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Show Structural-Functional Dissociation in Presumed Ethambutol Optic Neuropathy Daniel Masvidal, MD, Richard K. Parrish II, MD, Byron L. Lam, MD Abstract: A 55-year-old man with pulmonary Mycobacte-rium avium intracellulare infection developed decreased vision to 3/200 in the right eye, and 20/200 in the left eye, 11 months after starting ethambutol, rifampin, and isoniazid. A diagnosis of presumed ethambutol optic neuropathy was made, and the medications were dis-continued. Visual acuity gradually improved to 20/30 and 20/70 over a period of 34 months. Despite improved central vision and visual field, the patient developed progressive bilateral optic disc cupping, disc pallor, and diffuse nerve fiber layer loss on optical coherence to-mography. The observed optic nerve head structural changes in this patient did not correlate with the mark-edly improved visual function. Visual improvement may occur in ethambutol optic neuropathy despite progressive structural changes. Journal of Neuro-Ophthalmology 2010;30:305-310 doi: 10.1097/WNO.0b013e3181e08ecb 2010 by North American Neuro-Ophthalmology Society Ethambutol is an important oral medication in the treatment of Mycobacterium tuberculosis and is also used to treat infections due to the Myobacterium avium complex (1). In a review of 857 Korean patients treated with ethambutol, 1.5% of patients developed optic neuropathy attributable to ethambutol (2). Estlin and Sadun (3) per-formed a chart review and literature meta-analysis of a total of 70 cases and concluded that ethambutol optic nerve toxicity most likely occurs in patients with high-serum drug levels and is associated with renal risk factors or in those with a prolonged treatment course or both. Sadun and Wang (4) affirmed the importance of properly identifying patients who are at risk for toxicity; adjusting doses based on renal function, age, and weight; and monitoring regularly for early signs of toxicity. We report a patient with eth-ambutol optic neuropathy who had marked improvement of visual acuity and visual field after discontinuation of ethambutol despite the development of progressive bilateral optic disc pallor with cupping and loss of retinal nerve fiber layer (RNFL). CASE REPORT In June 2005, a 55-year-old African American man with no visual symptoms and a history of Mycobacterium avium intracellulare (MAI) pulmonary infection was evaluated for a baseline eye examination after the initiation of ethambutol therapy. His medical history included multiple in-tramuscular penicillin injections for primary syphilis as a teenager, previous ethanol abuse, lung cancer treated with lobe resection, and chronic obstructive pulmonary disease. Family history was negative for eye disease. The patient had received daily combination treatment consisting of 1800 mg ethambutol (26 mg/kg), 600 mg rifampin, and 300 mg isoniazid for 3 months for MAI infection. Renal function was normal with a serum creatinine of 0.9 mg/dL and blood urea nitrogen of 18 mg/dL. Best-corrected visual acuity was 20/15 in the right eye and 20/20 in the left eye. The patient accurately identified 10 of 15 and 11 of 15 Ishihara color plates in the right and left eyes, respectively. Pupillary re-actions were normal with no relative afferent pupillary defect. Intraocular pressures (IOPs) were 15 and 14 mm Hg with applanation tonometry, respectively. Automated perimetry (24-2 threshold, SITA-standard strategy, Humphrey Division, Zeiss, Dublin, CA) was normal. The patient was told of the importance of monitoring his vision and instructed to return to clinic immediately if he experienced visual loss. A follow-up visit was scheduled for 6 months. Bascom Palmer Eye Institute (DM, RKP, BLL), School of Medicine and Miami Children's Hospital, University of Miami Miller, Miami, Florida. D. Masvidal is visitor from Saint Luke's Episcopal Hospital, Ponce, PR. Supported by National Institutes of Health center grant P30- EY014801 and unrestricted grant to Bascom Palmer Eye Institute from Research to Prevent Blindness, Inc, New York, NY. Address correspondence to Byron L. Lam, MD, Bascom Palmer Eye Institute, 900 NW 17th Street, Miami FL 33136; E-mail: blam@med.miami.edu Masvidal et al: J Neuro-Ophthalmol 2010; 30: 305-310 305 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. The patient did not return until 1 year later (June 2006) and had developed progressive visual loss over 4 months. He had continued ethambutol, isoniazid, and rifampin with the dosage of ethambutol averaging 24 mg/kg per day. Sputum cultures for acid-fast bacilli were negative after 42 days. Visual acuity had decreased to 3/200 in the right eye and 20/200 in the left eye, and the patient could not identify any of the Ishihara color plates with either eye. Kinetic peri-metry demonstrated bilateral central field loss (Fig. 1A). He could not identify any Ishihara color plates. The IOP was 18 mm Hg in the right eye and 21 mm Hg in the left eye. The optic discs were normal in appearance (Fig. 2, top). Optical coherence tomography (OCT) demonstrated normal RNFL thickness in the right eye and moderate thinning in the left eye with average thickness of 112.60 and 77.23 mm, re-spectively (Fig. 3). Ethambutol, isoniazid, and rifampin were stopped, and the patient was evaluated for other po-tential causes of bilateral optic neuropathy. HIV-1 antibody screen; rapid plasma reagin test; fluorescent treponemal antibody absorption (FTA-ABS) test; screening serum vi-tamin B12 and folate levels; screening whole blood vitamin B1 levels; and genetic testing for mutations 3460, 11778, and 14484 of Leber hereditary optic neuropathy were performed. All studies gave negative or normal results ex-cept for a positive FTA-ABS. MRI of the brain and orbits with and without gadolinium showed no abnormalities. By November 2006, visual acuity had improved 20/200 in each eye. The IOPs were 17 and 19 mm Hg in the right and left eyes, respectively. The optic discs were noted to have increased pallor and cupping. In August 2007, visual acuity was 20/80 in the right eye and 20/100 in the left eye. The IOPs were 21 mm Hg in each eye, and latanoprost once daily was begun. In September 2007, visual acuity improved further to 20/60 and 20/300, respectively. Central corneal thickness measured with ultrasonic pachymetry was 522 and 509 mm, and IOPs were 16 and 17 mm Hg in the right and FIG. 1. Visual fields with ethambutol optic neuropathy. A. Kinetic perimetry 4 months after onset of visual loss. B. Automated perimetry 17 months after discontinuing ethambutol. C. Automated perimetry 30 months after cessation of ethambutol therapy. Original Contribution 306 Masvidal et al: J Neuro-Ophthalmol 2010; 30: 305-310 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. left eyes, respectively. In November 2007, despite increased pallor and cupping of both optic discs, visual fields con-tinued to improve (Fig. 1B). By December 2008, visual fields as tested by automated static perimetry had improved further with a mild central scotoma in the right eye and a centrocecal defect with constriction in the left eye (Fig. 1C). In April 2009, 34 months after discontinuing etham-butol, isoniazid, and rifampin, vision had improved to 20/ 30 in the right eye and 20/70 in the left eye, and the IOPs were 10 mm Hg in each eye. The patient was using travoprost once daily bilaterally. The optic discs were dif-fusely pale and cupped (Fig. 2, bottom). OCT demon-strated marked diffuse RNFL thinning with average thickness of 54.65 mm in the right eye and 50.34 mm in the left eye (Fig. 4). DISCUSSION The pathogenesis of ethambutol optic neuropathy is thought to be related to the accumulation of zinc in lyso-somes leading to lysosomal membrane permeabilization, resulting in subsequent alteration of mitochondrial function and apoptosis of retinal ganglion cells. Yoon et al (5) found that ethambutol caused severe vacuole formation in cultured retinal neurons, astrocytes, and photoreceptor cells from the retinas of newborn Sprague-Dawley rats. The same inves-tigators showed the vacuoles to be enlarged lysosomes containing labile zinc (6). Vacuole overproduction and eventual lysosomal membrane permeabilization appear to be a likely mechanism of ethambutol-induced toxicity. Lysosomal permeabilization causes the release of proteolytic enzymes that are capable of triggering mitochondrial dys-function and activation of caspases, a family of cysteine proteases that play a major role in apoptosis (7,8). These mitochondrial network abnormalities and bioenergetic al-terations increase the susceptibility of the retinal ganglion cell to programmed cell death. In addition to caspase ac-tivation, other potential cellular death pathways triggered by mitochondrial dysfunction include the caspase-independent necrotic programmed cell death pathway and the release of the apoptosis-inducing factor from the intermembrane space (9). In addition, Saddun and Wang (4) believe that etham-butol, as a metal chelator, disrupts mitochondrial oxidative phosphorylation by interfering with copper-containing complex IV. Because mitochondria are the major source of FIG. 2. Optic disc photographs with ethambutol toxicity. Top: Normal appearance 4 months after onset of visual loss. Bottom: Disc pallor and cupping 34 months after discontinuing ethambutol. RE = right eye; LE = left eye. Original Contribution Masvidal et al: J Neuro-Ophthalmol 2010; 30: 305-310 307 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. adenosine triphosphate for neurons and axonal transport is highly energy dependent on transporting mitochondria from the neuronal soma to distal synaptic terminals, the retinal ganglion cell with its long axon is highly susceptible to ethambutol toxicity (4). The retinal ganglion cells located in the papillomacular bundle have very narrow caliber axons rendering them even more susceptible to mitochondrial dysfunction (10). The prognosis of visual recovery from ethambutol optic neuropathy is highly variable. In a review of 857 patients, Lee et al (2) found that less than one-third of 13 patients with ethambutol optic neuropathy showed improvement in visual function after discontinuing ethambutol, and no patient with optic disc pallor at the time of diagnosis improved. Thinning of the RNFL detected by OCT has been reported in the early detection of ethambutol optic neuropathy (11,12). But as our case illustrates, reduction in the RNFL is not predictive of ultimate visual function. The clinical course of our patient demonstrates that a dissociation between functional and structural measures may occur during the recovery phase of ethambutol optic neuropathy and underscores the difficulty in predicting visual outcome in this patient population. Our patient had normal appearing optic discs with normal RNFL thickness in the right eye and reduced RNFL thickness in the left eye FIG. 3. Optical coherence tomography with ethambutol toxicity. Four months after onset of visual loss, there is normal retinal nerve fiber layer thickness in the right eye and thinning in the left eye. Original Contribution 308 Masvidal et al: J Neuro-Ophthalmol 2010; 30: 305-310 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. at the time of diagnosis. Ethambutol, rifampin, and iso-niazid were all discontinued. Yet vision gradually improved despite progressive bilateral optic disc cupping, disc pallor, and diffuse RNFL loss on OCT. While ethambutol optic neuropathy is a more frequent cause than isoniazid and rifampin, toxic effects from isoniazid and rifampin cannot be completely excluded. Ethambutol toxicity is also impli-cated in this patient because the average dosage (24 mg/kg per day) during the period that the patient was lost to follow-up exceeded the current preferred dosage (15-17 mg/kg per day). The progressive cupping in our patient coupled with decreased RNFL on OCT reflects the cumulative effect of nerve fiber loss in the retinal and prelaminar portion of the optic nerve head. Improvement in visual acuity as the nerve fiber layer progressively thinned suggests that while some axons suffered irreversible damage and underwent apoptosis, the function of the remaining axons improved as the toxic effect of ethambutol waned. Presumably some axons, in-cluding those in the papillomacular bundle, did not reach a threshold for apoptosis and were able to survive and recover function. This is in keeping with the findings of Yoon et al FIG. 4. Optical coherence tomography. Thirty-four months after stopping ethambutol, there is bilateral thinning of the retinal nerve fiber layer. Original Contribution Masvidal et al: J Neuro-Ophthalmol 2010; 30: 305-310 309 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (5) that after washout of ethambutol from their retinal cultures, most cells recovered their normal morphology. Structural-functional dissociation occurs in other optic neuropathies, most notably optic neuritis. During the re-covery phase of optic neuritis, optic disc pallor and thinning of the RNFL develop even though most patients experience significant visual recovery (13-17). However, in our pa-tient, the progressive optic disc cupping associated with visual improvement does not typically occur in optic neu-ritis. In compressive optic neuropathy, improvement of vision after surgical intervention is not usually associated with progressive cupping. Optic disc cupping is unusual in nonarteritic anterior ischemic optic neuropathy but does occur in the arteritic form (18). However, visual recovery in latter condition is exceedingly rare. Finally, it is unlikely that our patient had glaucoma since optic disc cupping worsened as the visual fields improved. 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