visul cuity (BCVA) ws determined using Snellen optotypes. Contrst sensitivity ws tested per eye t dim lighting using the CSV-1000 test. Color-vision testing ws performed using Frnsworth Munsell 100 Hue (Pul Grdner Co., Pompno Bech, FL, USA) test under the illumintion of 2 Philips fluorescent tubes (Philips, Eindhoven, The Netherlnds) color 57, plced 1.2 meters bove the test tble. These exms were done with undilted pupils by one exminer. Ech eye ws tested seprtely. Visul-field exmintion ws performed by single exminer using the Humphrey Field Anlyzer II (Crl Zeiss Meditec Inc., Dublin, CA, USA) using the centrl 30-2 threshold test progrm with dilted pupils. Initil fundus nd optic-nerve photogrphs were tken fter dilted funduscopic exm using Topcon TR-50X retinl cmer (Topcon, Fotn, Hong Kong). OCT ws performed using the Zeiss Strtus OCT 3000 (Crl Zeiss Meditec Inc., Dublin, CA, USA) RNFL nlysis protocol. The verge of three good-qulity mesurements for ech eye ws tken by single opertor nd the men RNFL vlue ws clculted in ech qudrnt (superior, inferior, temporl, nd nsl) nd twelve 30 o segments by the OCT softwre. CASE REPORTS Cse 1 A 70- yer- old mle noted blurring of vision of both eyes 5 months fter beginning qudruple nti-koch s therpy. Vision further deteriorted prompting consulttion on the ninth month. Visul cuity of both eyes t the time of presenttion ws counting finger (CF) t 1 foot with no subsequent improvement on follow-up exms. Cse 2 A 65-yer-old mle experienced deteriortion of vision of both eyes 6 months fter initition of qudruple nti- Koch s therpy. Visul cuity deteriorted to CF 3 months before the ptient consulted 2 yers fter discontinution of nti-koch s medictions. VEP done yer fter reveled severe conduction dely long the visul pthwys. No improvement of visul cuity ws noted on subsequent follow-ups. Cse 3 A 49-yer-old femle underwent qudruple nti-koch s therpy from August to November She complined of grdul decrese in vision described s centrl blurring in both eyes on the third month of tretment. Ethmbutol ws discontinued nd she ws mintined on triple nti- Koch s. BCVA deteriorted to 20/150 in both eyes despite discontinution of EMB. She consulted four months fter initition of nti-koch s tretment. RESULTS All ptients showed inbility to resolve the sptil frequencies t 3, 6, 12, nd 18 cycles per degree on contrst-sensitivity testing. Likewise, only ptient 3 ws ble to undergo Frnsworth Munsell 100 Hue test since ptients 1 nd 2 were unble to identify ny of the colors. Visul-cuity, contrst sensitivity, IOP, color perception, visul fields, nd fundus/disc findings re shown in Tble 1. Ptients 1 nd 2 experienced decrese in visul cuity to CF on the ninth month nd second yer respectively fter initition of qudruple nti-koch s 24 PHILIPP J OPHTHALMOL VOL 34 NO. 1 JANUARY - JUNE 2009

3 tretment. Ptient 3 hd decresed visul cuity on the fourth month of tretment with BCVA of 20/150. Tonometry ws within norml limits for ll ptients. All ptients were unble to resolve contrst-sensitivity, colorperceptul, nd visul-field tests. All showed typicl norml fundus. Ptients 1 nd 2 hd slight optic-nerve pllor. The RNFL thickness decresed in ll qudrnts in ptients 1 nd 2, both of whom hd profound vision loss (Tble 2). Ptient 3, however, showed slightly incresed RNFL thickness over the nsl nd inferior qudrnt of the right eye, nd temporl nd inferior qudrnts of the left eye (Tble 2). Vision loss ws greter in ptients 1 nd 2 (CF) thn ptient 3 (20/150) t the time of consulttion (Figure 1). Averge RNFL thickness showed decrese in ll qudrnts in ptients 1 nd 2 nd in 2 qudrnts per eye in ptient 3 (Tbles 2 nd 3). DISCUSSION As EMB is derivtive of butnol, 6,13 the mechnism of dmge in ETON is similr to tht of lcohol-induced toxic Tble 1. Ophthlmologic exms in 3 ptients dignosed with ethmbutol toxic optic neuropthy (ETON). Ophthlmologic Exm Time of consulttion Visul cuity Contrst sensitivity Tonometry Frnsworth-Munsell 100 hue test Visul-field exm Fundus/Disc photos Ptient 1 8th month from intke OD: CF 1 ft OS: CF 1 ft Cnnot resolve No color discrimintion Cn t locte points Norml fundus/ ple optic disc Ptient 2 2 yers from intke OD: CF OS: CF Cnnot resolve No color discrimintion Cn t locte points Norml fundus/ temporl disc pllor Tble 2. Retinl-nerve-fiber-lyer thickness (µm) nd percent loss. mblyopi nd includes demyelintion of the optic nerve, chism, nd trct Another mechnism of ETON described in 1975 explined tht EMB together with its metbolite, ethylenediiminodibutyric cid, 6 my be involved in the trnsformtion of metl ions into chelting gent leding to decresed levels of copper, iron, nd other metls ssocited with the cytochromes of the mitochondri. 4, 6, 17-18, In prticulr, EMB ppers to chelte the copper ions of cytochrome C oxidse within the optic-nerve xons. 6, 29 Without sufficient copper, cytochrome C oxidse is unble to trnsport electrons for pproprite ATP production. With decresed ATP levels, decrese in xonl trnsport of mitochondri distlly from the neuronl som ensues. This vicious cycle my led to energy depletion with subsequent xonl swelling. 24 It is theorized tht the increse in RNFL thickness in the inferior nd nsl qudrnts of ptient 3, could be due to this initil xonl swelling. After this initil swelling, ppillomculr-bundle-nerve necrosis nd optic-disc chnges follow, similr to those seen in Leber s hereditry optic Ptient 3 4th month from intke OD: 20/50 OS: 20/50 Cnnot resolve Poor color discrimintion Centrl scotom Norml fundus/ norml disc color neuropthy (LHON), mitochondril DNA-inherited disorder. This mitochondril insufficiency leds to poptosis (progrmmed cell deth) nd neuron loss. 31 Neuronl-cell deth would be mnifested s RNFL thinning nd would subsequently mke this ultrstructurl chnge detectble by OCT. Bsed on this proposed pthophysiologic mechnism, it is possible tht the RNFL thinning in ptients 1 nd 2, who consulted on their eighth nd sixth month of tretment respectively, could be due to this poptotic phenomenon. Ptient (Visul Acuity) OCT mesurement of RNFL thickness (µm) OD OS Temporl Superior Nsl Inferior Temporl Superior Nsl Inferior Averge Thickness nd Percent Chnge Ptient 1 (CF) Percent loss Ptient 2 (CF) Percent loss Ptient 3 (20/150) Percent chnge Totl verge thickness Totl verge % loss Norml ± ± ± ± ± ± ± ± ± 11 Denotes RNFL thickness increse. PHILIPP J OPHTHALMOL VOL 34 NO. 1 JANUARY - JUNE

4 Tble 3. Averge retinl-nerve-fiber-lyer thickness (µm) nd verge percent loss per qudrnt. Retinl-nerve-fiberlyer thickness (µm) per qudrnt Averge RNFL thickness (µm) per qudrnt Averge % loss per qudrnt Figure 1. Temporl Superior Nsl Inferior Visul cuity nd retinl-nerve-fiber-lyer thickness Furthermore, the initil incresed thickness of the RNFL in ptient 3 my be expected to slowly decrese with time. Like LHON, ETON ffects the ppillomculr bundle of the RNFL, which explins why generlized/diffuse optic-nerve-hed chnges of pllor re infrequently seen. 4, 6, 12, 15 Only ptient 1, who ws on 8 months of nti- Koch s therpy, showed more diffuse optic-nerve pllor. At the sfe dose of 15 mg/kg/dy, EMB remins prt of the first-line qudruple nti-tb therpy recommended by the World Helth Orgniztion. Becuse tuberculosis remins prevlent in the Philippines, rnking ninth worldwide in terms of prevlence, 10 EMB will continue to be used nd the risk for visul loss from ETON remins. Like those of Zoumln et l, 12 the results of this study suggest tht OCT my be useful ncillry procedure in detecting ETON. The use of OCT my be expnded to monitor progression of the disese once ptients re plced on qudruple nti-koch s therpy. A study with bigger smple needs to be undertken to strengthen our findings of RNFL chnges (thickening followed by thinning) in ptients dignosed to hve ETON. We lso need to evlute the possibility of including OCT s prt of the routine bseline nd monthly evlution s recommended by the WHO 3,11, 15 to detect ETON before the onset of potentilly irreversible visul symptoms. References 1. Roberts SM. Oculr toxicity of ethmbutol hydrochloride: n ntituberculous drug. Am J Optom nd Physiol Optics 1974; 51: Schmidt IG, Schmidt IH. Studies on the neurotoxicity of ethmbutol nd its rcemte for the rhesus monkey. J Neuropth nd Ex Neurol 1966; 25: Citron KM. Editoril: oculr toxicity from ethmbutol. Thorx 1986; 41: Sivkumrn P, Hrrisson AC, Mrschner J. Oculr toxicity from ethmbutol: review of four cses nd recommended precutions. NZ Med J 1998; 13: Choi SY, Hwng JM. Optic neuropthy ssocited with ethmbutol in Korens. Kor J Ophthlmol 1997; 11: Kozk SF, Inderlied CB, Hsu HY, et l. The role of copper on ethmbutol s ntimicrobil ction nd implictions for ethmbutol-induced optic neuropthy. Mycobcteriology 1998; 30: Inocencio FP, Cstillo TR. Toxic optic neuropthy secondry to ethmbutol. Philipp J Ophthlmol 1999; 24: Crr RE, Henkind P. Oculr mnifesttions of ethmbutol. Arch Ophthlmol 1962; 67: Pyle MM. Ethmbutol in the retretment nd primry tretment of tuberculosis: four-yer clinicl investigtion. Ann New York Acd Sci 1966; 135: WHO/CDS TB Tretment of Tuberculosis: guidelines for ntionl progrmmes, 3rd revision pproved by STAG, June WHO Country Helth Informtion Profile, Philippines, Western Pcific Region Helth Dtbnk, 2004 Revision. 12. Zoumln CI, Agrwl M, Sdun A. Opticl coherence tomogrphy cn mesure xonl loss in ptients with ethmbutol-induced optic neuropthy. Grefe s Arch Clin Exp Ophthlmol 2005; 243: Chtterjee VK, Buchnn DR, Friedmnn AI, et.l. Oculr toxicity following ethmbutol in stndrd dosge. Br J Dis Chest 1986; 80: Kss I. Chemotherpy regimens used in retretment of pulmonry tuberculosis. Prt II. Observtions on the efficcy of combintions of ethmbutol, cpreomycin nd compnion drugs. Tubercle London 1965; 46: Brron FG, Tepper I. Iovine G. Oculr toxicity from ethmbutol. Am J Ophthlmol 1974; 77: Lee RK, Lee YS. Reversibility of ethmbutol optic neuropthy. J Oculr Phrm nd Therpeutics 1977; 13: De Vit EG, Mio M, Sdun AA. Optic neuropthy in ethmbutol-treted renl tubercuosis. J Clin Neuroophthlmol 1987; 7: Khn LM. Toxic oculr effects of ethmbutol. Cn Med Assoc J 1987; 137: Fledelius HC, Petrer JE, Skjedt K, et l. Oculr ethmbutol toxicity: cse report with electrophysiologicl considertions. Act Opthlmol 1987; 65: Nsemnn J, Zrenner E, Riedel KG. Recovery fter severe ethmbutol intoxiction: psychophysicl nd electrophysiologicl correltions. Doc Opthlmol 1989; 71: Kho RC, Arnold AC. Bitemporl heminopi in ethmbuol optic neuropthy. Jules Stein Eye Institute (submitted for publiction). 22. Schmidt IG. Centrl nervous system effects of ethmbutol in monkeys. Ann New York Acd Sci 1966; 135: Polk BC, Leys M, Vn Lith FH. Blue yellow color vision chnges s erly symptoms of ethmbutol oculotoxicity. Ophthlmologic Bsel 1985; 191: Noche RR, Nicols MG, Gonzg NC. A study of the evolution of optic neuritis cused by ethmbutol in rbbits. Philip J Microbiol Infect Dis 1987; 17: Melmud A, Kosmorsky G, Lee M. Oculr ethmbutol toxicity. Myo Clinic Proc 2003; 78: Russo PA, Chglsin MA. Toxic optic neuropthy ssocited with ethmbutol: implictions for current therpy. J Amer Opto Asso 1994; 65: Hrcombe A, Kinner W, Britton J, et l. Oculr toxicity of ethmbutol. Resp Med 1991; 85: De Plm P, Frnco F, Brglini G, et l. The incidence of optic neuropthy in 84 ptients treted with ethmbutol. Metb Peditr Syst Ophthlmol 1989; 12: Woung LC, Jou JR, Liw SL. Visul function in recovered ethmbutol optic neuropthy. J Phrmcol Ther 1995; 11: Lesell S. The histology nd histochemistry of the rt s optic nerve nd chism. Am J Ophthlmol 1977; 84: Yucel Y. Brin pthology in glucom nd neuroprotection. Oculr Surgery News 2004: p Shumn JS, Pulifito CA. Fujimoto J. Opticl Coherence Tomogrphy of Oculr Diseses, 2nd ed. Thorofre, NJ: Slck Inc Wollstein G, Schumn J, Price L, et l. OCT longitudinl evlution of RNFL thickness in glucom. Arch Ophthlmol 2005; 123: Kumr A, Sndrmouli S, Verm L, et l. Oculr ethmbutol toxicity: is it reversible? J Clin Neuroophthlmol 1993; 1: PHILIPP J OPHTHALMOL VOL 34 NO. 1 JANUARY - JUNE 2009

5 35. Leibold JE. Drugs hving toxic effect on the optic nerve. Int Opthlmol Clin 1971; 11: Kss I, Mndel W, Cohen H, et l. Isonizid s cuse of optic neuritis nd trophy. JAMA 1957; 16: Jimenez-Lucho VE, Del Busto R, Odel J. Isonizid nd ethmbutol s cuse of optic neuropthy. Eur J Respir Dis 1987; 71: Ormerod LP, for the subcommittee of the Joint Tuberculosis Committee. Guidelines. Chemotherpy nd mngement of tuberculosis in the United Kingdom: recommendtions of the Joint Tuberculosis Committee of the British Thorcic Society. Thorx 1986; 41: Leibold JE. The oculr toxicity of ethmbutol nd its reltion to dose. Ann NY Acd Sci 1966; 135: Leopold IH. Zinc deficiency nd visul impirment. Am J Ophthlmol 1978; 85: Kuksu Y, Adchi, U, Mizot A. Doc Ophthlmol 1987; 67: PHILIPP J OPHTHALMOL VOL 34 NO. 1 JANUARY - JUNE