Delayed Visual Decline in Patients with ˝Stable˛ Optic Neuropathy

CLINICAL SCIENCES Delayed Visual Decline in Patients With “Stable” Optic Neuropathy

Jonathan W. Kim, MD; Joseph F. Rizzo, MD; Simmons Lessell, MD

Background: Histological studies on the human Results: All 3 patients had a monophasic illness in child- optic nerve have documented decreasing axonal nerve hood that caused bilateral optic atrophy and visual im- fiber counts with age. In patients with optic atrophy, a pairment. Following decades of stability, each suffered nonpathological dropout of ganglion cell axons as part a gradual, symptomatic visual decline that extended over of the normal aging process may become clinically sig- years. No new ophthalmologic, systemic, or neurologic nificant. disorder was found that explained the visual decline in any of these patients. Objective: To describe the occurrence of delayed visual loss in patients with presumably “stable” optic neu- Conclusion: We hypothesize that the late visual de- ropathy. cline in these 3 patients resulted from deleterious effects of age-related axonal loss on an already depleted Methods: We reviewed the medical records of 3 pa- population of neurons. tients who experienced slowly progressive visual loss in adulthood after suffering childhood optic nerve injury. Arch Ophthalmol. 2005;123:785-788

HE TACIT ASSUMPTION THAT superior defect extending across fixation on progression or recurrence the left side. Both optic discs were pale, but of an optic neuropathy re- there were no other fundus lesions. Lum- sults from the same mecha- bar puncture with examination of the ce- nism that inaugurated the rebrospinal fluid (CSF) gave normal re- disorderT has tended to obscure the possi- sults. The result of a serologic test for bility that in some cases these phenom- syphilis was negative. Plain skull radio- ena might have a pathogenesis indepen- graphs showed craniostenosis with a tower dent of the original. In this article we skull deformity. postulate such a scenario in 3 patients who, His vision had remained unchanged un- after decades of stable but impaired vi- til the patient was in his mid 40s when sion following childhood optic atrophy, de- worsening visual disability forced him to veloped a progressive visual decline. We stop working as a machinist. In 1965 (age hypothesize that the late visual decline in 50 years) he was examined reporting of a these patients resulted from deleterious ef- further loss of vision; his VA was 20/200 fects of age-related axonal loss on an al- OD and counting fingers OS. Findings from ready depleted population of neurons. an ophthalmologic examination showed no evidence of cataracts or macular degenera- REPORT OF CASES tion and the intraocular pressure was within normal limits in both eyes. Findings from a screening neurologic examination re- CASE 1 vealed no abnormalities; no new changes were detected on plain skull radiographs. The patient was born in 1915, and he lost Despite cerebral arteriography, pneumo- vision in both of his eyes during child- encephalography, and CSF analysis, no hood, allegedly after an episode of whoop- cause could be established for his progres- ing cough. Records of that illness are un- sive decline in vision. At the age of 75 years available. At his first formal ophthalmologic in1990 he reported that poor vision re- Author Affiliations: The Massachusetts Eye and Ear examination in 1943 (age 28 years), the vi- quired him to use a cane to ambulate safely. Infirmary and the Department sual acuity (VA) was 20/40 OD and count- His VA had declined to 2/100 OD and hand of Ophthalmology, Harvard ing fingers OS, and there was comitant left motions OS. There was bilateral optic at- Medical School, Boston. exotropia. There was generalized constric- rophy that was unchanged from previous Financial Disclosure: None. tion of the visual field of his right eye and a examinations. Findings from a general neu-

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Initial Vision Final Vision Age at Initial Onset of Late Age at End Patient No. Examination, y OD OSVisual Decline, y OD OS of Follow-up, y Diagnosis 1 28 20/40 CF 50 2/100 HM 75 Craniostenosis 2 10 20/70 20/50 42 4/200 6/200 65 Craniostenosis 3 11 LP 20/200 47 LP 2/200 63 Otitic hydrocephalus

Abbreviations: CF, counting fingers; HM, hand motions; LP, light perception.

rologic examination did not reveal any deficits. A com- tomy. Four days after surgery he developed headache and puted tomographic scan of the brain showed multiple ce- backache. Approximately 2 to 3 weeks later he awoke with rebral infarctions in nonvisual areas but no other markedly impaired vision in both eyes. By the next day abnormalities. he was unable to detect light with either eye, and there was bilateral papilledema. Burr holes were placed. Vi- CASE 2 sion only improved to light perception OD but to 20/ 200 OS. Vision remained unchanged until 1980 (age 47 The patient was born in 1930 and was well until the age of years) when he began to perceive a noticeable decline in 4 years when she developed episodes of vomiting and head- his ability to discern large objects with his left eye. Be- ache. Bilateral optic atrophy and nystagmus were recog- cause of increasing difficulty with ambulation, he began nized 5 years later leading to a diagnosis of craniostenosis training with a guide dog in 1981. In 1990 his VA was for which a decompressive craniotomy was performed. Her measured at light perception OD and 5/200 OS. Fundus first formal ophthalmologic examination in 1939 (age 10 examination showed stable bilateral optic atrophy. A mag- years) documented a VA of 20/70 OD and 20/50 OS. There netic resonance scan of the head in 1990 showed no ab- were bilateral optic atrophy, constricted visual fields, ex- normalities. Between 1991 and 1995 recorded VAs var- ophthalmos, and a comitant exotropia. Her intracranial pres- ied from 3/200 OS to 5/200 OS. In 1995 findings from sure was 170 mm; CSF and the fluid contents showed no an electroretinogram, vitamin B12 and folate levels, and abnormality. She was noted to have a reunion of her pre- a complete blood cell count were within normal limits vious bone flap and oxycephaly for which bilateral sub- except for evidence of thalassemia minor. He felt that VA temporal decompressions were performed. In 1944 her VA had further declined, but in 2001 his VA was still mea- was 20/100 OD and 20/50 OS. sured at 5/200 OS. There was no cataract or macular le- There were no changes until 1972 (age 42 years) when sions and intraocular pressure was normal in both eyes. she noticed that her vision was again declining. Visual acu- Magnetic resonance imaging showed only optic nerve at- ity was 20/200 OD and 20/70 OS. In 1988, she continued rophy. Two years later his VA was only 2/200 OS. to complain of failing vision and her VA had decreased to 3/100 OD and 20/100 OS. The right eye was completely color blind and she could only see the control Ishihara color COMMENT test plate with her left eye. There were bilateral central sco- tomas, nystagmus, and comitant exotropia. Apart from bi- All 3 of our patients had a monophasic illness in child- lateral optic atrophy her fundi were normal. Brain and or- hood that caused bilateral optic atrophy and visual im- bital computed tomographic scans showed only skull pairment (Table). Following decades of stability, each abnormalities consistent with craniostenosis. On lumbar suffered a gradual, symptomatic visual decline that ex- puncture there was normal CSF pressure and apart from a tended over years. The magnitude of the decline in each protein level of 57 g/dL, the CSF contents showed no ab- case was too great to be ascribed to intertest variability normality. Results from fluorescein angiography were nor- and was sufficiently severe to necessitate changes in oc- mal. Test results for the mitochondrial mutations of Leber cupation or lifestyle. No new ophthalmologic, systemic, hereditary optic neuropathy were negative. Ophthalmo- or neurologic disorder was found that explained the vi- logic examination showed no cataract or macular lesions; sual decline in any of the patients. The patients had evi- intraocular pressure were consistently normal in both eyes. dence of craniostenosis or increased intracranial pres- In 1995 (age 65 years) her VA was 4/200 OD and 6/200 sure when seen by us, disorders in which the visual loss OS. Fundus examination showed bilateral optic atro- is apt to result from atrophic papilledema. However, in phy, but no appreciable change in the contour of the op- 2 of these cases, the presence of persistently elevated in- tic discs was noted. She subsequently developed unex- tracranial pressure was ruled out by lumbar puncture or plained vertigo, but no neurologic or systemic disease has other testing methods during the period of visual de- been identified. cline. Absent other explanations, we hypothesize that the effects of neuronal loss secondary to aging might be re- CASE 3 sponsible for the late visual decline in these cases. The relation between VA and age has been exten- The patient was born in 1934. At age 11 years he devel- sively studied.1-4 There is a well-documented decline in oped right-sided mastoiditis necessitating a mastoidec- central acuity in normal individuals that is modest prior

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 to age 60 years but more impressive thereafter.1 Clini- nerve injury on the remaining population of axons and cally important eye disease, such as cataract, glaucoma, its long-term influence on the apoptotic threshold is un- and macular degeneration, were encountered in small known. It is possible that in cases of optic atrophy, the numbers in these population-based studies.1,4 Several au- metabolism of the remaining neurons may be impaired thors have also shown a decrease in the breadth and sen- with advancing age by the antecedent injury. sitivity of the visual field with age.5-7 Although increas- In otherwise healthy individuals, the decline in vi- ing miosis in older age groups may be invoked as a sual function with age, regardless of its pathogenesis, and contributing factor in this decline,8 the study by Drance anatomical and biochemical concomitants, is likely to re- et al6 showed a linear decrease in the size of both central main asymptomatic. Dolman et al14 commented that, de- and peripheral isopters despite pharmacological dila- spite the general trend reflecting a loss of axons with in- tion of the pupils in most subjects. Older individuals also creasing age, healthy patients did not report a diminution demonstrate a loss of contrast sensitivity at low spatial in vision. Even when there is depletion of ganglion cells frequencies, which is more consistent with neural than or their axons in a previously healthy individual, elemen- with optical factors.9,10 tary visual functions may remain preserved. Retinal gan- The neuroretinal basis for the decline in VA with ag- glion cell loss in chronic open-angle glaucoma is known ing is supported by anatomical data showing attenua- to occur before visual field changes can be detected.25,26 tion of the retinal nerve fiber layer in older subjects. Non- Quigley et al25 reported the case of a 44-year-old patient invasive imaging modalities such as optical coherence with glaucoma who retained normal VA and full visual tomography and confocal laser scanning tomography have fields despite having lost approximately 40% of his op- documented progressive thinning of the retinal nerve fi- tic nerve axons. In an experimental model a relative af- ber layer at the optic disc with age.11-13 The thinning is ferent pupillary defect could not be demonstrated in mon- thought to result from a nonpathological dropout of gan- keys who had lost 26% of their retinal ganglion cells.27 glion cell axons as part of the normal aging process.13 His- While the effects of aging on visual function generally tological studies on the human optic nerve have docu- remain subclinical in otherwise healthy individuals, those mented decreasing axonal nerve fiber counts with age, patients who had already incurred an optic neuropathy although the magnitude of the decline varies signifi- might suffer a late decline in visual function consequent cantly among studies.14-17 Dolman et al14 examined the to the age-related loss of axons and the age-related effect cross-sectional area of cadaver optic nerves in subjects on the metabolism of the surviving neurons. We hypoth- from birth to 96 years. They found that the optic nerves esize that this was the basis of the late progressive de- of patients older than 60 years displayed a diminished cline of vision in our patients. density of axons. Balazsi et al15 performed manual nerve There is a paradigm for the negative influence of aging fiber counts on high-power photomicrographs, sam- on neuronal function in the setting of neuronal depletion— pling 4% to 6% of the total neural area of the optic nerve. the postpolio syndrome. It is characterized by new neu- They concluded that age had an effect on the axonal count romuscular symptoms many years after recovery from acute of the human optic nerve, calculating a rate of decay of paralytic poliomyelitis. Postpolio syndrome is presumed 5637 axons per year. Johnson et al16 used a semiauto- to result from excessive metabolic stress on a compro- matic method, finding a small decrease in axonal counts mised population of motor neurons over many years that with age that was statistically significant, with a differ- results in the dysfunction or frank dropout of the surviv- ence of almost 100 000 axons between the young and el- ing motor neurons.28,29 This is supported by electromyo- derly groups. The optic nerve is not exceptional in this graphic and muscle biopsy studies that demonstrate a slow regard, axonal depletion having been demonstrated in sev- disintegration of individual nerve terminals in affected pa- eral areas of the cerebral cortex and in the anterior horn tients.30 Similar to patients with optic nerve injury, pro- of the spinal cord.18,19 gression of the postpolio syndrome tends to be slow and The pathogenesis of the age-related attrition of optic patients often have long periods of subjective stability. nerve axons has not been elucidated. Some authors have proposed programmed apoptosis of retinal ganglion cells, CONCLUSIONS initiated by mitochondrial dysfunction.20 Mitochondria are abundant in retinal ganglion cells and in the unmy- 20,21 We propose that age-related loss of neurons that sur- elinated portion of the axon at the optic nerve head. vived an initial damage to the optic nerve was respon- Dysfunction of axonal mitochondria has been impli- sible for the slow and delayed visual decline that was mani- cated in the death of retinal ganglion cells in both con- fested by each of our patients. Slow, delayed visual genital and acquired optic neuropathies.22 Although their impairment in the setting of severe bilateral visual loss role in aging-related apoptosis is unknown, mitochon- following a presumably static optic neuropathy may re- dria are known to represent an important source of free quire decades of careful observation and examination be- radicals in cells, as oxygen free radicals and hydroper- fore it can be detected clinically. We suspect that this clini- oxides are generated continuously in the mitochondrial cal phenomenon may be more common than generally respiratory chain.23,24 Over time, these mitochondrial by- recognized. products may cause cumulative oxidative damage to cellular proteins, lipids and DNA, even mitochondrial DNA. This destructive cycle of free radical generation and dam- Submitted for Publication: April 23, 2004; final revi- age is thought to produce a chronic oxidative stress that sion received August 18, 2004; accepted September 12, plays a key role in cellular aging.23 The effect of an optic 2004.

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Correspondence: Simmons Lessell, MD, 243 Charles St, 16. Johnson BM, Miao M, Sadun AA. Age-related decline of human optic nerve axon Boston, MA 02114 ([email protected] populations. Age. 1987;20:5-9. 17. Repka MX, Quigley HA. The effect of age on normal human optic nerve fiber num- .edu). ber and density. Ophthalmology. 1989;96:26-32. 18. Henderson G, Tomlinson BE, Gibson PH. Cell counts in human cerebral cortex REFERENCES in normal adults through life using an image analyzing computer. J Neurol Sci. 1980;46:113-136. 19. McComas AJ. Invited review: motor unit estimation: methods, results, and 1. Anderson B, Palmore E. Longitudinal evaluation of ocular function, In: Palmore E, ed. Normal Aging II, Reports From the Duke Longitudinal Studies. Durham, present status. Muscle Nerve. 1991;14:585-597. NC: Duke University Press;1970-1973;24-32. 20. Bossy-Wetzel E, Barsoum MJ, Godzik A, Schwarzenbacher R, Lipton SA. Mito- 2. Richards OW. Effects of luminance and contrast on visual acuity, ages 16 to 90 chondrial fission in apoptosis, neurodegeneration and aging. Curr Opin Cell Biol. years. Am J Optom Physiol Opt. 1977;54:178-184. 2003;15:706-716. 3. Slataper FJ. Age norms of refraction and vision. Arch Ophthalmol. 1950;43:466-481. 21. Lessell S, Horovitz B. Histochemical study of enzymes of optic nerve of monkey 4. Haegerstrom-Portnoy G, Schneck ME, Brabyn JA. Seeing into old age: vision func- and rat. Am J Ophthalmol. 1972;74:118-126. tion beyond acuity. Optom Vis Sci. 1999;76:141-158. 22. Carelli V, Ross-Cisneros FN, Sadun A. Optic nerve degeneration and mitochon- 5. Drance SM, Berry V, Hughes A. The effects of age on the central isopter of the drial dysfunction: genetic and acquired optic neuropathies. Neurochem Int. 2002; normal visual field. Can J Ophthalmol. 1967;63:1667-1672. 40:573-584. 6. Drance SM, Berry V, Hughes A. Studies on the effects of age on the central and 23. Vina J, Sastre J, Pallardo F, Borras C. Mitochondrial theory of aging: importance peripheral isopters of the visual field in normal subjects. Am J Ophthalmol. 1967; to explain why females live longer than males. Antioxid Redox Signal. 2003; 63:1667-1672. 5:549-556. 7. Shutt HK, Boyd TA, Slater AB. The relationship of the visual fields, optic disc ap- 24. Jacobs HT. The mitochondrial theory of aging: dead or alive? Aging Cell. 2003; pearance and age in non-glaucomatous and glaucomatous eyes. Can J Ophthalmol. 2:11-17. 1967;2:83-90. 25. Quigley HA, Addicks EM, Green WR. Optic nerve damage in human glaucoma, 8. Loewenfeld IE. Pupillary changes related to age. In: Thompson HHS, ed. Topics III: quantitative correlation of nerve fiber loss and visual field defect in glau- in Neuro-ophthalmology. Baltimore, Md: Williams & Wilkins;1979: 124-150. coma, ischemic neuropathy, papilledema, and toxic neuropathy. Arch Ophthalmol. 9. Sekuler R, Hutman LP. Spatial vision and aging, I: contrast sensitivity. J Gerontol. 1982;100:135-146. 1980;35:692-699. 26. Quigley HA, Hohman RM, Addicks EM, et al. Morphologic changes in the lamina 10. Hutman LP, Sekuler R. Spatial vision and aging, II: criterion effects. J Gerontol. cribrosa correlated with neural loss in open-angle glaucoma. Am J Ophthalmol. 1980;35:700-706. 1983;95:673-691. 11. Poinoosawmy D, Fontana L, Wu JX, Fitzke FW, Hitchings RA. Variation of nerve 27. Kerrison JB, Buchanan K, Rosenberg ML. Quantification of optic nerve axon loss fibre layer thickness measurements with age and ethnicity by scanning laser associated with a relative afferent pupillary defect in the monkey. Arch Ophthalmol. polarimetry. Br J Ophthalmol. 1997;81:350-354. 12. Alamouti B, Funk J. Retinal thickness decreases with age: an OCT study. Br J 2001;119:1333-1341. Ophthalmol. 2003;87:899-901. 28. McComas AJ, Quartly C, Griggs RC. Early and late losses of motor units after 13. Lovasik JV, Kergoat MJ, Justino L, Kergoat H. Neuroretinal basis of visual impair- poliomyelitis. Brain. 1997;120:1415-1421. ment in the very elderly. Graefes Arch Clin Exp Ophthalmol. 2003;241:48-55. 29. Cashman NR, Maselli R, Wollmann RL, Roos R, Simon R, Antel JP. Late dener- 14. Dolman CL, McCormick AQ, Drance SM. Aging of the optic nerve. Arch Ophthalmol. vation in patients with antecedent paralytic poliomyelitis. N Engl J Med. 1987; 1980;98:2053-2058. 317:7-12. 15. Balazsi AG, Rootman J, Drance SM, Schulzer M, Douglas GR. The effect of age 30. Dalakas MC, Elder G, Hallett M, et al. A long-term follow-up study of patients on the nerve fiber population of the human optic nerve. Am J Ophthalmol. 1984; with post-poliomyelitis neuromuscular symptoms. N Engl J Med. 1986;314: 97:760-766. 959-963.

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