Clinical background
Optic atrophy can be considered the wasting of a once-healthy optic nerve. This definition excludes conditions associated with optic nerve dysplasia, hypoplasia, or aplasia in which the optic nerve is developmentally and structurally abnormal. Optic atrophy is the final common result of injury to the retinal ganglion cells, nerve fiber layer, optic nerve, chiasm, or optic tract. Additionally, prenatal or perinatal injury of posterior structures including occipital cortex may result in transsynaptic degeneration of the optic nerves. The range and variety of potential insults to these structures are vast and include: vascular, infectious, metabolic, traumatic, toxic, neoplastic/paraneoplastic, autoimmune/inflammatory, compressive, and inherited etiologies. The evolution of optic atrophy depends on the location and extent of injury as well as the nature of the insult (i.e., rapid progression in the case of traumatic section of the optic nerve versus slow progression in the case of optic nerve sheath meningioma). Because optic atrophy is a late marker of irreversible optic nerve injury and not a disease itself, visual symptoms are directly related to the underlying pathology.
Localizing value of optic atrophy patterns
Segmental or regional atrophy of the retinal nerve fiber layer (RNFL) or pallor of the optic disc, in concert with the clinical history and other exam findings, may have localizing value. Nonarteritic anterior ischemic optic neuropathy (NAION) often preferentially affects the superotemporal fibers, producing inferonasal visual field loss. Segmental pallor of the optic disc can often be appreciated after the acute swelling has resolved. Segmental pallor not preceded by optic disc edema may result from a nonischemic optic nerve lesion ( Figure 44.1A ) and may be indistinguishable from post-swelling NAION.
Segmental atrophy has localizing value in the case of band atrophy ( Figure 44.2 ) or so-called “bowtie” atrophy, such as in lesions of the optic chiasm or optic tract ( Box 44.1 ).
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Band atrophy localizes to the contralateral optic tract if unilateral and the optic chiasm if bilateral
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Pallor of the temporal optic disc can be a normal finding; it should be judged in the context of all available clinical information
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Unilateral atrophy with optic disc edema in the fellow eye likely represents a subfrontal intracranial mass lesion or bilateral, nonsimultaneous nonarteritic anterior ischemic optic neuropathy
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“Pseudoatrophy” occurs when the optic disc appears pale without evidence of atrophy
Temporal pallor may be seen when a disease processes preferentially affects the maculopapillary bundle, such as toxicity, vitamin deficiency, inherited optic neuropathy, and demyelination. Apparent temporal pallor can be seen in normal individuals but does not represent atrophy; the nerve fiber layer coursing into the optic disc is thinnest in this region and so the neuroretinal rim may not be as pink in this sector. Additionally, there may be other factors such as an enlarged cup or a scleral temporal crescent that give the appearance of pallor when there is no atrophy.
Diffuse optic atrophy ( Figure 44.1C ) has less potential localizing value than segmental atrophy. If it is strictly unilateral, it localizes to the ipsilateral optic nerve. Bilateral diffuse optic atrophy has the least localizing value as it can be due to disorders of both optic nerves, optic chiasm, bilateral optic tracts or, in rare cases, bilateral postgeniculate visual structures occurring in the perinatal period (see discussion of transsynaptic degeneration, above).
Segmental atrophy in the form of pathological cupping is seen in the case of glaucoma as notching of the neuroretinal rim ( Figure 44.1D ).
Mimics of optic atrophy
Any condition that causes the disc to appear pale in the absence of atrophy may lead to misdiagnosis of optic atrophy. A common condition is aphakic or pseudophakic pseudopallor ( Figure 44.3E ). This results after lens extraction because of loss of the light-attenuating properties of the natural lens. In a unilateral pseudophakic patient who has a nuclear cataract in the fellow eye, the difference in the color of the discs is even more pronounced because nuclear sclerosis causes the disc to appear redder than normal.
Another condition which may mimic optic atrophy is the setting of resolved optic disc edema, in which there may be significant gliosis over the optic disc. The disc may look pale but there will be a normal or even thickened peripapillary RNFL by optical coherence tomography (OCT). Myelinated nerve fibers may also give the appearance of disc pallor ( Figure 44.3A ). This can be segmental (occurring in only one portion of the disc) or diffuse (covering the entire disc). Arteritic anterior ischemic optic neuropathy (AION) is occasionally associated with pallid swelling of the optic nerve during the acute stage due to optic nerve infarction ( Figure 44.3B ). Infiltrative diseases such as lymphoma may also present with a pale but not atrophic nerve. Buried drusen and retinitis pigmentosa ( Figure 44.3C and 44.3D ) are also occasionally associated with optic disc pallor, but not necessarily atrophy.
Pathophysiology
Pathogenic mechanisms of optic atrophy
Under experimental conditions, atrophy of the optic nerve occurs as a predictable, reproducible, and irreversible response to injury of retinal ganglion cells or their axons. Injured axons degenerate in both a retrograde (toward the cell body) and antegrade (wallerian degeneration – away from the cell body) fashion. An eventual additional consequence of axon injury is apoptosis of retinal ganglion cells (RGCs).
A murine model of antegrade degeneration has made use of a spontaneously occurring dominant mutation dubbed Wld s for “slow wallerian degeneration.” Mice with this mutation have significantly delayed wallerian degeneration after a variety of insults, including traumatic, toxic, and genetic insults. Studies indicate that important final common pathway features of antegrade degeneration include failure of antegrade axonal transport from the cell body followed by mitochondrial failure. These cause a rise in intra-axonal Ca 2+ which activates calpain, a proteolytic enzyme whose activation results in degradation of the cytoskeleton and membrane proteins. The genetic defect in the Wld s murine model appears to resist this series of events after an experimental crush injury, delaying but not preventing atrophy. A recent study by Wang et al demonstrated that axon degeneration and RGC body death proceed via different cellular mechanisms. They showed that, after optic nerve axotomy, Wld s mice showed the expected delay in axonal degeneration but no delay in RGC body (retrograde) degeneration, even though the Wld s gene product appears to be located in the RGC nucleus.
While optic atrophy secondary to transsynaptic retrograde axonal degeneration (from an injury to the occipital cortex or lateral geniculate body) has been rigorously demonstrated in primates, evidence that it occurs in humans is anecdotal and based only on case reports. There are conflicting opinions regarding its occurrence in older children and adults but most authors believe this phenomenon only occurs in patients who have sustained perinatal or prenatal cerebral injuries. The cellular mechanisms which underlie transsynaptic degeneration are not well understood. In addition, there is evidence that prenatal cerebral injury results not in optic atrophy but in a specific pattern of optic nerve hypoplasia.
Pathogenic mechanisms of optic disc pallor
The clinical hallmark of nonglaucomatous optic atrophy is pallor of the optic disc, seen ophthalmoscopically ( Box 44.2 ). Strictly speaking, “pallor” is a subjective and comparative term that is somewhat ill-defined. To state that a disc is pale requires appreciation of “normal” disc color, which can vary widely among individuals. Furthermore, factors which may influence perception of the disc color include the color of the background fundus (a darkly colored fundus may make a normal optic disc appear relatively pale), the size of the physiologic optic cup (a larger cup shows more of the white lamina cribrosa), and the patient’s refraction (a myopic eye may have a white scleral crescent adjacent to the disc, making it appear pale). It is often helpful to compare the color of the disc in the fellow eye in cases of suspected unilateral optic atrophy. It is important to understand the mechanisms responsible for the development of optic disc pallor when making a diagnosis of optic atrophy.
