Journal of Neuro-Ophthalmology, June 2008, Volume 28, Issue 2

Letters to the Editor

LETTERS TO THE EDITOR Leber Hereditary Optic Neuropathy Presenting in a 75-Year-Old Man We recently examined a white man who developed Leber hereditary optic neuropathy (LHON) at age 75. The patient was referred to us with bilateral visual failure of presumed psychogenic nature. He had presented to his local eye unit 6 months earlier with visual blurring initially in his left eye. Within 6 weeks visual acuity had dropped to counting fingers in the right eye and hand move-ments in the left eye. No ophthalmoscopic abnormalities were noted, findings from his neurological examination were normal except for well-controlled hypertension, and his medical history was unremarkable. He was a lifelong non-smoker, and for several years he had been drinking 48 to 96 fluid ounces of beer per day. Brain MRI was normal, and extensive investigation at the time had failed to identify an underlying cause for his visual loss. When we first examined him, visual acuities were unchanged; there was no afferent pupillary defect, but bilateral optic disc pallor and large central scotomas were evident. On closer questioning, he gave a clear family history of five other affected family members having experienced poor vision in their 20s to 40s, and some of them were registered as blind with social services. This prompted mitochondrial genetic analysis, which identified a m.3460G>A primary LHON mutation. He was homoplasmic for the mutation, belonged to the mtDNA haplogroup H, and genotyping revealed the DXS8090(160)-DXS1068(256) X-chromosomal haplotype at the Xp21.1 locus. This man is one of the oldest reported individuals to have LHON. More than 95% of carriers become affected by age 50 (1-3). What are the possible precipitants of visual loss in these late cases? The predominance of affected males has been linked to an X-linked nuclear modifier gene and we have recently identified a high-risk haplotype at Xp21.1, DXS8090(166)-DXS1068(268), which increases the risk of visual failure 35-fold for the m. 1178G>A and m.14484T>C LHON mutations but not for m.3460G>A (4). Our patient did not harbor this visual loss susceptibility haplotype, but he did have a high alcohol intake. Although it is tempting to link this in some way, there are conflicting data regarding the strength of the association between excessive alcohol consumption and a higher risk of developing visual symptoms in LHON (5,6). Furthermore, there is no suggestion that he had been exposed to other exogenous toxins that have previously been reported to precipitate visual loss among LHON carriers (2,3). The secondary factors influencing disease expression in LHON still need to be clarified and our patient highlights the difficulties of genetic counseling in this condition. Patrick Yu-Wai-Man, MRCOphth Department of Ophthalmology Royal Victoria Infirmary Mitochondrial Research Group The Medical School Newcastle University Newcastle upon Tyne, United Kingdom Patrick. [e-mail] David E. Bateman, FRCP Department of Neurology Cumberland Infirmary Carlisle, United Kingdom Gavin Hudson, PhD Mitochondrial Research Group The Medical School Newcastle University Newcastle upon Tyne, United Kingdom Philip G. Griffiths, FRCOphth Department of Ophthalmology Royal Victoria Infirmary Mitochondrial Research Group The Medical School Newcastle University Newcastle upon Tyne, United Kingdom Patrick F. Chinnery, FRCP Mitochondrial Research Group The Medical School Institute of Human Genetics Newcastle University Newcastle upon Tyne, United Kingdom REFERENCES 1. Man PY, Griffiths PG, Brown DT, et al. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet 2003;72:333-9. 2. Carelli Y Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res 2004;23:53-89. 3. Newman NJ, Biousse V Hereditary optic neuropathies. Eye 2004;18: 1144-60. 4. Hudson G, Keers S, Yu Wai Man P, et al. Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder. Am J Hum Genet 2005;77:1086-91. 5. Charlmers RM, Harding AE. A case-control study of Leber's hereditary optic neuropathy. Brain 1996;119:1481-6. 6. Kerrison JB, Miller NR, Hsu F, et al. A case-control study of tobacco and alcohol consumption in Leber hereditary optic neuropathy. Am J Ophthalmol 2000;130:803-12. 155 J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Letters to the Editor Leber Hereditary Optic Neuropathy in an Octogenarian Leber hereditary optic neuropathy (LHON) is a condition that typically affects young men in their second to fourth decades, causing acute or subacute painless loss of vision, often with a final visual acuity below 20/200 (1). However, people outside the typical age range of 15-35 years may still present with classic symptoms and test positively for a known LHON mutation (2). We recently examined an 81-year-old man who developed progressive bilateral vision loss due to LHON. A generally healthy 81-year-old white man with no family history of eye disease presented elsewhere in January 2006 with a 2-month history of painless progressive bilateral visual loss more in the left eye than in the right eye. His past medical history was significant for mild hypertension and coronary artery disease. He denied a history of diabetes mellitus, stroke, myocardial infarction, tobacco use, or alco-hol consumption. Visual acuity was 20/70 in the right eye and counting fingers in the left eye. Ishihara color testing showed that he could only identify 7/15 plates with the right eye and none with the left eye. The pupillary examination was normal. Intraocular pressures were 17 mm Hg in the right eye and 18 mm Hg in the left eye. Mild nuclear scle-rotic lens changes were noted in both eyes. Ophthalmoscopy through dilated pupils revealed a mild epiretinal membrane in the right eye and mild macular drusen in both eyes. Both optic discs demonstrated mild temporal pallor. Goldmann visual fields demonstrated bilateral central scotomas (Fig. 1). Results of MRI of the brain, orbits, chest, and abdomen, full-body positron emission tomogra-phy (PET) scanning, fluorescein angiography, full-field and focal electroretinography (ERG), and laboratory tests for autoimmune disease, infectious processes, and paraneo-plastic syndromes were negative. A lumbar puncture FIG. 1. Goldmann visual fields show bilateral central scotomas. revealed an opening pressure of 180 mmH20, colorless fluid with no cells, and 82 mg/dL of protein (normal: 15-45 mg/dL). On evaluation at The Massachusetts Eye and Ear Infirmary 6 months later, visual acuity was counting fingers at 1 foot in both eyes. A left afferent pupillary defect was present. Both optic discs showed diffuse pallor. All other aspects of his examination were normal. Genetic testing for LHON showed the patient to be positive for the 11778 mutation. The oldest reported patient with LHON was a 73- year-old man who also harbored the 11778 mutation (3). Although clinicians typically expect patients with vision loss from LHON to present relatively early in life, patients such as ours serve as an important reminder that LHON should be considered as a possible diagnosis in older adults who develop atypical bilateral optic neuropathies. Our case is atypical in that our patient initially developed bilateral and asymmetric vision loss at the age of 81. As our ability to confirm diagnoses by mutational analysis expands, so does our understanding of the clinical spectrum of this disease. Lora R. Dagi, BA Mount Sinai School of Medicine New York, New York Joseph F. Rizzo III, MD Dean M. Cestari, MD Massachusetts Eye and Ear Infirmary Boston, Massachusetts [e-mail] REFERENCES 1. Newman NJ. Hereditary optic neuropathies: from the mitochondria to the optic nerve. Am J Ophthalmol 2005;140:517-23. 2. Newman NJ, Biousse V Hereditary optic neuropathies Eye 2004; 18: 1144-1160. 3. Ajax ET, Kardon R. Late-onset Leber's hereditary optic neuropathy. J Neuroophthalmol 1998;18:30-1. Intracranial Hypertension in a Patient Using Topical Adapalene Intracranial hypertension has been associated with orally and parenterally but not topically administered vitamin A and retinoid-derivative medications (1-3). We report the case of a young mildly overweight woman who 156 © 2008 Lippincott Williams & Wilkins Letters to the Editor J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 FIG. 1. Fundus photography per-formed 15 weeks after the patient had started using topical 0.1% adapalene for acne. It shows mild optic disc edema bilaterally. developed intracranial hypertension 7-8 weeks after beginning treatment with topical adapalene (Differin Gel, 0.3% and 0.1% product inserts), a naphthoic acid deriva-tive with potent retinoid and comedolytic action that is prescribed as a topical preparation for treatment of acne (4,5). A 23-year-old woman presented to her primary care physician with 1 week of severe headaches and neck stiffness. Other than acne, she had no previous or current medical problems and denied remote headaches. The only medication she used was 0.1% adapalene, a topical gel prescribed for acne one time per day for 7-8 weeks before the onset of her symptoms. Her height was 64.75 inches and her weight was approximately 155 pounds. In the past year, she had gained between 10 and 20 pounds. Bilateral optic disc edema had been found by her optometrist. Results of brain MRI were unremarkable. Nine weeks after the onset of symptoms she was examined in our neuro-ophthalmology clinic. She had discontinued adapalene 1 week before the appointment after reading on the Internet of its similarities to other medications that may cause intracranial hypertension. Visual acuity was 20/20 in both eyes. Confrontation visual fields, extraocular motility, slit-lamp examination, pupils, and intraocular pressures were normal. Both optic discs were swollen (Fig. 1). The fundi were otherwise normal. Results of automated threshold perimetry (SITA standard 30-2) performed 1 week earlier by the optometrist were normal. Lumbar puncture performed in the left lateral decubitus position disclosed an opening pressure of 480 mmH20. Cerebrospinal fluid constitu-ents were normal. Because the patient's symptoms had been improving, she was followed without further intervention. At a follow-up visit 6 weeks later, the patient was asymptomatic and the optic disc edema had diminished. At a second follow-up visit 10 weeks after that, she remained asymptomatic, and the optic disc edema had diminished further (Fig. 2). Results of automated threshold perimetry (SITA standard 24-2) were again normal. The prompt resolution of signs and symptoms after discontinuation of adapalene suggests that this topical medication contributed to the patient's high intra-cranial hypertension. A confounding factor is that the patient was overweight, a typical finding in the idiopathic form of intracranial hypertension. Although it is delivered topically, this agent may achieve detectable serum levels with a mean half-life of 17.2 ± 10.2 hours and should be viewed as a potential contributor to intracranial hypertension. FIG. 2. Fundus photography per-formed 6 weeks after the patient had stopped using topical 0.1% adapalene shows resolution of the optic disc edema. 157 J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Letters to the Editor Syndee J. Givre, MD, PhD Departments of Ophthalmology and Neurology University of North Carolina Chapel Hill, North Carolina [e-mail] David Fleischman, BS Drexel University College of Medicine Philadelphia, Pennsylvania REFERENCES 1. Jacobson DM, Berg R, Wall M, et al. Serum vitamin A concentration is elevated in idiopathic intracranial hypertension. Neurology 1999;53: 1114-8. 2. Fraunfelder FW, Fraunfelder FT. Evidence for a probable causal relationship between tretinoin, acitretin, and etretinate and intracranial hypertension. J Neuro-ophthalmol 2004;24:214-6. 3. Friedman DI. Medication-induced intracranial hypertension in dermatology. Am J Clin Dermatol 2005;6:29-37. 4. Shroot B, Michel S. Pharmacology and chemistry of adapalene. J Am Acad Dermatol 1997;36:S96-S103. 5. Bikowski JB. Mechanisms of the comedolytic and anti-inflammatory properties of topical retinoids. J Drugs Dermatol 2005;4:41-7. Delayed Dark Adaptation Caused by Nilutamide Nilutamide is an androgen receptor blocker approved for treatment of prostate cancer. We report a patient treated with nilutamide who experienced impaired dark adaptation, a documented but seldom acknowledged side effect of the medication. The patient's symptoms were initially attrib-uted to reduced ocular or visual cortex perfusion. An 87-year-old man experienced several episodes of isolated painless bilateral loss of vision lasting from 10 to 15 minutes, always occurring as he moved from a bright environment to a darker one. The most prominent episode occurred upon entering a dimly lit restaurant after having been in direct sunlight. At first he could not see to read the menu. He reported no other symptoms. Over 15 minutes, his vision would gradually recover. His medical history included two brainstem strokes years earlier without residual deficits, prostate cancer, and ventriculoperitoneal shunt placement for low-pressure hydrocephalus. He was pseudophakic in both eyes and had mild chronic open-angle glaucoma treated with dorzolamide hydrochloride. For several months, he had been using 150 mg nilutamide daily for prostate cancer, as well as niacin, clopidogrel, aspirin, and simvastatin. The patient had previously been evaluated by an ophthalmologist and neuro-ophthalmologist. The visual episodes were initially interpreted as either transient ischemic attacks of the posterior circulation or light-induced amaurosis. The patient was referred for a second neuro-ophthalmologic consultation. Best-corrected visual acuity was 20/25 in both eyes. Humphrey 24-2 visual field examination showed nasal depression in the right eye and a slight inferior arcuate scotoma in the left eye, consistent with his history of glaucoma. The pupils were equal, and there was no afferent pupil defect. Results of slit lamp examination were normal with well-positioned posterior chamber intraocular lenses. Tensions by applanation tonom-etry were 17 mm Hg right eye and 19 mm Hg left eye. Gonioscopy was grade IV bilaterally. His cup-to-disk ratio was 0.4 right eye and 0.45 left eye, consistent with visual field loss. Findings from the fundus examination was otherwise normal. Complete blood count, erythrocyte sedimentation rate, and C-reactive protein showed normal values, and findings from carotid ultrasound and echocardi-ography were normal. MRI of the brain with gadolinium was unchanged. The patient discontinued use of nilutamide. His visual symptoms resolved completely within several weeks. Delayed dark adaptation caused by nilutamide has a prevalence ranging from 12.9 to 90% when patients are using a daily dose of 300 mg (1-8); this side effect is dose dependent (2,9). Nilutamide acts as an androgen inhibitor through receptor binding and is approved by the Food and Drug Administration (FDA) for treatment of metastatic prostate cancer in combination with surgical castration. To date, it is the only reported compound in its class to cause these visual symptoms and is not considered to offer any advantage in efficacy over other antiandrogens (10). To our knowledge, there has been only one published report quan-tifying this delayed dark adaptation effect via photostress recovery time (PSRT) (1). In that study, PSRT increased to an average of 9 minutes, with normal recovery time being 1-2 minutes. In other reported cases, patients have reported painless bilateral visual impairment upon transition into a darker area, particularly on entering a building on a bright day. The latency between first use of the medication and symptom onset has not been well documented. Patrick Chan, BA Jeffrey G. Odel, MD Department of Ophthalmology Columbia University College of Physicians and Surgeons New York, New York [e-mail] REFERENCES 1. Harnois C, Malenfant M, Dupont A, et al. Ocular toxicity of Anandron in patients treated for prostatic cancer. Br J Ophthalmol 1986;70:471-3. 158 © 2008 Lippincott Williams & Wilkins Letters to the Editor J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 2. Brisset JM, Boccon-Gibod L, Botto H, et al. Anandron (RU 23908) associated to surgical castration in previously untreated stage D prostate cancer: multicenter comparative study of two doses of the drug and of a placebo. Prog Clin Biol Res 1987;243A:411-22. 3. Janknegt RA, Abbou CC, Bartoletti R, et al. Orchiectomy and nilutamide or placebo as treatment of metastatic prostatic cancer in a multinational double-blind randomized trial. J Urol 1993;149: 77-83. 4. Namer M, Toubol J, Caty A, et al. A randomized double-blind study evaluating Anandron associated with orchiectomy in stage D prostate cancer. J Steroid Biochem Mol Biol 1990;37:909-15. 5. Beland G, Elhilali M, Fradet Y, et al. A controlled trial of castration with and without nilutamide in metastatic prostatic carcinoma. Cancer 1990;66(Suppl 5): 1074-9. 6. Navratil H. Double-blind study of Anandron versus placebo in stage D2 prostate cancer patients receiving buserelin: results on 49 cases from a multicentre study. Prog Clin Biol Res 1987;243A:401- 10. 7. Decensi AU, Boccardo F, Guarneri D, et al. Monotherapy with nilutamide, a pure nonsteroidal antiandrogen, in untreated patients with metastatic carcinoma of the prostate. J Urol 1991;146:377-81. 8. DRUGDEX® system (database). Greenwood Village, CO: Thomson Micromedex; 2007. Available from http://www.micromedex.com/ products/drugdex/. 9. Du Plessis DJ. Castration plus nilutamide vs castration plus placebo in advanced prostate cancer: a review. Urology 1991;37(Suppl 2):20-4. 10. Dole EJ, Holdsworth MT. Nilutamide: an antiandrogen for the treatment of prostate cancer. Ann Pharmacother 1997;31:65-7. Pitfalls in OCT Measurement of Peripapillary Retinal Nerve Fiber Layer Thickness in Nonglaucomatous Optic Neuropathy Chan and Miller (1) recently reported that in eyes with nonglaucomatous optic neuropathies and no light perception, the "peripapillary retinal nerve fiber layer thick-ness (PRNFLT)" seemed not to diminish below approxi-mately 45 microns in thickness on averaged optical coherence tomography (OCT) measurement. The authors offered three explanations for this phe-nomenon. Although the first two explanations (remnant or reactive glial tissue and remnant of non-functioning axons) are certainly possible, it is incorrect to attribute the mea-surement to an artifact generated by the built-in software of the OCT. This software measures the width of a signal peak above a specific or calculated threshold intensity, often represented by white or red on the pseudo-colored images. This band is generally assumed to be generated by the retinal nerve fiber layer and has a thickness that can be measured by the built-in software as well as third-party imaging software. In a study addressing the interpretation of retinal OCT images (2), we ablated the surface of cadaveric retinas with an excimer laser, progressively removing retinal layers from the inner retinal surface towards the retinal pigment epithelium. A high-intensity inner band of signal at the surface of the retinal specimen consistently measuring up to 36 microns was observed throughout. This is similar to the PRNFLT measurements reported by Chan and Miller (1) as well as by Sihota et al (3). OCT is an optical imaging sys-tem in which signal is generated by back-scattering of the incident light (4). The high-intensity signal we observed from the innermost aspect of the retina was generated by the interface between the immersion fluid (corresponding to vitreous in vivo) and the surface of the retina, independent of the anatomical layer exposed by the excimer laser. This measured up to 36 microns because that was the thickness of the signal peak at the threshold set for "RNFL" mea-surement in our study (2). Signal from the layers just beneath the surface is likely to be swamped by this peak. Chan and Miller (1) also found it difficult to explain the difference between PRNFLT measurements of the two eyes in their Case 3. Once again, although the explanations offered are reasonable, it is worth noting that the in vivo axial resolution of the Stratus OCT is, at best, of the order of 15 microns, and that the effects of polarization on the images from each eye are not known (2). Thus, a difference of less than 14 microns between eyes is outside the resolution limits of the instrument. A similar argument applies to the study of Fisher (5) showing a correlation between the reduction of 1 line of low contrast letter acuity per 4 microns of lost PRNFLT, to which the Chan and Miller (1) referred. The issues of tissue specificity of signal origin and axial resolution apply to all time and spectral domain OCT instruments currently available commercially and will only be addressed by empirical correlations of histology with images using ultra-high resolution OCT machines currently being investigated (6). Until this has been achieved, quantitative assessment of PRNFLT in optic neuropathy is fundamentally flawed. Devinder S. Chauhan, MBBS MD FRCOphth FRANZCO Melbourne, Australia [e-mail] REFERENCES 1. Chan CKM, Miller NR. Peripapillary nerve fibre layer thickness measured with optical coherence tomography in patients with no light perception from long-standing nonglaucomatous optic neuropathies. J Neouro-Ophthalmol 2007;27:176-179. 2. Chauhan DS, Marshall J. The interpretation of optical coherence tomography images of the retina. Invest Ophthalmo Vis Scil 1999;40: 2332-2342. 3. Sihota R, Sony P, Gupta V, et al. Diagnostic capability of optical coherence tomography in evaluating the degree of glaucomatous 159 J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Letters to the Editor retinal nerve fiber layer damage. Invest Ophthalmol Vis Sci 2006;47: 2006-10. 4. Pan Y, Arlt S, Birngruber R, Engelhard: R. Optical coherence tomography in turbid tissue: theoretical analysis and experimental results. Society of Photo-Optical Instrumentation Engineers 1996; 2628:239-48. 5. Fisher JB, Jacobs DA, Markowitz CE, et al. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthal-mology 2006;113:324-32. 6. Srinivasan VJ, Wojtkowski M, Witkin AJ, et al. High-definition and 3-dimensional imaging of macular pathologies with high-speed ultrahigh-resolution optical coherence tomography. Ophthalmology 2006;113:2054.el-14. Reply: We greatly appreciate Dr. Chauhan's comments regarding our paper (1). We are pleased that our finding that eyes that have no light perception from primary optic nerve damage have a nerve fiber layer thickness of about 40 microns by optical coherence tomography (OCT) not only is consistent with his own work in cadaver specimens (2) but also is not due to an artifact generated by the built-in software of the apparatus. We apologize for having missed that important article. We also appreciate his comments that a difference of less than 14 microns between eyes is outside the resolution limits of current OCT instruments. The increasing desire of physicians to use OCT to predict the potential for visual recovery in patients with various optic neuropathies and to use measurements of nerve fiber layer thickness as a surrogate marker for multiple sclerosis makes it essential that the type of information contained in Dr. Chauhan's letter be disseminated so that we can interpret appropriately the significance and limitations of nerve fiber layer analysis using this technique. Carmen K. M. Chan, MRCP, MRCOphth Neil R. Miller, MD Wilmer Eye Institute The Johns Hopkins Hospital Baltimore, Maryland REFERENCES 1. Chan CKM, Miller NR. Peripapillary nerve fibre layer thickness measured with optical coherence tomography in patients with no light perception from long-standing nonglaucomatous optic neuropathies. J Neuro-Ophthalmol 2007;27:176-179. 2. Chauhan DS, Marshall J. The interpretation of optical coherence tomography images of the retina. Invest Ophthalmo Vis Sci 1999;40: 2332-2342. 160 © 2008 Lippincott Williams & Wilkins