Delayed Visual Decline in Patients With “Stable” Optic Neuropathy FREE

The tacit assumption that progression or recurrence of an optic neuropathy results from the same mechanism that inaugurated the disorder has tended to obscure the possibility that in some cases these phenomena might have a pathogenesis independent of the original. In this article we postulate such a scenario in 3 patients who, after decades of stable but impaired vision following childhood optic atrophy, developed a progressive visual decline. We hypothesize that the late visual decline in these patients resulted from deleterious effects of age-related axonal loss on an already depleted population of neurons.

The patient was born in 1915, and he lost vision in both of his eyes during childhood, allegedly after an episode of whooping cough. Records of that illness are unavailable. At his first formal ophthalmologic examination in 1943 (age 28 years), the visual acuity (VA) was 20/40 OD and counting fingers OS, and there was comitant left exotropia. There was generalized constriction of the visual field of his right eye and a superior defect extending across fixation on the left side. Both optic discs were pale, but there were no other fundus lesions. Lumbar puncture with examination of the cerebrospinal fluid (CSF) gave normal results. The result of a serologic test for syphilis was negative. Plain skull radiographs showed craniostenosis with a tower skull deformity.

His vision had remained unchanged until the patient was in his mid 40s when worsening visual disability forced him to stop working as a machinist. In 1965 (age 50 years) he was examined reporting of a further loss of vision; his VA was 20/200 OD and counting fingers OS. Findings from an ophthalmologic examination showed no evidence of cataracts or macular degeneration and the intraocular pressure was within normal limits in both eyes. Findings from a screening neurologic examination revealed no abnormalities; no new changes were detected on plain skull radiographs. Despite cerebral arteriography, pneumoencephalography, and CSF analysis, no cause could be established for his progressive decline in vision. At the age of 75 years in 1990 he reported that poor vision required him to use a cane to ambulate safely. His VA had declined to 2/100 OD and hand motions OS. There was bilateral optic atrophy that was unchanged from previous examinations. Findings from a general neurologic examination did not reveal any deficits. A computed tomographic scan of the brain showed multiple cerebral infarctions in nonvisual areas but no other abnormalities.

The patient was born in 1930 and was well until the age of 4 years when she developed episodes of vomiting and headache. Bilateral optic atrophy and nystagmus were recognized 5 years later leading to a diagnosis of craniostenosis for which a decompressive craniotomy was performed. Her first formal ophthalmologic examination in 1939 (age 10 years) documented a VA of 20/70 OD and 20/50 OS. There were bilateral optic atrophy, constricted visual fields, exophthalmos, and a comitant exotropia. Her intracranial pressure was 170 mm; CSF and the fluid contents showed no abnormality. She was noted to have a reunion of her previous bone flap and oxycephaly for which bilateral subtemporal decompressions were performed. In 1944 her VA was 20/100 OD and 20/50 OS.

There were no changes until 1972 (age 42 years) when she noticed that her vision was again declining. Visual acuity was 20/200 OD and 20/70 OS. In 1988, she continued 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 test plate with her left eye. There were bilateral central scotomas, nystagmus, and comitant exotropia. Apart from bilateral optic atrophy her fundi were normal. Brain and orbital computed tomographic scans showed only skull abnormalities consistent with craniostenosis. On lumbar puncture there was normal CSF pressure and apart from a protein level of 57 g/dL, the CSF contents showed no abnormality. Results from fluorescein angiography were normal. Test results for the mitochondrial mutations of Leber hereditary optic neuropathy were negative. Ophthalmologic examination showed no cataract or macular lesions; intraocular pressure were consistently normal in both eyes. In 1995 (age 65 years) her VA was 4/200 OD and 6/200 OS. Fundus examination showed bilateral optic atrophy, but no appreciable change in the contour of the optic discs was noted. She subsequently developed unexplained vertigo, but no neurologic or systemic disease has been identified.

The patient was born in 1934. At age 11 years he developed right-sided mastoiditis necessitating a mastoidectomy. Four days after surgery he developed headache and backache. Approximately 2 to 3 weeks later he awoke with markedly impaired vision in both eyes. By the next day he was unable to detect light with either eye, and there was bilateral papilledema. Burr holes were placed. Vision only improved to light perception OD but to 20/200 OS. Vision remained unchanged until 1980 (age 47 years) when he began to perceive a noticeable decline in his ability to discern large objects with his left eye. Because of increasing difficulty with ambulation, he began training with a guide dog in 1981. In 1990 his VA was measured at light perception OD and 5/200 OS. Fundus examination showed stable bilateral optic atrophy. A magnetic resonance scan of the head in 1990 showed no abnormalities. Between 1991 and 1995 recorded VAs varied from 3/200 OS to 5/200 OS. In 1995 findings from an electroretinogram, vitamin B₁₂ and folate levels, and a complete blood cell count were within normal limits except for evidence of thalassemia minor. He felt that VA had further declined, but in 2001 his VA was still measured at 5/200 OS. There was no cataract or macular lesions and intraocular pressure was normal in both eyes. Magnetic resonance imaging showed only optic nerve atrophy. Two years later his VA was only 2/200 OS.

All 3 of our patients had a monophasic illness in childhood that caused bilateral optic atrophy and visual impairment (Table). Following decades of stability, each suffered a gradual, symptomatic visual decline that extended over years. The magnitude of the decline in each case was too great to be ascribed to intertest variability and was sufficiently severe to necessitate changes in occupation or lifestyle. No new ophthalmologic, systemic, or neurologic disorder was found that explained the visual decline in any of the patients. The patients had evidence of craniostenosis or increased intracranial pressure when seen by us, disorders in which the visual loss is apt to result from atrophic papilledema. However, in 2 of these cases, the presence of persistently elevated intracranial pressure was ruled out by lumbar puncture or other testing methods during the period of visual decline. Absent other explanations, we hypothesize that the effects of neuronal loss secondary to aging might be responsible for the late visual decline in these cases.

The relation between VA and age has been extensively studied.^{1 - 4} There is a well-documented decline in central acuity in normal individuals that is modest prior to age 60 years but more impressive thereafter.¹ Clinically important eye disease, such as cataract, glaucoma, and macular degeneration, were encountered in small numbers in these population-based studies.^{1 ,4} Several authors have also shown a decrease in the breadth and sensitivity of the visual field with age.^{5 - 7} Although increasing miosis in older age groups may be invoked as a contributing factor in this decline,⁸ the study by Drance et al⁶ showed a linear decrease in the size of both central and peripheral isopters despite pharmacological dilation of the pupils in most subjects. Older individuals also demonstrate a loss of contrast sensitivity at low spatial frequencies, which is more consistent with neural than with optical factors.^{9 - 10}

The neuroretinal basis for the decline in VA with aging is supported by anatomical data showing attenuation of the retinal nerve fiber layer in older subjects. Noninvasive imaging modalities such as optical coherence tomography and confocal laser scanning tomography have documented progressive thinning of the retinal nerve fiber layer at the optic disc with age.^{11 - 13} The thinning is thought to result from a nonpathological dropout of ganglion cell axons as part of the normal aging process.¹³ Histological studies on the human optic nerve have documented decreasing axonal nerve fiber counts with age, although the magnitude of the decline varies significantly among studies.^{14 - 17} Dolman et al¹⁴ examined the cross-sectional area of cadaver optic nerves in subjects from birth to 96 years. They found that the optic nerves of patients older than 60 years displayed a diminished density of axons. Balazsi et al¹⁵ performed manual nerve fiber counts on high-power photomicrographs, sampling 4% to 6% of the total neural area of the optic nerve. They concluded that age had an effect on the axonal count of the human optic nerve, calculating a rate of decay of 5637 axons per year. Johnson et al¹⁶ used a semiautomatic method, finding a small decrease in axonal counts with age that was statistically significant, with a difference of almost 100 000 axons between the young and elderly groups. The optic nerve is not exceptional in this regard, axonal depletion having been demonstrated in several areas of the cerebral cortex and in the anterior horn of the spinal cord.^{18 - 19}

The pathogenesis of the age-related attrition of optic nerve axons has not been elucidated. Some authors have proposed programmed apoptosis of retinal ganglion cells, initiated by mitochondrial dysfunction.²⁰ Mitochondria are abundant in retinal ganglion cells and in the unmyelinated portion of the axon at the optic nerve head.^{20 - 21} Dysfunction of axonal mitochondria has been implicated in the death of retinal ganglion cells in both congenital and acquired optic neuropathies.²² Although their role in aging-related apoptosis is unknown, mitochondria are known to represent an important source of free radicals in cells, as oxygen free radicals and hydroperoxides are generated continuously in the mitochondrial respiratory chain.^{23 - 24} Over time, these mitochondrial byproducts may cause cumulative oxidative damage to cellular proteins, lipids and DNA, even mitochondrial DNA. This destructive cycle of free radical generation and damage is thought to produce a chronic oxidative stress that plays a key role in cellular aging.²³ The effect of an optic nerve injury on the remaining population of axons and its long-term influence on the apoptotic threshold is unknown. It is possible that in cases of optic atrophy, the metabolism of the remaining neurons may be impaired with advancing age by the antecedent injury.

In otherwise healthy individuals, the decline in visual function with age, regardless of its pathogenesis, and anatomical and biochemical concomitants, is likely to remain asymptomatic. Dolman et al¹⁴ commented that, despite the general trend reflecting a loss of axons with increasing age, healthy patients did not report a diminution in vision. Even when there is depletion of ganglion cells or their axons in a previously healthy individual, elementary visual functions may remain preserved. Retinal ganglion cell loss in chronic open-angle glaucoma is known to occur before visual field changes can be detected.^{25 - 26} Quigley et al²⁵ reported the case of a 44-year-old patient with glaucoma who retained normal VA and full visual fields despite having lost approximately 40% of his optic nerve axons. In an experimental model a relative afferent pupillary defect could not be demonstrated in monkeys who had lost 26% of their retinal ganglion cells.²⁷ While the effects of aging on visual function generally remain subclinical in otherwise healthy individuals, those patients who had already incurred an optic neuropathy might suffer a late decline in visual function consequent to the age-related loss of axons and the age-related effect on the metabolism of the surviving neurons. We hypothesize that this was the basis of the late progressive decline of vision in our patients.

There is a paradigm for the negative influence of aging on neuronal function in the setting of neuronal depletion—the postpolio syndrome. It is characterized by new neuromuscular symptoms many years after recovery from acute paralytic poliomyelitis. Postpolio syndrome is presumed to result from excessive metabolic stress on a compromised population of motor neurons over many years that results in the dysfunction or frank dropout of the surviving motor neurons.^{28 - 29} This is supported by electromyographic and muscle biopsy studies that demonstrate a slow disintegration of individual nerve terminals in affected patients.³⁰ Similar to patients with optic nerve injury, progression of the postpolio syndrome tends to be slow and patients often have long periods of subjective stability.

We propose that age-related loss of neurons that survived an initial damage to the optic nerve was responsible for the slow and delayed visual decline that was manifested by each of our patients. Slow, delayed visual impairment in the setting of severe bilateral visual loss following a presumably static optic neuropathy may require decades of careful observation and examination before it can be detected clinically. We suspect that this clinical phenomenon may be more common than generally recognized.

Correspondence: Simmons Lessell, MD, 243 Charles St, Boston, MA 02114 (Simmons_Lessell@meei.harvard.edu).

Submitted for Publication: April 23, 2004; final revision received August 18, 2004; accepted September 12, 2004.

Financial Disclosure: None.