Optic Atrophy

Optic atrophy is the final common morphologic endpoint of disease process that causes degeneration of axons of the ganglion cells.[1] Clinically, optic atrophy manifests as changes in the color and the structure of the optic disc (cupping) associated with variable degrees of visual dysfunction. The term "atrophy" is a misnomer, since, in its strict histologic definition, atrophy implies involution of a structure due to prolonged disuse.[1]

The optic nerve comprises of approximately 1.2 million axons that originate at the ganglion cell layer of the retina. Upon exiting the eye ball, the axons are covered with myelin sheath provided by oligodendrocytes.Once injured they do not regenerate. Thus, the optic nerve behaves more like a white matter tract rather than a true peripheral nerve.

The optic nerve is divided into the following 4 parts: 


• Intraocular part (1 mm) (optic nerve head)
• Intraorbital part (25-30 mm)
• Intracanalicular part (5-10mm)
• Intracranial part (10-16 mm)

The average optic nerve head is 1 mm deep, 1.5 mm wide, 1.8 mm deep at the retinal level. The optic nerve head sits at a major transition between an area of high pressure to an area of low pressure (intracranial pressure) and is composed of 4 types of cells: ganglion cell axons, astrocytes, capillary-associated cells, and fibroblasts.

Clinically, the light incident from the ophthalmoscope undergoes total internal reflection through the axonal fibers, and subsequent reflection from the capillaries on the disc surface gives rise to the characteristic yellow-pink color of a healthy optic disc. Degenerated axons lose this optical property, explaining the pallor in optic atrophy.

The blood supply at the optic nerve head is provided by pial capillaries arising from the circle of Zinn-Haller. Alternatively, the loss of these capillaries can also be a cause to pale-appearing disc. The Kestenbaum capillary number index is the number of capillaries counted on the optic disc, which is normally around 10. Less than 6 indicates atrophy and more than 12 indicates hyperemic disc

Histopathologic changes noted in optic atrophy include the following:

• Shrinkage or loss of both myelin and axis cylinders
• Glial cell proliferation
• Deepening of the physiologic cup with barring of the lamina cribrosa
• Widening of the subarachnoid space with redundant dura with widening of the pial septa
• Severed nerve leads to bulbous axonal swellings (Cajal end bulbs); may be observed at the anterior cut end of the fibers

Classification

Optic atrophy is classified as pathologic, ophthalmoscopic, or etiologic.

1. Pathologic optic atrophy

Anterograde degeneration (Wallerian degeneration) - Degeneration begins in the retina and proceeds toward the lateral geniculate body (eg, toxic retinopathy, chronic simple glaucoma). Larger axons disintegrate more rapidly than smaller axons.

Retrograde degeneration - Degeneration starts from the proximal portion of the axon and proceeds toward the optic disc (eg, optic nerve compression by intracranial tumor).

Trans-synaptic degeneration - In trans-synaptic degeneration, a neuron on one side of a synapse degenerates as a consequence of the loss of a neuron on the other side (eg, in individuals with occipital damage incurred either in utero or during early infancy).

2. Ophthalmoscopic optic atrophy

a) Primary optic atrophy

In conditions with primary optic atrophy (eg, pituitary tumor, optic nerve tumor, traumatic optic neuropathy, multiple sclerosis), optic nerve fibers degenerate in an orderly manner and are replaced by columns of glial cells without alteration in the architecture of the optic nerve head. The disc is chalky white with sharply demarcated margins, and the retinal vessels are normal. The lamina cribrosa is well defined.

b) Secondary optic atrophy

In conditions with secondary optic atrophy (eg, papilledema, papillitis), the atrophy is secondary to disc edema (shown in the image below). Optic nerve fibers exhibit marked degeneration, with excessive proliferation of glial tissue. The surface architecture is lost, resulting in indistinct margins. The disc appears grey or dirty grey, with poorly defined margins. The lamina cribrosa is obscured due to proliferating fibroglial tissue. Hyaline bodies (corpora amylacea) or drusen may sometimes observed. 

c) Consecutive optic atrophy

Consecutive atrophy is an ascending type of atrophy (eg, chorioretinitis, pigmentary retinal dystrophy, cerebromacular degeneration) that usually results from diseases of the choroid or the retina. The disc is waxy pale with normal disc margins, marked attenuation of arteries.

d) Glaucomatous optic atrophy

Also known as cavernous optic atrophy,  there is marked cupping of the disc. The main features include vertical enlargement of optic cup, visibility of the laminar pores (laminar dot sign) with backward bowing of the lamina cribrosa, bayoneting or nasal shifting of the retinal vessels, and peripapillary halo and atrophy.

e) Temporal pallor

Temporal pallor may be observed in traumatic or nutritional optic neuropathy, and it is most commonly seen in patients with multiple sclerosis, particularly in those with a history of optic neuritis. The disc is pale with a clear, demarcated margin and normal vessels, and the physiologic pallor temporally is more distinctly pale.

3. Etiologic optic atrophy

Hereditary atrophy

This is divided into congenital or infantile optic atrophy (recessive or dominant form), Behr hereditary optic atrophy (autosomal recessive), and Leber optic atrophy.[2, 3] Several hereditary optic neuropathies, including optic atrophy type 1 and Leber optic atrophy, have been attributed to mitochondrial dysfunction in retinal ganglion cells.[1, 1]

Autosomal-dominant optic atrophy type 1 is caused by mutations in the OPA1 gene on chromosome 3q29. The OPA1 protein produced plays a key role in a process called oxidative phosphorylation and in self-destruction of cells (apoptosis). OPA1 is an integral pro-fusion protein within the internal mitochondrial membrane. Mutations in the OPA1 gene lead to vision problems experienced by people with breakdown of structures that transmit visual information from the eyes to the brain. Affected individuals first experience a progressive loss of nerve cells within the retina, called retinal ganglion cells. The loss of these cells is followed by the degeneration (atrophy) of the optic nerve.

X-linked optic atrophy type 2 is caused by mutation in the OPA2 gene with cytogenetic location Xp11.4-p11.21. The patient presents with early-onset childhood vision loss with slow progression of loss.

Hereditary optic atrophy type 3 is caused by mutation in the OPA3 gene with cytogenetic location 19q13.32. The mutation in this gene is associated with childhood-onset vision loss with cataract. It can also be associated with type III methylglutaconic aciduria.

Leber hereditary optic neuropathy results from mitochondrial point mutations in mtDNA 11778G>A, 14484T>C, or 3460G>A mutations.

Consecutive atrophy

Consecutive atrophy is an ascending type of atrophy (eg, chorioretinitis, pigmentary retinal dystrophy, cerebromacular degeneration) that usually follows diseases of the choroid or the retina.

Circulatory atrophy (vascular)

Circulatory atrophy is an ischemic optic neuropathy observed when the perfusion pressure of the ciliary body falls below the intraocular pressure. Circulatory atrophy is observed in central retinal artery occlusion, carotid artery occlusion, and cranial arteritis.

Metabolic atrophy

It is observed in disorders such as thyroid ophthalmopathy, juvenile diabetes mellitus, nutritional amblyopia, toxic amblyopia, tobacco, methyl alcohol, and drugs (eg, ethambutol, sulphonamides).

Demyelinating atrophy

It is observed in diseases such as multiple sclerosis and Devic disease.

Pressure or traction atrophy

It is observed in diseases such as glaucoma and papilledema.

Postinflammatory atrophy

It is observed in diseases such as optic neuritis, perineuritis secondary to inflammation of the meninges, and sinus and orbital cellulites.

Traumatic optic neuropathy

The exact pathophysiology of traumatic optic neuropathy is poorly understood, although optic nerve avulsion and transection, optic nerve sheath hematoma, and optic nerve impingement from a penetrating foreign body or bony fragment all reflect traumatic forms of optic nerve dysfunction that can lead to optic atrophy.[1]

Regardless of etiology, optic atrophy is associated with variable degrees of visual dysfunction, which may be detected by one or all of the optic nerve function tests.[1]

See Other Tests.

Radiation optic neuropathy

Radiation optic neuropathy more frequently occurs with radiation doses of at least 5,000 centigray. It may be result from radiation damage to the optic nerve vasculature or the optic nerve parenchyma itself.

Frequency

United States

According to Tielsch et al, the prevalence of blindness attributable to optic atrophy was 0.8%.[4]

The prevalence of visual impairment and blindness attributable to optic atrophy was found to be 0.04% and 0.12%, respectively.[5]

Mortality/Morbidity

Optic atrophy is not a disease but an end outcome thus, morbidity and mortality in optic atrophy depends on the etiology.

Race

Optic atrophy is more prevalent in African Americans (0.3%) than in whites (0.05%).

Sex

There is no sexual predisposition noted.

Age

Optic atrophy is seen in any age group.

Optic atrophy is an end-stage disease, although anecdotal reports have described significant vision improvement in the fellow eye following acute optic neuropathy or geographic atrophy.[6, 7] Early and intensive treatment in nutritional optic neuropathy can provide patients with near-normal vision.

RNFL (retinal nerve fiber layer)OCT measurements have revelaed marked optic nerve axon reserve before symptomatic presentation  after which  a small changes in nerve fiber loss lead to significant decrease in vision.[8]  Therefore, one should remember early identification and treatment of cause is the key to save useful vision.

When examining a patient with a pale disc, nonpathologic causes of optic atrophy must be ruled out (pseudo atrophy), as follows:

• Axial myopia: The optic disc has a segmental whitish appearance due to an oblique angle of insertion of the optic nerve and nasal displacement of the optic nerve contents.
• Myelinated nerve fibers: Feathery margins are due to the superficial location, usually adjacent to the disc.
• Optic nerve pit: Small colobomas are most often located in the inferotemporal portion of the disc.
• Tilted disc leads to confusion.
• Optic nerve hypoplasia is characterized by a small disc and peripapillary double ring sign, and the inner ring is actually the optic disc margin.
• Scleral crescent areas - devoid of retinal pigment epithelium.
• Optic disc drusen
• Fundus viewing through an intraocular lens implant
• Brighter-than-normal luminosity: The luminosity of an indirect ophthalmoscope is approximately 2000 lux and that of a direct ophthalmoscope is up to 900 lux. A disc appears pale if the luminosity of the instrument is brighter than normal.

Optic atrophy in young individuals

Hereditary and congenital optic atrophy generally presents in the first or second decade of life. They can be broadly classified into the following three major groups:

• Optic atrophy with generalized white matter disease (eg, adrenoleukodystrophy)
• Optic atrophy with seemingly unrelated systemic features (generally associated with OPA1 gene mutation)
• Isolated optic atrophy (may be autosomal dominant or recessive mitochondrial inheritance; eg, Leber hereditary optic neuropathy)

The type of neuroimaging study depends on the disease process.

• For tumors located in the orbit, ultrasonography can be performed in addition to CT scanning or MRI. For papilledema, B-scan ultrasonography may show optic sheath dilatation.

• To find out whether a lesion is cystic or solid (eg, cysticercoids), CT or MRI is recommended. For solid lesions, MRI (with contrast or fat suppression) is preferred in areas in close proximity to the bony wall.

• For fractures associated with trauma, a noncontrast CT scan is preferred.

• For multiple sclerosis, a gadolinium-enhanced MRI/fluid-attenuated inversion recovery (FLAIR) sequence is useful to detect hyperechoic areas.

Visual acuity testing

Visual acuity is measured using Snellen optotypes or a LogMAR chart. Visual acuity is reduced, occasionally to no light perception.

Stimulus parameters affecting visual acuity include contrast of the chart, refractive error, pupil size, stimulus eccentricity, duration of stimulus presentation, type of optotype used, illumination, and crowding phenomenon.

Color vision testing

Color vision is more decreased in patients with optic nerve disorders than in those with retinal disorders, especially among individuals with ischemic and compressive optic neuropathy. Prerequisites for color vision testing include proper lighting (both an adequate amount of light and the proper spectral distribution). Color vision is profoundly decreased compared to visual acuity in patients with ischemic and compressive optic neuropathy.

Color vision may be assessed with pseudoisochromatic tests (eg, Ishihara color blindness test, Hardy-Rand-Rittler polychromatic plates, Dvorine plates) or the Farnsworth-Munsell 100 Hues test or Farnsworth panel D-15 test.

Contrast sensitivity test

This test measures the ability to perceive slight changes in luminance between regions that are not separated by definite borders and is a sensitive test for optic nerve function.

Tests used to measure contrast sensitivity include the following:

• Pelli-Robson contrast sensitivity chart. Each letter subtends an angle of 3 degrees at a distance of 1 meter. Letters are organized in triplets with two triplets in each line. The contrast decreases from one triplet to the next. The log contrast sensitivity varies from 0.00-2.25.
• Cambridge low-contrast grating test
• Arden gratings

Factors that affect measurement include suboptimal refractive correction and duration of stimulus presentation.

Pupillary evaluation

Pupil size should be noted, as well as the magnitude and the latency of the direct and consensual responses to light and near stimulation. A relative afferent pupillary defect (RAPD) is a hallmark of unilateral afferent sensory abnormality or bilateral asymmetric visual loss. Occasionally, RAPD is the only objective sign of anterior visual pathway dysfunction. It is a sensitive optic nerve function test.

RAPD can be quantitatively graded by balancing the defect; successive neutral density filters are added in 0.3 logarithmic steps over the normal eye while performing the swinging flashlight test until the defect disappears. The most useful neutral density filters are from 80% (0.1 log unit) to 1% (2.0 log units).

Clinically, it is graded as follows:

• Immediate dilation of the pupil, instead of normal initial constriction (3-4+)
• No changes in initial pupillary size, followed by dilation of the pupils (1-2+)
• Initial constriction, but greater escape to a larger intermediate size than when the light is swung back to normal eye (trace)

Edge-light pupil cycle time

A thin beam of light is shown horizontally across the inferior aspect of the pupillary margin. The light induces pupillary constriction that moves the light out of the pupil. The pupil then redilates until the beam is once again at the edge of the pupillary margin, whereupon it constricts again, creating another cycle.

The time is calculated in milliseconds per cycle. Alternatively, the number of cycles in 1 minute is measured. The rate is normally 900 milliseconds per cycle.

Photostress recovery test

Principle-visual pigments bleach when exposed to an intense light source, resulting in a transient state of sensitivity loss and reduced central visual acuity.

To perform the test, the examiner should note the patient’s best-corrected visual acuity, shield one eye, and then ask the patient to look directly at a bright focal light that is held 2-3 cm from the eye for about 10 seconds. The time needed to return to within one line of best-corrected visual acuity level is measured; this time is the photostress recovery time.

Pulfrich phenomenon

In optic nerve damage, the transmission of impulses to the occipital cortex is delayed. In patients with unilateral or markedly asymmetric optic neuropathy, when an oscillating small target in a frontal plane is viewed binocularly, the target appears to move in an elliptic path rather than in a to-and-fro path.

Cranial nerve examination

All cranial nerves are examined to rule out associated nerve involvement to help determine the site of the lesion.

Extraocular movements

Restriction can be obtained in cases of compressive optic neuropathy due to either the mass effect or the involvement of the nerve supplying the muscle.

Ophthalmoscopic features

Optic disc

Optic disc changes can present with temporal pallor (as seen in toxic neuropathy and nutritional deficiency), focal pallor or bow-tie pallor (as seen in compression of the optic chiasma), and cupping (as seen in glaucomatous optic atrophy).

In the early stages of the atrophic process, the optic disc loses its reddish hue, and the substance of the disc slowly disappears, leaving a pale, shallow concave meniscus, the exposed lamina cribrosa. In the end stages of the atrophic process, the retinal vessels of the normal caliber still emerge centrally through the otherwise avascular disc.

Optic disc cupping also develops in patients with normal intraocular pressures and optic atrophy from various causes, including ischemia, compression, inflammation, hereditary disorders, and trauma.

Focal or diffuse obliteration of the neuroretinal rim with preservation of color of any remaining rim tissue is specific for glaucoma.

Peripapillary retinal nerve fiber layer

Early focal loss of axons is represented by the development of dark slits or wedges in the peripapillary retinal nerve fiber layer (RNFL). These slits or bands appear darker or redder than the adjacent healthy tissue. The slit defects are most easily identified in the superior and inferior arcuate regions, where the nerve fiber layer is particularly thick.

Retinal vessels

In most cases of optic atrophy, the retinal arteries are narrowed or attenuated. In cases of nonarteritic anterior ischemic optic neuropathy, the vessels may be focally narrowed or completely obliterated. Nonarteritic anterior ischemic optic neuropathy is shown in the images below.

Investigations

Visual field testing

Field testing methods include kinetic and static. In the kinetic method, the contours of the island are mapped at different levels, resulting in one isopter for each level tested. In the static method, the vertical contours of the island are mapped along a selected meridian.

As per the areas tested, the visual field is divided into the central visual field, which has a 30-degree radius, and anything beyond 30 degrees is called peripheral visual testing. The central visual field can be tested using an Amsler grid, confrontation techniques, a tangent screen, and a bowl perimeter. Peripheral visual testing includes automated perimetry and manual perimetry. Automated perimetry tests the central 60 degrees of the visual field, whereas manual perimetry tests the entire visual field.

In optic neuropathy, visual field changes can include enlargement of the blind spot and paracentral scotoma (eg, optic neuropathy), altitudinal defects (eg, anterior ischemic optic neuropathy, optic neuritis), and bitemporal defects (eg, compressive lesions, similar to optic chiasma tumors).

Optical coherence tomography

Optical coherence tomography (OCT) measurements of retinal nerve fiber layer (RNFL) provide an objective measurement of nerve atrophy, offering quantitative analysis of retinal thickness and retinal nerve fiber layer.[9]

Multiple sclerosis (MS)

OCT shows thinning of the RNFL and the ganglion cell layer, correlating with structural aspect and visual dysfunction. It is used as a marker in the follow-up of patients with MS. The decrease in peripapillary RNFL thickness (approximately 10-40 µm) is maximal at 3-6 months after the acute episode, and stabilization is observed at 7-12 months.[10]

NAION

Initially, OCT shows RNFL thickness owing to edema, but the RNFL thins by about 40% at 3-4 months compared a normal eye. Ganglion cell thickness analyses in the early stage reveals axonal damage when the RNFL is edematous.[11]

Compressive lesion

Axonal loss can be quantified by RNFL and ganglion cell analysis. Patients with normal RNFL analysis findings tend to experience improved vision and visual field compared with patients who have altered RNFL status.

Hereditary optic neuropathy

In late stages, OCT shows RNFL loss. In healthy carriers, OCT results show RNFL thickening in temporal quadrants.[12]

Electroretinography

Abnormal electroretinography (ERG) results that can be seen are as follows:

• Subnormal: Potential less than 0.08 microvolts; seen in toxic neuropathy
• Negative: When a large a-wave is seen; may be due to giant cell arteritis, central retinal artery occlusion, or central retinal vein occlusion
• Extinguished: Response seen in complete optic atrophy

Visually evoked response

In optic neuritis, the visually evoked response (VER) has an increased latency period and a decreased amplitude as compared to the normal eye.

Compressive optic lesions tend to reduce the amplitude of the VER, while producing a minimal shift in the latency.

Blood Tests and Other Tests

As optic atrophy is a sign of end-stage optic nerve damage and not a diagnosis in itself, further investigation is required if a cause is not established. The following additional tests may be used:

• MRI of the brain and orbits with contrast (in addition to space-occupying lesion [SOL], look for sinusitis, hyperpneumatized sinuses, fibrous dysplasia)
• Blood glucose level
• Blood pressure, cardiovascular examination
• Carotid Doppler ultrasonography
• Vitamin B-12 levels, heavy metal screen
• Venereal Disease Research Laboratory (VDRL)/Treponema pallidum hemagglutination (TPHA) tests
• Antinuclear antibody levels
• Sarcoid examination
• Homocysteine levels
• Antiphospholipid antibodies
• Enzyme-linked immunosorbent assay (ELISA) for toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus (TORCH panel)
• OPA1 blood testing in patients with a family history suggestive of dominant optic atrophy, especially young individuals with progressive bilateral vision loss and cecocentral scotoma with temporal disc pallor
• Leber hereditary optic neuropathy testing, especially in male patients with a family history of vision loss in maternal uncles

No proven treatment reverses optic atrophy. However, treatment that is initiated before the development of optic atrophy can be helpful in saving useful vision.

The role of intravenous steroids is proven in a case of optic neuritis and is controversial in arteritic anterior ischemic optic neuropathy. Early diagnosis and prompt treatment can help patients with compressive and toxic neuropathies.

Idebenone, a quinone analog, has been used and is the only clinically proven drug in the treatment of Leber hereditary optic neuropathy. The drug molecule bypasses the defective mitochondrial complex I, leading to improved energy supply and a functional recovery of retinal ganglion cells during the acute stage of the disease, thereby preventing further vision loss and promoting vision recovery.[13] So far, the results were noted to be modest and the treatment is quite expensive. Klopstock et al conducted a 24-week multicenter double-blind, randomized, placebo-controlled trial in 85 patients with Leber hereditary optic neuropathy. They did not find a statistically significant visual recovery in the intention-to-treat population. They did find, however, evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.[14]

Current clinical research in gene replacement therapy has demonstrated a good safety record but poor longevity of therapeutic results. The study results are promising and, with a better understanding of the pathophysiology of the neuropathies, should and will enable the development of future viable strategies in terms of prolonging vision.[15]

de Lima et al were able to restore some depth perception in mice with severe optic nerve damage. In addition, they found that the mice regained the ability to detect overall movement of the visual field and were able to perceive light. They found that using adequate stimulus, the fibers (1) are able to find their way to the correct visual centers in the brain, (2) are wrapped in the conducting insulation known as myelin, and (3) can make connections (synapses) with other neurons, allowing visual circuits to re-form. They discovered a molecule called oncomodulin. They achieved neuroregeneration in mice by simultaneously targeting the protein oncomodulin, elevating levels of the small signaling molecule cyclic adenosine monophosphate (cAMP) and deleting the gene that encodes the enzyme PTEN.[16]

In recent studies using hamster models, anterograde tracing and electrophysiologic responses reveal that a small number of axons can regenerate all the way back to the superior colliculus.[17] In other studies, remapping of the retina was noted in the superior colliculus following axon regeneration.[18] These findings have given hope to clinically meaningful regeneration of axons, which may become a reality in the near future.

Three-year results of gene therapy for LHON suggested that intravitreal injection of rAAV2-ND4 is safe and promising. However, the study sample size was small, and additional patients are currently being enrolled.[19]

At present, the best defense is early diagnosis, because, if the cause can be found and corrected, further damage can be prevented.

Low-vision aids for patients with some useful vision should be considered for occupational rehabilitation.

In any patient with unexplained optic atrophy, neuroimaging should be performed.

Class Summary

Essential to normal metabolism and DNA synthesis.

Cyanocobalamin (Nascobal)

Deoxyadenosylcobalamin and hydroxocobalamin are active forms of vitamin B-12 in humans. Vitamin B-12 synthesized by microbes but not by humans or plants. Deficiency may result from intrinsic factor deficiency (pernicious anemia), partial or total gastrectomy, or distal ileum diseases. Deficiency initially and typically manifests as macrocytic anemia, although neurologic symptoms may be present. Can also cause confusion or delirium in elderly patients.

Essential for normal erythropoiesis. Required for healthy neuronal functions and normal functions of rapidly growing cells.