Causes of Optic Neuropathy
Optic neuropathies may be classified as anterior (with ONH edema) or posterior (with a normal-appearing ONH at onset). When evaluating a patient with an optic neuropathy, it is best to consider the possible mechanisms of optic neuropathies (Table 4-3). Clinical characteristics such as the patient’s age, mode of onset, laterality, presence of pain, color vision, type of visual field defects, optic nerve appearance, and results of orbital magnetic resonance imaging (MRI) are very helpful in determining the underlying cause of the optic neuropathy.
Table 4-2 Glossary of Perimetric Terms
Biousse V, Newman NJ. Optic neuropathies. In: Neuro-Ophthalmology Illustrated. 2nd ed. New York: Thieme; 2015:179–244.
Papilledema refers to ONH edema resulting from increased intracranial pressure (ICP). On ophthalmoscopy, papilledema is indistinguishable from other causes of ONH edema. Acute papilledema produces hyperemia of the ONH, with dilation of the existing ONH surface capillary net and telangiectasia of the surface and radial peripapillary vessels. The edematous peripapillary retinal nerve fiber layer (RNFL) is grayish white and opalescent, with feathered, striated margins that obscure the ONH edge and the retinal vessels coursing through it. Early papilledema begins at the superior and inferior poles of the ONH. As papilledema worsens, it encompasses the nasal ONH, creating a C-shaped area of ONH edema with the opening along the temporal rim. The edema eventually involves the entire ONH and causes blurring of major vessels off the ONH head. Late findings include absence of the physiologic cup and obscuration of vessels on the ONH itself. Absence of spontaneous venous pulsations may reflect increased ICP, but absence at initial examination is of limited value; 20% of the general population have no spontaneous venous pulsations. The disappearance of these pulsations after prior documented presence, however, suggests ICP elevation. Other ophthalmoscopic findings may include ONH and peripapillary cotton-wool spots, exudates, and hemorrhage.
Figure 4-3 Patterns of visual field loss in optic neuropathies, as shown on automated perimetry. A, Cecocentral scotoma in the left eye (left; arrow); paracentral scotoma in the right eye (right; arrow). B, Central scotoma in the right eye (arrow). C, Arcuate scotoma in the right eye (arrow). D, Broad arcuate (altitudinal) defect in the left eye (arrow). E, Nasal arcuate (step) defects in both eyes (arrows). F, Enlarged blind spot in the right eye (arrow), worse than in the left eye.
(Parts E, F courtesy of Anthony C. Arnold, MD.)
Table 4-3 Mechanisms of Optic Neuropathies
Most patients with elevated ICP report symptoms such as headache, nausea, and vomiting. Patients may also note transient visual obscurations—episodes of unilateral or bilateral vision loss lasting seconds. These episodes are described as “grayouts,” “whiteouts,” or “blackouts” of vision, often occurring with orthostatic changes. In patients with idiopathic intracranial hypertension (IIH), these obscurations are not prognostic of optic nerve damage.
In early papilledema, optic nerve function, including visual acuity and color vision, is usually normal. Pupillary responses are also normal; visual fields demonstrate only enlargement of the blind spot (see Fig 4-1).
The clinician’s first step in managing suspected papilledema is to rule out pseudopapilledema. The following funduscopic features suggest true ONH edema:
microvascular abnormalities on the ONH surface, such as telangiectasia or flame hemorrhages
opacification of the peripapillary retinal RNFL
Most cases of pseudopapilledema result from optic disc drusen (Fig 4-4; also see discussion later in this chapter).
An elevated ONH appearance mimicking papilledema may also be caused by hyaloid remnants and glial tissue on the ONH surface, congenital “fullness” of the ONH associated with entry of the optic nerve into the eye through a relatively small scleral canal, or ONH fullness associated with hyperopia. Vitreopapillary traction can cause a swollen-appearing ONH. Obscuration of ONH margins can occur without ONH elevation from myelination of the RNFL (Fig 4-5). Myelination typically occurs at the ONH margin, where it obscures the ONH–retina border; myelination in the RNFL also obscures the retinal vessels and results in a feathered edge that resembles true edema. Myelination appears as a dense, white opacity compared with the partially translucent, grayish-white appearance of true edema. Papilledema may result from a variety of conditions, including
Figure 4-4 Appearance of optic disc drusen (ODD). A, Fundus photograph of the ONH with buried drusen. The ONH margin is blurred, with yellowish opacity of the deep peripapillary tissue. The retinal vessels are clearly visible overlying the ONH. B, Fundus photograph of the ONH with papilledema. The ONH margin is blurred, with grayish-white, opalescent thickening of the peripapillary nerve fiber layer (arrow). The retinal vessels are partially obscured at the ONH margin and within the peripapillary retina. There are exudates from chronic edema just temporal to the ONH. C, Surface drusen demonstrate prominent refractile nodules on the ONH surface, which do not obscure retinal vessels. D, Astrocytic hamartomas are nodular masses arising from peripapillary retina and obscure the retinal vessels.
(Parts A, B courtesy of Sophia M. Chung, MD; parts C, D reprinted from Arnold AC. Optic disc drusen. Ophthalmol Clin North Am. 1991;4:505–517.)
Figure 4-5 Myelinated nerve patches are often present within the arcuate bundles, occasionally abutting the ONH. When they are contiguous, these nerve patches may be mistaken for ONH edema or cotton-wool spots.
(Courtesy of Anthony C. Arnold, MD.)
Figure 4-6 Chronic atrophic papilledema with gliosis and retinal vascular sheathing.
(Courtesy of Anthony C. Arnold, MD.)
an intracranial mass
meningeal processes, such as an infection of the central nervous system (CNS) or infiltration by a granulomatous or neoplastic process
increased venous pressure from cerebral venous thrombosis or dural fistula
IIH (discussed later in this chapter)
Suspicion of papilledema warrants urgent brain imaging, ideally MRI and magnetic resonance venography (MRV) of the brain and orbits with contrast, to rule out an intracranial mass lesion and cerebral venous thrombosis. Normal brain imaging results should prompt evaluation of the cerebrospinal fluid (CSF) opening pressure and composition by lumbar puncture.
Katz BJ. The anomalous optic nerve. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2011, module 3.
Optic nerve function may deteriorate in patients with chronically (lasting months to years) elevated ICP and long-standing papilledema. The ONH may no longer appear hyperemic but may rather look pale as the result of chronic axonal loss (Fig 4-6). Additional features may include the following:
Gliosis of the peripapillary RNFL. The opacification appears grayish, less “fluffy,” and more membranous than with edema. Gliosis tends to follow retinal vessels, producing vascular sheathing.
Optociliary shunt vessels (retinochoroidal collaterals), which are preexisting venous channels on the ONH surface that dilate in response to chronic central retinal vein obstruction from elevated ICP. Unlike congenital ONH anomalies or the retinal vascular anomalies often accompanying drusen, these collateral vessels follow an evolving course of enlargement over time and characteristically penetrate deep into the choroid immediately adjacent to the ONH.
Refractile bodies of the ONH, which are the result of chronic lipid-rich exudation (Fig 4-7). Unlike drusen, these bodies tend to be smaller and noncalcified. They remain on the ONH surface rather than within its substance, with frequent clustering at the ONH margin, and disappear as papilledema resolves.
With chronic papilledema, visual field defects may include nasal field loss, arcuate scotomata, and generalized peripheral depression. Central visual field involvement with decreased visual acuity typically does not occur until late. The process is usually bilateral, but if asymmetric, an RAPD may occur.
Arnold AC. Differential diagnosis of optic disc edema. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 1999, module 2.
Idiopathic intracranial hypertension
Patients with IIH, also known as pseudotumor cerebri, present with symptoms and signs of elevated ICP. Headache is common. Other symptoms may include neck and back pain, transient visual obscurations, diplopia (secondary to abducens nerve paresis), pulsatile tinnitus (pulse synchronous bruit), and nausea. Almost all patients with IIH have papilledema. Neurologic abnormalities other than cranial nerve (CN) VI palsy are not associated with IIH. As with acute papilledema, early IIH shows normal visual acuity and enlarged blind spots on perimetry testing. Optic nerve function may deteriorate in long-standing, untreated, or severe cases.
Figure 4-7 Chronic papilledema. A, B, ONHs in chronic papilledema, with the development of refractile bodies (arrows) representing lipid exudates from chronic microvascular leakage. C, D, Visual field patterns confirm the presence of mild diffuse depression in sensitivity and superior and inferior arcuate defects.
(Parts A, B courtesy of Anthony C. Arnold, MD; parts C, D courtesy of Steven A. Newman, MD.)
The incidence of IIH peaks in the third decade of life. Ninety percent of patients are women, and 90% are obese. The disease is rare in prepubertal children (in whom obesity is less of a factor), men, and lean adults. Intracranial hypertension is associated with the use of exogenous substances such as vitamin A (>100,000 IU/day), tetracycline, minocycline, doxycycline, retinoic acid, and lithium, as well as the use of or withdrawal of use of corticosteroids. Sleep apnea may be associated with IIH. Although hormonal changes occurring during pregnancy and hormonal abnormalities have been implicated, IIH has not been definitively associated with any specific endocrinologic dysfunction. The reason for the increase in ICP in IIH remains obscure.
Cerebral venous disorders, such as cerebral venous thrombosis (resulting from trauma, childbirth, a hypercoagulable state, compression, or an ear or CNS infection), systemic or localized extracranial venous obstruction (eg, after radical neck dissection), a dural arteriovenous malformation, or systemic vasculitis, may lead to decreased venous outflow and thus increased ICP. Such conditions may resemble IIH, so patients with suspected IIH should undergo both neuroimaging with MRI to rule out a mass, hydrocephalus, or meningeal lesion and MRV to assess for venous sinus occlusion (see Chapter 2, Fig 2-13). Characteristic (but not specific) MRI findings of intracranial hypertension include flattening of the globes, enlarged optic nerve sheaths, partially empty sella, and narrowing of the distal transverse venous sinus. The clinician should always perform a lumbar puncture to confirm elevated ICP and to rule out infectious or inflammatory processes. Table 4-4 lists the diagnostic criteria of IIH.
The ophthalmologist plays a crucial role in the management of IIH. Careful longterm follow-up is essential to ensure that papilledema resolves and that vision remains normal. Regularly scheduled examinations should include testing of visual acuity, color vision, and quantitative perimetry to document the level of optic nerve function. Photographs of the ONH are essential to obtain during patient follow-up. Repeat OCT can also be used to document improvement of papilledema; however, OCT cannot be used in isolation to follow papilledema, because secondary optic atrophy from untreated papilledema will also result in apparent improvement of the RNFL thickness on OCT. The ganglion cell complex at the macula may be helpful in differentiating a decrease in RNFL thickness due to optic atrophy (in which the ganglion cell complex will also show thinning) from that due to resolution of papilledema (in which the ganglion cell complex will remain normal). The frequency of visual field testing depends on the severity of papilledema, the level of optic nerve dysfunction, and the patient’s response to treatment.
Table 4-4 Criteria for the Diagnosis of Idiopathic Intracranial Hypertension
Treatment for IIH depends on symptomatology and vision status. The disease may be self-limited. If headache is mild or absent and optic nerve function is normal, no medical therapy may be required. However, untreated papilledema may result in severe vision loss in 5%–10% of patients with IIH. Poor visual prognosis is associated with male gender, African American race, morbid obesity, severe papilledema, and anemia. Patients with a fulminant course, with abnormal visual field testing at presentation, or with an RAPD (suggesting asymmetric damage to the optic nerve from severe papilledema) are also at high risk of permanent vision loss.
For patients with obesity, weight loss can be an effective treatment and is always recommended; moderate weight loss alone can lead to resolution of the signs and symptoms of IIH. Referral to a nutritionist is helpful, and in some cases, bariatric surgery might be considered.
For patients requiring medical therapy, acetazolamide is usually the first choice. In 2014, a large randomized clinical trial, the Idiopathic Intracranial Hypertension Treatment Trial, showed that acetazolamide (1–4 g/day) in association with weight loss was effective in reducing ICP and improved papilledema in patients who had IIH and moderate visual field defects. Topiramate may also be helpful for such patients, especially those with chronic headaches. Topiramate has multiple beneficial effects, including headache control, appetite suppression, and carbonic anhydrase inhibition. Furosemide may also be used in patients who cannot tolerate acetazolamide or topiramate. Corticosteroids should be avoided; although ICP can improve with use of corticosteroids, recurrence commonly occurs during corticosteroid taper, and these drugs may result in weight gain with subsequent worsening of IIH. However, a short course of high-dose intravenous corticosteroids may benefit patients presenting with severe papilledema and vision loss (fulminant IIH). Repeat lumbar punctures are not recommended therapy for patients with IIH.
In cases of progressive vision loss despite maximally tolerated medical therapy, surgical therapy is recommended. In some patients with severe vision loss and papilledema, surgical intervention may be considered without waiting for definite evidence of progression. The primary surgical options are optic nerve sheath fenestration (ONSF) or a CSF diversion procedure (lumboperitoneal or ventriculoperitoneal shunt).
For patients with substantial loss of vision without prominent headache, ONSF is often the preferred surgical option because it directly protects the optic nerve and has lower morbidity than that associated with shunting. However, ONSF carries an overall risk of complication of approximately 10%–15%, including a 1%–2% risk of vision loss from optic nerve injury, central retinal artery occlusion (CRAO), or central retinal vein occlusion (CRVO). ONSF does not significantly lower ICP and thus often does not reliably treat headache. Papilledema in the contralateral eye might be reduced, but bilateral ONSF may be required. The long-term success rate of ONSF remains unclear. Repeat ONSF procedures may be performed but are technically more difficult because of scarring.
Lumboperitoneal or ventriculoperitoneal shunting procedures effectively lower ICP, leading to improvement of headache, CN VI palsy (if present), and papilledema. Moreover, shunting entails no direct risk to the optic nerve. A shunt, however, may become occluded, infected, or altered in position, requiring reoperation in many cases.
Endovascular stenting of a stenosed venous transverse sinus can also decrease CSF pressure and may improve headaches and papilledema. However, this procedure remains controversial and should be performed only in specialized centers.
Many patients with IIH have chronic headaches despite effective treatment of increased ICP and improvement of papilledema. Usually these headaches are not directly related to increased ICP, and they should be managed medically with the help of a neurologist.
IIH also occurs in children. It appears to be a different disorder in prepubertal children, as there is no gender predilection and more children without obesity are affected. Recent studies have shown that normal CSF opening pressure among children is higher than previously believed and may be as high as 28 cm H2O. The treatment for pediatric IIH is similar to that for adult IIH.
Bidot S, Bruce BB. Update on the diagnosis and treatment of idiopathic intracranial hypertension. Semin Neurol. 2015;35(5):527–538.
Friedman DI, Liu GT, Digre KB. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology. 2013;81(13):1159–1165.
Markey KA, Mollan SP, Jensen RH, Sinclair AJ. Understanding idiopathic intracranial hypertension: mechanisms, management, and future directions. Lancet Neurol. 2016;15(1):78–91.
Wall M, McDermott MP, Kieburtz KD, et al; NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee. Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial. JAMA. 2014;311(16):1641–1651.
The term optic neuritis refers to any cause of optic nerve inflammation. It may be isolated or related either to a neurologic inflammatory or infectious disorder or to a local or systemic inflammatory disease. It may affect any portion of the nerve. When it affects the posterior portion of the optic nerve, the ONH appears normal at the time of vision loss (retrobulbar optic neuritis); when the inflammation involves the anterior portion of the nerve, the ONH appears edematous, a condition that is sometimes called papillitis. The ONH edema is usually hyperemic and diffuse. Papillitis is more common in postviral and infectious neuritis than in demyelinating neuritis, but considerable overlap exists. Children, in particular, manifest postviral optic neuritis and papillitis, which typically presents with profound bilateral vision loss.
Beck RW, Trobe JD, Moke PS, et al; Optic Neuritis Study Group. High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial. Arch Ophthalmol. 2003;121(7):944–949.
Optic Neuritis Study Group. Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow-up. Arch Neurol. 2008;65(6):727–732.
Isolated optic neuritis
Isolated optic neuritis typically occurs in young (mean age, 32 years) female (77%) patients, and it presents as subacute monocular vision loss that develops over several days. Periorbital pain, particularly with eye movement, occurs in 92% of cases and often precedes vision loss. The retrobulbar form occurs in 65% of cases, and only one-third of patients have ONH edema. Unless the optic neuritis is bilateral and symmetric, an RAPD is also present. Perimetry testing most often shows a central depression or generalized reduction of sensitivity (48%), but any pattern of visual field loss may appear (Fig 4-8). Dyschromatopsia, particularly for red-green, is nearly universal and is often out of proportion to the loss of visual acuity. In the vast majority of cases, optic neuritis shows spontaneous improvement within 1 month.
Most cases of optic neuritis are either isolated (eg, clinically isolated syndrome [CIS]) or are part of a demyelinating disorder (eg, multiple sclerosis [MS]). Atypical features that should prompt further evaluation for alternative etiologies include older age, lack of pain, persistent pain or vision loss, significant swelling of the ONH with peripapillary hemorrhages or exudates, inflammatory ocular features (eg, uveitis, phlebitis, choroiditis, pars planitis), retinal changes, bilateral vision loss, involvement of other CNs, steroid-responsive optic neuropathy, and lack of any vision recovery by 1 month. Additional hematologic, serologic, or other testing may be of value in atypical cases but need not be performed routinely. Such studies may include the following:
Figure 4-8 Isolated optic neuritis. A, ONH photograph of acute retrobulbar optic neuritis, showing normal appearance. B, Automated perimetry shows a central scotoma in the right eye. C, T1-weighted axial magnetic resonance imaging (MRI) scan of the orbits with fat suppression and gadolinium administration, showing enhancement of the right intraorbital optic nerve (arrow). D, T2-weighted axial MRI scan of the brain, demonstrating multiple white matter hyperintensities (arrows) consistent with demyelination.
(Parts A, B courtesy of Steven A. Newman, MD; part C courtesy of Michael S. Lee, MD; part D courtesy of Anthony C. Arnold, MD.)
serum and CSF rapid plasma reagin and fluorescent treponemal antibody absorption testing for syphilis
serum testing for Bartonella infection
serum testing for Lyme disease (if endemic)
chest x-ray or chest computed tomography (CT), gallium scan or full-body positron emission tomography (PET), serum angiotensin-converting enzyme testing for sarcoidosis
erythrocyte sedimentation rate (ESR) determination, antinuclear antibody testing, and anti-DNA antibody testing for systemic lupus erythematosus or vasculitis
antineutrophil cytoplasmic antibodies (ANCA) for granulomatosis with polyangiitis (Wegener granulomatosis)
serum or CSF aquaporin-4 immunoglobulin G (AQP4-IgG) antibody testing and spinal MRI for neuromyelitis optica spectrum disorder (NMOSD) (see later in this chapter)
genetic testing for Leber hereditary optic neuropathy (LHON)
brain and orbit MRI with gadolinium contrast for compressive, infiltrative disorders
lumbar puncture with cytology for a meningeal process
Several studies have clarified the natural history of isolated optic neuritis. The Optic Neuritis Treatment Trial (ONTT) 10-year follow-up study reported that optic neuritis recurred in the affected or fellow eye in 35% of cases overall and in 48% of patients with conversion to MS. Most eyes with a recurrence regained normal or almost-normal vision. After 15 years of follow-up in the ONTT, 92% of patients with optic neuritis recovered visual acuity of 20/40 or better; 3% had final visual acuities of 20/200 or worse. Despite their seemingly excellent prognosis, patients with optic neuritis usually remain aware of visual deficits in the affected eye after recovery. Studies using measures of visual function other than Snellen visual acuity (ie, color vision, contrast sensitivity, motion detection, stereopsis, perimetry) show residual abnormalities in up to 90% of patients with visual acuities of at least 20/30.
In the absence of a known diagnosis of MS, MRI of the brain should be performed in every case of optic neuritis. Evaluation for periventricular white-matter lesions consistent with demyelination is the best way to assess the risk of future MS in patients with isolated optic neuritis and to guide subsequent decisions on the use of immunomodulation therapy (see the following section). The 15-year data from the ONTT found a risk for MS of 25% for patients with no lesions on MRI versus 72% for patients with at least 1 lesion, with the highest rate of conversion within the first 5 years. Patients with normal MRI results and no conversion to MS by year 10 had only a 2% risk of conversion by year 15 (see Chapter 14). Among patients with normal baseline MRI results, a lower risk of future MS was associated with male sex, ONH swelling, and atypical features of optic neuritis (absence of pain, no light perception vision, peripapillary hemorrhages, and retinal exudates).
Treatment of optic neuritis
The ONTT demonstrated that corticosteroid therapy for optic neuritis had no long-term beneficial effect on vision, although the use of intravenous methylprednisolone, 250 mg every 6 hours for 3 days, followed by oral prednisone, 1 mg/kg/day for 11 days (with a quick taper of 4 days), sped recovery by 1–2 weeks. Patients receiving oral prednisone alone experienced no improvement in vision, and their recurrence rate was twice as high as that of the other groups. Therefore, oral prednisone (1 mg/kg/day) is not recommended for the treatment of isolated optic neuritis. The use of high-dose intravenous corticosteroids reduced the rate of development of clinically definite MS after the initial optic neuritis only in the subgroup of patients with MRI scans showing 2 or more white matter lesions. At 2 years, the risk of MS was 36% for the untreated group versus 16% for the treated group. However, by follow-up year 3 and thereafter, this “protective” effect was lost.
Given that the benefits are uncertain, the value of therapy and of additional diagnostic evaluation for MS must be assessed for each individual patient. In cases in which a rapid return of vision is essential (eg, in monocular patients or patients with an occupational need), intravenous methylprednisolone may be considered. The main purpose of the MRI scan is to assess the future risk of MS, but additional evaluation, including CSF analysis, is probably best referred to a consulting neurologist.
Immunomodulatory therapy is of proven benefit for reducing morbidity in the relapsing-remitting form of MS, and studies have shown that such drugs can delay conversion to MS in patients with acute optic neuritis or another CIS associated with an abnormal MRI (see Chapter 14 for a discussion of MS treatment).
Beck RW, Cleary PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992;326(9):581–588.
Galetta SL, Villoslada P, Levin N, et al. Acute optic neuritis: unmet clinical needs and model for new therapies. Neurol Neuroimmunol Neuroinflamm. 2015;2(4):e135. http://nn.neurology.org/content/2/4/e135. Published July 23, 2015. Accessed January 31, 2017.
Optic Neuritis Study Group. Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow-up. Arch Neurol. 2008;65(6):727–732.
Optic Neuritis Study Group. Visual function 15 years after optic neuritis: a final follow-up report from the Optic Neuritis Treatment Trial. Ophthalmology. 2008;115(6):1079–1082.
Chronic relapsing inflammatory optic neuropathy
Chronic relapsing inflammatory optic neuropathy (CRION) is an isolated inflammatory optic neuritis that is very steroid responsive and steroid dependent. It usually occurs chronically over months or years and requires long-term corticosteroid and/or immunosuppressive therapy. CRION is not associated with MS. In cases of suspected CRION, other inflammatory disorders such as sarcoidosis must be ruled out.
Petzold A, Plant GT. Chronic relapsing inflammatory optic neuropathy: a systematic review of 122 cases reported. J Neurol. 2014;261(1):17–26.
Optic neuritis and acute myelitis characterize neuromyelitis optica (NMO), also known as Devic disease. NMOSD denotes a first attack or limited form of optic neuritis or transverse myelitis, as well as typical clinical NMO associated with cerebral, diencephalic, or brainstem lesions. Table 4-5 presents a set of diagnostic criteria for NMOSD developed by an international group of experts. These criteria provide 99% sensitivity and 90% specificity. The AQP4-IgG test alone has 76% sensitivity and 94% specificity.
Table 4-5 Criteria for the Diagnosis of NMOSD in Adult Patients
Although many patients experience myelitis and optic neuritis within weeks to months of each other, the episodes may be separated by several years. The vision and neurologic prognoses in NMO are poorer than in MS. The episodes of vision loss tend to recur; severe vision impairment (<20/200) is common in at least 1 eye. Testing for AQP4-IgG should be considered for patients with optic neuritis in the following scenarios:
The mainstay of treatment during the acute period remains high-dose intravenous corticosteroids. For poorly responsive NMO, administration of plasmapheresis or intravenous immunoglobulin, in addition to high-dose intravenous methylprednisolone, may be considered. Use of other immunosuppressive drugs such as azathioprine or rituximab can reduce the risk of relapse.
Papais-Alvarenga RM, Carellos SC, Alvarenga MP, Holander C, Bichara RP, Thuler LC. Clinical course of optic neuritis in patients with relapsing neuromyelitis optica. Arch Ophthalmol. 2008;126(1):12–16.
Wingerchuk DM, Banwell B, Bennett JL, et al; International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177–189.
Neuroretinitis is an inflammatory disorder characterized by acute loss of vision associated with ONH edema and a star pattern of exudates in the macula (Fig 4-9). Mild vitritis and choroidal lesions may also occur. The diffuse ONH edema spreads through the outer plexiform layer along the papillomacular bundle and around the fovea. As the fluid resorbs, the lipid precipitates in a characteristic radial pattern in the Henle layer. The macular star can appear at initial presentation or several days later. Recognizing fluid or lipid exudates in the papillomacular bundle is crucial for establishing the correct diagnosis and differentiating neuroretinitis from optic neuritis, as patients with neuroretinitis do not have an increased risk of MS. Neuroretinitis is usually an infectious or postviral autoimmune process, frequently associated with elevated antibody immunoglobulin M (IgM) titers for Bartonella quintana or Bartonella henselae—the most common cause of neuroretinitis and cat-scratch disease. No definitive evidence exists that corticosteroids and antibiotics have a beneficial effect on visual outcome.
Figure 4-9 A 23-year-old man with a 2-day history of blurred vision on the right (visual acuity: 20/40 OD, 20/20 OS). A, The ONH on the right side is elevated and hyperemic, with obscuration of the nerve fiber layer. B, Five weeks after onset, funduscopic examination shows a macular star, characteristic of neuroretinitis. ONH edema is now less prominent.
(Courtesy of Steven A. Newman, MD.)
Other potential infectious and inflammatory causes of neuroretinitis include Lyme disease, sarcoidosis, syphilis, toxoplasmosis, tuberculosis, and viruses. See BCSC Section 9, Uveitis and Ocular Inflammation, for a complete discussion of ocular bartonellosis and neuroretinitis, as well as other possible causes.
Chi SL, Stinnett S, Eggenberger E, et al. Clinical characteristics in 53 patients with cat scratch optic neuropathy. Ophthalmology. 2012;119(1):183–187.
Optic perineuritis is inflammation of the optic nerve sheath. Similarities between optic neuritis and optic perineuritis include acute, painful vision loss and a female predilection. However, patients are generally older (36% are older than 50 years), vision loss is often milder (central vision is relatively spared but with peripheral vision loss) and progresses over several weeks, and pain persists until treatment is initiated. Orbital MRI scans show enhancement of the optic nerve (dural) sheath rather than the optic nerve itself. Although the neuroimaging results can appear similar to those of optic nerve sheath meningioma, pain helps differentiate the 2 conditions. Distinguishing optic perineuritis from optic neuritis is important with respect to not only treatment, but also prognosis for the development of MS, as optic perineuritis is not associated with MS. Patients with optic perineuritis respond immediately and dramatically to corticosteroid treatment, but relapses are common with short courses of treatment. Without treatment, patients incur progressive loss of vision.
Purvin V, Kawasaki A, Jacobson DM. Optic perineuritis: clinical and radiographic features. Arch Ophthalmol. 2001;119(9):1299–1306.
Ischemic optic neuropathy
Ischemic optic neuropathy is classified as either anterior ischemic optic neuropathy (AION) or posterior ischemic optic neuropathy (PION), depending on which segment of the optic nerve is affected. AION accounts for 90% of all ischemic optic neuropathies.
Anterior ischemic optic neuropathy
AION is the most common acute optic neuropathy in patients older than 50 years. Patients with AION experience painless monocular vision loss that develops over hours to days. Visual acuity may be relatively preserved, but visual field loss always occurs. Altitudinal and other variants of arcuate defects are typical, although any defect may occur. An RAPD is present unless the optic neuropathy becomes bilateral. By definition, there is always ONH edema at onset, which may precede the vision loss.
Table 4-6 Arteritic Versus Nonarteritic Anterior Ischemic Optic Neuropathy
AION is subclassified as either arteritic anterior ischemic optic neuropathy (AAION), in which case it is associated with vasculitis, most commonly giant cell arteritis (GCA), or nonarteritic anterior ischemic optic neuropathy (NAION) (Table 4-6). The most important initial step in evaluating AION is to distinguish between these two subtypes.
Arteritic Anterior Ischemic Optic Neuropathy
AAION is less frequent (5%–10% of AION cases) than NAION and occurs in patients older than 50 years (mean age, 70 years). It is caused by inflammatory and thrombotic occlusion of the short posterior ciliary arteries. Systemic symptoms of GCA are usually present, including headache, scalp tenderness, jaw claudication, malaise, anorexia, weight loss, and fever. However, up to 25% of patients with vision loss from GCA have no systemic symptoms (so-called occult GCA). Although ESR and C-reactive protein (CRP) levels are usually elevated in GCA, 1 or both of these tests may be normal, at least initially. Transient vision loss or transient diplopia preceding AION is very suggestive of GCA.
Vision loss is typically severe (visual acuity is <20/200 in >60% of patients), and a lack of light perception vision should prompt an aggressive evaluation for GCA. Funduscopic clues to a diagnosis of AAION over NAION include the following:
chalky-white ONH edema (in NAION, the ONH is often hyperemic) (Fig 4-10)
cotton-wool spots away from the ONH, which indicate concurrent retinal ischemia (cotton-wool spots on or adjacent to the ONH can be present in NAION)
delayed choroidal filling on fluorescein angiographic studies (normally, the choroid fills completely within 3–5 seconds, before the retinal arteries do) (see Chapter 3, Fig 3-7)
normal or large cup in the fellow eye (in NAION, a small cup–disc ratio is common)
Figure 4-10 ONH appearance in nonarteritic anterior ischemic optic neuropathy (NAION) and arteritic anterior ischemic optic neuropathy (AAION). A, The healthy eye demonstrates a characteristic crowded appearance, which has been called “disc at risk.” B, ONH appearance in NAION. Edema is segmental, with mild superimposed pallor and flame hemorrhages. C, The healthy eye demonstrates a normal cup–disc ratio. Lack of a disc at risk should suggest an AAION. D, ONH appearance in AAION. Pallor is more pronounced.
(Parts A, B courtesy of Michael S. Lee, MD; parts C, D courtesy of Rod Foroozan, MD.)
When AAION due to GCA is suspected, immediate initiation of high-dose corticosteroid therapy is crucial. Adjunctive daily aspirin can also be added. A temporal artery biopsy should be done to confirm the diagnosis as soon as possible, but it can be delayed for 1–2 weeks without compromising test results. Intravenous methylprednisolone (1 g/day for the first 3–5 days) is usually recommended. Thereafter, oral prednisone (1 mg/kg/day) may be used (up to 100 mg/day, tapered slowly over 12 months or more, depending on response).
The primary goal of AAION therapy (apart from avoiding systemic vascular complications) is to prevent contralateral vision loss. Untreated, the fellow eye becomes involved in up to 95% of cases, within days to weeks. Although the initially affected eye may improve somewhat, the patient’s vision does not fully recover. The risk of recurrent or contralateral optic nerve involvement during corticosteroid withdrawal has been reported at 7%. Therefore, tapering must be done slowly and carefully. Recurrent symptoms or elevation of ESR or CRP levels should prompt reevaluation for disease activity. For a discussion of the systemic effects, diagnostic evaluation, and treatment of GCA, see Chapter 14.
Dasgupta B; Giant Cell Arteritis Guideline Development Group. Concise guidance: diagnosis and management of giant cell arteritis. Clin Med (Lond). 2010;10(4):381–386.
Hayreh SS, Biousse V. Treatment of acute visual loss in giant cell arteritis: should we prescribe high-dose intravenous steroids or just oral steroids? J Neuroophthalmol. 2012;32(3):278–287.
Lee AG, Brazis PW. Giant cell arteritis. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2005, module 6.
Parikh M, Miller NR, Lee AG, et al. Prevalence of a normal C-reactive protein with an elevated erythrocyte sedimentation rate in biopsy-proven giant cell arteritis. Ophthalmology. 2006; 113(10):1842–1855.
Nonarteritic Anterior Ischemic Optic Neuropathy
Compared with AAION, NAION is more common (accounting for 90%–95% of AION cases) and occurs in a relatively younger age group (mean age, 60 years), although it can occur at any age. The annual incidence is approximately 3.6–10.2 per 100,000. NAION is presumably related to compromised ONH microcirculation in eyes with structural “crowding” of the ONH. Histologic studies have shown that the area of infarction is located within the scleral canal alone, a finding supporting a potential local compartment syndrome. The initial course may remain static, in which case vision loss is stable from onset, or it may become progressive, which involves either episodic, stepwise decrements or a steady decline of vision over a few days to weeks before eventual stabilization. The progressive form occurs in approximately 12% of NAION cases and may be explained by the compartment syndrome theory. NAION is typically not associated with any systemic symptoms.
Vision loss is usually less severe in NAION (visual acuity >20/200 in >60% of cases) than in AAION. Visual acuity and color vision may be normal if fixation is spared but an RAPD is present. The most common pattern of visual field loss is an altitudinal defect, but any pattern may be observed. The ONH edema in NAION may be diffuse or segmental and is usually initially hyperemic (see Fig 4-10). The ONH in the contralateral eye is typically small in diameter and demonstrates a small or absent physiologic cup (“disc at risk”).
Within 6–8 weeks of NAION onset, the ONH usually becomes atrophic; persistence of edema past this point could suggest an alternative diagnosis. The 5-year risk of contralateral involvement is 15%. Occurrence in the second eye produces the clinical appearance of pseudo–Foster-Kennedy syndrome, in which the previously affected ONH is atrophic and the currently involved ONH is edematous. True Foster-Kennedy syndrome, by contrast, is secondary to intracranial mass and 1 ONH is atrophic because of chronic compression by the mass, whereas the other ONH is edematous because of elevated ICP.
NAION is associated with the following risk factors:
Neither carotid occlusive disease nor a cardiac source of emboli are proven risk factors. Hypercoagulable disorders rarely cause NAION and should be investigated in young patients and patients with known thrombophilia or a family history of thrombosis. Nocturnal hypotension has been suggested as a precipitating factor, but this remains controversial. An association with phosphodiesterase 5–inhibitor (PDE5-inhibitor) drugs used primarily to treat erectile dysfunction has been suggested but remains debated. Amiodarone may trigger an anterior optic neuropathy with ONH edema similar to NAION.
NAION must be differentiated from optic neuritis, especially in younger patients (Table 4-7). In unclear cases, contrast-enhanced MRI of the orbits (with fat suppression) can help in the differentiation. The affected optic nerve appears normal in NAION (95% of cases) but enhanced in optic neuritis (90% of cases).
Untreated NAION generally remains stable after visual function has reached its low point, but the Ischemic Optic Neuropathy Decompression Trial (IONDT) showed that 43% of patients with a visual acuity worse than 20/64 at presentation regained at least 3 lines of visual acuity on the Snellen eye chart within 6 months. Recurrent episodes of vision loss in the same eye after 3 months are unusual in NAION (up to 6.4%), and should trigger a more extensive evaluation for an underlying systemic disorder or an alternative cause of the optic neuropathy.
There is no proven therapy for NAION. The IONDT showed that ONSF had no benefit for NAION; therefore, ONSF is no longer used to treat this condition. Treatment with steroids or neuroprotective drugs is not supported by any high-quality clinical studies.
There is also no proven prophylaxis for the fellow eye. Although aspirin is known to reduce the risk of secondary stroke, its role in reducing the incidence of fellow eye involvement after the initial episode remains unproven. Because at least 60% of NAION patients have systemic vascular risk factors, the clinician should look for and treat these factors when present. Although some studies recommend screening NAION patients for sleep apnea, there is no evidence that treating sleep apnea prevents second eye involvement.
Table 4-7 NAION Versus Optic Neuritis: Typical Features
Patients with NAION are at increased risk for cerebral ischemic stroke and therefore should be referred for risk factor modification and management.
Arnold AC. Pathogenesis of nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol. 2003;23(2):157–163.
Campbell UB, Walker AM, Gaffney M, et al. Acute nonarteritic anterior ischemic optic neuropathy and exposure to phosphodiesterase type 5 inhibitors. J Sex Med. 2015;12(1): 139–151.
Hayreh SS, Zimmerman MB. Non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. Graefes Arch Clin Exp Ophthalmol. 2008;246(7):1029–1046.
Lee MS, Grossman D, Arnold AC, Sloan FA. Incidence of nonarteritic anterior ischemic optic neuropathy: increased risk among diabetic patients. Ophthalmology. 2011;118(5):959–963.
Lee YC, Wang JH, Huang TL, Tsai RK. Increased risk of stroke in patients with nonarteritic anterior ischemic optic neuropathy: a nationwide retrospective cohort study. Am J Ophthalmol. 2016;170:183–189.
Newman NJ, Scherer R, Langenberg P, et al; Ischemic Optic Neuropathy Decompression Trial Research Group. The fellow eye in NAION: report from the ischemic optic neuropathy decompression trial follow-up study. Am J Ophthalmol. 2002;134(3):317–328.
Pomeranz HD, Bhavsar AR. Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (viagra): a report of seven new cases. J Neuroophthalmol. 2005;25:9–13.
Rizzo JF 3rd, Andreoli CM, Rabinov JD. Use of magnetic resonance imaging to differentiate optic neuritis and nonarteritic anterior ischemic optic neuropathy. Ophthalmology. 2002; 109(9):1679–1684.
Posterior ischemic optic neuropathy
Acute ischemic damage to the retrobulbar portion of the optic nerve is characterized by abrupt, often severe vision loss, an RAPD, and initially normal-appearing ONHs. PION is rare and is a diagnosis of exclusion. It occurs in 3 distinct scenarios: (1) perioperative (most commonly in spine, cardiac, and head or neck procedures); (2) arteritic (especially from GCA); and, in rare instances, (3) nonarteritic (with risk factors and a clinical course similar to those of NAION).
Sadda SR, Nee M, Miller NR, Biousse V, Newman NJ, Kouzis A. Clinical spectrum of posterior ischemic optic neuropathy. Am J Ophthalmol. 2001;132(5):743–750.
Perioperative ischemic optic neuropathy
Both AION and PION may be precipitated by various nonocular surgeries, often with profound and irreversible bilateral vision loss. The 2 most common procedures associated with ischemic optic neuropathies are coronary artery bypass grafting and prolonged spinal-fusion surgery with the patient in the prone position. Although the total reported incidence of this complication makes up no more than 0.3% of nonophthalmic surgeries, perioperative AION and PION have gained more widespread scrutiny because of the increasing number of reports and the potential medicolegal implications. AION occurs more frequently with cardiac surgery, whereas PION occurs more often with spine surgery. The causes of PION are poorly understood, and the contributing factors are probably multifactorial and different in these two procedures.
Lee LA, Roth S, Posner KL, et al. The American Society of Anesthesiologists Postoperative Visual Loss Registry: analysis of 93 spine surgery cases with postoperative visual loss. Anesthesiology. 2006;105(4):652–659.
Lee MS, Armbrust KR. Perioperative visual loss in ocular and nonocular surgery. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2012, module 10.
Diabetic papillopathy, which is related to NAION, can occur in patients with either type 1 or type 2 diabetes mellitus. Patients may have no symptoms or have nonspecific symptoms of blurred vision or “distortion” without pain. Evidence of optic nerve dysfunction (found via testing of visual acuity and visual field and for an RAPD) is variable. The optic nerve reveals hyperemic edema, but 50% of patients show marked dilation of the ONH surface microvasculature (Fig 4-11) that appears similar to neovascularization of the disc (NVD). However, the vessels in NVD proliferate into the vitreous cavity and leak fluorescein in angiographic studies. Diabetic retinopathy is not universal among patients with diabetic papillopathy (63%–80%); therefore, the absence of retinopathy does not preclude a diagnosis of diabetic papillopathy.
Untreated, the dilated, radially oriented vessels and ONH edema resolve slowly over 2–10 months. In rare cases, diabetic papillopathy progresses to vision loss (ie, AION). The pathophysiology is unclear but is suspected to be mild, reversible ischemia. Therefore, the distinction of diabetic papillopathy as an entity unique from AION remains controversial; the 2 disorders may instead represent a spectrum.
There is no proven therapy for diabetic papillopathy. Diabetes mellitus is discussed in BCSC Section 1, Update on General Medicine; associated ocular disorders are discussed in BCSC Section 12, Retina and Vitreous.
Bayraktar Z, Alacali N, Bayraktar S. Diabetic papillopathy in type II diabetic patients. Retina. 2002;22(6):752–758.
Regillo CD, Brown GC, Savino PJ, et al. Diabetic papillopathy. Patient characteristics and fundus findings. Arch Ophthalmol. 1995;113(7):889–895.
Papillophlebitis, which represents a subset of CRVO, usually presents with vague blurring of vision or even transient visual obscurations. Visual acuity is typically normal or only mildly diminished. The pupils and color vision are normal, and visual field testing shows blind-spot enlargement. Fundus examination shows marked retinal venous engorgement associated with hyperemic ONH edema (Fig 4-12). Retinal hemorrhages extending to the equatorial region are common. Fluorescein angiographic studies typically show retinal venous staining and leakage associated with circulatory slowing, without the regions of capillary occlusion observed in ischemic CRVO. An evaluation for hypercoagulable disorders should be considered. The condition usually resolves spontaneously over 6–12 months, with either no vision loss or only mild impairment related to incompletely resolved maculopathy. For further discussion on CRVO, see BCSC Section 12, Retina and Vitreous.
Figure 4-11 Fundus photograph of an ONH in diabetic papillopathy shows ONH edema with prominent surface telangiectasia.
(Reprinted from Arnold AC. Differential diagnosis of optic disc edema. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 1999, module 2.)
Figure 4-12 Fundus photograph shows papillophlebitis. ONH edema in a 28-year-old woman with engorgement and tortuosity of retinal venous system. Visual acuity is 20/30.
(Reprinted from Kline LB, Foroozan R, eds. Optic Nerve Disorders. 2nd ed. Ophthalmology Monographs 10. New York: Oxford University Press, in cooperation with the American Academy of Ophthalmology; 2007:218.)
Compressive or infiltrative optic neuropathies
Patients with intraorbital or intracanalicular compressive lesions typically present with slowly progressive vision loss, an RAPD, and monocular visual field loss. There may be associated signs of orbital disease such as eyelid edema, eyelid retraction, lid lag, proptosis, ptosis, or ophthalmoplegia. The ONH may be normal or mildly atrophic at presentation, although anterior orbital lesions may produce ONH edema. Optociliary shunt vessels (also known as retinochoroidal collaterals) or choroidal folds may also be present.
The lesions that most commonly produce optic neuropathy include optic nerve sheath meningioma and optic nerve glioma. Cavernous hemangioma, although common in the orbit, only occasionally produces a compressive optic neuropathy. Infiltration (through inflammatory, infectious, or neoplastic mechanisms) of the optic nerve is usually a retrobulbar process, but anterior involvement may present with ONH edema. The ONH may simply be edematous or may display features of superimposed cellular infiltration. Visible prelaminar cellular infiltrate (diffuse or focal) tends to be more opaque, with a grayish or yellowish discoloration (Fig 4-13); the infiltrate may be denser and more opaque than in nonspecific edema. Focal granulomatous infiltration may consist of a focal nodule on the ONH surface. When edema and vision loss persist or progress in a way that is atypical for the common causes of optic neuropathy (eg, optic neuritis) or when prelaminar infiltrate is visible, ancillary testing for an infiltrative lesion should be performed.
Figure 4-13 Sarcoid optic neuropathy. Left fundus photograph of a 25-year-old man with a 1-month history of blurred vision. The patient’s visual acuity was 20/50, and he had a moderate left afferent pupillary defect. The dense white elevation on the ONH represents granulomatous inflammation. A chest x-ray showed hilar adenopathy, and bronchoscopy confirmed sarcoidosis.
(Courtesy of Steven A. Newman, MD.)
If an orbital compressive lesion is suspected, neuroimaging is indicated. Although MRI of the orbits with contrast and fat suppression is best for evaluating soft-tissue abnormalities in the orbit, particularly in differentiating meningioma from glioma, a thinsection CT scan of the orbits with contrast remains a satisfactory option and is preferred for evaluation of calcification and bony abnormalities.
Optic nerve sheath meningioma and intracranial meningioma
An optic nerve sheath meningioma (ONSM) arises from proliferations of the meningoepithelial cells lining the sheath of the intraorbital or intracanalicular optic nerve. Intracranial meningioma involving the optic nerve is the result of compression from the involved sphenoid wing or tuberculum sella (Fig 4-14; see also Chapter 2, Fig 2-7). Most meningiomas that involve the orbit represent extensions from intracranial sites, whereas true primary ONSMs are far less common and arise from the optic nerve sheath. Most ONSMs (95%) are unilateral.
Figure 4-14 Optic nerve sheath meningioma. A, Fundus photograph shows ONH atrophy, with optociliary shunt vessels (retinochoroidal collaterals; arrow) visible at the 8- and 12-o’clock positions. B, Computed tomography (CT) scan reveals “tram track sign,” diffuse enlargement of the right intraorbital optic nerve extending anteriorly to the globe, with enhancement of the optic nerve sheath. C, “Ring sign” in meningioma. Coronal orbital magnetic resonance imaging (MRI) scan shows similar optic nerve sheath enhancement surrounding a relatively normal, darker optic nerve on the right.
(Parts A, C reprinted from Arnold AC. Optic nerve meningioma. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2004, module 7. Part B courtesy of Steven A. Newman, MD.)
Although ONSMs are uncommon (1%–2% of all meningiomas), they account for one-third of primary optic nerve tumors, second only to optic nerve glioma. They are usually detected in middle-aged women and are rare in children. Some patients may present with the classic diagnostic triad:
painless, slowly progressive monocular vision loss (see Chapter 2, Fig 2-16)
optociliary shunt vessels
Optociliary shunt vessels or retinochoroidal collaterals are preexisting ONH channels that dilate in response to chronic obstruction of outflow through the central retinal vein. These vessels shunt retinal venous outflow to the choroidal circulation. They occur in approximately 30% of patients with ONSM but are nonspecific and can be seen in sphenoid wing meningioma, optic nerve glioma, CRVO, and chronic papilledema. Patients with ONSM also demonstrate an RAPD and an optic nerve–related visual field defect. Minimal to mild proptosis and mild ocular motility defects can also occur. ONH edema may be present, especially if the tumor extends anteriorly. Neuroimaging findings confirm the diagnosis (Table 4-8).
Fractionated radiation therapy is the treatment of choice for ONSM; it has been reported to produce stability or vision improvement in up to 95% of patients. However, it remains unclear whether radiation should be administered immediately upon diagnosis or when tumor growth or progressive vision loss is documented, because patients with ONSM may have minimal loss of vision for several years. In rare cases, radiation retinopathy and pituitary dysfunction have been reported as late radiation complications.
Surgery (ie, biopsy or excision) is typically ill-advised because of the considerable potential for significant vision loss. However, if the tumor extends intracranially or, in very rare cases, across the planum sphenoidale, the risk of contralateral vision loss may warrant surgical debulking, particularly when severe ipsilateral vision loss is present. Radiation therapy is often performed following surgery on a residual tumor.
Table 4-8 Comparative Neuroradiologic Features Between Optic Nerve Sheath Meningioma and Optic Nerve Glioma
Observation is appropriate if there is no change in visual function or tumor size. ONSMs in children may be more aggressive, with more rapid vision loss and more frequent recurrence after therapy. Therefore, children must be monitored more frequently.
Shapey J, Sabin HI, Danesh-Meyer HV, Kaye AH. Diagnosis and management of optic nerve sheath meningiomas. J Clin Neurosci. 2013;20(8):1045–1056.
Optic pathway glioma
Although optic pathway gliomas (OPGs; also known as pilocytic astrocytomas) are generally uncommon (accounting for only about 1% of intracranial tumors), they are the most common primary tumor of the optic nerve. They may involve the optic nerve, the chiasm, or both (Fig 4-15).
Approximately 70% of OPGs are detected during the first decade of life and 90% by the second; however, they may occur at any age. There is no definite sex predilection. The most common presenting findings are proptosis (94%), vision loss (87.5%), ONH pallor (59%), ONH edema (35%), and strabismus (27%). Patients infrequently present with asymptomatic isolated optic atrophy. An RAPD is usually present in unilateral or asymmetric cases, along with a typical optic nerve–related visual field defect. Optociliary shunt vessels may be present on the affected ONH, although they are observed less commonly than with ONSMs. Diagnosis is confirmed by neuroradiologic findings (see Table 4-8).
Figure 4-15 Optic pathway glioma. A, Contrast-enhanced axial orbital CT scan shows a right optic nerve glioma. The optic nerve is enlarged and kinked and demonstrates mild hypodense cystic change centrally. The tumor extends intracranially. B, T2-weighted axial MRI scan (non–contrast-enhanced) of the orbits shows an enlarged, hyperintense, globular glioma of the right optic nerve. C, T1-weighted coronal MRI scan shows prominent enlargement at the junction of the optic nerves and chiasm.
In patients with neurofibromatosis 1 (NF1), the prevalence of OPG is 7.8%–21%. In contrast, in patients with OPG, the prevalence of NF1 is 10%–70%. The wide variance probably relates to referral bias, differences in neuroimaging detection rates, and criteria for diagnosis. Similarly, the relationship between NF1 and the behavior of OPG is unclear, although patients with NF1 may have a more benign prognosis. Neurofibromatosis is discussed further in Chapter 14 of this volume and in BCSC Section 6, Pediatric Ophthalmology and Strabismus.
As with ONSMs, biopsy of OPGs is generally not required, because the advent of high-resolution neuroimaging has improved diagnostic accuracy, and biopsy of the optic nerve substance may cause additional vision loss.
OPGs involving the chiasm may show bitemporal or bilateral optic nerve–related visual field defects. Involvement of the chiasm (as with any tumor) may produce see-saw nystagmus or a monocular shimmering nystagmoid oscillation (pseudo–spasmus nutans). Large tumors may cause obstructive hydrocephalus with elevated ICP, headache, and papilledema. Involvement of the hypothalamus may result in precocious puberty or diencephalic syndrome.
There is no universally accepted treatment of OPGs. Observation is indicated for patients with relatively good vision and stable radiographic appearance. Most patients show stability or very slow progression over years and sometimes show spontaneous regression. Chemotherapy is offered as the initial treatment for patients with severe vision loss at presentation or evidence of progression. Radiotherapy is controversial because of inconclusive results and potential complications, including panhypopituitarism and cognitive impairment. Surgical excision may be indicated in patients with severe vision loss associated with disfiguring proptosis. Surgery has been suggested to prevent advancement into the chiasm; however, such extension is rare. Hydrocephalus may require CSF shunting.
Malignant gliomas of the anterior visual pathway, or malignant optic gliomas of adulthood (MOGAs), are rare neoplasms that almost always occur in adulthood. The mean age on presentation is in the 60s, and there is no gender predilection. Vision loss is often very rapid. Patients may present with acute-onset periorbital pain; in this scenario, these tumors may be misdiagnosed as optic neuritis or NAION. With unilateral lesions, the second eye invariably becomes involved (via the chiasm) within weeks. The ONH appears normal or pale at presentation in most cases, but ONH edema and retinal obstruction resulting in venous stasis retinopathy or CRVO can also occur. When the tumor originates in the distal portion of the optic nerve or the optic chiasm, vision loss may be simultaneously bilateral and associated with a pale or normal-appearing ONH.
An MRI scan most often shows diffuse intrinsic enlargement and enhancement of the affected optic nerves, chiasm, and optic tracts, with inhomogeneity due to cystic spaces within the tumor. Occasionally, a large exophytic component may encroach on the suprasellar cistern. Histologically, MOGAs are classified as either anaplastic astrocytomas or glioblastoma multiforme. Although radiotherapy and chemotherapy have been attempted, treatment is rarely successful, with blindness usually developing 2–4 months after onset of vision loss. The tumor is aggressively infiltrative, and death from hypothalamic and brainstem involvement usually occurs within 12 months.
Fried I, Tabori U, Tihan T, Reginald A, Bouffet E. Optic pathway gliomas: a review. CNS Oncol. 2013;2(2):143–159.
Lee AG. Neuroophthalmological management of optic pathway gliomas. Neurosurg Focus. 2007;23(5):e1. http://thejns.org/doi/abs/10.3171/FOC-07/11/E1. Published November 2007. Accessed January 31, 2017.
Listernick R, Ferner RE, Liu GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol. 2007;61(3):189–198.
Traber GL, Pangalu A, Neumann M, et al. Malignant optic glioma—the spectrum of disease in a case series. Graefes Arch Clin Exp Ophthalmol. 2015;253(7):1187–1194.
Thyroid eye disease
Thyroid eye disease (TED) often presents with progressive enlargement of extraocular muscles or orbital fat hypertrophy. In rare cases, progressive proptosis can stretch the optic nerve and cause dysfunction. The extraocular muscles can also enlarge, causing compression of the optic nerve at the orbital apex (Fig 4-16). Patients usually present with associated signs (eg, eyelid retraction and lid lag) and may show signs of orbital congestion (eg, eyelid and conjunctival edema) in addition to proptosis. However, some patients demonstrate only minimal orbital findings.
The vision loss associated with TED is usually slowly progressive, insidious, and bilateral. Dyschromatopsia may be an early sign of optic neuropathy. Visual field testing results show central or diffuse depression, and an RAPD is present when the optic neuropathy is asymmetric or unilateral. The ONH is commonly normal but may be mildly edematous. Optic atrophy may be present in chronic cases.
Use of systemic steroids in the acute phase reduces compression on the optic nerve. In some cases, surgical decompression of the posterior orbit is required. The use of radiation therapy alone is controversial and is not indicated for the treatment of acute optic neuropathy (unless it is combined with systemic steroids). TED is discussed at greater length in BCSC Section 7, Oculofacial Plastic and Orbital Surgery.
Infiltrative optic neuropathy
Infiltration of the optic nerve by neoplastic or inflammatory cells causes progressive, often severe, vision loss. This visual dysfunction, which is often associated with pain, progresses over days to weeks, with or without other cranial nerve involvement. The optic neuropathy may present in 1 or both eyes and can herald systemic disease. With retrobulbar infiltration, the ONH may initially appear normal. In cases of ONH edema, the cellular infiltrate creates a swollen appearance that may be distinct from that of simple edema (see Fig 4-13). The presence of vitreous cells or peripheral vasculitis may signal an infiltrative process. The most common causes of infiltration include leukemia, lymphoma, syphilis, and granulomatous inflammatory processes such as fungal infections, sarcoidosis, or tuberculosis. Metastasis to the optic nerve is rare, usually occurring from breast or lung carcinoma. Carcinomatous infiltration of the meninges at the skull base may cause not only vision loss, but also progressive involvement and dysfunction of multiple cranial nerves in 15%–40% of cases. Onset may precede, coincide with, or follow diagnosis of the underlying malignancy.
Figure 4-16 Thyroid eye disease (TED) in a 48-year-old man with a 6-month history of weakness, gradual swelling around the eyes, and progressively decreased visual acuity over the prior month. Visual acuity was 20/200 OD and 20/80 OS, with a mild right afferent pupillary defect. A, B, Automated perimetry testing shows bilateral central and inferior visual field loss. Axial (C) and coronal (D) CT scans show the optic nerve becoming compressed (arrows in C) by enlarged extraocular muscles. Enlargement of extraocular muscle in TED typically spares the muscle tendon.
(Parts A, B courtesy of Steven A. Newman, MD; parts C, D courtesy of Michael S. Lee, MD.)
Evaluation of cases of suspected infiltrative optic neuropathy should include an MRI of the brain and orbits with fat suppression and use of gadolinium contrast to rule out compressive lesions and to confirm pachymeningeal or meningeal infiltration. The MRI scan may show diffuse thickening and enhancement of the dura and the surrounding subarachnoid space in affected regions, including the optic nerve sheaths; however, abnormalities may not be visible in the early stages. Serologic testing includes screening tests for the myeloproliferative, inflammatory, and infectious disorders. Finally, CSF analysis may reveal malignant cells, an elevated white blood cell count, and elevated protein levels consistent with a neoplastic, infectious, or inflammatory cause. The sensitivity of a single lumbar puncture is low, and repeat testing is often necessary. Securing the correct diagnosis is essential to ensure timely treatment and to prevent life-threatening complications.
de Fátima Soares M, Braga FT, da Rocha AJ, Lederman HM. Optic nerve infiltration by acute lymphoblastic leukemia: MRI contribution. Pediatr Radiol. 2005;35(8):799–802.
Millar MJ, Tumuluri K, Murali R, Ng T, Beaumont P, Maloof A. Bilateral primary optic nerve lymphoma. Ophthal Plast Reconstr Surg. 2008;24(1):71–73.
Yeung SN, Paton KE, Dorovini-Zis K, Chew JB, White VA. Histopathologic features of multiple myeloma involving the optic nerves. J Neuroophthalmol. 2008;28(1):12–16.
Hereditary optic neuropathies
Leber hereditary optic neuropathy
LHON typically affects boys and men aged 10–30 years, but it may occur much earlier or later in life (the possible age range is 1–86 years of age). Symptomatic women account for only 10%–20% of cases. The syndrome presents with acute, painless, sequential, and severe vision loss (visual acuity, <20/200) associated with central or cecocentral visual field impairment (Fig 4-17). The classic fundus appearance triad includes
hyperemia and elevation of the ONH, with thickening of the peripapillary retina; although the ONH appears swollen, it does not leak on fluorescein angiography (“pseudoedema”)
tortuosity of the medium-sized retinal arterioles
These findings can be observed before vision loss begins. The fundus can also appear entirely normal on presentation. The unaffected eye typically becomes symptomatic within weeks to months; however, although rare, the interval between initial and fellow eye involvement can be longer (up to 8 years).
LHON results from a mitochondrial DNA mutation, most frequently at the 11778 position, less commonly at the 3460 or 14484 locations. Results of blood testing for these mutations confirm the diagnosis, permit genetic counseling, and provide information about prognosis. Children and adult 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 point 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). However, the vast majority of LHON cases are homoplasmic. 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 experience visual symptoms only infrequently. The reasons for this selective male susceptibility remains unknown.
The differential diagnosis of LHON includes all other causes of optic neuropathies, particularly optic neuritis, compressive optic neuropathy, and infiltrative optic neuropathy. For patients with a negative family history, neuroimaging should be performed. Mitochondrial testing for the 3 primary mutations is commercially available. Occasionally, patients demonstrate cardiac conduction abnormalities or other mild neurologic deficits that warrant further evaluation.
Figure 4-17 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 ONHs with blurred margins and moderately tortuous vasculature. The left ONH shows mild temporal pallor. C, There was no leakage on fluorescein angiographic studies.
(Parts B, C courtesy of Michael S. Lee, MD.)
No treatment has been shown to be effective for LHON. Corticosteroids are not beneficial. The effect of idebenone on visual outcome remains controversial. Tobacco use or excessive alcohol intake may stress mitochondrial function and thus contribute to vision loss; therefore, patients with LHON should avoid the use of tobacco and curtail alcohol consumption.
Fraser JA, Biousse V, Newman NJ. The neuro-ophthalmology of mitochondrial disease. Surv Ophthalmol. 2010;55(4):299–334.
Newman NJ. Treatment of hereditary optic neuropathies. Nat Rev Neurol. 2012;8(10): 545–556.
Autosomal dominant optic atrophy
The most common hereditary optic neuropathy (estimated prevalence, 1:50,000) is autosomal dominant optic atrophy (ADOA), which 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.
ADOA usually presents in the first decade of life, with insidious onset of vision loss; it is 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, ranging from 20/30 to 20/60, although acuity may decline progressively. Most patients preserve a visual acuity greater than 20/200. Color vision deficits, usually tritanopia (blue-yellow), are invariably present. These patients may pass evaluation with the Ishihara color plates, which test red-green deficits. Tritanopia detection may require testing by Hardy-Rand-Rittler plates or the Farnsworth panel D-15 or D-100 test. In most cases, visual field testing demonstrates central or cecocentral loss. The defects typically do not respect the vertical midline. Affected ONHs usually show focal, wedge-shaped temporal optic atrophy (Fig 4-18), but diffuse pallor can occur.
The clinical diagnosis is based on the examination findings and negative neuroimaging results (which should be performed in all suspected cases). Genetic testing is commercially available but does not test for all mutations that cause ADOA, so it is helpful only when positive. 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.
Skidd PM, Lessell S, Cestari DM. Autosomal dominant hereditary optic neuropathy (ADOA): a review of the genetics and clinical manifestations of ADOA and ADOA+. Semin Ophthalmol. 2013;28(5–6):422–426.
Yu-Wai-Man P, Chinnery PF. Dominant optic atrophy: novel OPA1 mutations and revised prevalence estimates. Ophthalmology. 2013;120(8):1712–1712;e1. http://www.sciencedirect.com/science/article/pii/S016164201300403X. Published August 2013. Accessed January 31, 2017.
Figure 4-18 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, Fundus photographs of ONHs 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.)
Patients with glaucoma do not usually note impaired vision until central vision is affected. Primary open-angle glaucoma is usually characterized by slowly progressive arcuate and peripheral visual field loss, sparing fixation until late in the course. Glaucoma is also distinguished from other optic neuropathies by the following features: preserved color vision, characteristic excavation of the optic cup (with increased diameter and depth of the physiologic cup, often with focal notching at the inferior or superior pole), and lack of pallor of the neuroretinal rim (until the disease is advanced). All aspects of glaucoma are discussed at length in BCSC Section 10, Glaucoma.
Excavation of the ONH may also be present in compressive, hereditary (LHON, ADOA), and severe ischemic (AAION) processes. However, in these cases, the nerve is pale in addition to being cupped. 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. In addition, the ONH may demonstrate early and more prominent pallor, with less severe excavation and notching than in glaucoma (Fig 4-19).
Figure 4-19 Optic nerve excavation. A, Fundus photograph of glaucomatous damage; the remaining temporal rim of neuroretinal tissue generally remains a relatively normal pink color despite severe excavation. B, Fundus photograph of nonglaucomatous damage; the rim is pale relative to the degree of excavation.
(Courtesy of Anthony C. Arnold, MD.)
Toxic or nutritional optic neuropathy
Optic neuropathies resulting from toxic exposure or nutritional deficiency constitute a heterogeneous group of conditions that are generally characterized by gradual, progressive, and painless vision loss that is bilateral and symmetric. Initial findings may include a subtle depression of central vision sensitivity on Amsler grid testing or perimetry testing focused within the central 10°. As the disturbance becomes progressively more severe, however, central vision loss worsens, accompanied by a decrease in visual acuity and color vision and a central scotoma (Fig 4-20). Occasionally, a more rapid onset of decreased vision may occur. Optic atrophy eventually develops if the cause is not corrected. In rare cases, the ONHs may exhibit mild to moderate edema on presentation. Diagnosis requires obtaining a thorough patient history for possible medication or other toxic exposure, substance abuse, or dietary deficiency (as may occur after bariatric surgery or colectomy). Causation is usually multifactorial, and definite proof of optic nerve toxicity by a single toxic agent or nutritional deficiency is rare.
The most commonly implicated agents in the development of toxic optic neuropathies include methanol, ethylene glycol, organic solvents, lead (in children), tobacco (usually cigars), ethambutol, linezolid, amiodarone, disulfiram, ciprofloxacin, and the antineoplastic drugs cisplatin and vincristine. Because it may contribute to malnutrition, ethanol abuse is probably associated indirectly with optic neuropathy. Methanol and ethylene glycol toxicity cause a rapid onset of severe bilateral vision loss with prominent ONH edema.
Other medications that are now recognized as potential causes of toxic optic neuropathies include interferon and anti–tumor necrosis factor alpha (anti-TNF-α) agents (eg, etanercept, infliximab, and adalimumab). TNF-α antagonists may cause an acute demyelinating optic neuritis. Some toxic optic neuropathies are more commonly associated with ONH swelling. Amiodarone toxicity may present with bilateral vision loss and ONH edema. It may be differentiated from NAION by its subacute onset, bilaterality, diffuse rather than altitudinal visual field loss, and slow resolution of ONH edema over months after discontinuance of the medication. Interferon-α administration has been reported as a cause of bilateral NAION. PDE5-inhibitor use has been associated with an increased risk of NAION, but this association is controversial.
Figure 4-20 Optic neuropathy caused by nutritional deficiency in a 42-year-old woman with a history of 4 bowel resections who presented with bilateral blurred vision and trouble recognizing colors. Visual acuity was 20/70 OD and 20/200 OS, without an afferent pupillary defect. A, B, Visual field results demonstrate a cecocentral scotoma on the left and a relative central scotoma on the right. C, D, Fundus appearance shows mild temporal optic atrophy in both eyes, with papillomacular nerve fiber layer dropout. After the patient was treated with multivitamins and hydroxycobalamin injections, the visual field defects resolved completely and visual acuity returned to 20/20.
(Courtesy of Steven A. Newman, MD.)
Dietary deficiencies of vitamin B12, copper, folate, and thiamine may cause optic neuropathy, but exact deficiencies are difficult to identify in cases of suspected nutritional optic neuropathy. Tobacco use has long been implicated in optic nerve dysfunction, but the evidence to support this implication is questionable. Diagnosing nutritional optic neuropathy may be difficult, particularly in patients whose symptoms are vague and who show little objective abnormality. Obtaining a careful and detailed dietary history may help, but ethanol abusers may obscure or falsify details of food and ethanol ingestion. Specific vitamin deficiencies are detected only infrequently on blood testing. It may be challenging to implicate a specific medication in patients using multiple medications.
The differential diagnosis of toxic or nutritional optic neuropathies includes subtle maculopathies and hereditary, compressive, demyelinating, and infiltrative optic neuropathies. Fluorescein angiographic studies, hematologic and serologic testing, and CSF analysis (in rare cases) are performed in questionable cases. Neuroimaging should be performed routinely to rule out a compressive etiology.
The goal of treatment is to reverse the inciting cause: stopping medication or substance abuse and resolving dietary deficiencies. Prognosis for vision recovery is good if optic atrophy has not supervened; however, recovery is highly variable. Improvement of vision typically occurs slowly over several months.
Campbell UB, Walker AM, Gaffney M, et al. Acute nonarteritic anterior ischemic optic neuropathy and exposure to phosphodiesterase type 5 inhibitors. J Sex Med. 2015;12(1): 139–151.
Fraunfelder FW, Sadun AA, Wood T. Update on ethambutol optic neuropathy. Expert Opin Drug Saf. 2006;5(5):615–618.
Peragallo J, Biousse V, Newman NJ. Ocular manifestations of drug and alcohol abuse. Curr Opin Ophthalmol. 2013;24(6):566–573.
Rucker JC, Hamilton SR, Bardenstein D, Isada CM, Lee MS. Linezolid-associated toxic optic neuropathy. Neurology. 2006;66(4):595–598.
Van Stavern GP. Metabolic, hereditary, traumatic, and neoplastic optic neuropathies. Continuum (Minneap Minn). 2014;20(4 Neuro-ophthalmology):877–906.
Wang MY, Sadun AA. Drug-related mitochondrial optic neuropathies. J Neuroophthalmol. 2013;33(2):172–178.
Traumatic optic neuropathy
The optic nerve may be damaged by trauma to the head, orbit, or globe. Direct traumatic optic neuropathy (TON) may be caused by injury to the nerve itself or by laceration with bone fragments (Fig 4-21) or other foreign bodies. Injuries may also cause compressive optic neuropathy secondary to intraorbital or intrasheath hemorrhage. Indirect trauma to the optic nerve is more common than direct optic nerve injury. Indirect TON may occur even with relatively minor head injury. The trauma involves the frontal or maxillary bone, and the transmitted forces damage the optic nerve at the orbital apex. Avulsion of the nerve may also occur. The pathophysiology presumably involves shear forces on the nerve and possibly its vascular supply in the optic canal. Vision loss is typically immediate and often severe (24%–86% of patients have no light perception at presentation). External evidence of injury may be scarce. An RAPD is invariably present if there is unilateral vision loss. Although the ONH usually appears normal at onset, it becomes atrophic within 4–8 weeks.
Figure 4-21 CT scan of an 18-year-old involved in a severe motor vehicle accident. He had noted decreased visual acuity on the left side. The CT scan shows fracture in the area of the left optic canal, with a bone fragment (arrow) impinging on the left optic nerve. Visual acuity improved after transethmoidal decompression of the canal.
(Courtesy of Steven A. Newman, MD.)
Management of suspected TON requires neuroimaging (head, orbit, and facial CT) to assess the extent of injury and to detect any associated intracranial and facial injury, intraorbital fragments, or hematoma. Orbital or cranial surgery may be necessary but may not affect the prognosis for the optic nerve. Therapy for indirect TON is controversial. Although the prognosis for vision recovery has generally been regarded as poor, numerous reports describe occasional spontaneous recovery of some visual function. The International Optic Nerve Trauma Study, a nonrandomized, multicenter, comparative analysis of treatment outcomes, found no clear benefit for treatment with intravenous corticosteroids or optic canal decompression, and no consensus exists for their use, whether alone or in combination. The Corticosteroid Randomization After Significant Head Injury (CRASH) study enrolled more than 10,000 patients with head injuries and compared results from treatment with high-dose corticosteroids (2 g methylprednisolone intravenous and then 0.4 g for 48 hours in a 20 mL/hour infusion) versus placebo within an 8-hour window after trauma. The study was terminated early after initial analysis revealed that the corticosteroid group had a statistically significantly higher rate of mortality than the placebo group. This finding raised safety concerns regarding the use of high-dose corticosteroids in the treatment of TON, particularly in patients with severe head trauma.
Carta A, Ferrigno L, Salvo M, Bianchi-Marzoli S, Boschi A, Carta F. Visual prognosis after indirect traumatic optic neuropathy. J Neurol Neurosurg Psychiatry. 2003;74(2): 246–248.
Edwards P, Arango M, Balica L, et al; CRASH trial collaborators. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury—outcomes at 6 months. Lancet. 2005;365(9475):1957–1959.
Levin LA, Beck RW, Joseph MP, Seiff S, Kraker R. The treatment of traumatic optic neuropathy: the International Optic Nerve Trauma Study. Ophthalmology. 1999;106(7): 1268–1277.
Steinsapir KD, Goldberg RA. Traumatic optic neuropathy: an evolving understanding. Am J Ophthalmol. 2011;151(6):928–933;e2. http://www.sciencedirect.com/science/article/pii/S0002939411001516. Published June 2011. Accessed January 31, 2017.
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 4-22). The reported prevalence ranges from 0.34% (clinical) to 2% (autopsy). 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 suggest a process of 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.
Although most patients with ODD do not experience symptoms, some (8.6%) may have transient visual obscurations if there is associated ONH swelling. 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, evaluation for other causes of vision loss should be performed 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 may be present in patients with asymmetric visual field loss.
Figure 4-22 Optic disc drusen. A, Fundus photograph showing blurred ONH margin with scalloped edge, refractile bodies on the ONH 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 ONH. C, B-scan ultrasonogram demonstrating focal, highly reflective (due to calcification) elevation within the ONH (arrow), which persists when the gain is decreased. D, Preinjection fundus photograph demonstrating autofluorescence (arrow). E, CT scan of the orbits. Calcified ODD 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.)
The ONHs of patients with ODD appear elevated and small in diameter, with indistinct or irregular margins and associated anomalous vascular branching patterns. Blurring of the ONH margin arises from axoplasmic stasis in the axons deep within the ONH, creating a yellowish, hazy appearance that obscures the border between ONH and retina but leaves the view of the retinal vessels intact. This appearance contrasts with the whitish, fluffy, striated appearance of RNFL edema in true papilledema. With ODD, the ONH does not show hyperemia or dilation of the surface microvasculature.
In children, ODD are initially buried, becoming more visible over the years. When visible, ODD appear as round, whitish-yellow refractile bodies. Frequently present at the nasal ONH margin, surface drusen may have a scalloped appearance. Occasionally, they are located within the RNFL just adjacent to the ONH.
Ancillary testing may be useful in differentiating ODD from ONH edema (eg, papilledema) (see Fig 4-22):
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); ODD do not produce widening of the intraorbital nerve (see Fig 4-22C).
Autofluorescence is also an effective method for distinction. Drusen that are close enough to the ONH surface demonstrate autofluorescence, in which refractile bodies appear brightly visible on preinjection images using the fluorescein filter (see Fig 4-22D).
Fluorescein angiography may show early diffuse hyperfluorescence, with late leakage overlying and adjacent to the ONH in true ONH edema. Conversely, ODD do not cause leakage. In cases where the ODD are associated with ONH edema, however, there may be leakage on fluorescein.
Neuroimaging may be indicated in rare cases to rule out an intracranial or optic nerve tumor and to attempt direct confirmation of calcified drusen. CT is 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 site of the globe and optic nerve on CT (see Fig 4-22E).
OCT using a line scan through the optic nerve can show the discrete hyperreflective drusen. Although newer OCT techniques such as enhanced depth imaging (EDI) offer improved imaging of drusen, this is not evident in all cases.
With chronic papilledema, refractile bodies occasionally develop on the ONH surface, simulating ODD (see Fig 4-7). These lesions (probably residual exudate) typically form near the temporal margin of the ONH 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 NF, may take the form of so-called mulberry lesions. When located adjacent to the ONH, they may closely resemble ODD, and they were initially termed giant drusen of the optic disc (see Fig 4-4). In contrast to true ODD, ONH hamartomas
originate at the ONH 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 tumor-like vascularity on fluorescein angiography
Auw-Haedrich C, Staubach F, Witschel H. Optic disk drusen. Surv Ophthalmol. 2002;47(6): 515–532.
Congenital optic nerve head 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. However, nearly all eyes affected by this condition have visual field loss, and 56%–92% of patients have bilateral involvement. The ONH is small, usually one-half to one-third of normal diameter; subtle cases may require a comparison of the 2 eyes. Comparing the horizontal ONH diameter with the ONH–macula distance may help in detection. Retinal vessel diameter may seem large relative to the ONH size, and the vessels may appear tortuous. The ONH 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 4-23).
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 or de Morsier syndrome) 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 evaluation is necessary, because hypoglycemic seizures or growth retardation may develop without appropriate 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.
Figure 4-23 Optic nerve hypoplasia. The small ONH 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 Monographs 10. New York: Oxford University Press, in cooperation with the American Academy of Ophthalmology; 2007:158.)
Congenital tilted disc syndrome
Congenital tilted disc syndrome is usually bilateral (80%) and should not be confused with simple myopic tilted ONHs 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 ONH remains relatively intact; the ONH appears tilted around a predominantly horizontal axis. The superior portion can sometimes seem elevated, simulating mild edema (Fig 4-24). The retinal vessels are often nasalized. 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 4-24 Congenital tilted disc syndrome. Visual field testing results (A, B) show bilateral relative superotemporal defects that do not respect the vertical midline. Fundus photographs show bilateral tilted ONHs in the right eye (C) and in the left eye (D).
(Parts A, B courtesy of Anthony C. Arnold, MD; parts C, D courtesy of Sophia M. Chung, MD.)
Excavated optic nerve head anomalies
Excavated ONH anomalies cover a spectrum of severity, ranging from optic pits through colobomas and dysplastic nerves to the morning glory ONH anomaly:
An optic pit is a depression of the ONH surface that is often gray or white, located inferotemporally, and associated with a mild visual field defect (usually paracentral or arcuate). Serous detachment of the macula develops in 25%–75% of cases, possibly related to liquefied vitreous entering the subretinal space through communication between the optic pit and the macula.
Colobomas of the nerve result from incomplete closure of the embryonic fissure and usually occur inferiorly; they occasionally extend to the adjacent choroid and retina. Visual field defects and an RAPD can occur, depending on the degree of abnormality. Colobomas of other structures, such as iris and choroid, may be present.
The dysplastic nerve of papillorenal syndrome or renal coloboma syndrome appears excavated with absence or attenuation of the central retinal vessels and multiple cilioretinal vessels emanating and exiting from the ONH edge. Visual acuity is often normal, but perimetry may reflect superonasal visual field defects. Controversy exists regarding whether the nerves are colobomatous from incomplete embryonic fissure closure or from a primary dysplasia of the optic nerve. This characteristic optic nerve appearance may indicate renal failure secondary to renal hypoplasia and is linked to mutations in the PAX2 gene (which are autosomal dominant).
The morning glory ONH anomaly is a funnel-shaped staphylomatous excavation of the optic nerve and peripapillary retina. It is more common in females and usually unilateral. The ONH is enlarged, pink or orange, and either elevated or recessed within the staphyloma. Chorioretinal pigmentation surrounds the excavation, and white glial tissue is present on the central ONH surface. The characteristic feature is the emanation of retinal vessels from the periphery of the ONH. Visual acuity can be normal but is often 20/200 or worse and accompanied by an RAPD. Nonrhegmatogenous serous retinal detachments occur in 26%–38% of cases. Neuroimaging is warranted to evaluate for a basal encephalocele and CNS vascular anomalies.
For additional discussion, see BCSC Section 6, Pediatric Ophthalmology and Strabismus.
Brodsky MC. Congenital optic disk anomalies. Surv Ophthalmol. 1994;39(2):89–112.
Lee BJ, Traboulsi EI. Update on the morning glory disc anomaly. Ophthalmic Genet. 2008; 29(2):47–52.
Nicholson B, Ahmad B, Sears JE. Congenital optic nerve malformations. Int Ophthalmol Clin. 2011;51(1):49–76.
Excerpted from BCSC 2020-2021 series: Section 5 - Neuro-Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.