using the vitrectomy probe, subtotal pars plana vitrectomy, and intravitreal injection of amphotericin B (7.5 mg/0.15 ml). Postoperative therapy included natamycin 5% drops 6 times daily, atropine 1% drops twice daily, and oral fluconazole 200 mg twice daily. Endothelial plaque and anterior chamber suppuration resolved within 48 hours. Culture from the aqueous humor showed dematiaceous mold in blood and chocolate agars and thioglycollate broth after 19 days, subsequently iden- tified as Microsphaeropsis olivacea at the Fungus Testing Laboratory, University of Texas Health Science Center at San Antonio. Topical natamycin and oral fluconazole were contin- ued for 2 months. Subsequent examinations showed slowly progressive improvement characterized by reduc- tion in the area and density of deep stromal opacity. Curettage of a suspicious granular area near a corneal laceration suture 117 days after initial antifungal ther- apy yielded no organisms to smear or culture. Low-grade smoldering corneal inflammation continued, and topical corticosteroid drugs (prednisolone acetate 1%) were initiated 34 days after the laboratory procedure. Two months of treatment resulted in a stable corneal scar without evidence of corneal or intraocular inflamma- tion. Topical corticosteroids were discontinued 8 weeks later. Best-corrected visual acuity, 10 months after the initial injury, was 20/100, attributable to focal corneal opacification and irregular astigmatism. We are unaware of previous reports of this ocular infection caused by M. olivacea and could find no reference to it in a computer search using Medline. The only report of this organism as a human pathogen involves dermatitis with clinical appearance similar to “ringworm.” 1 The fungus was isolated from a rapidly progressing superficial, maculopapular lesion of the left shoulder in an otherwise healthy patient. The species M. olivacea belongs to the order Sphaeropsidales, which are distinguished by the presence of pycnidial conidiomata, and the class Coelomy- cetes, which are parasitic to higher plants, lichen, and other fungi. Our case required long-term topical and oral antifungal therapy and subsequent topical corticosteroid therapy after initial aggressive treatment. The mechanism of prolonged corneal and intraocular inflammation remains uncertain. REFERENCE 1. Guarro J, Mayayo E, Tapiol J, Aguilar C, Cano J. Microspha- eropsis olivacea as an etiological agent of human skin infection. Med Mycol 1999;37:133–7. Leber Hereditary Optic Neuropathy Associated with Antiretroviral Therapy for Human Immunodeficiency Virus Infection Saad Shaikh, MD, Christopher Ta, MD, Arthur A. Basham, MD, and Sam Mansour, MD PURPOSE: Antiretroviral therapy has reduced the morbid- ity and mortality associated with human immunodefi- ciency virus (HIV) infection. However, side effects are increasingly recognized, including a commonly reported toxic mitochondrial myopathy. We report such a case of Leber hereditary optic neuropathy in a patient with antiretroviral therapy for HIV infection and speculate on Accepted for publication Jul 17, 2000. From the Department of Ophthalmology, Stanford University School of Medicine, Stanford, California (S.S., C.T., S.M.), and Los Gatos, California (A.A.B.). Inquiries to Saad Shaikh, MD, Department of Ophthalmology, Stan- ford University School of Medicine, Stanford, CA 94305; fax: (650) 723-7918; e-mail: [email protected]FIGURE 1. Right eye 6 weeks after the injury with corneal laceration suture in place, deep stromal infiltrate, and extension of fibrous processes into the anterior chamber (noted by arrow). FIGURE 2. Right eye 6 weeks after the injury. Higher mag- nification of deep corneal stromal infiltrate and extension of fine fibrous processes into the anterior chamber. BRIEF REPORTS VOL. 131,NO. 1 143
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using the vitrectomy probe, subtotal pars plana vitrectomy,and intravitreal injection of amphotericin B (7.5 mg/0.15ml). Postoperative therapy included natamycin 5% drops 6times daily, atropine 1% drops twice daily, and oralfluconazole 200 mg twice daily.
Endothelial plaque and anterior chamber suppurationresolved within 48 hours. Culture from the aqueous humorshowed dematiaceous mold in blood and chocolate agarsand thioglycollate broth after 19 days, subsequently iden-tified as Microsphaeropsis olivacea at the Fungus TestingLaboratory, University of Texas Health Science Center atSan Antonio.
Topical natamycin and oral fluconazole were contin-ued for 2 months. Subsequent examinations showedslowly progressive improvement characterized by reduc-tion in the area and density of deep stromal opacity.Curettage of a suspicious granular area near a corneallaceration suture 117 days after initial antifungal ther-
apy yielded no organisms to smear or culture. Low-gradesmoldering corneal inflammation continued, and topicalcorticosteroid drugs (prednisolone acetate 1%) wereinitiated 34 days after the laboratory procedure. Twomonths of treatment resulted in a stable corneal scarwithout evidence of corneal or intraocular inflamma-tion. Topical corticosteroids were discontinued 8 weekslater. Best-corrected visual acuity, 10 months after theinitial injury, was 20/100, attributable to focal cornealopacification and irregular astigmatism.
We are unaware of previous reports of this ocularinfection caused by M. olivacea and could find no referenceto it in a computer search using Medline. The only reportof this organism as a human pathogen involves dermatitiswith clinical appearance similar to “ringworm.”1 Thefungus was isolated from a rapidly progressing superficial,maculopapular lesion of the left shoulder in an otherwisehealthy patient. The species M. olivacea belongs to theorder Sphaeropsidales, which are distinguished by thepresence of pycnidial conidiomata, and the class Coelomy-cetes, which are parasitic to higher plants, lichen, andother fungi. Our case required long-term topical and oralantifungal therapy and subsequent topical corticosteroidtherapy after initial aggressive treatment. The mechanismof prolonged corneal and intraocular inflammation remainsuncertain.
REFERENCE
1. Guarro J, Mayayo E, Tapiol J, Aguilar C, Cano J. Microspha-eropsis olivacea as an etiological agent of human skin infection.Med Mycol 1999;37:133–7.
Leber Hereditary Optic NeuropathyAssociated with AntiretroviralTherapy for HumanImmunodeficiency Virus InfectionSaad Shaikh, MD, Christopher Ta, MD,Arthur A. Basham, MD, and Sam Mansour, MD
PURPOSE: Antiretroviral therapy has reduced the morbid-ity and mortality associated with human immunodefi-ciency virus (HIV) infection. However, side effects areincreasingly recognized, including a commonly reportedtoxic mitochondrial myopathy. We report such a case ofLeber hereditary optic neuropathy in a patient withantiretroviral therapy for HIV infection and speculate on
Accepted for publication Jul 17, 2000.From the Department of Ophthalmology, Stanford University School
of Medicine, Stanford, California (S.S., C.T., S.M.), and Los Gatos,California (A.A.B.).
Inquiries to Saad Shaikh, MD, Department of Ophthalmology, Stan-ford University School of Medicine, Stanford, CA 94305; fax: (650)723-7918; e-mail: [email protected]
FIGURE 1. Right eye 6 weeks after the injury with corneallaceration suture in place, deep stromal infiltrate, and extensionof fibrous processes into the anterior chamber (noted by arrow).
FIGURE 2. Right eye 6 weeks after the injury. Higher mag-nification of deep corneal stromal infiltrate and extension of finefibrous processes into the anterior chamber.
trilineal disorder characterized by progressive bilateraloptic nerve degeneration and severe visual loss. Thepenetrance is incomplete in Leber hereditary optic neu-ropathy families, and men are more often affected. Ini-tially, the optic disks may appear normal or have thepathognomonic findings of hyperemia and peripapillarytelangiectatic vessels. In the course of the disease, opticatrophy develops and the vascular changes become lessprominent. Leber hereditary optic neuropathy and Leberhereditary optic neuropathy-like presentations have beenassociated with multiple sclerosis and cystic fibrosis. Wereport a case of Leber hereditary optic neuropathy in apatient receiving antiretroviral therapy for human immu-nodeficiency virus (HIV) infections and speculate on apossible mechanism of pathogenesis.
● CASE REPORT: A 38-year-old HIV-infected African-American man presented to our ophthalmology clinic witha 3-month history of decreased vision in both eyes. Hismedications included zalcitabine, lamivudine, nelfinavir,trimethoprim/sulfamethoxazole, oxycodone/acetaminophen,and fluconazole for oral candidiasis. He had previouslybeen treated with zidovudine, but this was discontinued 8months before because of hepatotoxicity. Additionally, hehad recently completed a 1-month course of amikacin forMycobacterium avium complex prophylaxis. A CD4 countwas 110 cells/ml, and viral load was 49020 copies/ml.Family history was positive for Leber hereditary opticneuropathy (Figure 1).
Eight months before presentation, on a routine exam-ination, his visual acuity and ophthalmic examinationwere noted to be normal. However, at presentation, his
best-corrected visual acuity was counting fingers (right)and 20/100 (left). His ophthalmic examination, includ-ing pupillary and funduscopic findings, were withinnormal limits. Goldmann visual fields were normal, andfluorescein angiography revealed mild retinal pigmentepithelial mottling in the macula, but was otherwisenormal.
A neuro-ophthalmology consultation 1 month laterrevealed color plate deficiencies, greater for the right eye,and stereo vision testing to only 4000 seconds of arc.Optokinetic testing was normal, and no afferent pupillarydefect was noted. Trace mottling and a subtle thinnedappearance were noted in the macula of both eyes, but theoptic nerve heads appeared completely normal withoutevidence of pallor or changes in the vasculature. DNAtesting revealed a mutation in the mitochondrial DNA atnucleotide position 11,778 consistent with Leber heredi-tary optic neuropathy.
Over the next 5 months, the patient’s visual acuitydecreased to counting fingers bilaterally, and he was notedto have temporal pallor of his optic nerves on follow-upexamination (Figure 2). Humphrey visual field testingrevealed dense bilateral central scotomas with extensioninto the periphery.
Leber hereditary optic neuropathy involves a degenera-tion of the ganglion cell layer of the retina and theaccompanying axons of the optic nerve. The incompletepenetrance suggests that secondary etiological factors arenecessary for the development of disease. Accordingly,Howell outlines a “trigger” model for the development ofoptic neuropathy in Leber hereditary optic neuropathy.1 Inthis model, a primary mitochondrial mutation, commonlyat nucleotides 3460, 11,778, or 14,484, is necessary but notsufficient for manifestation of the optic neuropathy. The 3primary mutations are associated with respiratory chaindysfunction and may impair ganglion cell metabolismwithout producing substantially increased neuronal death.Additional environmental insults or conditions, such asheavy alcohol/tobacco use, X-linked susceptibility, or cu-mulative damage from normal aging in these at-risk indi-viduals, would then “trigger” a wave of neurodegeneration
FIGURE 1. Pedigree of patient with Leber hereditary opticneuropathy.
AMERICAN JOURNAL OF OPHTHALMOLOGY144 JANUARY 2001
resulting in the clinical changes observed at the opticnerve on examination.
In our patient who was at risk for Leber hereditary opticneuropathy, it is conceivable that antiretroviral therapymay have “triggered” the development of optic nervedisease. Zidovudine and other antiretroviral drugs interferewith the action of viral reverse transcriptase but at thesame time interfere with mitochondrial DNA polymerase-gamma, the enzyme responsible for mitochondrial DNAreplication. A toxic mitochondrial myopathy is a well-known side effect of antiretroviral therapy. Studies oncultured human cells reveal that zidovudine, didanosine,and zalcitabine all induce functional alterations of mito-chondria through cytotoxic effects, including but notlimited to mitochondrial DNA depletion.2,3 In addition,biochemical studies suggest that inhibition of mitochon-drial DNA polymerase may be integral to the pathogenesisof zidovudine-induced myopathy.4
In the 1950s and 1960s, chloramphenicol was used totreat children with cystic fibrosis, but this treatment wasdiscontinued when it was found to cause an opticatrophy akin to Leber hereditary optic neuropathy.Patients presented with bilateral sudden loss of vision,central scotomas, papilledema, and subsequent palloroften associated with the engorgement and tortuosity ofthe retinal veins.5 It was later discovered that patientswith cystic fibrosis display altered kinetics of the mito-chondrial electron transport system and that chloram-phenicol is a specific inhibitor of mitochondrial proteinsynthesis.6 In retrospect, the systemic application of aninhibitor of mitochondrial protein synthesis in a patientpopulation at risk produced a Leber hereditary opticneuropathy-like pathology, analogous to our patientpredisposed to developing Leber hereditary optic neu-ropathy who was treated with inhibitors of mitochon-drial DNA synthesis—namely, antiretroviral drugs.
Alternatively, it is possible that amikacin, an aminogly-coside that inhibits bacterial protein synthesis, may alsohave been involved in the development of optic nervedisease in our patient. Recently, mutations in mitochon-drial ribosomal DNA have been linked to matrilinealaminoglycoside ototoxicity, although conclusive bio-chemical evidence is still lacking.7 Therefore, in pa-tients at risk for Leber hereditary optic neuropathy, theuse of antiretroviral drugs and perhaps aminoglycosideantibiotics may “trigger” the development of Leberhereditary optic neuropathy.
REFERENCES
1. Howell N. Leber hereditary optic neuropathy: respiratorychain dysfunction and degeneration of the optic nerve. VisionRes 1998;38:1495–1504.
2. Benbrik E, Chariot P, Bonavaud S, et al. Cellular andmitochondrial toxicity of zidovudine (AZT), didanosine (ddI)and zalcitabine (ddC) on cultured human muscle cells. J Neu-rol Sci. 1997;149(1):19–25.
3. Medina DJ, Tsai CH, Hsiung GD, Cheng YC. Comparison ofmitochondrial morphology, mitochondrial DNA content, andcell viability in cultured cells treated with three anti-humanimmunodeficiency virus dideoxynucleosides. AntimicrobialAgents Chemother 1994;38:1824–1828.
4. Lewis W, Simpson JF, Meyer RR. Cardiac mitochondrialDNA polymerase-gamma is inhibited competitively and non-competitively by phosphorylated zidovudine. Circ Res 1994;74:344–348.
5. Harley RD, Huang NN, Macri CH, Green WR. Optic neuritisand optic atrophy following chloramphenicol in cystic fibrosispatients. Trans Am Acad Ophthalmol Otolaryngol 1970;74:1011–1031.
6. Shapiro BL. Evidence for a mitochondrial lesion in cysticfibrosis. Life Sci 1989;44:1327–1334.
7. Pandya A, Xia X, Radnaabazaar J, et al. Mutation in themitochondrial 12S rRNA gene in two families from Mongoliawith matrilineal aminoglycoside ototoxicity. J Med Genet1997;34:169–172.
FIGURE 2. Bilateral temporal pallor of the optic nerves observed on follow-up examination.
