infiltration. Visible prelaminar cellular infiltrate (diffuse or focal) tends to be more opaque, with a grayish or yellowish discoloration (Fig 4-12); the infiltrate may be denser and more opaque than in nonspecific edema. Focal granulomatous infiltration may consist of a focal nodule on the disc surface. When edema and vision loss persist or progress in a way that is atypical for the common causes of optic neuropathy or when prelaminar infiltrate is visible, ancillary testing for an infiltrative lesion should be performed.
Figure 4-12 Sarcoid optic neuropathy. Left fundus of a 25-year-old man with a 1-month history of blurred vision. Visual acuity was 20/50, and he had a moderate left afferent pupillary defect. The dense white elevation on the disc represents granulomatous inflammation. A chest x-ray showed hilar adenopathy, and bronchoscopy confirmed sarcoidosis. (Courtesy
of Steven A. Newman, MD.)
Anterior Optic Neuropathies Without Optic Disc Edema
Optic disc drusen
Optic disc drusen (ODD), also known as hyaline or colloid bodies, represent refractile, often calcified nodules located within the optic nerve head (Fig 4-13). Their reported prevalence ranges from 0.34% (clinical) to 2% (autopsy) of population studies. ODD occur with equal frequency in
males and females but rarely affect nonwhites. They are often bilateral (75%–86%) but can be asymmetric. They may be isolated or dominantly inherited. The pathophysiology of ODD is unclear. Most theories invoke impaired ganglion cell axonal transport, probably related to a small scleral canal and mechanical obstruction. Metabolic abnormalities associated with impaired transport may result in intra-axonal mitochondrial damage. The drusen represent the product of deteriorating axons, which extrude their contents into the interstitial space. Over time, the extruded material congeals and calcifies. ODD may be associated with retinitis pigmentosa and pseudoxanthoma elasticum.
Figure 4-13 A, Fundus photograph of optic disc drusen, showing blurred disc margin with scalloped edge, refractile bodies on the disc surface and at the superior pole, mild pallor, and no obscuration of retinal blood vessels. B, Visual field patterns confirmed the presence of a nasal step produced by drusen involving the right disc. C, B-scan ultrasonogram, demonstrating focal, highly reflective (due to calcification) elevation within the optic disc (arrow), which persists when the gain is decreased. D, Preinjection fundus photograph demonstrating autofluorescence (arrow). E, CT scan of the orbits. Calcified optic disc drusen are visible bilaterally at the posterior globe–optic nerve junction (arrows). (Part A courtesy of Steven
A. Newman, MD; part B courtesy of Michael S. Lee, MD; parts C, E courtesy of Anthony C. Arnold, MD; part D courtesy of Hal Shaw, MD.)
Although most patients with ODD do not experience symptoms, some (8.6%) may have transient visual obscurations. In rare cases, vascular complications (eg, flame hemorrhage, AION, or peripapillary subretinal neovascularization) occur. Nerve fiber bundle defects occur in 75%–87% of
cases, but most go unnoticed by the patient. Visual field defects either remain stable or worsen very slowly. Visual field patterns should be monitored over time. Visual acuity rarely declines; thus, other retrobulbar lesions warrant evaluation if visual acuity declines or progressively worsens. The location of visible drusen does not necessarily correlate with the location of visual field loss. An RAPD can be present in patients with asymmetric visual field loss.
The optic discs of patients with ODD appear elevated and small in diameter, with indistinct or irregular margins and associated anomalous vascular branching patterns. Blurring of the disc margin arises from axoplasmic stasis in the axons deep within the optic disc, which creates a yellowish, hazy appearance that obscures the border between disc and retina but leaves the view of the retinal vessels intact. This appearance contrasts with the whitish, fluffy, striated appearance of NFL edema in true papilledema. With ODD, the disc does not show hyperemia or dilation of the surface microvasculature.
In childhood, ODD begin buried, and the drusen become more visible over the years. When visible, ODD appear as round, whitish-yellow refractile bodies. Frequently present at the nasal disc margin, surface drusen may produce a scalloped appearance. Occasionally, they are located within the NFL just adjacent to the disc.
Ancillary testing may be useful in differentiating drusen from papilledema (see Fig 4-13):
B-scan ultrasonography may differentiate calcified drusen from papilledema in 2 ways. First, ODD are highly reflective. Calcified drusen maintain this high echogenicity with lowering of the ultrasound gain. With papilledema, the signal intensity decreases along with the remainder of the ocular signal. Ultrasonography may help identify drusen in suspected cases, but this technique may not detect noncalcified, buried ODD. Second, with papilledema, the intraorbital portion of the optic nerve is typically widened and will decrease in width with prolonged lateral gaze (the so-called 30° test); drusen do not produce widening of the intraorbital nerve (Fig 4-13C).
Fluorescein angiography is also an effective method for distinction. First, drusen that are close enough to the disc surface demonstrate autofluorescence, in which refractile bodies appear brightly visible on preinjection images using the fluorescein filter (Fig 4-13D). Second, papilledema results in early diffuse hyperfluorescence, with late leakage overlying and adjacent to the disc. Conversely, ODD do not cause leakage.
Neuroimaging may be indicated in rare cases to rule out an intracranial or optic nerve tumor and to attempt direct confirmation of calcified drusen. A CT scan remains superior to an MRI scan for detection of drusen because calcium is poorly imaged by MRI. Calcified drusen produce a bright, easily detected signal at the junction of the posterior globe and optic nerve on a CT scan (Fig 4-13E).
Optical coherence tomography using a line scan through the optic nerve can show the discrete hyperreflective drusen. This is not evident in all cases.
With chronic papilledema, refractile bodies occasionally develop on the nerve head surface, simulating ODD (see Fig 4-7). These lesions (probably residual exudate) typically form near the temporal margin of the disc rather than within its substance, are usually smaller than ODD, and disappear with resolution of the papilledema.
Astrocytic hamartomas of the retina, most common in tuberous sclerosis and neurofibromatosis, may take the form of so-called mulberry lesions. When located adjacent to the disc, they may closely resemble ODD, and in early reports they were termed giant drusen of the optic disc (see Fig 4-4). In
contrast to true ODD, disc hamartomas
originate at the disc margin, with extension to the peripapillary retina arise in the inner retinal layers and typically obscure retinal vessels may have a fleshy, pinkish component
do not autofluoresce and may show tumorlike vascularity on fluorescein angiography
Auw-Haedrich C, Staubach F, Witschel H. Optic disk drusen. Surv Ophthalmol. 2002;47(6):515–532.
Leber hereditary optic neuropathy
Leber hereditary optic neuropathy (LHON) typically affects boys and men age 10–30 years but may occur much earlier or later in life; women may account for 10%–20% of cases. The syndrome presents with acute, severe, painless, sequential vision loss (visual acuity, <20/200) and central or cecocentral visual field impairment (Fig 4-14). The classic fundus appearance triad includes
1.hyperemia and elevation of the optic disc, with thickening of the peripapillary retina; although the disc appears swollen, it does not leak on fluorescein angiography (“pseudoedema”)
2.peripapillary telangiectasia
3.tortuosity of the medium-sized retinal arterioles
Figure 4-14 Leber hereditary optic neuropathy. A 17-year-old experienced severe, painless vision loss in his left eye. A, Visual field testing demonstrated a central scotoma in the left eye. Two months later, the patient lost vision in the right eye. Mitochondrial genetic testing revealed the 11778 mutation. B, Fundus photographs demonstrate hyperemic optic discs with blurred margins and moderately tortuous vasculature. The left optic disc shows mild temporal pallor. C, There was no leakage on fluorescein angiographic studies. (Parts B, C courtesy of Michael S. Lee, MD.)
These findings can develop before vision loss begins. The fundus can also appear entirely normal (in >40% of cases in one referral series). The unaffected eye becomes symptomatic within weeks to months. Though rare, the interval between initial and fellow eye involvement can be longer (up to 8 years). Although vision loss is usually permanent, recovery of vision can occur in 10%–20% of cases. Recovery can take several years, with slow improvement in the central visual field.
LHON is related to a mitochondrial DNA mutation, most frequently at the 11778 position, less commonly at the 3460 or 14484 locations. The corresponding single base-pair nucleotide substitution results in impaired mitochondrial adenosine triphosphate production, which tends to affect highly energy-dependent tissues such as the optic nerve. Results of blood testing for these mutations may confirm the diagnosis, permit genetic counseling, and provide information about prognosis. Patients with the 14484 mutation have a higher chance (up to 65%) of late spontaneous improvement in central visual function, whereas those with the 11778 mutation have a lower chance (estimated at 4%).
The mutation is transmitted by mitochondrial DNA, which is inherited only from the mother, thus only women transmit the disease. As mitochondria replicate, the mitochondrial DNA is variably divided among the progeny cells (heteroplasmy). When the fraction of mutated mitochondrial DNA reaches a threshold, the phenotype expresses clinically. Family history may be negative because of a de novo mutation or lack of phenotypic expression. Not all men with affected mitochondria experience vision loss, and affected women only infrequently experience visual symptoms. The reasons for this selective male susceptibility may relate to a protective effect of estrogen. In vitro cell lines with LHON mutations develop less apoptosis in the presence of estrogen.
Differential diagnosis includes optic neuritis, compressive optic neuropathy, and infiltrative optic neuropathy. For patients with a negative family history, neuroimaging is advisable to rule out a treatable cause of vision loss. Mitochondrial testing for the most common mutations is commercially available, but results may take several weeks to return. Occasionally, patients demonstrate cardiac conduction abnormalities or other mild neurologic deficits that warrant further evaluation.
No treatment has been shown to be effective. Corticosteroids are not beneficial. Idebenone may increase mitochondrial energy production and may improve the outcome of LHON. Novel therapies such as estrogen and gene therapy are being explored. Controversy exists whether tobacco or excessive alcohol intake, which might stress mitochondrial function, plays an initiating role in LHON.
Giordano C, Montopoli M, Perli E, et al. Oestrogens ameliorate mitochondrial dysfunction in Leber’s hereditary optic neuropathy. Brain. 2011;134(Pt 1):220–234. Epub 2010 Oct 13.
Newman NJ, Biousse V, Newman SA, et al. Progression of visual field defects in Leber hereditary optic neuropathy: experience of the LHON treatment trial. Am J Ophthalmol. 2006;141(6):1061–1067.
Autosomal dominant optic atrophy
The most common hereditary optic neuropathy (estimated prevalence is 1:50,000), autosomal dominant optic atrophy (ADOA) has a dominant inheritance pattern with variable penetrance and expression. Genetic linkage studies have localized an ADOA gene (OPA1) to a region on chromosome 3. The OPA1 protein is widely expressed and most abundant in the retina. It encodes dynamin-related
GTPase, which is anchored to mitochondrial membranes; thus, mutations result in loss of mitochondrial membrane integrity and function, with subsequent retinal ganglion cell degeneration and optic atrophy.
Presentation is usually in the first decade of life, with insidious onset of vision loss, often first detected during routine school vision screenings. Involvement is usually bilateral and relatively symmetric. At detection, visual acuity loss is usually mild to moderate, in the range of 20/30–20/60, although it may decline progressively. The majority of patients preserve visual acuity of greater than 20/200. Color vision deficits, usually tritanopia (blue-yellow) are invariably present. Therefore, these patients may pass evaluation with the Ishihara color plates, which test red-green deficits. Tritanopia detection may require testing by Hardy-Rand-Ritler plates or the Farnsworth Panel D-15 or D-100 test. Visual field testing demonstrates central or cecocentral loss in most cases. The defects typically do not respect the vertical midline. Affected optic discs usually show focal, wedge-shaped temporal optic atrophy (Fig 4-15), but diffuse pallor can occur.
Figure 4-15 Autosomal dominant optic atrophy findings in a 34-year-old man who had been aware of difficulty reading the blackboard in fourth grade, with a mild, gradual decrease in visual acuity bilaterally since then. A, B, Optic discs show temporal atrophy and papillomacular nerve fiber layer dropout. C, D, Visual field patterns demonstrate bilateral cecocentral scotomata, which extend superotemporally. (Courtesy of Steven A. Newman, MD.)
The clinical diagnosis is based on findings of the examination and negative results on neuroimaging, which should be performed in all suspected cases. Genetic testing is commercially available but does not test for all mutations that cause dominant optic atrophy. The clinical course is generally one of stability or very slow progression over the patient’s lifetime (loss of approximately 1 Snellen line per decade). No treatment is available.
Olichon A, Baricault L, Gas N, et al. Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem. 2003;278(10):7743–7746. Epub 2002 Dec 31.
Yu-Wai-Man P, Griffiths PG, Hudson G, Chinnery PF. Inherited mitochondrial optic neuropathies. J Med Genet. 2009;46(3):145–158. Epub 2008 Nov 10.
Glaucoma
Patients with glaucoma usually do not note impaired vision. Chronic open-angle glaucoma typically produces slowly progressive arcuate and peripheral visual field loss, sparing fixation until late in the course. The optic disc characteristically appears excavated (with increased diameter and depth of the physiologic cup, often with focal notching at the inferior or superior pole). Cup pallor develops only with relatively advanced damage. Intraocular pressure is often (but not invariably) elevated. Glaucoma with intraocular pressure <21 mm Hg (normal-tension glaucoma) is more likely to produce paracentral scotomata, but even this condition usually spares visual acuity. All aspects of glaucoma are discussed at length in BCSC Section 10, Glaucoma.
Excavation of the optic nerve head may also be present in compressive, hereditary (LHON) and severe ischemic (AAION) processes. Chiasmal compressive lesions typically produce temporal (hemianopic) rather than nasal visual field loss. These other optic neuropathies affect visual acuity and color vision, which are late findings in glaucoma. Additionally the optic disc can demonstrate early and more prominent pallor, with less severe excavation and notching than in glaucoma (Fig 4- 16).
Figure 4-16 Optic nerve excavation. A, With glaucomatous damage, the remaining temporal rim of neuroretinal tissue generally remains a relatively normal pink color despite severe excavation. B, With nonglaucomatous damage, the rim is pale relative to the degree of excavation. (Courtesy of Anthony C. Arnold, MD.)
Congenital optic disc anomalies
Optic nerve hypoplasia Visual acuity in eyes with optic nerve hypoplasia ranges from 20/15 with minimal visual field defects to no light perception vision. However, nearly all eyes have visual field
loss, and 56%–92% of patients have bilateral involvement. The optic disc is small, usually one-half to one-third of normal diameter, but subtle cases may require a comparison of the 2 eyes. Comparison of horizontal disc diameter to the disc–macula distance may help in detection. Retinal vessel diameter may seem large relative to the disc size, and the vessels may appear tortuous. The disc may seem pale, gray, or (less commonly) hyperemic and may be surrounded by a yellow peripapillary halo, which in turn is bordered by a ring of increased or decreased pigmentation (the double-ring sign) (Fig 4-17).
Figure 4-17 Optic disc hypoplasia. The small optic disc is surrounded by a relatively hypopigmented ring of tissue (double-ring sign). The retinal vessels have normal appearance. (Reprinted from Kline LB, Foroozan R, eds. Optic Nerve Disorders.
2nd ed. Ophthalmology Monograph 10. New York: Oxford University Press, in cooperation with the American Academy of Ophthalmology; 2007:158.)
Unilateral or bilateral optic nerve hypoplasia may be associated with midline or hemispheric brain defects, endocrinologic abnormalities (deficiency of growth hormone and other pituitary hormones), and congenital suprasellar tumors. Skull-base defects may be associated with basal encephaloceles. The syndrome of optic nerve hypoplasia, absent septum pellucidum, and pituitary dwarfism (septo-optic dysplasia) is the most common. The corpus callosum may be thinned or absent. An MRI scan is recommended in all cases of optic nerve hypoplasia, and endocrinologic consultation should be considered, because hypoglycemic seizures or growth retardation may develop without treatment. Recognized teratogens associated with optic nerve hypoplasia include quinine, ethanol, and anticonvulsants. A variant called superior segment hypoplasia occurs most often in children of
mothers with diabetes mellitus; the affected eyes have a corresponding inferior visual field defect. For further details on optic nerve hypoplasia, see BCSC Section 6, Pediatric Ophthalmology and Strabismus.
Congenital tilted disc syndrome Congenital tilted disc syndrome is usually (80%) bilateral and should not be confused with simple myopic tilted optic discs with temporal crescent. The congenital syndrome produces an inferonasal colobomatous excavation of the nerve tissue, often associated with thinning of adjacent RPE and choroid. The remaining superotemporal portion of the disc remains relatively intact such that the disc appears tilted around a predominantly horizontal axis. The superior portion can sometimes seem elevated, simulating mild edema (Fig 4-18). The retinal vessels are often nasalized. The superotemporal visual field defects can be partially overcome through refractive correction. The visual field defects may mimic those of chiasmal compression but are differentiated by their failure to respect the vertical midline and their partial improvement with myopic refractive correction.
Figure 4-18 Congenital tilted disc syndrome. Visual field testing results (A, B) show bilateral relative superotemporal defects not respecting the vertical midline. Fundus photographs show bilateral tilted discs OD (C) and OS (D). (Parts A, B
courtesy of Anthony C. Arnold, MD; parts C, D courtesy of Sophia M. Chung, MD.)
Excavated optic disc anomalies Excavated optic disc anomalies cover a spectrum of severity, ranging from optic pits through colobomas and dysplastic nerves to the morning glory disc anomaly (for additional discussion, see BCSC Section 6, Pediatric Ophthalmology and Strabismus):