Ganglion Cells and the Intraocular Optic Nerve

Light stimulates the retinal photoreceptors, and in turn signals are modified by the horizontal, bipolar, and amacrine cells in the inner plexiform layer of the retina, where they synapse with the cell bodies and dendrites of the retinal ganglion cells. The retinal ganglion cell axons then travel through the optic nerve, chiasm, and optic tract before synapsing at the lateral geniculate bodies (LGBs).

The concept of parallel processing was introduced to recognize that different types of visual information are processed parallel streams throughout the pregeniculate and postgeniculate visual pathways. Three broad pathways are generally thought to exist: the magnocellular, the parvocellular, and the koniocellular systems. The first is largely responsible for high spatial resolution, color vision, and fine stereopsis and is referred to as the parvocellular or P pathway based on the layers in the lateral geniculate body to which they project. The second (magnocellular, M or luminance) pathways are responsible for low spatial resolution, motion, and coarse stereopsis. The third (koniocellular, K) is not well defined but has been shown to be involved in detection of rapid movement. For the purposes of understanding retinal neurophysiology, ganglion cell types generally can be divided into two different broad categories, M (large) and P (small) cells. M cells project to the magnocellular layer and P cells project to the parvocellular layer of the LGB. As would be expected, the macula (fine spatial resolution) contains mostly P cells; in the peripheral retina the difference in numbers of each type of cell is much less. These two distinct populations of cells persist throughout the retrogeniculate pathways into the ocular dominance columns of the striate cortex, at which there are probably extensive interactions between the various pathways. The relationship between magnocellular and parvocellular pathways and higher cortical areas is discussed in Chapter 9 . Recently a class of melanopsin-containing intrinsically photosensitive retinal ganglion cells has been described. Comprising approximately 0.2% of total retinal ganglion cells, these cells are able to drive phototransduction without the need for signals from cones and rods. These cells likely play a role in light-dependent, nonimage-forming behaviors such as circadian rhythms, pupillary light reflex, and photophobia.

Each of the retinal ganglion cells projects to a specific portion of the striate cortex to preserve the strict point-to-point correspondence (retinotopy). Temporal retinal nerve fibers are arranged on either side of the horizontal raphe and arch around the fovea (arcuate bundles) to divert the retinal elements, except the photoreceptors, away from the fovea ( Fig. 5.1 ). These fibers enter the superior and inferior poles of the disc. Immediately adjacent to the disc, the nerve fiber layer reaches its maximal thickness of 200 µm. The horizontal raphe divides the superior and inferior retinal fibers and is the anatomic basis for several types of visual field defects (e.g., nasal steps, altitudinal defects). Nasal macular ganglion cells travel directly to the temporal portion of the disc in the papillomacular bundle. Ganglion cells from the central 5 degrees of the visual field constitute approximately one-third of the total number of axons at the disc. Fibers from the retina nasal to the disc enter the nasal portion of the optic nerve. As they enter the optic nerve head, ganglion cell axons reorganize so that the axons from peripheral ganglion cells are most superficial in the nerve fiber layer and form the more peripheral portions of the optic nerve, and macular ganglion cell axons form the center of the nerve. As they turn to exit the eye at the scleral canal, the optic nerve fibers exit through the lamina cribrosa.

Distribution of retinal ganglion cell axons as they travel to the optic nerve. Fibers from the nasal, superonasal, and inferonasal retina travel directly to the disc with the thickest nerve fiber layer at the superior and inferior poles of the disc. Fibers from the nasal half of the macula extend directly to the temporal portion of the optic nerve in the papillomacular bundle. Fibers from the temporal macula are separated by the horizontal raphe, above and below which they originate and arch around the fovea to enter the superior and inferior portions of the disc. These nerve fiber bundles are the basis for the different types of visual field defects that result from optic nerve disease.

All of the blood supply to the optic nerve is ultimately derived from the ophthalmic artery. The nerve fiber layer of the retina receives its blood supply from branches of the central retinal artery, and, when present, cilioretinal arteries also contribute to the peripapillary nerve fiber layer. A capillary bed from the central retinal artery provides the blood flow to the superficial optic nerve head. Branches of the short posterior ciliary arteries are the major blood supply to the optic nerve head below its surface. The area of the nerve served by each posterior ciliary artery is variable and segmental. Because anastomoses between the posterior ciliary arteries are scant, the optic nerve head can be a watershed area. The nature of the blood supply by the posterior ciliary arteries to the optic nerve head is the likely explanation for the segmental disc swelling and atrophy that often accompanies ischemic processes. Twigs of the posterior ciliary arteries reach the capillary plexus in the area of the lamina choroidalis and lamina cribrosa through branches of the intrascleral circle of Zinn–Haller and from branches of choroidal vessels that supply the choriocapillaris ( Fig. 5.2 ). Capillaries in the region of the lamina cribrosa are within the laminar beams and surround the nerve fiber bundles.

The circulation of the optic nerve head. The blood is derived primarily from the arteriolar anastomotic circle of Zinn–Haller, which is supplied by the posterior ciliary arteries, the pial arteriole plexus, and the peripapillary choroid.

Intraorbital Optic Nerve

Several structural changes occur as the axons pass through the lamina cribrosa, which is essentially at the level of the sclera. Optic nerve myelination begins (oligodendrocytes) and the pressure gradient on the axons increases as they are subjected first to intraocular pressure then to the intracranial pressure, which is transmitted through the subarachnoid space to the nerve–globe junction. The differences in pressure between the intraocular and intracranial compartments may account for the propensity for papilledema and glaucoma in an individual patient. The intraorbital optic nerve is between 20 and 30 mm in length and is always longer than the distance from the globe to the orbital apex. Therefore, there is always slack (the optic nerve usually takes on an S shape) to allow for unrestricted eye movements. Each axon is surrounded by myelin and glial cells, which provide metabolic support at the nodes of Ranvier. The entire nerve is surrounded by closely adherent pia mater. Arachnoid trabeculae connect the pia to the surrounding dura, which at the apex of the orbit is contiguous with the annulus of Zinn. The optic nerve is divided into septae by collagenous connective tissue, which also contains the centripetally penetrating capillaries from the pia. These are supplied largely by recurrent branches of the short posterior ciliary arteries and capillary branches of the ophthalmic artery. Capillaries are also supplied anteriorly by branches from the central retinal artery, which pierces the optic nerve 10–15 mm from the nerve–globe junction. There may also be collateral circulation to the intraorbital optic nerve through anastomotic branches from the external carotid artery. These branches can be supplied from the middle meningeal, superficial temporal, and transverse facial arteries.

Nerve fiber orientation within the optic nerve is highly specific. In the first third of the optic nerve, macular fibers lie temporally and then move to occupy the central portion of the optic nerve. Nasal retinal fibers remain in the nasal portion of the intraorbital optic nerve. The superior temporal fibers are located above the temporally located macular fibers, and the inferior fibers are located below the macular fibers.

Intracanalicular Optic Nerve

After leaving the orbit, the optic nerve enters the optic canal, which sits within the two bases of the lesser wing of the sphenoid bone ( Fig. 5.3 ). The medial wall of the canal forms the lateral wall of the sphenoid sinus and in some patients, such as those with neurofibromatosis type I (NF-1), is absent, causing the meninges to contact the sinus mucosa directly. The thickest bones of the canal are located at the orbital apex. The orbital plate of the frontal bone separates the canal from the overlying frontal lobe. Contained within the canal are also the ophthalmic artery, the meninges, and the sympathetic plexus. The dura and therefore the optic nerve are fixed to the periosteum throughout the canal, which is usually around 10 mm in length. This tight space makes the optic nerve particularly vulnerable to trauma and small space-occupying lesions in this area. Intracranially, the two optic canals course medially towards each other and rise at a 15-degree angle. In the optic canal, the pial plexus of blood vessels is usually supplied by the internal carotid artery.

The optic canal sits between the two bases of the lesser wing of the sphenoid bone and contains the optic nerve, meninges, sympathetic plexus, and ophthalmic artery. Anteriorly the dura coalesces to form the annulus of Zinn. The space is tight and the dura is fixed to the bone. The sphenoid sinus forms the medial wall of the canal. The chiasm sits behind the sphenoid sinus, and the intracranial opening of the canal is formed by the anterior clinoid process. Lateral to the chiasm is the cavernous sinus, which contains the carotid artery.

Intracranial Optic Nerve

The length of the intracranial optic nerve is variable (4–15 mm), depending on the position of the chiasm in relation to the sella turcica (above the sella, prefixed, or postfixed; see Chapter 7 ). The course of the intracranial optic nerve is upward at a 45-degree angle to reach the chiasm. Immediately above the nerves lie the anterior cerebral and anterior communicating arteries, and above these lie the olfactory nerves and frontal lobes. Just lateral to each nerve lies the internal carotid artery, and the ophthalmic artery arises from the internal carotid just below the optic nerve. Just under each optic nerve and above the pituitary gland lies the planum sphenoidale. The blood supply to the pial plexus of vessels supplying the optic nerve can arise from branches of the internal carotid artery, the anterior cerebral arteries, or the anterior communicating artery.

Systemic Evaluation

The examination of a patient with suspected optic neuropathy begins with the general evaluation of the patient’s physical health, mental status, and vital signs. Markedly elevated blood pressure in a patient with swollen discs suggests the presence of malignant hypertension. An irregular pulse from atrial fibrillation suggests that an acutely acquired visual field defect might be the result of an embolic arterial occlusion. A rapid pulse might suggest hyperthyroidism, and obesity and recent weight gain would point to idiopathic intracranial hypertension. Profound cachexia might suggest cancer spread, temporal arteritis, or nutritional optic neuropathy. Odd or inconsistent behavior might be an early indicator of the possibility of nonorganic or functional visual loss.

Visual Acuity

Although visual acuity is commonly reduced in optic neuropathies, this finding is highly variable. In fact, visual acuity is the least sensitive of all the tested functions and is not always helpful in identifying the presence of optic neuropathy or its cause. For instance, profound optic nerve dysfunction with an afferent pupillary defect, dyschromatopsia, and visual field loss may be present with 20/15 visual acuity. Furthermore, virtually any of the causes of optic nerve dysfunction can be associated with any level of visual acuity loss.

Color Vision

Dyschromatopsia and, in particular, the mismatch of good acuity and poor color vision are very important and sensitive indicators of optic nerve dysfunction. The basis for this mismatch is not completely understood. It may reflect the fact that the optic nerve is largely composed of ganglion cell axons arising in the macular region, and these axons have a one-to-one relationship with the high density of cones in this region. However, there are many patients with profound optic nerve dysfunction that may do relatively well with color plate testing and notice only a mild difference in color saturation between the two eyes.

Contrast Sensitivity

Abnormal contrast sensitivity is another sign of optic nerve dysfunction and may be the most valuable test in terms of long-term follow-up and in clinical trials. Some patients with optic neuropathy have good acuity but may have reduced contrast sensitivity thresholds. Contrast sensitivity is also helpful in patients with congenital dyschromatopsia who are suspected of having an optic nerve problem in whom color plate testing cannot be used. Less commonly, it can be used to document visual recovery in optic neuritis, which is almost always associated with a reduction in contrast sensitivity. Recently low-contrast sensitivity testing has been incorporated in the evaluation of new drugs for the treatment of multiple sclerosis (MS) and optic neuritis. A related type of low-contrast vision testing, low-contrast letter acuity, is similar to clinical trial–based high-contrast visual acuity testing with Early Treatment Diabetic Retinopathy Study (ETDRS) charts and is a sensitive indicator of visual pathway dysfunction in MS, optic neuritis, and other neurologic disorders associated with optic neuropathy. Such testing can be performed monocularly or with both eyes open, thus capturing binocular inhibition that may impair function in the setting of unilateral optic neuropathy. Deficits in low-contrast acuity are associated with structural measures of optical coherence tomography (OCT) that indicate axonal and neuronal loss in the optic nerve and anterior visual pathway.

Pupils

The identification of a relative afferent pupil defect (RAPD) is very helpful in localizing unilateral or asymmetric vision loss to the optic nerve and is the hallmark of asymmetric disease of the anterior visual pathway (Video 2.3). The swinging flashlight test is described in detail in Chapter 2 .

Pulfrich Phenomenon

Pulfrich described a phenomenon that is occasionally reported as a symptom in patients with unilateral or asymmetric optic neuropathy. The Pulfrich phenomenon is a stereo illusion in which an object, such as a ball on a string, is swung in a to-and-fro motion within the plane facing the subject with an optic neuropathy. Because of the delay in visual information reaching the cortex via the affected optic nerve, this is seen as an elliptical movement with the closer arc moving towards the affected eye. The Pulfrich phenomenon is only infrequently seen in patients with decreased vision due to media opacities or retinal disease. The Pulfrich phenomenon may be lessened by the use of neutral-density filters over the unaffected eye to balance the visual signaling from the optic nerves.

Visual Fields

One hallmark of an optic neuropathy is an abnormal visual field. Concepts of visual field testing and the various types and their advantages and disadvantages are discussed in Chapter 3 . Patients with optic neuropathy have visual field defects that generally fall into three different categories: (1) generalized constriction, (2) central defects, and (3) nerve fiber bundle defects.

Generalized constriction. This type of field defect ( Fig. 5.4 ) is the least specific and the hardest to localize. In these patients, kinetic perimetry shows reduced size of the peripheral isopters, and on automated perimetry peripheral rim defects are seen with a general reduction in sensitivity. The examiner must be careful in interpreting fields with generalized constriction as there are many non–neuro-ophthalmic causes of this type of defect, including media opacities, small pupils, poor patient cooperation, retinal degenerations, and nonorganic visual loss. However, diffuse suppression of the visual field on automated perimetry is in fact the most common defect in patients with optic neuritis.

Paired examples of static threshold perimetry gray scale ( left ) and kinetic perimetry visual fields ( right ) seen in optic neuropathies. Note the threshold and kinetic perimeters have different scales. The first pair of fields ( A ) demonstrate generalized constriction, which is the least specific, and hardest to localize, type of visual field defect. It can also be seen with media opacities or retinal disease or simply from slow reactions during testing. Altitudinal ( B ), nasal step ( C , note the incomplete connection to the blind spot), and arcuate ( D ) defects are characteristic of optic neuropathies and represent nerve fiber bundle defects. Central scotomas ( E ) and centrocecal defects ( F , central defects attached to the blind spot) are also commonly seen with optic neuropathies.

Central defects. These include central scotomas, paracentral defects, and centrocecal scotomas (see Fig. 5.4 ). These three types of visual fields are related and imply involvement of the central portion of the optic nerve. Centrocecal scotomas are common defects in patients with hereditary, nutritional, and toxic optic neuropathies but can be seen in any of the optic neuropathies. Any patient who has reduced central visual acuity must have a central scotoma by definition, although such defects are not always measurable on perimetry. Sometimes the only abnormality on computerized perimetry is a reduction in the foveal threshold. Central field defects are also the rule in patients with macular disease.

Nerve fiber bundle defects. The third category includes arcuate defects, altitudinal defects, and nasal steps (see Fig. 5.4 ). These defects, as they are so named, imply a localization to a particular group of nerve fibers. In general, they respect the horizontal meridian because of the anatomic boundary of the horizontal raphe. These field defects occasionally may also respect the vertical meridian, but this finding should be considered atypical, and patients with such fields should be investigated for the possibility of intracranial disease (see Chapter 7 ). The nerve fiber bundle types of visual field defects can be seen in all of the different optic neuropathies, but certain patterns are more common. For instance, altitudinal defects are the most common defects in ischemic optic neuropathy, and arcuate defects with enlarged blind spots were most commonly seen in patients with mild vision loss due to papilledema enrolled in the Idiopathic Intracranial Hypertension Treatment Trial. In general, visual field defects will help to confirm the presence of an optic neuropathy but will not be diagnostic of a specific etiology.

Ophthalmoscopy

Optic disc appearance. The normal optic nerve ( Fig. 5.5 ) has a pinkish, orange color with sharp margins. The nerve fiber layer is best seen at the 6 and 12 o’clock positions, where it is thickest. A central cup is identifiable, and the vessels can be seen clearly as they cross the margin of the disc. The normal optic disc area varies between 2.1 and 2.8 mm ² . Highly myopic eyes (>−8.00) may have abnormally large discs, while highly hyperopic eyes (>+4.00) may have abnormally small discs.

The normal-appearing optic nerve. Margins are sharp and color is diffusely pink. Nerve fiber striations are seen best at the 10 to 12 o’clock and 6 to 8 o’clock positions just beyond the disc edge ( arrows ). Despite this, the vessels are clearly seen traversing the nerve fiber layer and are not obscured by these fibers.

Disc swelling . Optic neuropathies are frequently associated with disc swelling or edema. The term edema might not be accurate, however, since there may not be interstitial fluid as a cause of the swelling, and instead axoplasmic stasis may be the final common pathway for most disc swelling. The term papilledema is used only for discs that are swollen from elevated intracranial pressure. Ophthalmoscopic features of a swollen optic nerve include hyperemia, elevation of the optic nerve head, and edema of the nerve fiber layer blurring the disc margins. The cup may be obliterated in severe swelling, and there may be associated retinal or choroidal folds. There may be venous dilation, associated splinter hemorrhages, dilated capillaries, exudates, or cotton-wool spots. Swollen optic nerves resulting from anterior visual pathway compressive lesions may have features that suggest chronicity (absence of hemorrhages, pseudodrusen from axoplasmic stasis, pallor) or collateral vessels from retinal to ciliary circulation (“shunt vessels”).

Disc atrophy or pallor. Although this technically implies a histopathologic diagnosis, the term optic atrophy is often substituted for the ophthalmoscopic observation of optic nerve head pallor or loss of pinkness, which commonly accompanies permanent damage to the optic nerve. A combination of the loss of the superficial capillary bed along with the loss of tissue volume and astrocytic proliferation is responsible for this change in optic nerve head color. Reduced blood flow to the optic nerve head may be demonstrated by fluorescein angiography, OCT angiography, and direct blood flow measurements. By using the term optic atrophy, the examiner is identifying ganglion cell death, not reduction or involution of function as the term atrophy implies in other conditions. Atrophy can be graded as mild to severe and may take on a characteristic pattern (altitudinal, sectoral, bow tie, or temporal), which can be a clue to disease pathogenesis or localization. For instance, superior sectoral atrophy might be associated with inferior field loss. Not infrequently, optic atrophy is accompanied by cupping. This may simply be a normal evolution of appearance or may reflect a defective structural integrity of the optic nerve in the setting of atrophy.

Primary optic atrophy occurs without significant swelling or reactive gliosis. Secondary atrophy implies previous swelling and subsequent gliotic reaction, which accompanies the nerve atrophy. In the former (primary optic atrophy) the disc pallor is associated with sharp disc margins and easily visible details on the disc surface and vasculature ( Fig. 5.6 ). Most patients (even those with some swelling initially) with acute optic neuropathies later develop primary optic atrophy. In the latter case (secondary optic atrophy) there is a haze to the disc surface or overlying nerve fiber layer which obscures the disc margin and the ophthalmoscopic view of the disc’s surface details ( Fig. 5.7 ). The typical setting for secondary optic atrophy is atrophic papilledema (see Chapter 6 ), compressive optic neuropathy with prior disc edema, or severe inflammatory disc edema. In some cases, pallor of the disc might not yet be evident, but the examiner can identify defects in the nerve fiber layer. In this setting there is a sharp cut-off from the normal-appearing nerve fibers to an area with an absence of fibers ( Fig. 5.8A ). These defects can be more easily seen with red-free light ( Fig. 5.8B ), and an alternating “rakelike” pattern of normal and defective nerve fibers may be observed.

Primary optic atrophy. The disc shows temporal pallor and has sharp, distinct margins.

Secondary optic atrophy (developing after disc swelling). As with primary atrophy, the disc is pale but there is haziness to the area of the disc margin from previous swelling and reactive gliosis.

A . Left optic nerve with minimal temporal pallor and a sharp cut-off in the nerve fiber layer demarcating corresponding loss of ganglion cell axons entering the temporal aspect of the disc. The arrow delineates the beginning of the normal nerve fibers. B . Red-free photograph of right eye of a different patient demonstrates optic disc pallor with nerve fiber layer defect ( arrows ). The area of normal striations of the nerve fibers abruptly begins ( arrows ).

Related retinal lesions. When the disc is swollen, other fundus findings may aid in the diagnosis. For instance, dilated and tortuous retinal veins accompanied by retinal hemorrhages suggests a retinal vein occlusion, while macular lipid deposition suggests neuroretinitis. When the disc is normal, the examiner should be absolutely certain a macular lesion is not mimicking an optic neuropathy.

Slit-Lamp Examination

Other causes of visual acuity loss, such as corneal, lens, or vitreous opacities, should be excluded. The presence of iritis or uveitis would suggest an inflammatory disorder.

Anomalous Discs

Anomalous discs are due to congenital anomalies, and they are listed in Box 5.1 .

Swollen Optic Nerves

Box 5.2 lists optic neuropathies that may present with disc swelling. The most common diagnoses to consider in adults are anterior ischemic optic neuropathy and optic neuritis. Patients with anterior ischemic optic neuropathy will generally be older with vasculopathic risk factors such as diabetes and hypertension. Those with optic neuritis are typically younger and often have periocular pain exacerbated by eye movements.

Papilledema or disc edema from elevated intracranial pressure is discussed elsewhere (see Chapter 6 ), but it is important to note the relative mismatch between the amount of disc swelling and visual function in papilledema. A markedly swollen optic nerve with relatively preserved visual acuity is the hallmark of papilledema in its early stages. In patients with disc swelling, acuity loss and central field defects would be more characteristic of a process directly affecting the optic nerve such as ischemia or inflammation.

In more rare circumstances other features of the examination will help to identify the cause of the swollen disc with vision loss. The presence of vitritis would suggest the possibility of infectious disc swelling, as in syphilitic uveitis with optic neuropathy. The presence of a macular star makes neuroretinitis the most likely diagnosis. Other infiltrative conditions such as leukemia might be associated with retinal hemorrhages or a distinct mass in the optic nerve head.

Normal-Appearing Optic Nerves

In retrobulbar optic neuropathies, the normal fundus appearance acutely implies that the disease process is occurring in the optic nerve behind the lamina cribrosa in its intraorbital, intracanalicular, or intracranial portions. Entities that commonly present with a normal-appearing fundus are listed in Box 5.3 . The examiner should be aware of overlap in certain conditions, such as optic neuritis, in which one-third of patients will have a visibly swollen optic nerve head; Leber’s hereditary optic neuropathy, in which the nerve can have a pseudoswollen appearance; or radiation-induced optic neuropathy, in which stigmata of radiation retinopathy may be present with an acutely swollen nerve. Whenever the optic nerve appears normal in a suspected optic neuropathy, the macular region should be carefully examined. Chapter 4 contains a discussion of the differentiation between optic neuropathy and maculopathy.

Optic Disc Pallor

Optic atrophy (disc pallor) may be evident on the initial examination or can evolve on subsequent evaluations. All of the conditions listed in Boxes 5.2 and 5.3 , when associated with permanent visual dysfunction, will eventually be accompanied by the development of optic atrophy. In this setting the examiner will identify a history of a previous episode consistent with the clinical picture; for example, a previous inflammatory, ischemic, or traumatic injury to the optic nerve. In some instances, patients become suddenly aware of their visual loss at a time after the process began (pseudosudden onset), and their initial examination will reveal optic atrophy. Entities that commonly present in this fashion are listed in Box 5.4 . Most importantly, chronic progressive visual loss accompanied by disc pallor strongly suggests a compressive lesion. Thus, in patients with unexplained optic atrophy, neuroimaging is the most important diagnostic test. Other laboratory testing, such as serologies, vitamin levels, or genetic evaluation, should be guided by historical and examination findings.

Rarely, some individuals with long-standing, “stable” visual loss from a distant history of optic atrophy due to a childhood neoplasm, for instance, may later in adulthood experience gradual visual loss not due to tumor recurrence or any other obvious cause. This phenomenon has been attributed to normal age-related axonal loss in an individual with an already compromised optic nerve. Similar observations have been made regarding patients with congenital disc anomalies.

In summary, in most cases of suspected optic neuropathy, careful consideration of historical details, general examination, and the ophthalmoscopic appearance of the optic nerve head will lead to the correct diagnosis long before any ancillary tests are ordered. The specific optic neuropathies are discussed in greater detail in the following sections.

Hypoplasia

Characterized ophthalmoscopically by an optic disc with a small diameter ( Fig. 5.11 ), optic nerve hypoplasia (ONH) is a variable condition that can be associated with a spectrum of potential visual dysfunction, ranging from normal vision to marked dysfunction. Hypoplasia can be unilateral or bilateral and may or may not be associated with a more widespread neurologic developmental disorder. This is the most common congenital optic nerve abnormality. It has been identified as the third most prevalent cause of vision impairment in children aged 3 years or younger in the United States and the most likely diagnosis to cause legal blindness in this age group.

The optic nerve hypoplasia spectrum. A . Mild hypoplasia appreciated when comparing the size of the optic nerve head with the caliber of the retinal vessels (see Fig. 5.5 for the normal ratio). The edge of the hypoplastic nerve is marked by the arrows . The black dashed circle approximates the size of a normal optic nerve. The nerve is about one-half of the normal size when judged by the vessels, which are of normal caliber. B . More severe optic nerve hypoplasia ( black arrows on nerve edge) accompanied by peripapillary pigmentary abnormalities and anomalous “spokelike” take-off of the retinal vessels. The classic double ring sign is present and is the result of the white ring of visible bare sclera ( white arrows ) bordered by the pigment epithelium that surrounds the optic nerve.

Embryologically, the reduced number of functioning axons may result from the exaggeration of a normal developmental process. That is, at 16–17 weeks of gestation, there are approximately 3 million optic nerve axons that ultimately are reduced to approximately 1 million at the time of birth. Hypoplasia may therefore be an overdone, but normal, process of involution. The most commonly reported risk factors for ONH are young maternal age, maternal recreational drug use, maternal smoking, and fetal alcohol syndrome.

Affected patients can have any level of visual function ranging from minimal acuity or field loss to no light perception (NLP), and bilateral ONH is more common than unilateral cases. Severe reduction in disc diameter on the fundus examination is often simple to identify, particularly when it is unilateral and comparison with the normal eye can be made. However, when mild, this finding may be subtle and hard to recognize, and sometimes the loss of the nerve fiber layer is best viewed using red-free light during ophthalmoscopy. Because the examination in young infants may be difficult, the diagnosis of a mild degree of hypoplasia in this age group can be extremely problematic and can often be made only subjectively. The appearance of hypoplastic nerves can be quite variable, and the key to making the diagnosis is identifying the true edge of the optic nerve (see Fig. 5.11 ).

There are several visual aids that may assist the examiner in diagnosing ONH. First, one can compare the caliber of the overlying retinal vessels to the diameter of the optic disc and determine whether the vessels appear to be relatively large compared with the disc diameter. Second, the examiner may note a peripapillary halo, or the so-called “double-ring sign” (see Fig. 5.11B ), which is due to the presence of a ring of visible sclera and pigmentation surrounding the optic nerve. Occasionally, this ring may be associated with hyperpigmentation, presumably due to migration of the retinal pigment epithelium to the edge of the optic disc. Finally, in cooperative patients, the examiner can estimate the ratio between the disc diameter and the distance between the disc and macula. This ratio is typically greater than 0.35 in full-term children. A ratio of less than 0.3 may indicate that a patient’s optic nerve is hypoplastic. Recent studies of patients with unilateral optic nerve hypoplasia have demonstrated that there is also an associated thinning of both the inner and outer retinal layers on macular OCT.

Magnetic resonance imaging (MRI) frequently demonstrates a reduced cross-sectional area of the optic nerves and chiasm. In general, more severely hypoplastic nerves are associated with poorer vision, because a smaller disc has fewer ganglion cell axons passing through it. However, even patients with very small nerves can occasionally achieve remarkably good vision; this phenomenon is likely due to sparing of the papillomacular fibers.

In addition, rarely, the optic nerves fail to form at all, a condition known as optic nerve aplasia. Aplasia may be unilateral or bilateral and in monocular cases is often associated in the same eye with microphthalmos in an otherwise healthy individual.

Associated features. ONH may occur in isolation or in combination with other midline developmental abnormalities which share the same embryologic forebrain derivation. This association, previously known as de Morsier’s syndrome, or septooptic dysplasia, includes ONH and an associated absence of the septum pellucidum ( Fig. 5.12 ). Recent prospective studies have assigned less significance to the absence of a septum pellucidum and have shown its absence is not associated with laterality of ONH, visual acuity, pituitary dysfunction, or developmental outcomes. A dysgenetic, thin, or absent corpus callosum may also be seen in this disorder. Corpus callosum hypoplasia has been found to be associated with developmental delay but not with hypopituitarism in this disorder. The condition likely has a genetic etiology with environmental factors altering the penetrance and phenotype. Abnormalities in the developmental genes, HESX1, SOX2, and SOX3, have been identified in several pedigrees.

Absence of the septum pellucidum ( asterisk in single midline ventricle) in septooptic dysplasia demonstrated on a coronal T1-weighted magnetic resonance imaging. The chiasm ( arrow ) is extremely thin. For comparison with normal suprasellar structures, see Chapter 7 .

In 1970 Hoyt and colleagues reported the association of septooptic dysplasia and pituitary dwarfism. Since then, the symptom complex of ONH and hypopituitarism has been well recognized and well studied. Growth hormone (GH) deficiency is the most common endocrinologic abnormality, but decreased secretion of thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and antidiuretic hormone (ADH) may be seen individually or in combination. Although hypopituitarism occurs only in a minority of patients with ONH, the consequences can be devastating. In one series of patients with bilateral ONH, 11.5% had panhypopituitarism. Pituitary abnormalities are seen on MRI in 13–34% of children with ONH and in the great majority of those with hypopituitarism. Pituitary abnormalities most commonly seen include posterior ectopic pituitary tissue, usually seen as an abnormal area of hyperintensity at or near the tuber cinereum on T1-weighted MRI ( Fig. 5.13 ), or absence of the normal posterior pituitary bright spot. In one purported mechanism, posterior pituitary ectopia is attributed to a perinatal insult to the hypophyseal portal system, resulting in necrosis of the infundibulum. However, other authors have suggested an earlier dysembryogenesis of the developing optic nerves and pituitary stalk. Other forms of hypothalamic dysfunction can be found in patients with ONH, such as abnormal sleep cycle and circadian rhythm and abnormal temperature regulation.

Ectopic pituitary ( solid arrow ) at the area of increased signal intensity at the tuber cinereum and agenesis of the corpus callosum ( open arrows point to the area where the corpus callosum is normally situated) in septooptic dysplasia demonstrated on a sagittal T1-weighted unenhanced magnetic resonance imaging. For comparison with normal suprasellar structures, see Chapter 7 .

ONH is also associated with schizencephaly, a cortical migrational abnormality producing cerebral clefts extending from and including the ventricular lining to the cortical surface ( Fig. 5.14 ). Schizencephaly may manifest clinically with developmental delay, contralateral hemiparesis, and seizures. Kuban et al. have suggested that the combination of septooptic dysplasia and schizencephaly may result from a perinatal insult at or around the sixth week of embryogenesis, at which time cerebral morphogenesis, development of the eye, and delineation of the lamina terminalis, which forms the septum pellucidum, take place. Other associated cortical migrational abnormalities seen in association with ONH include cortical heterotopias, polymicrogyria, and pachygyria. Cortical migrational and corpus callosum abnormalities tend to correlate with developmental delay and neurologic symptoms such as seizures, but unfortunately cognitive and neurologic problems can still occur in the setting of a relatively normal brain MRI in children with ONH.

Examples of cortical migrational abnormalities in patients with optic nerve hypoplasia. A . Nodular foci of heterotopic gray matter ( arrows ) along the walls of the lateral ventricles seen on axial T2-weighted magnetic resonance imaging (MRI). B . Dysplastic cortex in the left frontal lobe ( arrow ); the gyral pattern is different on the left side compared with the right (T2-weighted MRI). Also, the septum pellucidum is absent ( asterisk ). C . Open lip schizencephaly, with associated polymicrogyria, demonstrated on a coronal T2-weighted MRI in an infant with bilateral optic nerve hypoplasia. The arrows point to a cleft containing cerebrospinal fluid that extends from the cerebral convexity to the atrium of the left lateral ventricle. Associated distortion and outpouching of the lateral ventricular wall where the cleft entered the ventricle is seen ( asterisk ). The cleft is lined by abnormal nodular gray matter. The septum pellucidum is intact.

ONH may also occur in association with congenital suprasellar tumors such as craniopharyngiomas, chiasmal/hypothalamic gliomas, and teratomas. The mechanism in these cases is believed to be tumor compression of the visual pathways early in life, precluding normal optic nerve development.

Evaluation. In all young children, because the new diagnosis of ONH has several potential ophthalmologic, neurologic, developmental, and endocrinologic implications, a thorough clinical and radiologic assessment is mandated. Pediatric ophthalmologic evaluations are necessary for assessment and management of possible visual impairment, superimposed amblyopia, refractive error, nystagmus, and strabismus. Brodsky and Glasier’s careful clinical–radiologic study demonstrated that some children with unilateral ONH, who seem normal otherwise, may have posterior pituitary ectopia evident on MRI. In addition, a normal pituitary on MRI does not rule out pituitary insufficiency.

Therefore, in our approach, all young children with ONH, whether unilateral or bilateral, should undergo (1) MRI with attention to the pituitary region and cortex and (2) a complete evaluation and hormone screen by a pediatric endocrinologist, independent of MRI findings. Radiographic demonstration of cortical migrational or corpus callosum abnormalities should prompt an evaluation by a pediatric neurologist. Otherwise normal older children or adults with newly detected ONH without historical evidence of endocrinologic (e.g., normal growth), neurologic, or developmental abnormalities usually need no further workup because any radiographic anomalies will be incidental.

Segmental hypoplasia. A peculiar variant is superior segmental ONH, which can occur for unclear reasons, most commonly in children of diabetic mothers. One study found 8.8% of offspring of diabetic mothers at risk had this condition, but it may also occur without a history of maternal diabetes. Inferior visual field defects are detected in patients who are usually asymptomatic or perhaps have a long history of tripping or bumping into objects at their feet. The field defect corresponds to the segmental superior hypoplasia of the optic nerve ( Fig. 5.15 ). Typically the superior rim of the disc is thin and the central retinal artery appears to arise out of the superior portion of the disc (see Fig. 5.15 ). OCT can be helpful in securing the diagnosis in cases that are ophthalmoscopically unclear. There may also be abnormal peripapillary pigment superiorly. Another variant of the segmental hypoplasia of the disc has been described by Yamamoto et al. in a review of fundus photographs in a large series of patients. The findings were present in 0.3% of photographs, but there was no clinical correlation with visual field loss. Patients generally had larger cups and more segmental areas of disc hypoplasia seemingly distinct from the “topless” disc of diabetic mothers. In another form of segmental ONH, the nasal portion of the disc is poorly formed. Nasal hypoplasia ( Fig. 5.16 ) is often associated with dense visual field defects which attach to the blind spot and extend to the periphery.

Superior segmental optic nerve hypoplasia in two patients. A . Optic nerve in a patient with superior segmental hypoplasia of the optic disc demonstrating only a small thin area of nerve tissue superiorly (between numbers 1 (top of disc) and 2 (center of cup), compared with the distance between 2 and 3 (bottom of disc)). The retinal vessels seem to arise out of the superior portion of the disc. B . Similar appearance and asymmetry of nerve substance above the center of the cup (between 1 and 2 ) compared with below the center of the cup ( 2 and 3 ) in another patient with superior segmental optic nerve hypoplasia. C . Goldmann visual field from the left eye of a patient whose optic nerve is pictured in B demonstrating characteristic inferior visual field loss. The patient’s mother was diabetic.

Right ( A ) and left ( B ) optic nerves of a patient with bilateral nasal disc hypoplasia. The discs appear tilted, and the vessels seem to originate from the nasal portion of the disc. There is peripapillary atrophy, and the nasal neuroretinal rim ( arrows in B ) is very thin compared with the temporal rim. C . Goldmann visual fields of the same patient. There is a “bitemporal hemianopia,” as the field defects break to the periphery from the blind spot. However, the defects do not respect the vertical meridian, as seen best in the superior aspect of the left eye visual field.

Segmental hypoplasia has also been described in patients with periventricular leukomalacia, whereby an abnormally large cup and thin neuroretinal rim can be seen secondary to intrauterine injury and transsynaptic retrograde degeneration of retinogeniculate axons after the scleral canal had established a normal diameter. If the injury occurs earlier in gestation, when the scleral canal size has not yet been established, a more classical appearance of ONH is seen.

Hemiopic hypoplasia. Finally, the term hypoplasia has also been applied to the entity of homonymous hemiopic hypoplasia. This condition results from transsynaptic atrophy of the optic nerve in patients with congenital hemispheric lesions (often also associated with hemiplegia). The disc classically takes on a pattern of bow-tie atrophy in the eye contralateral to the hemispheric lesion and of subtle hypoplasia on the side of the hemispheric lesion.

Tilted Disc Anomaly

Tilted discs arise when the optic nerve enters the sclera at an oblique angle and the typical crescent creates a disparity in the opening of the retina compared with the sclera. They are associated with medium myopia, astigmatism, decreased visual acuity, and visual field defects. The discs typically appear tilted and turned, and the vessels arise anomalously from the disc ( Fig. 5.17 ). When present, the corresponding temporal visual field defects ( Fig. 5.18 ), which do not respect the vertical meridian, are important to distinguish from acquired bitemporal hemianopias. Color vision abnormalities are seen in about half of eyes with a tilted disc anomaly. Nerve fiber layer measurement and multifocal electroretinogram (ERG) most commonly show abnormalities in the superior nerve fiber layer.

Optic nerve appearance of the ( A ) right and ( B ) left eye of a patient with severe tilted disc anomaly. The optic nerves enter the sclera at an oblique angle, and the normal disc architecture is difficult to identify.

Goldmann visual field of a patient with tilted discs. The defects appear in the smaller isopters and are worse superiorly. The defects slant across the temporal field and do not respect the vertical meridian, distinguishing them from the bitemporal hemianopia of chiasmal disease.

Optic Colobomas and Pits

Faulty closure of the inferonasal quadrant of the embryonic fetal fissure of the optic stalk and cup may cause incomplete formation, termed a coloboma, of the iris, optic nerve, retina, and choroid. The anatomic defects are usually located inferiorly. Children with colobomas may present with microphthalmos, microcornea, iris defects, visual loss, and strabismus. Colobomatous involvement of the optic disc is highly variable but can affect a portion of, or the entire, nerve head. Alternatively, only the peripapillary retinal pigment epithelium and choroid may be involved. Ophthalmoscopically, the typical finding is a large excavated disc with visible nerve tissue at the superior rim and a white egg-shaped defect inferiorly ( Fig. 5.19A ). Optic disc colobomas are frequently associated with chorioretinal colobomas. Acuity and visual field loss, often superiorly, may be evident. Visual acuity loss is dependent on the integrity of the papillomacular bundle. On neuroimaging, misshapen globes and enlargement of the optic nerve near the globe may be seen ( Fig. 5.19B ). Patients with colobomas also should be investigated radiographically for the possibility of other forebrain abnormalities, especially basal encephaloceles (see Morning Glory Disc Anomaly ).

Optic coloboma. A . Fundus photo of an extensive coloboma involving the peripapillary posterior pole. The optic nerve ( arrow ) is seen at the superior edge of the coloboma within the excavated area. B . From another patient with bilateral colobomas, axial T2-weighted magnetic resonance imaging demonstrating irregular outpouching and globe contour changes posteriorly in both eyes ( arrows ).

Colobomas may occur in association with other systemic abnormalities and chromosomal syndromes. The CHARGE syndrome consists of c oloboma, h eart defect, a tresia choanae, r etarded growth and development, g enital anomalies, and e ar deformities and deafness. In patients with this syndrome, the colobomas are most often bilateral and associated with chorioretinal colobomas, and affected individuals should be screened for the CHD7 gene. Renal–coloboma syndrome is an autosomal dominant disorder associated with renal abnormalities and optic nerve defects, caused by mutations of the PAX2 gene. The term papillorenal syndrome has also been used and may be more appropriate for this condition, as other disc anomalies such as optic pits, morning glory discs, and dysplastic discs can be seen ( Fig. 5.20 ).

Papillorenal syndrome. Fundus photographs ( A , right eye, and B , left eye) from a woman with a history of a renal transplantation for focal segmental glomerulosclerosis. Vision was normal. The optic discs were dysplastic, enlarged, and cupped with pits temporally.

Optic pits ( Fig. 5.21 ) are small excavations of the neural retinal rim of the optic disc, usually involving the inferotemporal portion of the optic nerve. In the Beijing Eye Study, in which fundus photographs were examined, 1 patient out of 4000 was found to have an optic pit, suggesting the prevalence is less than 0.1%. The area of the “missing” disc is often associated with a corresponding superior arcuate field defect. These temporal disc abnormalities can lead to serous detachment of the macula and macula retinal schisis. Serous detachments are thought to occur from fluid flowing from the vitreous cavity through the pit and elevating the sensory retina. Membranes demonstrated on OCT spanning the optic cup may protect against the development of maculopathy. Acquired pitlike defects have been described involving the temporal disc rim and are found most commonly in patients with glaucoma. It has been suggested that congenital optic pits and colobomas share the same embryologic mechanism, and the former represents a milder variant of the latter.

Optic pits in two different patients. The pits appear as focal gray excavations (outlined by arrows ) in the temporal portion of the optic nerve head and can extend into the retina ( B ).

Morning Glory Disc Anomaly

The morning glory disc is a congenital anomaly named after the flower that it resembles ( Figs. 5.22A and 5.23A ). A congenital funnel-shaped excavation of the posterior fundus typically incorporates the optic disc. Other characteristic features include disc enlargement, orange color, and surrounding choroidal pigmentary disturbances. OCT findings include enlargement of the nerve head, a thick nerve fiber layer, and thinning of the retina in the macula. The retinal vessels curve from the disc edge and travel radially, producing a spokelike vessel configuration. The normal central retinal vasculature is conspicuously absent ophthalmoscopically. Arteriovenous connections may branch between the major retinal vessels, sometimes creating a rosette or arcade appearance on fluorescein angiography. Fluorescein angiography of the peripheral retina may reveal retinal nonperfusion. The disc excavation is often filled with white glial tissue and vascular remnants. The vision is usually poor in the affected eye. Transient vision loss and retinal detachments associated with the anomaly leading to acquired visual loss have been described. Coexistent persistent hyperplastic primary vitreous has also been reported in a large series of patients with morning glory syndrome.

Morning glory disc and moya-moya vessels. A . Fundus photograph of the left eye demonstrating a morning glory disc and macular hole ( arrow ). The macular hole appears closer to the disc than normal due to the enlargement of the optic disc rim. B . Coronal reconstruction of three-dimensional time-of-flight magnetic resonance angiography, with segmentation to show the anterior circulation of the carotid arteries, demonstrating a decrease in size of the caliber of the left internal carotid artery relative to the normal-sized right internal carotid artery with more focal marked narrowing of the distal portion ( long arrow ). The bifurcation into the middle and anterior cerebral artery is also involved and markedly narrowed. There is an increase in the size of the lenticulostriate vessels ( short arrow ), producing a moya-moya appearance at this site.

Morning glory disc and transsphenoidal encephalocele. A . Morning glory disc. B . This patient has hypertelorism (increased distance between the two orbits), and the right pupil is pharmacologically dilated. Sagittal ( C ) and coronal ( D ) T1-weighted gadolinium-enhanced magnetic resonance imaging demonstrating a transsphenoidal encephalocele, with herniation of the chiasm ( arrow ) into the sella.

The anomaly is likely related to defective closure of the embryonic fissure, similar to a coloboma, but others purport a mesenchymal abnormality due to the presence of a central glial tuft, scleral defect, and vascular anomalies combined with histologic findings of adipose and smooth muscle tissue. The glial and vascular abnormalities are felt to result from primary neuroectodermal dysgenesis. Contractile and dilation movements of the optic disc have been noted and may be due to a communication between the subretinal and subarachnoid space.

In addition, there have been several reports of patients with morning glory disc anomaly and moya-moya disease ( Fig. 5.22 ), which is a rare idiopathic cerebrovascular disorder characterized by progressive bilateral stenosis or occlusion of the distal internal carotid arteries and formation of a collateral vascular network in the basal ganglia region. The term moya-moya refers to the Japanese term for “puff of smoke,” which describes the angiographic appearance of the abnormal vessels. Other similar intracranial vascular anomalies have been reported. The association of morning glory disc and these blood vessel anomalies suggests the disc anomaly may in some cases result from intracranial vascular dysgenesis. Morning glory syndrome also can be seen in children with hemangiomas and PHACE syndrome ( p osterior fossa malformation, large facial h emangioma, a rterial anomalies, c ardiac anomalies, and e ye anomalies).

Morning glory disc anomaly is also associated with transsphenoidal basal encephalocele ( Fig. 5.23 ), a condition which encompasses a complex series of malformations characterized by herniation of the chiasm, hypothalamus, pituitary, and anterior cerebral arteries through a bony defect in the anterior skull base. Other abnormalities include hypertelorism (see Fig. 5.23 ), depressed nasal bridge, midline upper lid notch, cleft palate, panhypopituitarism, and callosal agenesis. Herniated brain tissue may present as a pulsatile posterior nasal mass, and surgical removal of this tissue may have disastrous vascular, endocrine, and visual consequences. Morning glory discs have also been described in neurofibromatosis type II (NF-2).

Evaluation . Patients with morning glory disc should undergo an MRI to exclude a basal encephalocele, and MRI angiography should also be considered to exclude moya-moya vessels and other intracranial vascular anomalies, which may place the individual at risk for cerebrovascular ischemia. Neuroimaging often demonstrates the widened, excavated nature of the optic nerve head and distal optic nerve.

Staphyloma

In addition to disc colobomas and morning glory disc anomaly, staphylomas should also be considered in the differential diagnosis of excavated disc anomalies. The entire disc lies within a deep peripapillary excavation, but features which distinguish it from the other two related anomalies include a relatively normal disc, preservation of the normal retinal vasculature, and absence of a central glial tuft. There are no commonly associated CNS abnormalities. Staphylomas are most often unilateral and associated with high myopia, poor vision, and amblyopia.

Optic Neuropathy Associated With Optic Disc Drusen

Pseudopapilledema, optic nerve head drusen, and their distinction from true papilledema are discussed in detail in Chapter 6 . However, because visual loss associated with disc drusen is an optic neuropathy, it is reviewed here.

Many patients with disc drusen are completely asymptomatic, although between 50% and 70% will have visual field defects. Although most patients will be identified during a routine examination ( Fig. 5.24 ), some are detected after an abnormal visual field test is obtained in the setting of vague, progressive (insidious) vision loss. Others are identified when elevated optic nerves are evaluated for possible papilledema (drusen are visible on the disc surface in only about 50% of patients). Contact between disc drusen and nearby nerve fibers presumably results in nerve fiber layer thinning and axonal dysfunction. Optic nerve–type visual field defects are produced that may be progressive and are more common in patients with visible as opposed to buried drusen. Drusen are almost never associated with central vision loss unless there is an associated hemorrhage in the macular region. In the absence of macular injury, all patients with central visual acuity loss and optic nerve head drusen should be investigated for superimposed conditions such as a compressive lesion. Typical nerve fiber bundle–type defects are seen, including arcuate defects and nasal steps ( Fig. 5.25 ), and optic disc pallor may develop (see Fig. 5.24 ). Either ultrasound or OCT can be used to identify buried drusen, but OCT can also be used to follow the peripapillary nerve fiber layer thickness. With SD-OCT, drusen may exhibit internal reflectivity that can be homogenous or nonhomogenous. A characteristic appearance of the outer nuclear layer of the retina extending over and around drusen is often seen. Eyes with larger drusen and a larger area of the optic canal occupied by drusen are at higher risk for RNFL thinning.

Optic disc drusen associated with visual loss. Drusen are evident as translucent crystalline deposits, and significant optic disc pallor has developed.

Static perimetry demonstrates typical nasal visual field constriction in a patient with optic disc drusen.

On rare occasions patients present with sudden and more catastrophic vision loss. This is most often on the basis of a superimposed ischemic optic neuropathy, which may or may not be associated with true disc edema and splinter hemorrhages ( Fig. 5.26 ). Patients with drusen-associated ischemic optic neuropathy tend to be younger but otherwise have a similar prevalence of vasculopathic risk factors as non–drusen-associated cases. Nonarteritic ischemic optic neuropathy in association with optic disc drusen has been reported in patients as young as 12 years. Transient vision loss before the fixed deficit and a reasonably favorable visual prognosis have been noted with drusen-associated ischemic optic neuropathy. Other ocular ischemic conditions have been observed in association with optic nerve head drusen, including central retinal artery, branch retinal artery, and central vein occlusions.

Optic disc drusen with associated anterior ischemic optic neuropathy in the right eye. A . The right optic nerve is hyperemic with nerve fiber layer edema and associated splinter hemorrhage ( arrow ). B . Buried disc drusen ( arrows point to yellow areas under disc surface) can be seen in the patient’s uninvolved left eye.

Vision loss associated with optic disc drusen can also be caused by peripapillary neovascularization, which can be identified by its characteristic yellow or gray appearance. There may be an associated hemorrhage or serous detachment of the retina. Best identified with fluorescein angiography, neovascularization is thought to result from chronic optic disc ischemia.

Treatment . There is no known treatment for visual loss associated with optic disc drusen. Repeat computerized visual fields over years will generally show only slight changes and therefore can be done to comfort and reassure the patient on an annual basis. However, serial visual fields in asymptomatic patients with optic disc drusen is unnecessary. Some have suggested that a lower threshold for treatment of intraocular pressure should be considered in patients with optic disc drusen, deteriorating visual fields, and borderline intraocular pressures. Some neuro-ophthalmologists have advocated the use of intraocular pressure-lowering agents even in the presence of a normal intraocular pressure. Optic nerve sheath fenestration appears to convey no benefit in the treatment of this disorder, but experience has been limited. Neovascularization may be observed or treated with laser photocoagulation, anti–vascular endothelial growth factor (VEGF) agents, or surgery.

Myelinated Retinal Nerve Fibers

Lacking oligodendrocytes, the retina is usually unmyelinated. Myelinated retinal nerve fibers are anomalous white patches of myelin which are often contiguous with the optic disc and typically contained within the nerve fiber layer (see Figs. 4.34B and 6.2C ). When viewed with high magnification, the edges appear serrated or feathery as the myelination aligns along the nerve fibers. This feature distinguishes these lesions from cotton-wool spots. Occasionally the myelinated nerve fibers are large, extending along the temporal vascular arcades. They can also be located away from the disc in the retinal periphery. Although usually asymptomatic, some involved eyes are myopic with associated anisometropic amblyopia. When the myelinated area is extensive, visual field defects may occur. With rare exceptions, myelinated retinal nerve fibers are static and, when found incidentally, require no treatment. Although most cases of myelinated nerve fibers are congenital, acquired cases have been reported in disease states with disruption of the lamina cribrosa, such as optic nerve tumors, optic disc drusen, and papilledema. It is important to recognize these benign retinal lesions in the differential diagnosis of retinal ischemia and pseudopapilledema.

Leber’s Hereditary Optic Neuropathy

LHON, first described by Leber in 1871, typically causes a subacute, sequential optic neuropathy in young healthy individuals. This section reviews the demographics, characteristic presentation and fundus findings, and genetics of this unique mitochondrial disorder.

Demographics. Eighty to ninety percent of affected individuals are males, but the reason for this male predominance is unclear. In Newman’s series, the age at onset ranged from 8–60 years, with a mean of 27.6 years, and the vast majority were between 26 and 37 years. Women develop the disease at an older age than men in the same pedigree; however, the age at which initial symptoms occur varies. LHON is transmitted through the mother.

Neuro-ophthalmic symptoms. LHON causes an acute or subacute failure of vision in one or both eyes. The average interval between first and second eye involvement is 2–3 months, with a range from simultaneous presentation (which occurs in 25–55% of cases) to 9 months. Many simultaneous cases may represent sequential involvement of the eyes in which the attack in the first eye went unrecognized. The vision loss is usually painless, although headache occasionally occurs. Uhthoff’s symptom (worsening of vision associated with elevation of body temperature; see Optic Neuritis) and recurrent visual loss have been reported in LHON.

Neuro-ophthalmic signs. Patients present with signs of an acute optic neuropathy, with loss of central vision and dyschromatopsia. Visual acuity measurements reflect the dense central field defect and are typically between 5/200 and 20/200 but only rarely are reduced to the hand movements or light perception level. Total blindness from LHON is exceedingly unusual. In a recent randomized controlled trial of idebenone for the treatment of LHON, 8.5% of patients were deemed “legally blind,” with bilateral visual acuity worse than 20/200. Color vision was affected in more than 90% of patients. Visual field testing shows a central or centrocecal scotoma in virtually all cases. In the uninvolved fellow eye mild subclinical central visual field abnormalities can be found before more dramatic visual loss ensues. Although pupillary light reflexes had been thought to be normal, more definitive studies have demonstrated that afferent pupillary defects are typically present when visual loss is unilateral or asymmetric. This issue is still controversial, however, as some investigators have suggested that pupillary afferent fibers are relatively spared compared with those mediating vision. This phenomenon may be due to a relative sparing of the melanopsin-containing retinal ganglion cells, which are thought to be more resistant to metabolic insults from mitochondrial dysfunction compared with other types of retinal ganglion cells.

The classic disc appearance in patients with acute LHON was emphasized by Smith et al. in 1973. Characteristic findings include “circumpapillary telangiectatic microangiopathy” and “pseudoedema” or swelling with hyperemia of the nerve fiber layer around the disc ( Fig. 5.27 ) and the absence of true edema or staining of the disc on fluorescein angiography. If these fundus features are identified, genetic testing should be performed without additional testing for other acute causes of optic neuropathy. These findings can also be used to identify patients within a family at risk for developing the disease, as they are present in a subset of patients who are in the preclinical phase of the disease. About two-thirds of the male and one-third of the female asymptomatic descendants of affected females have the characteristic fundus changes.

Spectrum of optic nerve abnormalities in acute Leber’s hereditary optic neuropathy. A . This patient has mild nerve fiber elevation inferiorly with dilated capillaries ( arrow ). B . This patient’s disc appears more hyperemic, with dilated surface capillaries and swelling and haziness to the nerve fiber layer best seen superiorly ( arrow ). C . This patient has more extensive pseudoswelling with obscuration of the disc margin. However, fluorescein angiography ( D ) in the same patient shows no disc leakage or staining.

However, there are many cases in which the acute nerve fiber layer and vascular changes are absent, and the disc may have a normal appearance. Patients with LHON subsequently develop optic atrophy regardless of the fundus appearance acutely. After the onset of optic atrophy, it is difficult to identify patients with LHON ophthalmoscopically, because the acute findings of pseudopapilledema and telangiectasias have resolved ( Fig. 5.28 ). Fortunately, spontaneous visual recovery may occur in 4–32% of cases, depending on the specific mutation (see later discussion).

Subacute appearance of the right optic nerve of a patient with Leber’s hereditary optic neuropathy who had presented months earlier. There is still nerve fiber layer prominence, but temporal pallor with loss of nerve fibers in the papillomacular bundle has developed, as evidenced by the sharp cut-off from the normal nerve fibers ( arrows ) with rakelike defects.

Magnetic resonance imaging, particularly with short time inversion recovery (STIR) sequences, may demonstrate optic nerve high signal abnormalities, and optic nerve enhancement and chiasm enlargement have also been reported. On OCT, thinning of the nerve fibers subserving the papillomacular bundle are involved early, then thinning occurs in the superior and inferior quadrants. In the presymptomatic state, the papillomacular fibers may be thicker than normal.

Other associations. The ophthalmoscopically visible local changes have led many to conclude that there are unique features that place the intraocular optic nerve and perhaps only the papillomacular bundle ganglion cells at greatest risk for damage in LHON. However, central and peripheral nervous system and systemic abnormalities have also been reported. For instance, nonspecific white matter lesions have been observed on MRI scans of some affected individuals. In addition a disease resembling MS or actual MS has also been reported to occur with LHON. Uncommonly, patients with LHON also have a peripheral neuropathy. An “LHON-plus” syndrome has also been described by several authors and presents with severe psychiatric disturbance, spastic dystonia, ataxia, and encephalopathy in addition to vision loss.

Cardiac conduction defects and arrhythmias and skeletal deformities have been associated with LHON. Abnormal electrocardiograms (ECGs), specifically conduction abnormalities, have been convincingly demonstrated in various pedigrees. The cardiac disease is often asymptomatic and can be found in patients with no evidence of optic neuropathy. Patients with LHON have also been found to have skeletal deformities including congenital hip dislocation, arachnodactyly, pes cavus, talipes equinovarus, kyphoscoliosis, arched palate, and spondyloepiphyseal dysplasia.

Mitochondrial genetics. Because mothers transmit LHON vertically to their offspring and men do not pass on the disease, mitochondrial inheritance became the most plausible explanation. In their seminal studies, Wallace and colleagues demonstrated a mitochondrial DNA point mutation in which a nucleotide substitution occurred at position 11778 in 9 of 11 families with LHON. A guanine to adenine substitution causes a change of the basic amino acid arginine to histidine. The result is an abnormal subunit 4 (ND4) of the NADH dehydrogenase:coenzyme Q1 reductase subunit (complex I), which is the first enzyme in the pathway of oxidative phosphorylation. The 11778 mutation has been identified in pedigrees and spontaneous singleton cases. In addition, other causative mutations at position 3460 and 14484 have been identified. These mutations affect the ND1 and ND6 subunit genes of complex I, respectively. A number of other mutations have been reported, but many are still awaiting full confirmation for pathogenicity. Alone, these mutations do not explain the variable occurrence of the disease within the same pedigree, its wide spectrum of phenotypic expression, and the susceptibility of male offspring. Variable phenotypic expression of the mitochondrial DNA (mtDNA) mutation is, as of now, unexplained. The four theories that have been advanced to explain this are (1) heteroplasmy (coexistence of mutant and normal mtDNA; there appears to be a threshold of 60% mutational load that must be exceeded for visual loss to occur ), (2) a second genetic factor possibly on the X-chromosome that acts synergistically with the primary mitochondrial mutation, (3) hormonal factors (low estrogen state), and (4) environmental factors. Although it is most likely that all of these factors contribute to the phenotypic expression of the disease, there is increasing evidence to suggest that a nuclear and/or an X-linked factor contribute to the development of the disease. External factors capable of damaging oxidative phosphorylation, such as cyanide poisoning (cigarette smoking), alcohol, and environmental toxins, may also contribute to the onset of visual loss.

Genetic testing. Patients with suspected LHON should be tested for one of the three primary mutations: 11778 (69% of cases), 3460 (13% of cases), and 14484 (14% of cases). The rate of spontaneous recovery is highest in patients with the 14484 mutation and lowest with the 11778 and 3460 mutations. In a recent prospective study of patients with the 11778 mutation, 18% of eyes recovered 15 ETDRS letters or more, while 86% of patients remained stable or had improvements of less than 15 letters. Genetic counseling can be offered if a mutation is identified. Prenatal testing and counseling is limited by incomplete penetrance and marked phenotypical variability.

Treatment. Many agents such as steroids, cyanide antagonists, and hydroxycobalamin have been tried without effect for the treatment or prevention of LHON. Some physicians recommend that family members in LHON pedigrees and patients affected in one eye with LHON avoid tobacco and heavy alcohol use. Some success has been reported in other diseases that affect mitochondrial energy production with the use of cofactors such as succinate and coenzyme Q. However, their value in treating or preventing LHON remains to be proven. Recently idebenone, a synthetic analog of coenzyme Q10, has been tested in a randomized placebo-controlled treatment study for LHON. Initial reports have been promising, but long-term follow-up and larger studies are still required. A third-generation quinine molecule, EPI-743, is also under early investigation for treatment of this disease. In the future it may be possible to treat LHON with allotypic gene therapy using an adenovirus vector carrying the nuclear encoded version of the gene normally made by mitochondria. The missing protein can then be synthesized in the cytoplasm and transported to the mitochondria. The superficially located ganglion cells of the eye may prove uniquely amenable to this type of treatment.

Dominant Optic Atrophy

In his description of 19 affected families, Kjer reported the details of a dominantly inherited optic neuropathy that now bears his name. Dominant optic atrophy (DOA) is the most common hereditary optic neuropathy and has a penetrance of 70–100%.

Patients typically present before the end of the first decade of life with the insidious onset of bilateral (although often asymmetric) vision loss. Acuities range from 20/20 to 20/200, and patients typically have central and centrocecal visual field defects with intact peripheral isopters. Forty percent of patients retain acuity of 20/60 or better. Presentation with nystagmus is uncommon. Progression of vision loss is very variable, with many patients remaining stable after the second decade and others losing vision very slowly over decades. Color vision loss typically occurs along the blue–yellow or tritanopic axis (see Chapter 2 ). The associated optic disc pallor often takes on a striking wedgelike appearance with temporal excavation of the neuroretinal rim ( Fig. 5.29 ), although the whole disc sometimes is pale. The condition usually occurs in isolation, but other neurologic findings may be present. A syndromic description of DOA (“DOA plus ”) has been described and may occur in up to 20% of cases. DOA plus includes a spectrum of associated findings such as neurosensory deafness (most common), myopathy, cerebellar ataxia, and peripheral neuropathy. OCT studies have demonstrated isolated involvement of the nerve fiber and GCL with normal outer retina and photoreceptor layers.

Genetically confirmed OPA1-dominant optic atrophy. Fundus photographs ( A , right eye, and B , left eye) demonstrate temporal optic nerve atrophy bilaterally. C . Spectral-domain optical coherence tomography sector thickness plots reveal temporal thinning of both optic nerves with an overall decrease in the mean retinal nerve fiber layer thickness to 59 µm in the right eye and 55 µm in the left eye.

Since the disease is dominantly inherited, examination of first-degree relatives often aids in the diagnosis of patients suspected of having dominant optic atrophy. Because of the highly variable degree of visual dysfunction, seemingly asymptomatic adult and child relatives can often be identified if visual acuity or color loss or optic atrophy are present.

Most families with DOA have deletions and insertions (over 70 mutations have been reported) in this region, the OPA1 gene at the 3q27–3q28 chromosome. Mutations at OPA1 are responsible for more than 75% of all DOA cases. In addition, other loci (OPA4 and OPA5) have been described for pure DOA, and OPA3 and OPA8 have been associated with syndromic DOA. It may be reasonable to screen for OPA1 gene abnormalities in patients with sporadic otherwise unexplained optic atrophy. Cohn and associates have emphasized, however, that the OPA1 mutations are only found in only about two-thirds of patients, and that there are likely to be other genetic and environmental factors that contribute to the disease development and presentation. The OPA1 gene product, a dynamin-related GTPase, is believed to be involved in mitochondrial fusion, cristae organization, and control of apoptosis, and OPA1 mutations may lead to mitochondrial DNA dysfunction.

Histopathologic studies have demonstrated diffuse loss of retinal ganglion cells, suggesting primary ganglion cell death as the mechanism of disease. Spontaneous improvement has not been reported.

Management. There is no known effective treatment at this time. When dominant optic atrophy is considered in children without affected family members, compressive lesions and other causes of optic neuropathy with pallor should be excluded. Patients should be screened for sensorineural hearing loss, as this occurs with increased frequency in this subgroup of patients. In addition, features of the OPA plus syndrome should be sought, which include myopathy, progressive external ophthalmoplegia, peripheral neuropathy, stroke, demyelination, and spastic paraplegia.

Recessive Optic Atrophy

Both simple (isolated) and complex (associated defects) forms of recessively inherited optic neuropathy exist. As is typical of most genetic conditions, the recessive form of hereditary optic atrophy is generally much more severe than the dominant form. Patients present in early childhood (age 2–4 years) with more profound visual acuity loss and searching nystagmus. There is often a history of parental consanguinity. Visual acuity is usually stable, and whether the visual loss occurs congenitally is unknown. There is usually diffuse disc pallor and attenuation of retinal vessels. Complicated, recessive optic atrophy, when associated with spinocerebellar degeneration, cerebellar ataxia, pyramidal tract dysfunction, and mental retardation, is termed Behr syndrome.

DIDMOAD (Wolfram Syndrome)

Wolfram or DIDMOAD ( d iabetes i nsipidus, d iabetes m ellitus, o ptic a trophy, and d eafness) syndrome encompasses the above findings and presents in childhood or adolescence. The classic presentation of this rare syndrome is optic atrophy with progressive vision loss, usually worse than 20/200, and hearing loss with juvenile-onset diabetes. Other reported abnormalities include ptosis, ataxia, seizures, cognitive impairment, nystagmus, abnormal ERG, abnormal cerebrospinal fluid (CSF) protein, and short stature. Most patients die in their 30s and 40s. Neuropathologic studies have demonstrated atrophy of the optic nerve, chiasm, brainstem, and cerebellum. The inheritance pattern is autosomal recessive, and there is now extensive evidence to suggest localization to chromosome 4p and the WFS1 gene. Mutations in this gene lead to altered production of the protein wolframin. Wolframin is now known to be involved in endoplasmic reticulum homeostasis in pancreatic β cells and retinal ganglion cells, as well as the brain, heart, and muscle. Early reports of treatment with idebenone have been promising but are limited by exceedingly small numbers of patients.

Optic Atrophy Associated With Neurologic and Metabolic Disease

Optic atrophy and progressive visual dysfunction frequently accompanies a variety of other inherited, degenerative neurologic conditions ( Box 5.5 ). In each of these conditions progressive visual loss occurs with dyschromatopsia, central or centrocecal field defects, and optic atrophy. Visual loss progresses along with systemic neurologic syndrome, but vision loss usually remains moderate. Optic atrophy occurs in conjunction with spinocerebellar degenerations (see Chapter 16 ), ataxias, and sensory motor peripheral neuropathies. Friedreich’s ataxia and Charcot–Marie–Tooth are classic neurologic syndromes associated with optic atrophy. In Harding’s series, of 90 patients with Friedreich’s ataxia, visual acuity was usually not affected but 25% of patients had optic atrophy. Progressive optic atrophy is also recognized in patients with congenital deafness and in mitochondrial protein-import disorders such as Mohr Tranebjærg syndrome (also known as deafness-dystonia-optic neuropathy (DDN) syndrome) and 3-methyl-glutaconic aciduria, type III and type V. More recently primary retinal degenerations have been recognized to occur in conjunction with these inherited ataxias (see Chapter 4 ). The spinocerebellar ataxias (SCAs), particularly SCA1 and less so for SCA3, are associated with primary optic atrophy.

Lysosomal storage diseases (inherited deficiency of an enzyme required for normal metabolism of lysosomal macromolecules) are associated with a variety of ocular manifestations. In particular, optic atrophy results from ganglion cell damage from these accumulated materials. The conditions in this category which can be associated with optic atrophy are Tay–Sachs disease, Niemann–Pick (see Chapter 16 ), and metachromatic leukodystrophy. Storage disorders with retinal manifestations are also discussed in Chapter 4 . Patients with mucopolysaccharidoses (Hurler and Scheie syndromes) and adrenoleukodystrophy (see Chapter 8 ) can also develop optic atrophy.

Optic Neuritis

The vast majority of patients with inflammatory optic neuropathy have optic neuritis, a nerve inflammation secondary to demyelination. In many patients optic neuritis is the heralding manifestation of MS.

The Optic Neuritis Treatment Trial (ONTT) has provided the best prospective data regarding the clinical presentation, visual outcome, and rate of development of MS in patients with optic neuritis. The implications of the ONTT have been profound and far reaching, and new findings with regard to visual prognosis have emerged. Over two decades later, new clinical trials are underway to examine therapies in acute optic neuritis that can repair and protect anterior visual pathway axons and neurons. OCT imaging (discussed previously) has revolutionized the evaluation of acute optic neuritis and our understanding of its clinical course with regard to structure and function.

The ONTT was a multicenter, randomized clinical trial that enrolled 448 patients. Participants were randomized to intravenous methylprednisolone followed by oral corticosteroid taper, oral placebo, or oral corticosteroids alone. Each patient had a detailed history and ophthalmic and neurologic examinations. Visual acuity, color vision, contrast sensitivity, and Humphrey computerized and Goldmann visual fields were recorded for each patient. Every patient had blood work for syphilis and lupus, and a fraction who consented underwent lumbar puncture. Patients were followed for all four of the measurable visual parameters and for the development of clinically definite MS, defined as development of a second clinical demyelinating event.

Demographics. Patients with optic neuritis are typically young, with a peak incidence in the third and fourth decade, and more women than men are affected. In the ONTT, 77% of the patients were women, 85% were white, and the mean age was 32 years. Prevalence rates vary with race, geography, and latitude, with whites of northern European ancestry at latitudes distant from the equator being most susceptible. In African Americans and Asians the condition is relatively uncommon. Some studies have demonstrated a seasonal pattern to its incidence.

Neuro-ophthalmic symptoms. Vision loss is rapid in onset, usually over a period of hours to a few days. Symptoms commonly reported by patients with optic neuritis are summarized in Box 5.6 . Vision loss can progress for up to 1–2 weeks. Reduced color vision invariably accompanies the vision loss in optic neuritis. Patients frequently report a darkening or reduced vividness of color. Red objects may be described as either pinker or browner in patients with dyschromatopsia.

Characteristic pain precedes the vision loss by a few days and is present in the majority of patients (92% in the ONTT). Globe tenderness and worsening of pain on eye movements are typical. The exact origin of the pain is unknown but presumably is the result of the pulling on the dura (in contact with the inflamed nerve) by the eye muscle origin from the annulus of Zinn. Because this pain characteristically disappears after 3–5 days, pain persisting for longer than 7 days should be considered atypical and prompt an investigation for other causes of pain and optic neuropathy such as a systemic inflammatory condition, scleritis, malignant glioma, orbital inflammatory syndrome, aneurysm, or a sinus mucocele.

Phosphenes or flashing lights described by patients with optic neuritis generally take a variety of forms, including lights, sparkles, and shifting squares. They may be exacerbated by eye movements or loud noises. These symptoms were present in 30% of patients in the ONTT. These phosphenes can accompany the acute loss of vision and can also persist for months after resolution. They are not unique to inflammatory optic neuropathies but can occur in the setting of compressive lesions as well. The presence of phosphenes should also raise the possibility of concomitant retinal disease, as in neuroretinitis.

Uhthoff’s symptom is a transient visual obscuration associated with elevation in body temperature. The symptom can be provoked by as little as hot food or cooking but most typically is brought on by physical exertion or a hot shower. Vision loss generally takes the form of blurring, graying, or reduced color vision and begins minutes after exposure to heat. Minutes to 1 hour later, vision returns to baseline without residual deficits. This symptom is not unique to patients with optic neuritis and has been described in hereditary, toxic, compressive, and sarcoid optic neuropathies. Uhthoff’s symptom tends to relapse and remit, and return of the symptom after a period of time does not necessarily herald the onset of recurrent inflammation. For unclear reasons, the presence of Uhthoff’s symptom may be a poor prognostic indicator, as it correlates with white matter lesions on MRI and with the subsequent development of MS and recurrent optic neuritis.

Neuro-ophthalmic signs ( Box 5.7 ). Patients typically have reduced visual acuity ranging from nearly normal to NLP. In the ONTT, 10% of patients had 20/20 vision, 25% had between 20/25 and 20/40 acuity, 29% had 20/50 to 20/190, and 36% had between 20/200 and NLP.

Dyschromatopsia can usually be easily identified by testing with pseudoisochromatic color plates and noting asymmetry between the eyes. Subjective intereye differences can usually be brought out by asking patients to describe their perception of these plates or a red test object.

Contrast sensitivity was measurably abnormal in 98% of patients in the ONTT compared with age-matched controls. In fact, contrast sensitivity in optic neuritis was found to be the most sensitive indicator of visual dysfunction in acute and recovered optic neuritis.

Patients with optic neuritis almost always have some visual field loss. On manual kinetic perimetry and tangent screen testing, the most common visual field defects in optic neuritis are central scotomas. The ONTT used static threshold perimetry as their standard and found 45% of the patients had diffuse field loss and 55% had local defects. Of these localized visual field defects, the most common were altitudinal defects (20%) and “three-quadrant defects” (14%). Combined, central, and centrocecal defects occurred in 16% of patients. Overall these patterns of visual field loss represent the full spectrum of “optic nerve”–type field defects and do not aid the examiner in distinguishing optic neuritis from other causes of optic nerve dysfunction.

The ONTT carefully studied fellow eye abnormalities in patients with acute unilateral optic neuritis. Visual field defects were the most common (48% of patients), although abnormalities in acuity, color vision, and contrast sensitivity were also identified. Most of these deficits resolved over several months. Because all of the abnormal visual function parameters tended to improve with time, they were not thought to be false positives or spurious results. The question remains as to whether these represent subtle simultaneous bilateral attacks or unrecognized previous attacks. Also, whether these patients with bilateral findings are at increased risk of developing MS is uncertain.

On the fundus examination about one-third of patients have mild optic nerve-head swelling ( Fig. 5.30 ). This finding is generally much less marked than the swelling in papilledema, and it is less sectoral and unassociated with the capillary dilation and splinter hemorrhages typical of anterior ischemic optic neuropathy. Ocular imaging studies subsequent to the ONTT have demonstrated that optic disc swelling is likely to be more common than is evident by clinical examination and ophthalmoscopy alone. Peripapillary RNFL thickening by OCT has been noted, while GDx imaging has shown evidence for early axonal injury. OCT may thus be used clinically in acute optic neuritis to assess for subclinical optic disc swelling or for macular abnormalities that could otherwise explain visual loss.

Spectrum of fundus findings in patients with optic neuritis with mild ( A ) vs diffuse ( B ) prominent disk swelling. The absence of hemorrhages, cotton-wool spots, and exudates is notable. C . Peripheral retinal venous sheathing ( arrows ) seen rarely in patients with optic neuritis and multiple sclerosis.

Less than 5% of patients have retinal exudates, phlebitis, or vitreous cells. When present, retinal abnormalities such as nerve fiber layer atrophy and periphlebitis may predict the severity of demyelinating disease. Extensive vitritis and retinal vein sheathing (see Fig. 5.30 ) is unusual in optic neuritis, and in this setting alternative diagnoses such as sarcoidosis and syphilis should be considered. Patients with typical optic neuritis do not develop a macular “star.” The development of a macula star is more consistent with neuroretinitis (see later discussion), a condition that is believed not to be a precursor of MS. Atypical findings of acute demyelinating optic neuritis include (1) NLP vision, (2) optic disc or retinal hemorrhages, (3) severe optic disc swelling, (4) macular exudates, (5) absence of pain, (6) uveitis, and (7) bilateral visual loss. Although bilateral simultaneous optic neuritis is unusual in adults and requires a full evaluation including neuromyelitis optica (NMO) testing, the majority of cases are still demyelinating.

Diagnostic studies. The ONTT demonstrated that in typical patients (young patients with subacute vision loss and pain on eye movements), no laboratory test (blood studies, lumbar puncture, or MRI) aided in the diagnosis of idiopathic optic neuritis. These tests were done on patients entering the study, and they did not alter the course, treatment, or ultimate visual outcome of any of the patients. However, more recently it has become clear that in patients with optic neuritis, clinicians should have a low threshold for testing for the aquaporin-4 (AQP4) antibody, which suggests a diagnosis of NMO rather than typical optic neuritis associated with MS.

MRI abnormalities consistent with demyelinating lesions in the white matter of patients with optic neuritis are well recognized ( Fig. 5.31 ). Abnormalities and enhancement are the result of breakdown of the blood–brain barrier. In the ONTT, 59% of patients with a previous normal neurologic history had clinically silent white matter lesions. The most typical findings are >3 mm in diameter, T2 hyperintense lesions in the periventricular white matter, subcortical white matter, and pons. These findings may be nonspecific and have been seen in “normal” patients and patients with other systemic inflammatory conditions. Enhancement of the lesions on T1 images indicates active plaques. The use of STIR and fluid level attenuated inversion recovery (FLAIR) sequences increases the sensitivity of detecting these white matter lesions. In the ONTT only 41% of patients had normal MRIs. The significance of the baseline MRI scans is discussed in the section on the relationship of optic neuritis to MS.

A–C . Fluid level attenuated inversion recovery (FLAIR) magnetic resonance imaging of the brain, three axial slices, in a patient with optic neuritis but no known history of multiple sclerosis (clinically isolated syndrome). Numerous high signal abnormalities in the cerebral white matter consistent with demyelination are visible at all three levels. Characteristic lesions in the corpus callosum ( arrow in A ) and periventricular white matter ( arrows in B ) are seen.

Over 90% of patients with optic neuritis have demonstrable lesions in the affected optic nerve using STIR sequences with fat-suppressed views of the orbit and an orbital surface coil ( Fig. 5.32 ). Poor visual function may correlate with optic nerve lesion size and location in the optic canal. The lesions in the canal may be the most damaging because the tight bony canal causes secondary compression as the nerve swells. This site is relatively uncommon, as the anterior and midorbital portions of the optic nerve are most frequently involved. Enhancement with gadolinium indicates an active process. Eye pain is more common when the orbital portion of the optic nerve or >10 mm of the nerve enhances. When recovery occurs with the restoration of the blood–brain barrier, the nerve no longer enhances with gadolinium.

Axial T1-weighted, fat-suppressed, gadolinium-enhanced orbital magnetic resonance imaging (MRI) in patients with acute optic neuritis. A . The MRI demonstrates focal enhancement ( arrow ) of the left optic nerve. B . In another patient, more diffuse enhancement of the right optic nerve ( arrow ) is seen. These patients had idiopathic optic neuritis. C . Bilateral enhancement of the optic nerves, extending posteriorly ( arrows ), in a patient with neuromyelitis optica (NMO).

Visual-evoked potentials (VEPs) are only an extension of the neuro-ophthalmic examination and should not be used to make a diagnosis of optic neuritis in the setting of unexplained vision loss. Although changes in the VEPs can provide objective information to help confirm the diagnosis of optic neuritis, the diagnosis will always be a clinical one. In general, the occipital pattern VEPs will show marked latency changes with amplitude changes that generally correlate with the level of acuity loss. Usually the hallmark of optic neuritis would be markedly prolonged latency (p100) with relative preservation of amplitude. The development of multifocal VEPs (mVEPs), which measure the conduction from multiple segments of the visual field (see Chapter 3 ), may be a more sensitive instrument than conventional VEP. In one study, 97.3% of eyes with optic neuritis had an abnormal mVEP; abnormalities included decreased amplitude in 96% of patients and increased latency in 68.4%. Other optic neuropathies (presumably with more direct axonal injury) generally have lower amplitudes with less effect on latency. Recovery of the latency and improved conduction speed over time after optic neuritis likely reflect recovery of the blockade related to inflammatory changes and edema.

OCT is now widely recognized for its role in patients with optic neuritis, both clinically and for documenting structural outcomes in research and trials. The pathophysiology of optic neuritis is characterized by acute inflammation of the optic nerve with consequent loss of axons. Over time, degeneration of retinal ganglion cell axons results in thinning of the RNFL, which is composed of axons destined to form the optic nerve. OCT has made it possible to assess axonal loss quantitatively and noninvasively, and this technique has applications to both optic neuritis and MS.

OCT studies have confirmed reductions in RNFL thickness in eyes with a history of optic neuritis and have demonstrated a potential threshold of RNFL thinning below which visual function may remain significantly impaired. Current ongoing clinical trials of neurorepair therapies thus aim to prevent or reduce the generally observed 5- to 40-µm thinning of the peripapillary RNFL after a single acute episode of optic neuritis ( Fig. 5.33 ). Eyes with a history of optic neuritis in the setting of MS have also been shown to have reduced RNFL as well as GCL thickness. The majority of the thinning of the RNFL and GCL occurs in the first 2 months after the optic neuritis episode, and it is particularly severe in the GCL layer. Compared with MS eyes without a history of optic neuritis and disease-free control eyes, degrees of both axonal and neuronal loss are greatest among eyes with a history of acute optic neuritis. These data emphasize the particular unmet need in optic neuritis to reduce degrees of visual pathway axonal and neuronal loss through new reparative and neuroprotective therapies.

Spectral-domain optical coherence tomography sector thickness plots from a patient with multiple sclerosis but no known history of optic neuritis showing mild asymptomatic retinal nerve fiber layer (RNFL) thinning in the left eye ( red sections ). Light blue sections are slightly thickened. The overall average peripapillary RNFL thickness for the left eye (number in center circle of grid) is in the “green,” normal range at 91 µm but is 20 µm less than the average for the right eye and shows temporal thinning.

There has been a paradigm shift in recent years that has included the use of MRI of the spinal cord earlier in the initial management of patients with optic neuritis in attempt to establish a diagnosis of clinically definite MS more expeditiously. CSF analyses may also be helpful as an adjunct to brain and spinal cord MRI scanning in the initial evaluation of patients with isolated optic neuritis. Among the 83 patients in the ONTT who had spinal fluid analysis, the protein and glucose were usually normal, and only one-third of patients had a pleocytosis, usually between 6 and 27 white blood cells (WBCs)/mm ³ . Myelin basic protein was detected in about one-fifth of patients, and immunoglobulin (Ig)G synthesis in about two-fifths. Oligoclonal banding occurred in approximately half of the patients and was associated with the future development of clinically definite MS. However, oligoclonal banding usually occurred in the presence of white matter lesions on MRI, which is less invasive and had a greater predictive value for the development of MS. Other studies have found the combination of an abnormal MRI scan and the presence of oligoclonal banding to be strongly associated with the development of MS. In general, we would recommend CSF examination as most helpful for patients with atypical clinical features or course of optic neuritis, or for patients whose brain MRI findings are not characteristic of the demyelinating lesions seen in MS.

Course and recovery. The ONTT clearly demonstrated that the long-term visual prognosis in optic neuritis without treatment was the same as when either oral or intravenous corticosteroids were administered. Intravenous methylprednisolone in the ONTT increased the rate of visual recovery, but at 1 year all treatment groups tested similarly. This finding was confirmed in another study that compared intravenous methylprednisolone with placebo in patients with either short or long segments of optic nerve enhancement on MRI. In the ONTT, oral prednisone was associated with an increased rate of recurrent optic neuritis, particularly at the 2- and 5-year follow-up periods. At 10 years follow-up, the risk of optic neuritis recurrence remained higher in the oral prednisone (44%) than in the placebo (31%, p = 0.07) and methylprednisolone groups (29%, p = 0.03), although these patterns were not as evident as those seen earlier in the trial follow-up. At 10 years, 72% of the eyes in the ONTT had visual acuity of at least 20/20 and 66% of patients had better than 20/20 high-contrast visual acuity in both eyes. While these results were said to provide evidence that the visual prognosis in acute optic neuritis is excellent, vision-specific quality of life (QOL) remained impaired among ONTT participants even at 5–8 years after the acute episode. In this cohort, 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) scores were lower among patients with decreased vision and in those with neurologic disability due to MS.

Recovery from optic neuritis is fairly prompt, usually beginning within 2–4 weeks after the onset of symptoms. In fact, in almost all of the patients in the ONTT (regardless of treatment type), recovery began within 1 month. The ONTT and other reports have shown that patients with initial poor acuity (20/400 to NLP), more severe visual field loss, and more profound reductions of contrast sensitivity have a poorer prognosis. Furthermore, those patients with a visual acuity of 20/50 or worse at 1 month will usually have moderate to severe residual visual impairment. However, there is great variability in the quality of the “20/20” vision that remains. Recovery to 20/20 vision does not truly capture the types of visual dysfunction and the symptomatology that many patients report following recovery from optic neuritis.

In the ONTT, 63% of patients thought that their vision had not recovered to normal, although only a few reported any difficulty carrying on daily activities. Among 215 patients who reported their vision to be somewhat or much worse than it was before their optic neuritis, 43% had either normal results or only one abnormal result on all four measures of visual function tested (acuity, color, contrast, field). Stereoacuity (despite normal Snellen acuity) was found to be abnormal in 85% of 27 patients in an earlier study. In addition, patients with MS report significant reductions in vision-specific QOL despite having normal high-contrast visual acuity. These deficits in QOL have been shown to correlate with greater RNFL and GCL thinning in patients with MS both with and without a history of acute optic neuritis.

One study suggested that visual loss in optic neuritis in African Americans was more severe at onset and after 1 year of follow-up than that in Caucasians. A subsequent investigation of the ONTT cohort confirmed that black race and ethnicity were associated with worse contrast sensitivity and visual acuity outcomes in affected eyes.

Multiple sclerosis. Because of the close association between optic neuritis and MS, the features of afferent visual function and general paradigms for the treatment of MS are summarized here.

MS is characterized by transient neurologic dysfunction, lasting days or weeks, owing to focal demyelination in the CNS. In addition to optic neuritis, other common clinical manifestations include double vision related to involvement of the medial longitudinal fasciculus (internuclear ophthalmoplegia (INO)) (see Chapter 15 ), ataxia and nystagmus due to cerebellar white matter tract involvement (see Chapter 17 ), extremity weakness, bladder difficulty, and sensory abnormalities. Rarely, patients may also have uveitis (pars planitis and panuveitis). MS primarily affects young adults, most often women, but children and older adults may also develop the disease.

In most individuals, the initial course of MS is relapsing–remitting, with neurologic exacerbations separated by weeks, months, or years. Spontaneous recovery or near-recovery is the rule at this stage. Unfortunately, more severely affected patients may exhibit a progressive course. This is manifested by a continuous decline in neurologic function that may have a profound effect on vision, ambulation, and cognition. Although the observations have been inconsistent and the reasons unclear, there may be an increased risk of attacks in the initial 6-month postpartum period in women with relapsing–remitting disease. A recent revision of the MS subtype categories illustrates the heterogeneity of disease course that patients may manifest and their implications for future trials and therapeutic strategies.

Pathologically, new demyelinative lesions, or plaques, are characterized by perivascular inflammatory cell infiltration. Chronically, the plaques typically exhibit myelin destruction, disappearance of oligodendrocytes, and astrocyte proliferation. It is also now well recognized that axonal transection may be seen in many instances, perhaps explaining the irreversibility of some neurologic deficits. Radiographically, the white matter lesions are typically periventricular and often project perpendicularly from the ventricular surface. However, recent attention has been directed at MRI demonstration of brain atrophy, magnetic resonance spectrographic evidence of neuronal cell loss, pathologic evidence of axonal transection, and cortical lesions in MS.

The underlying cause is unclear, but MS is likely to be primarily an autoimmune process that occurs in genetically susceptible individuals following an environmental exposure. An immune cross-reaction to viral antigens has been implicated. A greater incidence of MS in Caucasians and first-degree relatives of affected individuals, and single-nucleotide polymorphisms found in families with MS, support the notion that genetic factors may also play a role. The possibility of an environmental factor is also supported by the preponderance of cases in northern latitudes. Reduced sun exposure and related hypovitaminosis D in these regions may explain this observation.

The diagnosis of MS is primarily a clinical one and can be formally established when a patient has an idiopathic syndrome consistent with inflammatory demyelination of the optic nerve, brain, and spinal cord. However, MRI abnormalities are playing a larger role in making the diagnosis of MS. The McDonald criteria were originally established to enable the diagnosis of MS when a patient has had one or more clinical events consistent with demyelination and then has MRI evidence of disease dissemination in time and space ( Table 5.1 ). These criteria have advanced to the degree that an MS diagnosis can be made based on a single brain MRI scan in a patient with acute optic neuritis as a first demyelinating event. Low baseline macular RNFL values in patients with clinically isolated syndrome may predict new T2 lesions over the ensuing year.

In 2017, new changes were made to the McDonald criteria including the ability to use the presence of CSF oligoclonal banding to establish dissemination in time in a patient with a typical clinically isolated syndrome who has MRI evidence of dissemination in space. In addition, the symptomatic lesions of the brainstem and spinal cord can now be used to demonstrate dissemination in space or time. Previously, the symptomatic lesion was excluded in the lesion count but new evidence shows that incorporation of such lesions improves MS diagnostic sensitivity without compromising diagnostic specificity. Importantly, it should be noted that the symptomatic optic nerve lesion is not counted in the new criteria because there was insufficient evidence to include it as a lesion site. Thus, further investigation should examine the criteria for incorporating the optic nerve as an imaging lesion site. We think establishing OCT criteria for an optic nerve lesion holds great promise. Finally, cortical lesions or juxta-cortical lesions can count for dissemination in space as the importance of cortical lesions has been established with advanced neuro-imaging in MS patients.

Treatment options in MS may be classified as symptomatic or immunomodulatory. Although most exacerbations are self-limited, those causing weakness, incoordination, visual dysfunction or acute vertigo are usually treated with a short course of high-dose intravenous methylprednisolone. Other treatment options that are rarely used for acute attacks in relapsing-remitting disease include intramuscular adrenocorticotropic hormone (ACTH) and intravenous immune globulin. Plasma exchange may be used in patients with severe neurologic dysfunction poorly responsive to corticosteroids.

The immunomodulatory medications, now termed the “platform” therapies for MS—interferon β-1a, interferon β-1b, and glatiramer acetate—have been approved for use in patients with relapsing–remitting MS and are the mainstays of MS therapy. In large randomized clinical trials, each decreased the frequency of exacerbations and slowed the rate of appearance of development of new white matter lesions on MRI. Interferon β-1a also delayed the progression of sustained neurologic disability in MS trials.

The chemotherapeutic agent mitoxantrone is approved for patients with more advanced forms of MS, but it is rarely used now because of the potential side effects of cardiotoxicity and secondary leukemia. Natalizumab, a monoclonal antibody that reduces T-cell trafficking across the blood–brain barrier, is approved for the treatment of the relapsing forms of MS. However, the use of natalizumab has been associated with progressive multifocal leukoencephalopathy (PML; see Chapter 8 ), and thus natalizumab is primarily used as a second-line therapy for patients who are not responsive to MS platform therapies. Patients who are at particularly high risk for multiple relapses, such as those with numerous gadolinium-enhancing MRI lesions, may also benefit from natalizumab. Recently, ocrelizumab, a monoclonal antibody that binds to CD20 on the surface of B cells, has been approved for relapsing MS and primary progressive MS.

Several oral agents for treatment of MS have emerged within the past 5 years; these include fingolimod, teriflunomide, and dimethyl fumarate. These agents are highly effective in reducing both clinical and MRI-evident disease activity in MS. While the oral route is very convenient for many patients, potential side-effects of infection and other factors specific to each medication need to be weighed against the potential benefits. At this time, these agents are first-line therapy for patients unable or unwilling to self-inject the platform therapies. Further evaluation of these oral therapies postmarketing is in progress and will provide additional guidance regarding risks. Because low serum levels of 25(OH)D were associated with higher relapse rates, vitamin D supplementation for MS patients has also been suggested.

With the development of immunomodulatory therapy options for MS, four subsequent independent clinical trials were also performed to determine whether initiation of platform MS therapies could also be effective in the setting of a first demyelinating event (including optic neuritis) and a brain MRI demonstrating white matter demyelinating lesions. This scenario has been termed clinically isolated syndrome. Indeed, the most reliable predictor for the future development of clinical demyelinating events consistent with clinically definite MS is the presence of white matter lesions on MRI. In long-term follow-up, the risk of clinically definite MS is approximately 60–90% with a positive MRI and 20–25% when the baseline MRI scan is normal ( Table 5.2 ). Other clinical and demographic features are also predictive. In the 15-year follow-up in the ONTT, MS did not develop in any patient with a normal MRI scan who had (1) painless visual loss, (2) severe optic disc edema, (3) disc or peripapillary hemorrhage, (4) macular exudates, or (5) NLP vision. In patients with a normal baseline brain MRI, male gender and the presence of disc swelling were associated with a smaller risk of converting to clinically definite MS. Fifteen years after acute optic neuritis, 50% of patients had developed MS—72% of those with one or more brain MRI lesions at presentation and 25% of those with no lesions.

In a prospective study of 320 patients with clinically isolated syndromes, the rates of conversion to MS were the same regardless of the type of clinically isolated syndrome. After a median follow-up period of 39 months, approximately 70% of patients with clinically isolated syndromes and abnormal baseline MRI had developed MS. Of note, only 49% of the patients with optic neuritis had a positive MRI at baseline compared with 76% with brainstem and spinal cord syndromes. The authors emphasize that those patients with a positive baseline MRI and a clinically isolated syndrome act similarly in their conversion to MS. Patients with optic neuritis as a first demyelinating event tend to have brain MRI lesions less frequently than do those with spinal cord or brainstem presentations. Although less predictive, CSF oligoclonal bands are also associated with the development of MS if positive at the time of the first attack of optic neuritis.

Treatment in typical cases. Intravenous (IV) corticosteroids followed by a short course of oral prednisone should be considered for patients with acute optic neuritis, particularly in these in two instances:

• 1.
  

  In patients with white matter lesions on MRI, steroid treatment should be offered to reduce the risk of developing clinically definite MS for the first 2 years. The ONTT demonstrated that a course of intravenous steroids given at the time of an acute attack of optic neuritis, particularly in patients with abnormal MRI scans, reduced the rate of development of clinically definite MS in the first 2 years. Although controversial, and potentially affected by reanalysis bias, these findings led to the broad recommendation that patients with optic neuritis and abnormal MRI scans should be treated with steroids to reduce the risk of developing MS. After 3 years that beneficial effect disappeared.

  
  
• 2.
  

  We have a low threshold to use intravenous corticosteroid treatment in patients with severe unilateral or bilateral visual loss because of their slightly poorer visual prognosis and because steroids may hasten recovery. The protocol established by the ONTT is methylprednisolone 250 mg intravenously q.i.d. for 3 days, followed by prednisone 1 mg/kg q.d. for days 4–14, then 20 mg of prednisone on day 15, and 10 mg on days 16 and 18. As home therapy, intravenous steroids (1 g methylprednisolone every day for 3 days) can be administered safely in relatively young healthy individuals, and, if there are no relative contraindications such as diabetes, peptic ulcer disease, or coronary artery disease, the risk is small. Hospitalization may be required in older individuals and in those with the aforementioned medical illnesses. Because of the increased risk of recurrent episodes, patients with optic neuritis should not be given oral prednisone alone. Despite the abundance of class I clinical trial evidence, disappointingly ophthalmologists and neurologists around the world have not universally adopted the protocol outlined here. There are still many practioners who prescribe oral steroids and others who prescribe steroids with the false notion that they improve final visual outcome.

Therapy for the patient with the clinically isolated syndrome. In patients with a clinically isolated syndrome and a brain MRI with typical white matter lesions, interferon β-1a, interferon β-1b, or glatiramer acetate can be given to reduce the risk of developing MS. Supportive evidence comes from several large clinical trials. In practice, many of these patients can now also qualify for the diagnosis of MS by MRI criteria and can be treated either with injectable or oral MS therapy.

Other therapies for optic neuritis. Although the use of oral high-dose methylprednisolone in one study was not associated with an increased risk of recurrent attacks, the small size of this study precluded any definite conclusions regarding its use in acute optic neuritis. Small studies have suggested that intravenous immunoglobulin (IVIg) may have some benefit in patients with substantial visual deficits following optic neuritis. However, subsequent randomized trials in which the outcome measure was either visual acuity or contrast sensitivity failed to demonstrate a significant benefit with this treatment. Furthermore, the routine use of IVIg in optic neuritis and MS remains limited by cost and availability.

Plasma exchange, used successfully in other inflammatory and demyelinating disorders, may have a role in treating patients with optic neuritis who are unresponsive to other therapies. In a retrospective review of 10 patients with steroid-refractory optic neuritis, plasma exchange was associated with short-term improvement in visual acuity in 7. However, a large prospective controlled trial is necessary to better understand the role of plasma exchange in this refractory patient population.

Evaluation of optic neuritis in atypical cases. Criteria for atypical optic neuritis include (1) marked disc swelling with hemorrhages and exudates, (2) simultaneous bilateral involvement, (3) vitritis, (4) progression of visual loss after 1–2 weeks, (5) lack of partial recovery within 4 weeks of onset of visual loss, and (6) persistent pain. A suggested workup with diagnostic considerations in these cases is given in Table 5.3 . Compressive lesions should be excluded by MRI; other etiologies require additional testing.

Neuromyelitis Optica (Devic Disease)

NMO is classically described as a severe demyelinating disease that preferentially targets the optic nerves and spinal cord; however, occasional patients may have a more benign course resembling that of MS. Patients typically present with acute-onset optic neuritis, often preceded or followed by paraparesis or paraplegia. It tends to occur in young adults but is also well recognized in children. Both monophasic illnesses and recurrent attacks have been described. Patients tend to present with visual loss and evidence of spinal cord dysfunction within 8 weeks of each other.

In contrast to typical demyelinating optic neuritis, the vision loss observed in NMO is often bilateral and severe, occasionally progressing to blindness. Some patients may have frequent recurrent episodes of optic neuritis. Periorbital pain, an almost universal feature in typical demyelinating optic neuritis, may not be as common in NMO. The optic disc may appear normal or swollen, and varying degrees of visual recovery can occur. Like idiopathic optic neuritis, NMO-associated optic neuritis is associated with significant thinning of the nerve fiber layer on OCT, which correlates with visual function and quality of life.

MRI of the optic nerves in affected patients often shows more posterior, chiasmal, and bilateral involvement than MS-related optic neuritis (see Fig. 5.32C ). Lesions of the spinal cord are longitudinally extensive, involving at least three vertebral segments. Although diagnostic criteria for NMO originally excluded patients with brain lesions on MRI, it is now believed that brain lesions may be seen in as many as 60% of patients with NMO. However, these lesions are typically nonspecific, and only about 10% have the typical MS morphology.

Spinal fluid abnormalities may include a pleocytosis of greater than 50 cells/mm ³ , and oligoclonal bands may be observed in 20–30% of patients. This contrasts with established MS, in which a moderate pleocytosis is rare, and oligoclonal banding is seen in 70–90% of patients.

Autopsy studies have demonstrated typical demyelinating plaques (like MS) in some patients, while in others a necrotizing myelitis (unlike MS) with thickened blood vessel walls was found. Astrocytosis, reactive gliosis, and microcavitation may be seen pathologically in the optic nerves. Because of the necrotizing nature of the lesions, the prognosis for recovery may be worse from both a visual and neurologic standpoint, especially in elderly patients.

NMO is believed to be a humorally mediated disease distinct from MS. A serum antibody, NMO-IgG, which targets the autoantigen AQP4, may be a useful marker in diagnosing NMO. The identification of NMO-IgG in patients either without optic neuritis or without myelitis has led to an expanded definition of NMO spectrum diseases. The antibody has also been detected in patients with NMO without optic nerve involvement.

New criteria proposed by the Mayo Clinic help to distinguish NMO from MS. These criteria eliminate the requirement that symptoms must be referable to the optic nerves and spinal cord exclusively; similarly, brain lesions on MRI no longer preclude a diagnosis of NMO. Currently, the diagnosis of NMO is best established when a patient has had at least one episode of optic neuritis, transverse myelitis, and a longitudinally extensive spinal cord lesion on MRI (more than three segments long). The diagnosis is bolstered by detecting the NMO antibodies and by having a normal or nondiagnostic baseline brain MRI. Isolated optic neuritis accompanied by the presence of NMO antibodies would satisfy the diagnosis of NMO spectrum disorder. Recently, anti-MOG antibodies have emerged as a potential marker of recurrent optic neuritis, neuromyelitis optica, and acute disseminated encephalomyelitis (ADEM) in NMO negative patients.

There is no standard treatment for optic neuritis in the context of NMO, although high-dose intravenous corticosteroids may be beneficial in lessening the severity of the attack and speeding recovery of visual function. Plasmapheresis may be beneficial in the acute stage for those failing to respond to corticosteroids.

Long-term immunosuppression should be considered in patients with NMO, even in those who present with just atypical optic neuritis, given the risk of subsequent devastating paralysis related to myelopathy. Treatment with rituximab (a chemotherapeutic monoclonal antibody that depletes B cells) may be an effective disease-modifying agent for the long term. Mycophenolate mofetil and azathioprine are other agents that may be used as preventative treatment for NMO.

NMO is also well recognized in children. Visual acuity prognosis in NMO is relatively poor, with approximately 80% of children in one series having visual acuity of 20/200 or worse in at least one eye.

Other systemic conditions may be associated with Devic disease. These include systemic lupus erythematosus, other connective tissue diseases such as Sjögren’s syndrome, and pulmonary tuberculosis.

Recently, anti-MOG antibodies have emerged as a potential marker of recurrent optic neuritis, neuromyelitis optica, and acute disseminated encephalomyelitis (ADEM) in NMO negative patients.

Pediatric Optic Neuritis and Multiple Sclerosis

Inflammatory disease of the optic nerve in children is quite different from that in adults. While there are some children and adolescents who have unilateral attacks of demyelinating optic neuritis and later develop MS, there are many others with an illness that seems to be quite distinct from the adult variety of the disease. Like adults, most children experience acute loss of vision associated with an afferent pupil defect and visual field defects. Unlike adults, however, children have a much higher likelihood of having bilateral involvement (50–75%) and disc swelling (50–75%), particularly when younger than 10 years of age.

There have been no formal studies evaluating the optimal treatment of childhood optic neuritis. However, because of the patients’ young ages, we favor more aggressive evaluation and treatment when visual loss is unilateral and severe or bilateral at any level. Workup includes MRI, serologies, and lumbar puncture to exclude other causes. Hospitalization and 3–5 days of intravenous methylprednisolone (4 mg/kg q.i.d. or 15 mg/kg q.d.) therapy is initiated, followed by an oral prednisone taper (starting at 1 mg/kg, then reduced over 2–4 weeks). Prognosis for recovery in children is generally excellent, with more than 80% of children returning to 20/20 or better, and 96% returning to 20/40 or better. Good et al., however, reported a series of 10 children, 7 of whom remained at 20/200 or worse.

Etiologic considerations in childhood optic neuritis suggest that there may be three distinct subsets of patients. One group has their neurologic event (immune mediated) in the setting of postinfectious ADEM, with or without radiographically demonstrable white matter lesions. Typically following a febrile illness or vaccination, this group of patients has a monophasic demyelinating illness with recovery and without recurrence. The second group may present with “idiopathic” (genetic predisposition with environmental trigger) demyelination, recover, but later develop a recurrent neurologic illness suggestive of MS or NMO. The possibility that these two groups are linked and that viral illness or vaccinations are important triggers of MS has also been proposed. For instance, cases of childhood optic neuritis and MS have been reported after viral illnesses and varicella. A third group of pediatric patients have a benign condition characterized by isolated optic neuritis, typically with bilateral involvement and with disc swelling, and a normal brain MRI. Although recurrences of optic neuritis may occur in this group, patients in this category tend not to develop MS. The presence of antimyelin oligodendrocyte glycoprotein (anti-MOG) antibodies may be associated with recurrent optic neuritis rather than with MS or NMO.

Overall, between 10% and 50% of children with optic neuritis eventually develop MS. In one series of children with optic neuritis and an average follow-up of 7.3 years, brain MRI abnormalities were found to be a very important prognostic factor, as three of the seven children with white matter lesions developed MS, while none of the 11 patients without white matter lesions developed MS. Furthermore, in a recent metaanalysis of 282 children with optic neuritis, age was identified as a second important factor in determining risk of conversion to MS, with an odds ratio of 1.32 for increasing age (years) and the development of MS after unilateral optic neuritis, and after adjusting for the presence of MRI lesions.

MS in children is recognized in patients as young as 2 years old. Compared with adult MS patients, children with MS take longer to convert to the secondary progressive form (median 28 years) but do so at a relatively younger age (median 41 years). Optic neuritis is often the first clinical attack in pediatric patients with MS. Many of the same disease-modifying therapies used in adults are being used in younger patients as well.

Optic neuritis may also be a presenting sign of NMO in children. In a large case series of pediatric patients with NMO, 40% of them presented initially with unilateral optic neuritis, while 20% presented with bilateral optic neuritis and 15% presented with transverse myelitis. At the last follow-up, 55% of the children with NMO had at least one clinical demyelinating event involving the brain.

Sarcoidosis

Sarcoidosis is a multisystem disorder of unknown etiology, characterized pathologically by noncaseating epithelioid cell granulomas. It is much more common in African Americans and slightly more common in women than in men. The initial onset of the systemic illness may be an isolated visual or neurologic presentation, or there may be systemic symptoms including rash, fevers, night sweats, diarrhea, pulmonary symptoms, and lymphadenopathy. Most patients will have hilar adenopathy detectable on chest radiograph, as extrapulmonary sarcoidosis without hilar adenopathy is rare. The most commonly involved organ is the lung, which is involved in over 90% of cases. CNS involvement in sarcoidosis occurs in about 5% of cases. The most common neurologic complication is seventh nerve palsy (see Chapter 14 ), followed by involvement of other cranial nerves, aseptic meningitis, and peripheral neuropathy.

On the other hand, ocular involvement in sarcoidosis occurs in about 25% of patients. In the vast majority this takes the form of a relapsing and remitting anterior uveitis, often associated with ocular hypertension. Conjunctival nodules are also relatively common. In patients with posterior segment involvement, sarcoidosis most commonly presents with retinal vasculitis, vitreous infiltrates, and choroidal lesions, often with associated disc swelling (see Chapter 4 ).

Optic nerve involvement in the setting of sarcoidosis can take many different forms. Some patients present with a syndrome similar to idiopathic optic neuritis. Other patients have an optic nerve head or subretinal granuloma ( Fig. 5.34 ), while others may have a swollen nerve (due to either optic nerve or optic nerve sheath infiltration). Also common is a pure retrobulbar presentation with a normal-appearing optic nerve head. Sarcoidosis is also a well-recognized cause of perineuritis (see below) and can cause gaze-evoked amaurosis. Sarcoid optic neuropathy has been reported to occur in conjunction with AQP4-positive NMO.

Optic nerve head appearance in a patient with sarcoidosis and swelling of the optic nerve head and peripapillary subretinal granulomas ( arrows ).

Patients can present with progressive vision loss and in general have less pain than patients with idiopathic optic neuritis. NLP vision is common and should heighten the suspicion for sarcoid in patients with optic neuropathies. Vision loss initially may be steroid responsive. Other patients have a relentless downhill course, despite the use of steroids, and develop profound visual impairment. Cases with spontaneous improvement and isolated disc swelling without optic nerve dysfunction have been reported. Sarcoidosis with optic nerve involvement must be considered in all patients thought to have inflammatory or compressive disease of the anterior visual pathway (also see Chapter 7 ). Important clues include the presence of a steroid-responsive optic neuropathy and findings atypical for ordinary optic neuritis such as vitritis, retinal vasculitis, or enlargement of the optic nerve on MRI. Sarcoidosis can also present as an orbital inflammatory syndrome (see Chapter 18 ).

Diagnostic studies/evaluation. Sarcoidosis can present with a markedly thickened optic nerve sheath on MRI, mimicking an optic nerve sheath meningioma. Imaging of the orbit will often reveal a “mass lesion,” lacrimal gland enlargement, or optic nerve and/or sheath enhancement. MRI may also demonstrate periventricular multifocal white matter lesions in CNS sarcoidosis or leptomeningeal enhancement.

When sarcoidosis is suspected, chest radiograph, angiotensin-converting enzyme (ACE) level, and, if necessary, a gallium scan or positron emission tomography (PET) should be obtained. ACE levels and chest imaging may be normal in a significant minority of patients. Whenever possible, the diagnosis should be confirmed by biopsy (often pulmonary via bronchoscopy or of hilar nodes via mediastinoscopy). On occasion conjunctival or lacrimal gland biopsies, which are less invasive than the pulmonary or hilar biopsies, can be used and are diagnostic. In general we do not favor blind biopsies of any organ but prefer to biopsy tissue that is visibly affected or is abnormal on radiography, imaging, or gallium scan. Finally, it is reasonable to consider sarcoidosis in all cases of unexplained optic neuropathy, and screening with chest radiography and ACE levels will occasionally suggest the diagnosis.

Treatment. Treatment with systemic steroids is likely to be required for a protracted time (weeks to months). Other patients require chronic immunosuppression with alternative cytotoxic drugs. Methotrexate, azathioprine, infliximab, cyclosporine, mycophenolate mofetil, and cyclophosphamide have been used in cases of steroid failure or inability to wean from high steroid doses.

Optic Perineuritis and Orbital Inflammatory Syndromes

Optic perineuritis is a term used to describe an optic neuropathy presumably caused by inflammation of the optic nerve sheath. In many cases the etiology is unknown. The clinical constellation of bilateral optic neuropathy (often with relative central vision sparing), associated with pain, typical MRI findings of sheath enhancement, and steroid responsiveness is highly suggestive of this condition. Histopathologically, these patients have been shown to have nonspecific chronic inflammation, occasionally granulomatous and often associated with varying degrees of fibroplasia and collagen deposition.

In our experience, patients with this condition fall into three broad categories. The first are patients with optic neuropathy but with other evidence of an acute orbital inflammatory syndrome (orbital pseudotumor) such as proptosis, eyelid swelling, eye muscle involvement, and posterior scleritis. Neuroimaging reveals orbital inflammatory changes as well as optic nerve sheath enhancement. This entity is discussed in more detail in Chapter 18 . The second group of patients have optic perineuritis in the setting of a systemic condition, most commonly sarcoidosis, syphilis, Lyme disease, herpes, or tuberculosis. In the final group the condition is idiopathic with no evidence of orbital disease or systemic infection.

The distinction of optic neuritis from optic perineuritis is based largely on clinical presentation and radiographic demonstration of optic nerve sheath thickening or enhancement in the latter. Patients tend to be older and the disease is often bilateral in perineuritis. Vision loss may be mild initially, and the optic nerve head is often swollen with secondary retinal venous stasis changes, dilation of vessels, and peripheral retinal hemorrhages ( Fig. 5.35 ). Clinically it must be distinguished from papilledema since both may share the clinical features of bilateral disc swelling and relatively good visual function. In most patients with perineuritis, the CSF exhibits a normal opening pressure with a mild pleocytosis. Patients may also have an acute presentation that mimics optic neuritis, or they may present with an insidiously progressive optic neuropathy.

A and B . Optic perineuritis with bilateral optic nerve swelling. C . On coronal T1-weighted, gadolinium-enhanced magnetic resonance imaging, enhancement of the optic nerve sheaths is seen ( arrows ).

Rarely IgG4-related orbital disease can result in optic nerve involvement (see Ch. 18 ). Optic neuropathy may be due to compression from orbital apex mass lesions or direct optic nerve involvement in the setting of sclerosing orbital disease.

Diagnostic studies/evaluation. The presence of associated vitreous cells and infiltrates is suggestive of a systemic condition associated with the perineuritis, and extensive workup for sarcoidosis, syphilis, Lyme disease, herpes virus, and tuberculosis should be initiated in such cases. In addition, if the clinical scenario warrants, evaluation for giant cell arteritis, granulomatosis with polyangiitis, and Crohn disease should be sought. Optic nerve sheath thickening can be documented with orbital ultrasound and either CT or MRI scanning. Contrast enhancement of the sheath is more prominent than enhancement of the nerve itself (see Fig. 5.35 ). Radiographically, perineuritis can be difficult to distinguish from optic nerve sheath meningioma. If there is more widespread evidence of meningeal involvement then syphilitic, cryptococcal, tuberculous, and carcinomatous meningitis are more likely. If papilledema is considered, patients with headache should undergo lumbar puncture to rule out elevated intracranial pressure.

Treatment. Treatment for perineuritis is directed either at the systemic infection or relies on systemic steroids. In our experience, patients with infectious perineuritis are often successfully treated, with good recovery of vision. However, the idiopathic variety, or that associated with orbital inflammation, can take a chronic form that is resistant to steroid treatment and is associated with significant fibrosis of the optic nerve sheath. Optimal treatment of IgG4-related disease is not yet known but typically involves glucocorticoids and other steroid-sparing agents such as rituximab or mycophenolate mofetil when indicated.

Uveitis-Associated Disc Swelling

Patients with uveitis, particularly with posterior segment involvement, can have disc swelling. A nonspecific process resulting from simple breakdown of the blood–retina barrier in posterior uveitis should be distinguished from an inflammatory process involving the optic nerve itself. The former is more common, for instance in pars planitis, where disc swelling may be accompanied by cystoid macular edema. In this setting, there is usually only enlargement of the blind spot without evidence of optic neuropathy. In the second group of patients, an inflammatory or infectious process, often granulomatous (commonly sarcoid or syphilis), involves the nerve itself, and significant visual dysfunction with optic neuropathy is often present. Optic disc swelling can also accompany hypotony, which may occur with chronic uveitis.

Optic Neuropathy Related to Systemic Lupus Erythematosus

Optic neuropathy is an important but uncommon neuro-ophthalmic complication of systemic lupus erythematosus. In one series approximately half of the cases of lupus-related optic neuropathy were associated with transverse myelitis. This pattern of optic neuropathy with transverse myelitis mimics Devic NMO (see previous discussion).

Optic nerve dysfunction can take different forms, including optic neuritis, papillitis, and anterior or posterior ischemic optic neuropathy (AION, see next section). The disc swelling may be associated with exudates ( Fig. 5.36 ). It is unclear, but the pathogenesis is related to either demyelination or varying degrees of small vessel vasoocclusive disease. Vision loss is often profound and when suspected should be treated promptly with steroids. MRI may show enhancement of the optic nerve. These patients require initial treatment with high-dose intravenous methylprednisolone, and many require chronic steroids. Retinal vasculopathy may manifest with painless retinal ischemic changes. In this situation, an associated hypercoagulable state should be excluded and anticoagulation considered. A recent metaanalysis of several case reports revealed that although relapses are common, visual loss is not usually permanent if appropriate treatment is initiated.

Optic nerve appearance in a patient with systemic lupus erythematosus and optic neuritis. Chronic disc swelling and retinal exudates are present.

Other neuro-ophthalmic complications of lupus are detailed in Chapters 4 and 8 .

Autoimmune (or Relapsing or Recurrent) Optic Neuropathy

This distinct variety of optic nerve inflammation is similar to lupus optic neuropathy. This likely represents a heterogeneous group of conditions, some with recognized systemic autoimmune disease, with isolated, recurrent, often bilateral, steroid-responsive optic neuropathy and various autoimmune markers on serologic testing, including NMO antibodies. Excluding those patients whose optic neuropathy is associated with known systemic disease or NMO antibodies, there remains a very small group of patients that might be labeled as having autoimmune optic neuropathy. Autoimmune optic neuropathy may be an isolated single event, or it may be a chronic relapsing process known as chronic relapsing inflammatory optic neuropathy (CRION). Additionally, it may coexist with an autoimmune retinopathy and is then known as autoimmune-related retinopathy and optic neuropathy (ARRON). Diagnostic criteria for ARRON have been suggested and include a requirement that the patient demonstrates (1) visual loss either in visual acuity or visual field, (2) no evidence of malignancy after extensive evaluation, (3) optic nerve or retinal abnormalities, and (4) no identifiable cause for the optic neuropathy and retinopathy. In addition, patients must either demonstrate serum autoantibodies against the retina or optic nerve (see later discussion) or demonstrate a response to immunomodulation.

In many of these patients no specific connective tissue diagnosis can be made using strict clinical or serologic criteria, despite extensive searching. Its similarity to lupus optic neuropathy suggests that an optic nerve antigen may be susceptible to an autoimmune attack. An alternative possibility is that optic nerve dysfunction arises in the setting of autoimmune disease as a result of small vessel occlusion from immune complex deposition or a hypercoagulable state. Some cases have had abnormal skin biopsies, with perivascular infiltrate and immune complex deposition within the dermis. Affected patients are generally adults aged 25–55 years, but the condition probably occurs at any age. Bee sting optic neuropathy is felt to be a unique autoimmune-type optic neuropathy.

Evaluation and treatment. We recommend a search for an autoimmune condition in any patient that has “optic neuritis” that worsens for more than 1 week after initial steroid therapy, or in any patient who fails to begin to improve by the third week after onset of visual loss (see Evaluation of Optic Neuritis in Atypical Cases). In suspected cases, antinuclear antibody (ANA) testing, NMO antibodies, Sjögren antibodies, and skin biopsy should be considered. Additionally, testing for antioptic nerve autoantibodies has been suggested, but these autoantibodies have not yet been proven to be pathogenic and are of questionable clinical significance at this time. Rheumatologic consultation, consideration of a skin biopsy to exclude vasculitis, and serologies should be considered in these patients to identify a possible systemic autoimmune condition. ERG abnormalities and nonspecific retinal changes are seen in most patients with suspected ARRON. In addition, multiple autoantibodies have been reported in association with ARRON-like presentations, including antibodies against a 22-kDa neuronal antigen found in the retina and optic nerve, a 35-kDa component of Mueller cells, and alpha-enolase. Early recognition of autoimmune optic neuropathy, CRION, and ARRON can lead to successful treatment with high doses of steroids. Other immunosuppressive therapies such as IVIg, methotrexate, cyclophosphamide, chlorambucil, and azathioprine may be required to supplement steroid therapy in this chronic and relapsing condition. In most patients the optic neuropathy remains isolated without development of another systemic autoimmune disease or specific syndrome.

Idiopathic Hypertrophic Pachymeningitis

This condition is characterized by localized or diffuse thickening of the meninges. Affected patients present with headache, optic neuropathy, or other cranial neuropathies. MRI may demonstrate dural thickening and enhancement, and lumbar puncture often shows a lymphocytic pleocytosis and elevated protein. When unclear, the diagnosis may depend on a biopsy of the leptomeninges, which typically reveals nonspecific inflammation but is needed to exclude IgG4, sarcoidosis, infection, or neoplasm. Most patients are treated effectively with corticosteroids, but many additionally require steroid-sparing immunosuppressive agents.

Sinusitis and Mucoceles

Paranasal sinus disease (sinusitis and mucoceles) may cause either an acute optic neuropathy plus pain on eye movements, similar to optic neuritis, or a chronically progressive optic neuropathy ( Fig. 5.37 ). The optic nerve disturbance results from compression or inflammation from a nearby mucocele. In other cases contiguous inflammation in the posterior ethmoid and sphenoid sinus causes optic nerve dysfunction without mass effect. This may occur more commonly in patients with no medial wall of the optic canal (meninges in direct contact with sinus mucosa), an anatomic variant which occurs in about 4% of normal patients. Antibiotics and often surgery should be considered.

Sphenoid sinusitis causing optic nerve dysfunction. A . Axial T2-weighted magnetic resonance imaging (MRI) showing extensive ethmoid and sphenoid sinusitis ( asterisk ) adjacent to the optic canal ( arrow ). B . On coronal T1-weighted MRI the optic nerve ( arrow ) is seen adjacent to the area of infection and inflammation ( asterisk ).

Neuroretinitis

The term neuroretinitis refers to the combination of optic neuropathy and retinal “inflammation” characterized ophthalmoscopically with the unique association of disc edema and peripapillary or macular hard exudates, which form a “star” or sunburst pattern around the fovea ( Fig. 5.38 ). The condition was first described by Leber and is therefore frequently referred to as Leber’s stellate neuroretinitis. Neuroretinitis is frequently a manifestation of a systemic infection, so an etiology should be sought when the diagnosis is made. Although the initial presentation can be very similar to idiopathic (demyelinating) optic neuritis, a macular star associated with optic neuritis is not associated with an increased risk of developing MS.

Fundus appearance in a patient with neuroretinitis. A . Acutely there is focal pale disc swelling superiorly (arrow). B . Within 1 week the classic macular star developed.

The macular star results from fluid leakage from optic disc capillaries into Henle’s layer (outer plexiform), which retains the lipid precipitates and can be seen on OCT ( Fig. 5.39 ). All of the leakage is believed to be from the disc since the retinal vasculature does not leak on fluorescein angiography. In fact, the presence of these exudates can be a nonspecific finding in any patient with disc swelling. For instance, at least a partial star can occasionally be seen in patients with a variety of different causes of optic disc swelling, such as ischemic optic neuropathy or papilledema (see Chapter 6 ).

Ocular coherence tomography findings in neuroretinitis. Discrete areas of high reflectivity ( arrows ) are seen in the nerve fiber layer of Henle and correspond to retinal exudates. The asterisk indicates subretinal fluid.

Therefore, we group patients with the finding of optic disc edema with a macular lipid star into two groups:

• 1.
  

  Idiopathic or infectious neuroretinitis. Patients in this group present with decreased vision and a swollen optic nerve, and initially a diagnosis of optic neuritis may be made, but within 1–2 weeks the macular star is evident. Patients in this group are generally aged 10–50 years with no sex predilection. Occasionally they have pain around the eye or bilateral involvement. Neuroretinitis has been reported in children and behaves similarly to the disease in adults. In up to 50% of patients with neuroretinitis, a preceding viral illness is reported.

  
  

  The examination is notable for moderate acuity loss (usually 20/40–20/200) but can be as poor as light perception. Typical features of optic nerve dysfunction are present with decreased color vision, nerve fiber defects on visual field testing, and afferent pupil defects. Vitreous cells are present in about 90%. The disc swelling can either be focal or diffuse, and sometimes it has a pale quality. Development of the lipid star is often preceded by serous detachment of the macula or evidence of inflammation in the peripheral retina. The prognosis for visual recovery is excellent, although recurrent neuroretinitis with poor visual outcome has been reported. Bilateral cases occur rarely.

  
  

  Important infectious causes of neuroretinitis include cat scratch disease ( Bartonella henselae bacillus), syphilis, Lyme disease, toxoplasmosis, and tuberculosis. Patients with Bartonella infection frequently describe cat scratches and a recent viral illness with fever and adenopathy. The diagnosis can be confirmed by detecting positive antibody titers or by finding Bartonella DNA by polymerase chain reaction (PCR).

  
  
• 2.
  

  Macular star related to other causes of disc swelling. These patients have a fairly typical presentation of an optic neuropathy associated with disc edema (e.g., ischemic optic neuropathy ) then a few weeks from presentation develop a macular star. The original diagnosis may be rethought, and consideration should be given to papilledema associated with increased intracranial pressure or malignant hypertension as the cause of the swelling and exudates. As in the first group of patients, development of a macular star is often preceded by serous macular detachment.

Evaluation and treatment. At the time of diagnosis of neuroretinitis, an appropriate historical review and laboratory tests should be ordered to rule out the infectious etiologies mentioned previously. Many cases of neuroretinitis will be titer negative and presumably idiopathic, and most instances these cases can be treated with high-dose intravenous or oral steroids. Recurrent idiopathic neuroretinitis may require chronic immunosuppression. Appropriate antibiotic therapy is indicated when syphilis, Lyme disease, or toxoplasmosis is diagnosed.

However, the most common diagnosis confirmed in patients with neuroretinitis is Bartonella species infection (cat scratch disease). Bartonella infection is considered to be self-limited, and no treatment has been proven to be beneficial in cat scratch–associated neuroretinitis. Reed and associates reported that treatment with doxycycline and rifampin seemed to shorten the course compared with historic controls. We consider using doxycycline if visual loss is severe or disc swelling persists beyond 3 weeks. Most patients recover, but some are left with residual visual symptoms secondary to optic nerve dysfunction.

Syphilis

After a steady decrease in cases, ophthalmic presentations of syphilis have become more common over the last several years, particularly in individuals coinfected with human immunodeficiency virus (HIV). Therefore, syphilis should always be in the differential diagnosis of unexplained optic nerve disease. Optic neuropathy is not uncommon in patients with secondary syphilis. Patients can develop retrobulbar optic neuritis, papillitis with retinal vasculitis, and perineuritis and neuroretinitis. Disc swelling, hemorrhages, dilated veins (phlebitis), and subretinal infiltrates ( Fig. 5.40 ) are highly suggestive of syphilis. The severity of visual symptoms is variable and depends on the site of the infection. Patients with syphilitic perineuritis tend to have more mild visual loss (sometimes none at all) compared with patients with direct optic nerve involvement. Bilateral disease is almost always present, often with other evidence of secondary syphilis such as rash, uveitis, and mild signs of meningeal inflammation. MRI scanning in perineuritis shows diffuse thickening and enhancement of the optic nerve sheath. In contrast, progressive vision loss with optic atrophy can also been seen as a manifestation of tertiary syphilis. This is a slowly progressive (generally not episodic) visual deterioration not associated with other active inflammation of the eye. Optic atrophy resulting from tertiary syphilis can rarely present with optic disc cupping that may be difficult to distinguish from glaucoma.

Examples of syphilitic optic neuropathy. A . Optic disc swelling in syphilitic optic neuropathy with inferior subretinal granulomas ( arrows ). B . More marked disc swelling secondary to syphilis with dilated veins and intraretinal hemorrhages.

Diagnostic studies/evaluation. Syphilitic optic neuropathy can almost always be diagnosed with appropriate serum and CSF serologies, except in the setting of HIV infection, which can alter test results with seronegative disease. In an individual who is not infected with HIV, the serum microhemagglutinin assay for Treponema pallidum (MHA-TP) or the fluorescent treponemal antibody–absorption (FTA-ABS) test should almost always be positive in the presence of neuro-ophthalmic signs and symptoms suggestive of syphilis. The serum Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) tests are also useful for screening, but they may be negative in neurosyphilis. Although a positive CSF VDRL is confirmatory of a diagnosis of neurosyphilis, it is often negative and therefore cannot be used solely to exclude this diagnosis. Often, one relies on the presence of a positive serum test and the presence of elevated CSF white blood cell count or protein concentration to determine disease activity. Since the presentation of syphilitic optic neuropathy is quite variable, the clinical suspicion for this condition must exist in all cases of atypical inflammatory optic neuropathy and unexplained progressive optic atrophy. A postinfectious illness similar to NMO has been described in patients with syphilis.

Treatment. Treatment of syphilitic optic neuropathy with positive CSF VDRL and presumed tertiary syphilis must be with intravenous aqueous penicillin. Secondary syphilis with perineuritis and normal CSF has been treated successfully with intramuscular procaine penicillin. Sometimes after successful treatment with antibiotics, steroids can used to treat persisting inflammation. The disease in patients with HIV is similar. Syphilitic optic nerve involvement has been reported as an initial manifestation of HIV infection and tends to have an excellent prognosis with appropriate treatment.

Lyme Disease

Lyme-associated optic neuritis and perineuritis are rare, and the diagnosis should be made primarily in patients who have a history of erythema migrans, a bout of arthritis, and positive titers in serum and CSF whenever possible. A positive serum Lyme titer should be confirmed by Western blot testing since there is a relatively high rate of false positives seen with conventional serum antibody titer level testing. In a series of 28 patients with optic neuritis and a positive Lyme titer, only one patient with papillitis and posterior uveitis had convincing evidence of Lyme disease; there were no definite cases of Lyme-associated retrobulbar neuritis or neuroretinitis in this study. Many of the reported cases of Lyme-associated optic neuritis and ischemic optic neuropathy are suspect. They were based simply on recent exposure and presence of serum titers, neither of which is adequate to implicate Lyme as the definite cause of optic nerve dysfunction. For instance, Jacobson performed follow-up on four of his previously reported patients with optic neuritis and Lyme seropositivity. Two were found to have developed MS, suggesting the seropositivity was coincidental. Reported cases of Lyme optic neuropathy have been successfully treated with both oral doxycycline and parenteral treatment (e.g., ceftriaxone).

Lyme is also an important cause of low-grade meningitis associated with elevated intracranial pressure and a pseudotumor cerebri-like presentation (see Chapter 6 ). When the optic nerve is involved, the picture is usually one with uveitis-associated neuroretinitis and unusual fluorescein angiographic criteria including neuroretinal edema and patchy and diffuse hyperfluorescence. In some patients, neuroretinitis can be resistant to antibiotic treatment.

HIV-Associated Optic Neuropathies

Systemic immunosuppression is an important risk factor for primary infection of the optic nerve from a variety of pathogens. In acquired immunodeficiency syndrome (AIDS), infectious optic neuropathy may result from primary HIV infection of the nerve, cytomegalovirus infection, or acute retinal necrosis associated with herpesvirus. In addition optic neuropathy can develop in the setting of granulomatous inflammation of the meninges associated with cryptococcus, toxoplasmosis, tuberculosis, aspergillus, or syphilis. These can also cause elevated intracranial pressure with papilledema and associated progressive visual loss. Primary HIV optic neuropathy can present as an acute retrobulbar optic neuritis with pain on eye movements or a slowly progressive condition. Treatment with steroids or antivirals may be effective. The condition likely results from direct HIV infection of the optic nerve, or alternatively nerve damage can result from the immune reaction directed against the infected optic nerve.

Cytomegalovirus (CMV) infection is the most common opportunistic infection to involve the posterior segment of the eye. The majority of patients develop retinitis with associated hemorrhagic necrosis. This herpesvirus can primarily infect the optic nerve and cause a papillitis, or the optic nerve can be involved secondarily by contiguous spread from adjacent retina. Papillitis occurs in about 4% of patients with CMV retinitis. Patients require management with high and prolonged doses of intravenous foscarnet or ganciclovir, and the prognosis for visual recovery is highly variable. CMV papillitis has also been described in an immunocompetent individual.

Fungal disease can involve the optic nerves through granulomatous inflammation of the meninges. Cryptococcus is the most common fungal infection of the CNS and the most common cause of optic neuropathy. Patients can present with either sudden vision loss or progressive vision loss from papilledema associated with elevated intracranial pressure. The mechanisms for vision loss include direct fungal invasion and adhesive arachnoiditis along with elevated intracranial pressure. Optic nerve sheath fenestration may be beneficial in some patients along with systemic treatment with amphotericin B (see Chapter 6 ).

Long-term follow-up of the patients enrolled in the Long Study of Ocular Complications of AIDS (LSOCA) has revealed that there is commonly a thinning of the temporal RNFL on SD-OCT over time, even in patients who do not have any history of ocular disease. The investigators have suggested that the maculopapillary bundle may undergo axonal loss as a result either of HIV infection or antiretroviral therapy. These changes have been correlated with diminished contrast sensitivity, color vision, and visual field defects.

Herpes Zoster

Optic neuropathy can occur in patients with recent herpes zoster ophthalmicus. This complication must be very rare given the paucity of reported cases compared with the prevalence of this infection. Vision loss can take the form of a catastrophic ischemic event, perhaps from an angiitis, or behave more like an inflammatory optic neuropathy related to zoster infection of the nerve. This condition is well recognized in both immune-competent and immune-incompetent patients. In immunocompromised patients varicella zoster optic neuritis can be precede retinitis and result in severe permanent vision loss. The visual loss may occur soon after the onset of the rash but may also be delayed by weeks and in immunocompromised patients may occur without the characteristic rash. The vision loss is usually unilateral and severe. There may be papillitis ( Fig. 5.41 ) with a macular star, or the fundus may be normal. MRI may show optic nerve or nerve sheath enhancement. Treatment with acyclovir and steroids can be attempted with variable results. An optic neuritis–like illness has also been described after primary varicella (chickenpox) infection.

Optic disc swelling ( A ) in a patient with acute optic neuritis in the setting of a typical V1-distribution herpes zoster eruption ( B ).

Nonarteritic Ischemic Optic Neuropathy

AION is the most common cause of unilateral optic nerve swelling and optic neuropathy in adults older than 50 years.

Demographics . The majority of patients are 60–70 years of age, but there is no absolute age range. Although there was a minimum age requirement of 50 years for eligibility, the Ischemic Optic Neuropathy Decompression Trial (IONDT) found a mean age of 66 ± 8.7. This study randomized patients with AION and visual acuity worse than 20/64 to either optic nerve sheath decompression or observation.

Population studies suggest an increased rate in Caucasians compared with African Americans or Hispanic individuals. In the IONDT 47% of the patients had hypertension and 24% had diabetes mellitus. The prevalence of these systemic risk factors was lower in patients who were not randomized because their affected eye had vision better than 20/64. This suggests hypertension and diabetes may be risk factors for more significant vision loss. A recent metaanalysis of 12 case-controlled studies revealed that diabetes is an independent risk factor for NAION.

The condition is less common but well reported in individuals younger than 50 years, although many such patients are referred to tertiary centers because of their atypical age (23% in one series). There is an increased risk in younger patients with diabetes mellitus, hypercholesterolemia, ischemic heart disease, and systemic hypertension. Additionally, migraine and chronic renal failure tend to be more common in younger patients with NAION. Familial ION has been described, and it tends to affect individuals at a younger age and is more often bilateral. Genetic studies of affected families have suggested a mitochondrial or X-linked transmission state. Other investigators have proposed a genetic predisposition to thrombosis to explain familial cases.

Nocturnal hypotension, in some cases related to the treatment of arterial hypertension, may be a separate and distinct risk factor that may explain the high rate of vision loss which occurs upon awakening. Decreased blood pressure at night has been demonstrated in patients with progressive vision loss.

Another important risk factor is the disc at risk or crowded optic nerve head. The fellow eye is often found to have a small or absent cup. The high prevalence of a small cupless disc as a risk factor for ION has been confirmed with modern optic nerve head imaging methods. The proposed mechanism is believed to be crowding at the level of the lamina cribrosa leading to a “compartment syndrome” phenomenon.

Studies have also shown hyperopic refractive errors and smoking to be possible risk factors, although a different study found no increased risk from smoking. Patients with nonarteritic ION do not have an increased incidence of carotid disease on the affected side compared with age-matched controls.

In addition, sleep apnea may be a separate and distinct risk factor for the development of nonarteritic ION. The possible mechanisms of sleep apnea contributing to the development of ION include effects on optic nerve head blood flow autoregulation, possible increased intracranial pressure, and prolonged hypoxia.

Erectile dysfunction drugs and ION. In 2002 Pomeranz et al. reported a series of patients who developed ION in the hours after taking erectile dysfunction drugs (phosphodiesterase-5 (PDE-5) inhibitors). Since then there have been numerous similar case reports, and much debate as to whether the relationship is causal or a coincidence given that both the use of these drugs and ION tend to occur in the same vasculopathic population. Most compelling are the cases associated with repeated episodes of either transient, permanent, or sequential vision loss with repeated doses of PDE-5 inhibitors. McGwin et al. did not find a higher incidence of erectile dysfunction drug use in men with a history of ION compared with age-matched controls. Gorkin et al. reviewed the data from over 100 clinical trials of sildenafil and found only one case of ION and estimated the annual incidence to be 2.8/100 000, which is not different from the reported incidence of ION in population studies. A review of 67 double-blind, placebo-controlled trials and the postmarketing safety database for sildenafil reviewed a total of 39 277 patients and revealed an event rate for NAION of 0.8%. Almost half of the cases for which medical history was available revealed predisposing vascular risk factors, again arguing for very low risk of ION related directly to the medication. However, since the PDE-5 inhibitor does lower systemic blood pressure slightly and since the medications are often taken at night (and PDE-5 inhibitor–associated ION is most often noted in the morning), it is possible that they contribute to nocturnal hypotension. In a case-crossover study, NAION was found to be two times more likely to have occurred in association with use of PDE-5 inhibitors than without. In healthy individuals, there is no significant change in optic nerve rim or foveolar choroidal blood flow after a dose of 100 mg of sildenafil, although other investigators have shown small changes in choroidal thickness after a 200-mg dose. Most experts agree, however, that patients who have had ION in one eye should be cautioned against subsequent use of PDE-5 inhibitors, particularly if they have systemic risk factors and a disc at risk.

Ischemic optic neuropathy has also been reported in young children taking sildenafil for pulmonary hypertension and congenital heart disease.

Neuro-ophthalmic symptoms. Most patients with ION describe a sudden onset of monocular visual loss, often upon awakening (40% in the IONDT study ). It usually is maximal when noted, and often does not progress. There are usually no prodromal ocular symptoms and no associated systemic symptoms. The presence of prodromal amaurosis fugax or diplopia should increase the suspicion for temporal arteritis. Pain is rare in idiopathic ION but can occur in about 10% of patients.

Neuro-ophthalmic signs. Examination findings are typical of an optic neuropathy with reduced acuity (at any level), dyschromatopsia, an afferent pupil defect, visual field loss which is most often inferior altitudinal, and (again by definition) disc edema which is often pale and sectoral with splinter hemorrhages and dilated capillaries on the disc surface ( Fig. 5.43 ). In the IONDT, 49% of patients had better than 20/64 visual acuity at the time of presentation and 34% had worse than 20/200. Patients typically have dyschromatopsia. However, many patients will identify color plates correctly, and the dyschromatopsia is detected only by subjective comparison between the eyes. An afferent pupillary defect should be present unless the other eye had a similar previous problem. Visual field defects comprise any “optic nerve” type in addition to the classic altitudinal field loss. Up to one-quarter of patients have central scotomas. Vitritis is absent, so its presence should increase the clinical suspicion for alternative inflammatory and infectious diagnoses.

Typical appearances of the optic nerve in acute anterior ischemic optic neuropathy. In each case there is disc edema. Initially swelling may only be mild ( A ) and can be confused with the appearance of optic neuritis. Other commonly associated findings are segmental swelling and splinter hemorrhages ( B ), more diffuse swelling with a cotton-wool spot ( C , arrow ), and dilated capillaries or luxury perfusion ( D , arrow ) on the disc surface.

The characteristic disc appearance (see Fig. 5.43 ) has sectoral swelling and splinter hemorrhages, often with attenuation of the peripapillary arterioles. If a previous attack in the other eye resulted in a pale disc, the term pseudo–Foster Kennedy syndrome applies with ischemic swelling in the newly affected eye and old atrophy in the other eye ( Fig. 5.44 ; see also Chapter 6 ). Sequential attacks of ischemic optic neuropathy are distinguished from the true Foster Kennedy syndrome by inferior field loss and visual acuity reduction in the eye with the swollen optic nerve in consecutive ION.

Right and left optic nerves of a patient with acute vision loss in the right eye associated with disc swelling ( A ) and disc pallor in the left eye ( B ) from preexisting optic neuropathy. This appearance of pallor in one eye and swelling in the other most commonly results from sequential attacks of ischemic optic neuropathy, as in this case, and is termed the pseudo–Foster Kennedy syndrome .

Diagnostic studies/evaluation. Usually no further diagnostic studies need be obtained, although the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels should be checked to screen for temporal arteritis (see later discussion). However, carefully timed fluorescein angiography may also be able to distinguish ION disc swelling from other causes of disc swelling by demonstrating delayed optic nerve head filling. OCT studies have demonstrated a mild amount of subretinal fluid in some patients with ION. This observation might explain some of the visual acuity recovery that occurs in certain patients.

MRI does not have a major role in the diagnosis of acute anterior ION, but research studies have revealed that it may be useful in differentiating optic neuritis from NAION in difficult cases; unlike NAION patients, patients with optic neuritis are more likely to demonstrate enhancement of the optic nerve after intravenous contrast administration and increased short T1-inversion recovery signal. In addition, MRI is occasionally necessary to exclude compressive and infiltrative conditions mimicking simple ION. Gadolinium enhancement of the optic nerve may occur but is rare and more common in arteritic ION. Patients with nonarteritic ION have been shown to have an increased number of white matter ischemic changes compared with age- and disease-matched controls. This likely reflects the presence of vasculopathic risk factors. Because ION is likely not related to embolic phenomena (see later discussion), carotid and cardiac evaluations are not necessary in this setting.

Clinical course. The majority of patients have a fixed deficit, but either progressive vision loss in the first month or alternatively spontaneous recovery can occur. In the IONDT, a surprising 43% of the patients who received no treatment recovered three or more lines of vision. In addition to proving surgery to be unhelpful, much was learned about the clinical profile and natural history of ION in the IONDT. Other studies have also demonstrated spontaneous visual improvement. OCT can be used to follow the initial RNFL swelling associated with ION and the subsequent thinning (see Fig. 5.9 ) that usually correlates well with the area of visual field loss. Optic atrophy, often with altitudinal disc pallor ( Fig. 5.45 ), develops as the disc edema resolves, and there may be “luxury perfusion” or presumed upregulated capillaries on the surface of the ischemic disc. Disc edema may resolve faster in patients with more prominent vision loss, perhaps because more severely diseased axons die more quickly.

Superior segmental atrophy in a patient with inferior vision loss after a previous attack of anterior ischemic optic neuropathy.

Some patients will be examined during a peculiar asymptomatic phase of the disease in which no visual dysfunction is measured, but the disc is swollen. This premonitory phase of disc swelling often progresses to cause visual loss but may also resolve spontaneously. Development of symptomatic ION with vision loss in these patients occurs in about 45% of patients, on average 6 weeks after the disc swelling is noted. OCT studies have revealed a stabilization of RNFL measurements by 6 months after the acute event.

One study suggested a lifetime risk of 30–40% of second eye involvement ; however, in the cohort of patients in the IONDT, the 5-year risk was only 14.7%. The cumulative incidence rates are even higher in older patients and patients with diabetes and hypertension and may also be higher in younger patients. In one study, which has been criticized, an increased risk of cerebrovascular and cardiovascular disease was found in ION patients.

Pathogenesis. Although the pathogenesis of nonarteritic ION remains obscure, Hayreh has provided insight into the disorder. AION may result from insufficiency in the posterior ciliary artery circulation as histologic studies have demonstrated infarction at the level of the retrolaminar optic nerve (supplied by the short posterior ciliary arteries) and Doppler studies have further corroborated reduced blood flow in the short posterior ciliary arteries. Experimental occlusion of the posterior ciliary arteries in monkeys results in a similar clinical appearance to ION with pale disc swelling. How systemic microvascular disease, a crowded optic nerve head, and possibly nocturnal hypotension ultimately lead to a final common pathway of axonal edema and subsequent axonal degeneration is still unknown. Intuitively it is postulated that microvascular, atherosclerotic capillary disease compromises already narrowed lumens (from the crowded disc). Ultimately relative poor perfusion and catastrophic infarction occurs when perfusion pressure is reduced to below a critical level. Impaired autoregulation may also play a role in pathogenesis—a loss of autoregulation is a known consequence of systemic hypertension —or certain humoral factor levels, such as endothelin-1, may be altered. It is also possible that axons within a small crowded optic nerve which swells are more vulnerable to tissue ischemia, as in a compartment syndrome. There is little evidence to suggest that an embolic event may cause nonarteritic ION. An unproven theory has been put forth that nonarteritic ION may actually be secondary to a papillary vitreous detachment in certain individuals who may be more susceptible due to their optic disc configuration.

Several other factors support a vascular occlusive etiology: sudden onset, association with diabetes, hypercholesterolemia and hypertension, lack of evidence of inflammation, similarities in presentation to the arteritic variety, and the fact that a similar syndrome can be created in animals with an experimental vascular occlusion. However, there are several factors that cast some doubt on a simple vasoocclusive pathogenesis in nonarteritic AION :

• 1.
  

  There is no good autopsy evidence of occluded vessels.

  
  
• 2.
  

  The cilioretinal and choroidal circulations are usually spared.

  
  
• 3.
  

  Occurrence soon after cataract surgery is well recognized. Half of these patients have involvement of the second eye if operated, regardless of anesthesia type. These patients have a lower prevalence of vasculopathic risk factors and crowded optic nerve heads, indicating that this may have a distinct pathogenesis. It has been suggested that elevated intraocular pressure may be a factor.

  
  
• 4.
  

  AION is only rarely associated with carotid disease.

  
  
• 5.
  

  Sequential attacks in two eyes are separated by months or years without intervening evidence of vascular occlusion affecting other organs.

  
  
• 6.
  

  Patients may have months of premonitory disc edema before visual loss.

  
  
• 7.
  

  One cause for ION is major blood loss (see later discussion). In this setting there may be a delay of hours to days before vision loss occurs.

  
  
• 8.
  

  There are well-recognized cases of progression over weeks.

  
  
• 9.
  

  Cases of embolic ION are only rarely reported and are distinctly different from the typical presentation.

  
  
• 10.
  

  Repeated attacks in the same eye are unusual. A protective effect from the first attack is certainly atypical for other kinds of vasoocclusive disease such as stroke or myocardial infarction.

Some authors have hypothesized that the pathogenesis of ION may be related to venous obstruction in the nerve head. In this scheme, venous occlusion leads to the development of a compartment syndrome and disc swelling. Ultimately, the pathogenesis and treatment of ION may be aided by animal models of ION using laser-induced photothrombotic induction of ischemia.

Other systemic associations with nonarteritic AION. A hypercoagulable state secondary to antiphospholipid antibodies has been reported to occur in patients with AION; thus “young” patients with ION should be investigated for this possibility. However, prothrombotic states in general are not associated with AION. Elevated serum homocysteine levels has been implicated in some series as a risk factor for ION, but other studies’ levels have not confirmed this association. Patients with uremia have been described with vision loss and optic nerve swelling, presumably on an ischemic basis. Visual loss is bilateral, and improvement with hemodialysis has been reported. Other patients with acute hypertensive crisis, as in the setting of preeclampsia, have been reported to develop ION. Although perhaps an example of two common, unrelated conditions occurring in the same patient, typical migrainous episodes followed by AION have also been reported.

Treatment . There is no known effective therapy. Although steroids are usually considered to be ineffective, a controversial retrospective study showed better vision and quicker resolution of disc swelling with the use of steroids. The significance of these findings is uncertain, and there has not been widespread adaptation of steroid treatment in ION, although they are occasionally used in practice. Optic nerve sheath fenestration or decompression has been used and seemed to improve vision in some progressive cases. Other series did not support the findings of these authors, and ultimately the IONDT concluded that the surgery was not beneficial and may be harmful since the group receiving surgery had a lower rate of visual recovery and a higher rate of loss of three or more lines of acuity.

Hyperbaric oxygen, aspirin, heparin, and warfarin have also been shown to be ineffective in altering the course of ischemic optic neuropathy. In contrast, levodopa and carbidopa have been shown to improve visual acuity in patients with even long-standing vision loss from ischemic optic neuropathy, but the results were not reproduced. Small groups or single patients have been reported to improve with transvitreal optic neurotomy and triamcinolone. Intravitreal bevacizumab has recently garnered more attention due to promising reports demonstrating improved visual acuity in almost half of bevacizumab-treated patients with NAION. However, these studies were small and nonrandomized. A more recent prospective, controlled, nonrandomized study of 25 patients failed to show any significant effect on visual field or visual acuity after administration of bevacizumab compared with observation.

Finally, the protective effect of a previous attack of ION is powerful, as recurrence within a previously affected eye is rare. In part this may result from retinal ganglion cell atrophy and decreased crowding at the optic nerve head. Thus Burde suggested prophylactic panretinal photocoagulation to produce controlled optic atrophy, a treatment that has not yet been pursued or tested. Intravitreal injection of prostaglandin J2 in rat models has been shown to be neuroprotective in NAION.

There is also no effective prophylaxis for second-eye involvement. For this purpose we often place patients with nonarteritic AION on daily low-dose aspirin therapy, but there is no prospective proof of its efficacy.

Clinical distinction between optic neuritis and ischemic optic neuropathy . The clinical profile of these two groups of patients can overlap significantly, particularly in adults between the ages of 30 and 50 years, when they present with disc swelling but without pain on eye movements. There are no laboratory tests to distinguish the two entities. However, in most instances the distinction is easily made based on consideration of the patient’s age, associated symptoms, and examination findings. Otherwise healthy patients younger than 40 years almost never get ION. The presence of pain is common in optic neuritis, while it is present in less than 10% of ION patients, and generally is not exacerbated by eye movements. Also, a normal-appearing nerve is common in ON and by definition not seen in AION. Warner et al. found that altitudinal swelling, pallor, arterial attenuation, and hemorrhage were more common in AION than in ON. Factors that are not helpful in distinguishing the two entities are sex, presenting visual acuity, and laboratory tests. Depending on the type of defect, the visual fields may be helpful in identifying typical ION from ON, as patients with ION typically have inferior altitudinal field loss. However, there is enough overlap to make the distinction based on field criteria alone impossible. Maximal visual loss within 24 hours is not uncommon in optic neuritis, and progression for up to 10 days can occur with ION.

Temporal Arteritis and Ischemic Optic Neuropathy

Visual symptoms related to temporal (giant cell, cranial, granulomatous, Horton’s) arteritis are a neuro-ophthalmic emergency. The most common mechanism is arteritic ION, referring to sudden optic nerve infarction due to vessel lumens narrowed by vasculitis. A nonocular cause of visual loss in temporal arteritis, occipital lobe infarction, is reviewed in Chapter 8 . Since many cases of blindness in giant cell arteritis are preventable with immediate administration of corticosteroids, suspected patients require emergent diagnosis and intervention.

Demographics . There is an increased incidence in woman (3 : 1). Most affected individuals are Caucasian, but patients in other racial groups may be affected. The prevalence of giant cell arteritis increases with age. Most patients are older than 70 years, and cases in individuals younger than 50 years are exceedingly rare, making patients with AION due to giant cell arteritis on average older than patients with nonarteritic AION.

Pathology . The vasculitis involves large and midsized arteries, usually extradural, containing an elastic lamina. The arteritis has a predilection for the superficial temporal, vertebral, ophthalmic, and posterior ciliary arteries. This distribution explains the high frequency of blindness and the occasional cerebellar, brainstem, and occipital lobe strokes observed in this disorder. Optic nerve infarction typically occurs at a retrolaminar or prelaminar–retrolaminar watershed zone supplied by branches of the short ciliary arteries and branches of the ophthalmic artery. Other vessels less commonly involved include the internal carotid, external carotid, and central retinal arteries. In addition, dissection related to involvement of the proximal aorta and myocardial infarction from vasculitis in the coronary arteries have both been reported.

Histologically, early cases are characterized by lymphocytes limited to the internal or external elastic lamina or adventitia of the vessel wall, with destruction of those layers. More marked involvement is typified by involvement of all vascular layers. Necrosis and granulomas containing multinucleated histiocytic and foreign body giant cells, histiocytes, and lymphocytes may be seen. Inflammation of the arterial wall narrows the vessel lumen and causes thrombosis and vascular occlusion.

Pathogenesis. The greater incidence in Caucasians and an association with HLA antigens DR3, DR4, DR5, DRB1, and Cw3 suggest giant cell arteritis may have a genetic component. Immunologic studies have demonstrated involvement of humoral and cellular immunity, particularly of T-cell function. Tissue and T-cell production of interferons and macrophage secretion of interleukins are also likely important.

The simultaneous occurrence of giant cell arteritis in a husband and wife and demonstration of the DNA of various infectious agents supports a possible but unconfirmed environmental exposure or infectious etiology. For example, evidence of Chlamydia pneumoniae, parvovirus B19, human papillomavirus, and human herpesvirus have all been isolated from temporal artery specimens. Most recently, varicella zoster virus DNA has been detected in some patients with biopsy-negative giant cell arteritis. Initial reports of the presence of a Burkholderia- like bacterial pathogen in temporal arteries were not confirmed.

Neuro-ophthalmic symptoms. Patients may have premonitory episodes of transient monocular blindness before visual loss (sometimes when rising from a supine position) related to impaired ocular blood flow. Another complaint may be bright-light amaurosis, caused by the increased metabolic demands of photoreceptors for which blood supply is unavailable. Transient episodes of binocular diplopia and formed visual hallucinations may occur as well.

Visual loss is usually sudden and severe, and sometimes there is accompanying pain. Simultaneous bilateral vision loss occurs in 20–62% of patients with temporal arteritis. In untreated patients, one study found second eye involvement occurs in approximately 75% of patients within days, and usually within a week.

In contrast, simultaneous bilateral presentation with nonarteritic ION is rare and usually occurs only as a complication of surgery or with significant blood loss. Table 5.4 contrasts the clinical presentations of arteritic and nonarteritic ischemic optic neuropathy.

Table 5.4

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