© Springer Nature Switzerland AG 2019
Andrew G. Lee, Alexandra J. Sinclair, Ama Sadaka, Shauna Berry and Susan P. Mollan (eds.)Neuro-Ophthalmologyhttps://doi.org/10.1007/978-3-319-98455-1_13

13. Workup for Optic Atrophy

Bart Chwalisz1  , Dean M. Cestari1, 2   and François-Xavier Borruat3  
(1)
Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA
(2)
Center for Thyroid Eye Disease and Orbital Surgery, Massachusetts Eye and Ear, Boston, MA, USA
(3)
Unité de Neuro-ophtalmologie, Hôpital Ophtalmique Jules-Gonin, Université de Lausanne, Lausanne, Switzerland
 
 
Bart Chwalisz
Email: bchwalisz@mgh.harvard.edu
 
Dean M. Cestari (Corresponding author)
Email: Dean_Cestari@meei.harvard.edu
 
François-Xavier Borruat
Email: francois.borruat@fa2.ch

Keywords

Optic atrophyOptic neuropathyVision lossOptic disc pallorOCT

Introduction

Optic atrophy refers to degeneration of the optic nerve together with associated changes in the retinal nerve fiber layer and retinal vessels. It can occur as ascending degeneration after destruction of ganglion cells in the retina, or as descending atrophy following destruction of nerve fibers after either a lesion of the pregeniculate (optic nerve, chiasm or optic tracts), or less commonly, the retrogeniculate visual pathways (optic radiations, occipital cortex) via transsynaptic retrograde degeneration (TRD). Transneuronal degeneration has long been considered of minor clinical importance in human adults [1, 2], but recent studies have demonstrated that TRD happens more frequently than thought, thanks to the recent advances in OCT technology and software [3]. However, optic atrophy from TRD is rarely obvious during funduscopy, being revealed mostly by OCT. Descending degeneration proceeds more slowly than ascending degeneration, and is more pronounced with lesions close to the globe [1]. In animal experiments, optic disc pallor appears between 5 and 6 weeks after optic nerve section in the orbit [4, 5].

Optic atrophy generally produces a clinical picture of decreased visual function and a characteristic ophthalmoscopic appearance of a pale optic nerve head with changes in the surrounding retinal nerve fiber layer (RNFL) and blood vessels, although some patients may have no clinically detectable decrease in vision. The process may be unilateral or bilateral. Pallor of the optic disc may or may not be accompanied by enlargement of the optic disc cup and thinning of the optic nerve rim.

Optic atrophy is not a disease in and of itself. It is a pathologic change that results from a myriad of causes. Consequently, the workup of optic atrophy must be tailored to the clinical presentation and guided by the patient’s history and physical examination. For the evaluating clinician, the key task is to determine whether the patient with optic atrophy, unilateral or bilateral, is stable or whether there is an on-going process causing destruction of ganglion cells.

There are two main scenarios to consider (Box 13.1): First, the patient is asymptomatic, and the optic atrophy found during a routine eye examination. Second, a symptomatic patient is seeking medical attention due to progressive loss of vision. Asymptomatic unilateral optic atrophy may be congenital, or from a prior insult such as trauma, optic neuritis or ischemic optic neuropathy (ION). Asymptomatic bilateral atrophy may also be congenital, or due to neonatal ischemia, trauma, meningitis, toxic-nutritional exposures, prior optic neuritis or sequential ION, or from a hereditary optic atrophy. The differential diagnosis of ongoing, symptomatic unilateral optic atrophy includes compression, infiltration and inflammation. The differential diagnosis of symptomatic bilateral optic atrophy includes compression, infiltration, inflammation, infection, toxic/nutritional and hereditary causes, chiefly dominant optic atrophy (DOA).

Box 13.1 Triaging Optic Atrophy

  1. 1.
    Incidentally discovered optic atrophy in an asymptomatic patient
    1. (a)
      Sequela of previously unnoticed optic nerve injury
      • Careful history

        • Clear history (e.g., trauma, perinatal insult) and no progression documented: no further investigations, good prognosis

        • Unclear history: investigate (mostly with MRI)

       
    2. (b)

      Very slowly progressive disorder: Investigations needed

       
     
  2. 2.
    Symptomatic patient
    1. (a)

      Implies an active, ongoing process: investigations mandatory

       
     

It is generally much more important to elucidate the etiology of symptomatic, progressive optic atrophy. Although the presence of atrophy implies some permanent loss of ganglion cells, determining its cause may allow halting further progression of vision loss, and in some cases, visual recovery, e.g., after removal of toxic insults or compressive lesions [2]. The history and physical examination suffice to identify an etiology in most cases of prior optic neuritis, ischemic optic neuropathy (ION), toxic-nutritional optic neuropathy, hereditary optic neuropathy, or optic atrophy after prior papilledema [6]. However, in some cases, optic atrophy remains unexplained despite careful and complete history and neuro-ophthalmic examination, requiring a further workup [6] (Box 13.2).

Box 13.2 Optic Atrophy Work-up

  1. 1.
    Standard evaluation (every patient)
    1. (a)
      Extensive and careful history

      • Premature birth and/or neonatal hospitalization

      • Previous head trauma

      • Visual loss following surgery

      • Previous history compatible with optic neuritis

      • Previous meningitis

      • Episodes of uveitis

      • Exposure to toxins/medications potentially toxic to the optic nerve, including occupational or vocational exposure

      • Nutritional risk factors (e.g., vegan diet, weight loss surgery, nutritional deprivation)

      • Infectious risk factors (e.g., tick bites, assessment of risk for sexually transmitted infection)

       
    2. (b)
      Neuro-ophthalmic examination

      • Visual function: acuity, color vision, peripheral vision, pupillary reactions

      • Complete ophthalmic exam

      • Fundoscopic assessment : distribution of pallor, and adjunctive clues (cupping, RNFL defects, vascular attenuation, contralateral optic nerve)

      • Targeted neurologic exam

       
    3. (c)

      Consider OCT

       
     
  2. 2.

    Consider imaging (usually MRI of brain and orbit with contrast)

     
  3. 3.
    If neuroimaging unrevealing → tailored blood studies
    1. (a)
      Infections (based on geographic and epidemiologic risk)

      • Lyme

      • Syphilis

      • HIV

      • Tuberculosis

       
    2. (b)
      Autoimmune/inflammatory disorders

      • ANA, SS-A/SS-B, other extractable nuclear antigens, ANCA

      • Sarcoidosis workup: ACE +/− lysozyme, chest CT, consider whole-body PET

       
    3. (c)
      Nutritional (esp. bilateral optic atrophy, cecocentral scotoma)

      • B12/methylmalonic acid, copper

       
    4. (d)
      Hereditary

      • LHON mutations (3460, 11778, 14484). If negative and history/visual function suggestive of LHON → whole mitochondrial DNA genome

      • DOA mutations OPA1 and OPA3. If negative, other loci can be sought (OPA2, 4–8)

       
     

History

Symptoms

The primary symptom of optic atrophy is monocular or binocular vision loss, although occasionally patients may not report symptoms if atrophy is incidentally discovered during an ophthalmic exam. Patients usually perceive vision loss from optic nerve disease as darkening, either as a scotoma or more generalized dimness across the entire visual field or portions thereof [2]. Vision may be worse in dim light conditions. Some patients become aware of a color vision deficit in the affected eye, and may describe colors as “washed out” or “faded”. A characteristic (but uncommon) symptom of optic nerve sheath meningioma is gaze-evoked transient vision loss with abduction, caused by cessation of retinal arterial flow in the eccentric position [7]. Positive phenomena such as phosphenes (sparkles or bright spots) occur only rarely in optic neuropathies and may suggest demyelinating disease, i.e., optic neuritis. Photophobia or sometimes dazzle can be a symptom in nutritional optic neuropathy [8].

The rate at which vision was lost and the circumstances under which this occurred are among the most important aspects of the patient’s history [2]. Sudden monocular vision loss suggests a vascular etiology such as an ION or central retinal artery occlusion (CRAO). Similarly, a history of unilateral or bilateral vision loss immediately following surgery or severe hemorrhage is consistent with hypoperfusion injury (shock optic neuropathy). Compressive lesions typically cause gradual progression of vision loss but they may occasionally present in an accelerated or even apoplectic fashion [9, 10]. Gradual progression of vision loss can also be seen in infiltrative or granulomatous optic neuropathy [11].

A sudden discovery of a long-standing problem can sometimes create diagnostic confusion. For instance, traumatic optic neuropathy can occur with relatively mild head trauma, and may not be fully appreciated by the patient at the time [9, 12]. A history of trauma should therefore be specifically sought, especially with force to the face or forehead. On occasion, slowly progressive vision loss may not be recognized as such by the patient until each eye is tested individually, or may even be discovered during visual acuity testing.

Acute Vision Loss

Patient demographics can provide helpful clues to the cause of optic atrophy. Non-arteritic ischemic optic neuropathy (NAION) becomes more frequent in middle age, and arteritic ION secondary to giant cell arteritis is primarily a disease of the elderly, with an increasing incidence over the age of 80 years. Vascular risk factors such as systemic hypertension, diabetes mellitus, dyslipidemia and smoking are common in ION and also in central retinal artery occlusion (CRAO) [13]. Optic neuropathy in a younger patient is more likely to be inflammatory but vascular and other causes need to be considered, including Leber’s hereditary optic neuropathy (LHON).

Patients should be queried regarding their symptoms at the time that the vision was lost. LHON typically affects young men with acute or subacute vision loss that occurs sequentially (median inter-eye delay of 6–8 weeks) or simultaneously but vision loss can develop anytime during the first to seventh decade of life [14, 15]. A family history of vision loss in the maternal line, especially affecting young men supports LHON, and there can be history of additional neurologic disturbances, such as extrapyramidal disorders, cerebellar ataxia and peripheral neuropathy [16]. In some kindred with LHON, cardiac conduction defects may occur (pre-excitation and long QT syndromes) [17]. Some cases of LHON also show partial or even complete spontaneous improvement particularly when associated with the 14484T > C mutation or 3460G > A mutation [15, 18]. This is characterized by the development of “fenestrations” within visual field defects or more general return of central acuity and color vision, usually in both eyes [17].

A history of pain with eye movements in the acute phase supports optic neuritis. In many cases of optic neuritis, there is an infectious prodrome, although this is also sometimes reported in LHON. There may be a history of other episodes of neurologic decompensation, which would suggest multiple sclerosis or one of its mimics, such as neuromyelitis optica (NMO) or sarcoidosis. In NMO, there can be a history of episodes of weakness, sensory loss or sphincter disturbance that implies prior myelitis, or a history of vomiting or hiccuping that would suggest an area postrema syndrome. Less common presentations of NMO include narcolepsy, and attacks affecting the brainstem, diencephalon and cortex [19]. Importantly, relapses in multiple sclerosis frequently resolve with minimal or no residual loss of function, whereas untreated attacks in NMO are much more likely to leave the patient with permanent disability.

It is important to review whether an ophthalmoscopic exam was performed in the acute phase after an episode of vision loss, as particularly the presence of disc edema would suggest ION, anterior optic neuritis, or papilledema. Disc hemorrhages are common in acute NAION and papilledema. In acute LHON, the fundus often shows characteristic changes of circumpapillary telangiectasias (telangiectatic microangiopathy), vessel tortuosity and whitish opaque swelling of the RNFL surrounding the disc that is frequently mistaken for papilledema but does not stain on fluorescein angiography (“pseudoedema”) [14, 20]. However, fundus findings can be normal in up to 50% of patients with acute LHON [16]. Disc hyperemia as well as dilation and tortuosity of small retinal vessels within the arcuate areas of the RNFL can also be seen in acute tobacco-alcohol amblyopia [8, 21].

Sudden binocular vision loss is rare but can occur with damage to the posterior optic nerves or chiasm, e.g., in bilateral posterior ischemic optic neuropathy (in perioperative vision loss, or from giant cell arteritis) or pituitary apoplexy. Sequential bilateral vision loss can occur in LHON, bilateral optic neuritis and occasionally in NAION. Unfortunately, it can be difficult to clearly distinguish bilateral simultaneous vision loss from sequential vision loss, especially when one eye is so severely affected that symptoms in the other eye were missed. For instance, vision loss in both arteritic and non-arteritic ischemic optic neuropathy can occasionally be simultaneous or nearly so.

Subacute Vision Loss

The differential diagnosis of subacute vision loss includes compressive, inflammatory, infiltrative, toxic/metabolic and nutritional etiologies. It is important to review whether improvement occurred at any point. Optic neuritis often develops acutely or subacutely, stabilizes, and then commonly demonstrates improvement whether treated or not. A history of improvement in vision or pain after steroids (or return of symptoms after discontinuation of steroids) is consistent with optic neuritis, but can also be seen in other inflammatory conditions such as granulomatous optic neuropathy from sarcoidosis [11].

Subacute symmetric vision loss is characteristic of most nutritional and metabolic optic neuropathies, including tobacco-alcohol amblyopia, although notably the onset may also be asymmetric [9]. Risk factors for toxic and nutritional optic neuropathy include alcohol and tobacco consumption and a nutritionally impoverished diet. Although vitamin B12 deficiency is the one classically associated with bilateral vision loss, in many cases, deficiencies of other vitamins are probably contributory, including vitamin B1 (thiamine), B2 (riboflavin), B3 (niacin), B6 (pyridoxine), folic acid, as well as low ingestion of protein [8]. Vitamin B12 deficiency can occur in vegans, after small bowel resection or bariatric surgery (particularly gastric bypass), or with disease of the terminal ileum (e.g., in Crohn’s disease) [22]. Importantly, LHON can occasionally masquerade as tobacco-alcohol amblyopia, probably because the environmental insults trigger expression of the disease [8, 17, 23]. Rarely, one may encounter cases of epidemic or endemic toxic-nutritional optic neuropathy such as described in Cuba or Tanzania [8]. A number of exogenous agents have been reported in association with optic neuropathy (Box 13.3).

Box 13.3 Exogenous Agents Associated with Optic Neuropathy

Alcohols—methanol, ethylene glycol

Antiarrhythmics—amiodarone, digoxine

Antibiotics—chloramphenicol, dapsone, linezolid, sulfonamides

Antituberculous—ethambutol, isoniazid, streptomycin

Chemotherapeutic agents—5-fluorouracil, cisplatin, carboplatin, nitrosureas, paclitaxel, vincristine

Heavy metals—lead, mercury, thallium

Immune modulators—α-interferon2b, cyclosporine, methotrexate, tacrolimus, TNF-α inhibitors

Toxins—carbon monoxide, organophosphates, toluene

Others—benoxaprofen, chlorpropamide, cimetidine, clioquinol, disulfiram, iodochlorhydroxyquinoline

A social and travel history may also provide certain clues, for instance in infectious optic neuropathy. In the United States, Lyme disease is most prevalent in the Northeast, Upper Midwest and certain areas on the Pacific coast, but it also occurs in large areas of Northern Eurasia. The incidence of syphilis has continued to rise in the last two decades, particularly in men who have sex with men.

Chronic Vision Loss

Insidious monocular or binocular vision loss can be seen with compressive etiologies such as tumor or aneurysm [9], and chronic bilateral loss of vision occurs in hereditary neuropathy such as dominant optic atrophy (DOA), and also in bilateral optic neuropathy of primary or secondary progressive multiple sclerosis. Acute-on-chronic decompensation can suggest an acute process involving a compressive lesion, such as pituitary apoplexy or sudden expansion of an aneurysm [9].

Although compressive optic neuropathy can occur at any age, it is more frequent in middle-aged or older patients [9]. The majority of patients with meningiomas intrinsic to the optic nerve sheath or externally compressing the optic nerve are middle-aged women [7]. However, optic nerve and anterior visual pathway gliomas are primarily diseases of young patients, typically diagnosed in children under 8 years but they can occur in the second decade or beyond [10, 24].

A negative family history does not rule out DOA or Leber’s Hereditary Optic Neuropathy (LHON) as the majority of affected individuals have a negative family history. Vision loss in DOA may be slowly progressive or relatively static over long periods of time [17]. A family history of progressive vision loss or unexplained poor vision with autosomal dominant inheritance pattern favors DOA, which is highly penetrant [17].

DOA is frequently misdiagnosed as normal tension glaucoma, a much more common cause of progressive optic neuropathy with cupping, which however generally does not cause pallor of the neuroretinal rim. In patients with cupped optic discs, a family history of glaucoma favors a final diagnosis of glaucoma over non-glaucomatous optic atrophy [25].

Optic atrophy also occurs in certain forms of spinocerebellar ataxia, hereditary spastic paraplegia, Charcot-Marie-Tooth disease (CMT2A), deafness-dystonia-optic neuronopathy syndrome (DDON), Friedreich ataxia, and Wolfram syndrome (DIDMOAD—diabetes insipidus, diabetes mellitus, optic atrophy, and deafness ). Autosomal recessive forms of optic neuropathy are almost always associated with other neurologic manifestations, and usually present early in life. It may occasionally be helpful to examine the family members of affected patients, as some individuals with LHON or DOA mutations may have characteristic fundus findings despite being asymptomatic [17].

Examination

Visual Function: Acuity, Color Vision, Visual Fields

Visual acuity in optic atrophy can vary widely, and may even be normal [26] (Fig. 13.1). It is difficult to predict the level of visual acuity based on the appearance of the optic nerve head. CRAO and arteritic ischemic optic neuropathy typically cause severe vision loss (light perception or hand motion vision). Vision loss worse than 20/200 (i.e., legal blindness) is also the typical result of LHON [17]. Mild-moderate vision loss usually characterizes tobacco-alcohol amblyopia and DOA. Visual acuity of 20/40 or better can occur in optic neuropathies that tend to spare central visual function such as NAION, partially recovered optic neuritis, or a slowly progressive compressive or infiltrative process with relative sparing of central fibers [9].
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Fig. 13.1

Left optic atrophy secondary to optic nerve glioma in a patient with neurofibromatosis type 1. The affected eye had 20/20 visual acuity. MRI shows the tumor expanding the left optic nerve

Color vision is typically reduced early in most optic neuropathies, much more severely so than in macular disease. In DOA, tritanopic (blue-green) defects were initially reported, but it was shown in subsequent studies that the majority of patients have more generalized dyschromatopsia [17].

Automated perimetry can be helpful to elucidate the cause of optic atrophy better than visual acuity or color vision alone [26]. Cecocentral scotomas (connecting the physiologic blind spot with central visual field loss) result from damage to the papillomacular fibers, and are characteristic of hereditary and metabolic neuropathies (Fig. 13.2). Arcuate visual field defects imply damage to the superior or inferior arcuate nerve fiber bundles or the corresponding ganglion cells, and are less specific with regard to etiology. Arcuate field defects occur in ischemic, inflammatory, compressive or infiltrative neuropathies, and in glaucoma. It should be noted that any of the visual field defects that are characteristic of open angle glaucoma may be indistinguishable from defects in various nonglaucomatous optic neuropathies, including paracentral arcuate scotomas, nasal steps, and coalescence of arcuate scotomas to form a ring-shaped scotoma [2].
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Fig. 13.2

Ethambutol toxicity: Mild bitemporal pallor of optic discs. Visual fields show cecocentral scotomas

Generally, visual field defects that respect the horizontal meridian imply disease of the retina or visual pathways anterior to the optic chiasm, whilst defects at the vertical meridian suggest injury to the chiasm or retrochiasmatic pathways. Altitudinal defects are particularly suggestive of ischemic optic neuropathy, particulary when they affect the inferior visual field, but similar defects can also occur in low-tension glaucoma [27, 28]. Compression of the optic chiasm classically causes bitemporal hemianopia due to damage to the crossing fibers that originate nasal to the macula (Fig. 13.3). Retrochiasmal dysfunction will cause a homonymous defect, whereas an anterior chiasmatic lesion will produce a junctional scotoma. A careful perimetric evaluation of the fellow eye is necessary to exclude subtle temporal or supero-temporal defects [9].
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Fig. 13.3

Right junctional scotoma: Bilateral temporal pallor and visual field defects (OD: central and inferior, OS: temporal hemianopia). Visual acuity was 20/20 OD and 20/100 OS. MRI demonstrates a large sellar pituitary adenoma

Pupillary Examination

In an asymmetric optic neuropathy, a relative afferent pupillary defect (RAPD) should be present. An RAPD can be further quantified with the use of neutral density filters [29]. The corollary to this is that symmetric optic neuropathies will not show a RAPD, such as glaucoma, papilledema, and toxic, nutritional and hereditary optic neuropathies [30]. Brightness sense is diminished and can be assessed subjectively or semi-quantitatively by using cross-polarizing filters to reduce light transmission [31].

Optic Disc Pallor

Historically, pallor was ascribed to a paucity of blood vessels in atrophic tissue. However, based on the experimental evidence, it has been postulated that the normal pink color of the optic nerve rim is produced by light entering the tissue along the transparent nerve fiber bundles in a manner that is analogous to fiber optic cables, diffusing among the adjacent columns of glia and capillaries, and taking on the pink color of the blood vessels [5]. Pallor then occurs in the atrophic disc because of a combination of factors that includes tissue thinning, allowing shine through of the underlying white sclera and lamina cribrosa, and replacement of fibers by astrocytes at right angles to the entering light, reflecting back the light [5].

The first task in the examination is to distinguish between genuine optic atrophy and non-atrophic pseudopallor of the optic disc. Importantly, a pale disc appearance alone is not sufficient evidence of atrophy, and should be supported by a demonstrable change in visual function or additional anatomic evidence of nerve fiber loss. Certain pitfalls should be noted. When comparing one side to the other, it is especially important to take into account the ocular media. For instance, pseudophakia can easily create the appearance of optic disc pallor, especially when compared to a phakic eye with nuclear sclerotic cataract. In axial myopia, it is common for the disc to look white due to the oblique insertion of the optic nerve into the globe, which displaces the nerve fibers and vessels nasally and creates the appearance of extension of the temporal margin of the cup and relative temporal pallor [2]. A large cup can create the visual appearance of pallor due shine through of the lamina cribrosa, thus special attention should be paid to the color of the remaining neuroretinal rim.

Assessing optic disc pallor and grading its severity is challenging. The color hue and degree of pallor are influenced by the light source and the clarity of the ocular media. Based on the appearance of the optic disc, optic atrophy has customarily been divided into primary and secondary degeneration [1]. Primary atrophy results from intrinsic damage to the optic nerve, with an orderly replacement of degenerating nerve fibers by columnar gliosis. Historically, the optic atrophy associated with tabes dorsalis was considered a paradigm of this sort of injury. Secondary atrophy is characterized by replacement of nerve tissue with an excessive proliferation of tangled glial tissue, as occurs for instance with resolution of papilledema or papillitis. Most of the additional ophthalmoscopic clues that may have been present in the acute phase (such as edema, hemorrhages, or vessel tortuosity) will in the chronic phase give way to a nonspecific picture of optic disc pallor with vessel attenuation. It is therefore hazardous to attempt a diagnosis based on the appearance of optic atrophy only. Notably, in a blinded assessment of 15 papillitis eyes and 21 ION eyes, only 4 (11%) had clear evidence of previously documented disc edema [28]. The classic teachings about primary and secondary optic atrophy notwithstanding, once the acute phase is passed, it is difficult to separate inflammatory or ischemic papillopathy by fundoscopy alone from other causes of optic atrophy [32]. Nevertheless, careful ophthalmoscopic examination of an atrophic disc can provide some important diagnostic clues, and when graded by experienced ophthalmologists, the severity of optic nerve pallor correlates with visual function [26].

The distribution of optic disc pallor is important, and should be characterized as diffuse or segmental. Pallor of the temporal aspect of the optic disc indicates that the papillomacular bundle is predominantly affected. It usually corresponds to selective damage to central vision and the central visual field. However, temporal paleness should be interpreted carefully, as it is normal for the temporal aspect of the optic disc to have less color [2]. Unilateral temporal pallor is typical of prior optic neuritis and also common in compressive optic neuropathy [22, 32]. When it is bilateral, it can suggest a hereditary, toxic or nutritional neuropathy [33] (Fig. 13.2). Superior or inferior pallor makes an ischemic etiology more likely [2]. NAION in particular can cause generalized or less commonly altitudinal pallor, which is most likely to affect the superior aspect of the disc, in keeping with the visual field defect most commonly affecting the inferior field [34] (Fig. 13.4).
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Fig. 13.4

NAION: Sectoral superior pallor and inferior pseudohemangioma of the optic disc. Inferior altitudinal visual field loss

Band (or “bowtie”) atrophy is a specific pattern where the temporal and nasal aspects of the disc become pale due to chiasmal or optic tract compression of the crossing retinal fibers that originate nasal to the macula, with relative sparing of the superior and inferior arcuate bundles (Fig. 13.5). This is sometimes more easily appreciated on RNFL analysis by OCT [35]. In optic tract lesions associated with pregeniculate homonymous hemianopia, the eye contralateral to the lesion may show band atrophy (and a temporal hemianopia), whereas the ipsilateral eye will incur damage primarily to the fibers originating temporal to the macula (and a nasal hemianopia) and thus there will be damage to the superior and inferior nerve fiber bundles, and usually more diffuse optic pallor [2].
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Fig. 13.5

Bowtie Atrophy: Temporal pallor OD and bowtie atrophy OS. This is better appreciated on the red-free photo

Optic Disc Cupping

Enlargement of the optic cup can occur in non-glaucomatous optic neuropathies , although usually not to the same extent as in glaucoma. The optic cup should be assessed on the basis of contour and not pallor. The normal cup-to-disc ratio is about 0.3 but in general, the size of the cup is correlated with the size of the whole optic disc [36–38].

In addition to glaucoma, physiologic cupping , and congenital anomalies enter the differential diagnosis of the cupped-appearing optic disc, including colobomas, pits, optic hypoplasia or megalopapilla. Optic disc anomalies may be either unilateral or bilateral and should generally not associated with any visual dysfunction apart from possibly peripheral visual field defects [39, 40].

Optic disc cupping, has been described in compression by tortuous internal carotid arteries or chiasmal tumors, syphilis, hereditary optic neuropathies (Leber’s and autosomal dominant), methanol poisoning, radiation optic neuropathy, shock optic neuropathy and ischemic optic neuropathy, especially of the arteritic variety [12, 34, 40] (Fig. 13.6). In one series of 252 eyes of patients with non-glaucomatous optic neuropathies and no documented elevation of elevated intraocular pressure, 20% were found to have pathologic cupping, and this was most common in the hereditary and compressive optic neuropathies [32]. In a quantitative masked retrospective review, it was found that the median cup/disc ratio was 0.37 in compressive optic neuropathies as compared to 0.10 in control subjects, a statistically significant difference [41]. In the same study, the intereye difference in compressive optic neuropathy , was 0.13, compared with 0.04 in controls, and in almost every case of unilateral compromise, the larger cup was associated with reduced visual acuity, dyschromatopsia, RAPD and visual field defects.
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Fig. 13.6

Severe pallor, cupping, arterial attenuation and loss of RNFL, in a patient with gradual symmetric vision loss presumed secondary to dominant optic atrophy. OCT shows the cupping, and macular GCC analysis demonstrates circumferential GCC thinning

The cup is usually more shallow in optic atrophy than in glaucoma, although in arteritic ION , it can be deep and excavated, with drawing backwards of the lamina cribrosa by cicatricial changes in the infarcted retrolaminar optic nerve [12, 40, 42, 43]. A peculiar triangular cupping of the temporal portion of the optic disc has been described in DOA [33, 44].

Distinguishing between glaucomatous and non-glaucomatous cupping can be challenging, and when shown photographs of cupped discs without additional clinical evidence, even experts in the field have a high rate of misdiagnosis, with the most significant error being overdiagnosis of glaucoma in nonglaucomatous optic atrophy [32, 45, 46]. In the Optic Disc Assessment Project, based on optic disc appearance alone without any additional clinical information DOA was correctly identified 27% and LHON 16% of the time [46]. Even when optic disc appearance and visual fields are considered together, some neuro-ophthalmic conditions can be misdiagnosed as glaucoma, including cases of NAION, compressive optic neuropathy and hereditary optic neuropathy [47]. The most important distinguishing feature is pallor of the neuroretinal rim, which was 94% specific for nonglaucomatous atrophy, whereas preservation of color of rim was 87% specific for glaucoma [45]. Both generalized and sectoral disc pallor , favors nonglaucomatous cupping [40, 42]. Focal or diffuse obliteration of the neuroretinal rim is extremely rare in normotensive optic atrophy, and necessitates excluding glaucoma [40, 45]. Optic disc cupping in glaucoma is frequently most pronounced vertically, sometimes with localized vertical notching that creates an hour-glass shaped pattern of atrophy [37, 48], whereas concentric enlargement of the cup is more characteristic of nonglaucomatous atrophic cupping [36, 49]. For instance, in cupping after arteritic ION, neuroretinal rim thinning was found to be diffuse rather than segmental [42]. However, even in glaucoma different patterns of cupping occur, including concentric enlargement of the cup, and have been speculated to represent distinct subgroups of the disease [50].

A careful history and clinical exam , usually allows one to distinguish between glaucoma and non-glaucomatous optic atrophy [30]. Generally, visual field defects and especially loss of central visual acuity are late sequelae of glaucoma that occur after extensive cupping has developed, whereas in nonglaucomatous atrophy these visual functions are affected early and disproportionately to the cupping [2]. Optic disc hemorrhages are a useful diagnostic sign in glaucoma when present but are uncommonly seen [37, 48, 49]. Peripapillary chorioretinal atrophy is a common feature of the glaucomatous disc but importantly not of non-glaucomatous optic atrophy even in those cases where the optic disc is cupped [36, 38, 42]. Peripapillary atrophy is differentiated into a peripheral alpha zone with irregular pigmentation and a central beta zone with good visibility of the large choroidal vessels and sclera, and it is beta zone atrophy that is specific to glaucoma. Perhaps most importantly, glaucoma is a progressive disease, and thus re-examination of the patient can help distinguish glaucoma , from an isolated ischemic event that may mimic it in terms of visual field and appearance of the optic disc [48].

Retinal Nerve Fiber Layer

Evaluation of the peripapillary retinal nerve fiber layer (RNFL) is an important adjunct to the assessment of the optic disc itself. It can complement assessment of the optic disc by confirming an impression of optic atrophy, and owing to its greater sensitivity for mild atrophy, it can add useful information in borderline cases where the disc appearance is neither clearly normal nor clearly abnormal [51, 52]. The RNFL is best visualized against the dark background of a red-free light, a bright light source and at adequate magnification (direct ophthalmoscope or with a high-magnification fundus lens) through a dilated pupil. Fundus photographs can be helpful [52]. The normal appearance of the RNFL consists of fine striations that overlie the retinal vessels and blur the first and second branchings of arterioles and venules, especially in the superior and inferior arcuate bundles where the RNFL is thickest [52, 53]. Early loss of axon bundles causes slit- or wedge-like defects in the RNFL, and multiple nerve fiber bundle defects can create a “raked” appearance to the nerve fiber layer [2]. As atrophy of the RNFL becomes more extensive, the vessels appear denuded, stand out in sharper relief and become darker in color [52] (Fig. 13.6). Despite these well-described clinical associations, however, the RNFL is difficult to assess ophthalmoscopically and requires an experienced observer [49]. It may also be most easily appreciated in glaucomatous damage, which disproportionately damages the normally thicker superior and inferior RNFL layers, but may be more difficult to assess for instance in band atrophy, which affects primarily the thinner horizontal and nasal RNFL. Similar information can now be obtained with greater precision by quantitative analysis of the RNFL with optical coherence tomography (OCT) technology (see below), and analysis of the ganglion cell complex may have even greater sensitivity.

Retinal Vasculature

Generally, the retinal arteries become attenuated in optic atrophy . This is more pronounced with injuries to the retina or proximal optic nerve, and much less so when the retrolaminar optic nerve is damaged [2]. However, narrowing of the retinal arterioles has also been documented quantitatively in descending optic atrophy [54]. Trobe et al. found retinal arteriolar attenuation to be most helpful in differentiating vascular injuries (CRAO and ION) from other optic neuropathies, though it was also common in traumatic optic neuropathy [32]. Sheathing of the retinal arterioles and dilated venous collaterals were found to be particularly characteristic of CRAO, which generally causes very severe optic disc pallor [32]. Arteriolar attenuation is also very prominent in certain retinal diseases such as retinitis pigmentosa [55].

Acquired optociliary shunt veins are connections between the retinal and choroidal venous circulations that enlarge and can be seen in the setting of chronic impairment of retinal venous outflow (spheno-orbital meningioma [2, 56], optic nerve sheath meningioma, optic nerve glioma [10], granulomatous optic neuropathy [11], and following CRVO) (Fig. 13.7). In these cases, fluorescein angiography can demonstrate that blood in the central retinal vein is diverted into peripapillary choroidal channels [56]. Shunt vessels are diagnostically helpful when present but uncommon, e.g., occurring in 1 out of 30 cases of compressive optic neuropathy in one study [32].
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Fig. 13.7

Optociliary shunt vessels on the right optic disc of a patient with an optic nerve sheath meningioma. T1 post-contrast fat-saturated MRI showing optic nerve sheath thickening and contrast enhancement

In LHON, some vascular tortuosity may persist in the chronic phase, even though the more specific acute findings of disc hyperemia, telangiectasias and swelling of the peripapillary RNFL will no longer be present. In some cases of NAION, segmental hyperemic “luxury perfusion” of the optic disc can also persist for several weeks or months, coexisting with pallor of the remainder of the disc, and in extreme cases this can take on the appearance of a pseudohemangioma [57, 58]. These lesions characteristically affect the segment of the optic disc least affected by ischemia and corresponding to spared visual field [58] (Fig. 13.4). They disappear over time.

General Ophthalmic Exam

A complete ophthalmic exam should be always be performed. The eyes should be examined for clues to an orbital etiology, including proptosis, chemosis, injection and restrictions of ocular motility. Thyroid ophthalmopathy can cause unilateral or bilateral optic nerve compression, and is suggested by the presence of lid retraction and scleral show, lid lag, resistance to retropulsion, and erythema over the insertions of the extraocular muscles. Other findings can include stigmata of neurofibromatosis including café-au-lait spots, axillary freckling, neurofibromas, Lisch nodules of the iris, and Yasunari choroidal nodules visible on infrared fundus photographies. These findings in a patient with optic atrophy would raise the suspicion of an optic pathway glioma [10]. Intraocular pressure should be recorded, especially if the disc appears cupped, but it should be borne in mind that intraocular pressure alone does not necessarily distinguish glaucoma from other causes of optic atrophy, as in population-based surveys 25 to 50% of individuals with glaucomatous optic disc damage have normal intraocular pressures [37].

Sometimes additional ophthalmoscopic features of the optic disc and peripapillary retina can provide helpful cues. A grey temporal crescent has been described in DOA [17]. Optic disc drusen (hyaline bodies) can occur as sequelae of prior papilledema or papillitis [32]. The ophthalmic exam should also search for evidence of prior chorioretinitis or pigmentary degeneration of the retina [6]. In optic atrophy associated with retinal disease, the disc has been described as having a yellow waxy appearance with extreme attenuation of the retinal vessels in advanced cases [1, 12, 32]. The presence of subtle or overt pigmentary retinopathy may be a diagnostic clue towards a mitochondrial disorder [17].

In unilateral optic atrophy, some clues may come from examining the other eye. In NAION, the uninvolved eye frequently has a crowded appearance with a small cup-to-disc ratio, the so-called “disc at risk” [9, 59]. Ipsilateral optic atrophy and contralateral papilledema, often associated with anosmia, constitutes the Foster Kennedy syndrome, usually caused by olfactory groove meningiomas or other compressive frontal lobe lesions [2, 60] (Fig. 13.8). However, this is now much less common than the “pseudo-Foster Kennedy sign” due to optic atrophy on one side and optic nerve head edema on the other side caused mostly by sequential NAION [2].
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Fig. 13.8

Foster-Kennedy syndrome. OD: the optic disc is pink and edematous; OS: the optic disc is minimally swollen and atrophic. MRI FLAIR sequence shows a large astrocytoma centered in the left inferior frontal lobe

Neurologic Examination

The optic chiasm lies in close proximity to the superior orbital fissures and cavernous sinuses, thus special attention should be paid to the function of cranial nerves III, IV, VI, V1 and V2. Nystagmus occurs in some patients with anterior pathway gliomas that involve the chiasm, and can be vertical, horizontal, seesaw or rotatory [10, 61].

A more extensive neurologic exam should be performed if additional neurologic symptoms are elicited by the history. There may be evidence of myelopathy in multiple sclerosis or NMO. In vitamin B12 deficiency, a characteristic pattern of myeloneuropathy is seen, with long-tract signs affecting the dorsal columns and corticospinal tracts (subacute combined degeneration of the cord). However, vision loss often precedes neurologic signs [22]. An essentially identical neurologic presentation can occur in copper deficiency. In some patients with “LHON plus” or “DOA plus” syndromes, there may be additional neurologic findings such as dystonia, spasticity, external ophthalmoplegia, ptosis, myopathy or neuropathy [17]. Neurologic deficits may also be found in individuals that have optic atrophy as a component of a more generalized neurogenetic disorder.

Ophthalmic Imaging

Optical coherence tomography (OCT) uses interference patterns of reflected light in a manner analogous to ultrasound waves. It was introduced in 1991 as a technique to analyze layers of the retina, and commercially available OCT machines have now become widely available in ophthalmology practice. OCT analysis of the optic nerve was initially focused on an assessment of the RNFL. Some OCT algorithms can also measure the disc area and rim area, aiding in the assessment of optic disc cupping. Since the RNFL originates in the ganglion cell layer in the retina, and accounts for up to 40% of the thickness in the macular area, assessments of macular volume and thickness have also been found useful in the assessment of optic nerve atrophy [62].

While its contribution to the diagnostic evaluation is probably limited when optic atrophy is clearly established, OCT is certainly useful to confirm a clinical impression of optic atrophy in questionable or borderline cases or if the clinical exam is difficult. RNFL loss by OCT has been documented in most optic neuropathies, including compressive, traumatic, LHON, ION and after optic neuritis. Even more specifically, algorithms have been developed that can measure the macular ganglion cell-inner plexiform layer (GCL-IPL). Thinning of the macular GCL-IPL has been found to be strongly correlated with RNFL loss and loss of visual function in a variety of optic neuropathies, including glaucoma, optic neuritis, ION, toxic optic neuropathy, idiopathic intracranial hypertension and optic nerve glioma [63] (Fig. 13.9).
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Fig. 13.9

Vitamin B12 deficiency: Subtle temporal pallor in both eyes. OCT of RNFL normal; OCT of retinal GCC confirms bilateral thinning

If segmental pallor or RNFL thinning is clinically evident, OCT will mainly substantiate that clinical impression. However, in certain situations the pattern of atrophy is more apparent on OCT than clinically. For instance, band atrophy of the optic disc and RNFL caused by chiasmal compression can be difficult to assess by fundoscopy but is often clearly revealed by OCT , which can show a significant difference in the reduction between the horizontal and vertical RNFL measurements [35, 61, 64], and significant decrease in the thickness of the nasal macula and GCL-IPL [62].

RNFL thinning is correlated with loss of visual performance after optic neuritis and NAION [65, 66]. It can also be very helpful in quantitatively following RNFL and GCL-IPL thickness over time.

RNFL analysis by OCT can be particularly useful in the assessment of the cupped optic disc. The temporal sector of the RNFL, corresponding to the papillomacular bundle, has been found to be highly abnormal in DOA and other forms of non-glaucomatous optic nerve cupping, whereas it is relatively spared in glaucoma [67, 68], which typically leads to RNFL loss in the superior and inferior quadrants. Eyes with non-glaucomatous cupping also had lower macular volume and lower average macular thickness in the superior, nasal and inferior outer macular ring [68]. Given that hereditary optic neuropathies frequently mimic glaucoma, the use of OCT may be particularly helpful in distinguishing these entities, particularly when visual field testing and clinical examination are not definitive, or when progressive cupping occurs despite adequate control of intraocular pressure [46, 68].

Despite its advantages, OCT introduces additional potential artifacts and errors of interpretation [63]. Segmentation of the macula and GCL-IPL measurement is especially complex and prone to misinterpretation in eyes with pathology, such as age-related macular degeneration or optic disc edema [63]. RNFL analysis can be confounded by wrongly entered age of the patient, poor signal strength, inaccurate segmentation of the retinal layers, short or long axial eye length, cyclotorsion, peripapillary atrophy, ocular diseases that cause increased RNFL thickness, and interindividual differences in RNFL thickness and spatial distribution [63]. Familiarity with these potential confounders is necessary when OCT analysis is integrated into clinical practice.

Neuroradiology

MRI of the brain and orbits with and without gadolinium contrast is an appropriate study in essentially all cases of unexplained optic atrophy, especially if it is unilateral or significantly asymmetric between the eyes [6]. Lee et al. in a retrospective review found that in the workup of optic atrophy, neuroimaging had a much higher yield than other diagnostic studies, revealing optic nerve compression in 20% of cases of isolated optic atrophy [6]. Dedicated orbit sequences should be requested to rule out intraorbital masses or orbital soft tissue or extraocular muscle swelling (e.g., in thyroid eye disease or orbital pseudotumor) [69]. Neuroimaging is also particularly pertinent when there is evidence of chiasmal or postchiasmal compression, such as band atrophy or visual field deficits that respect the vertical meridian. In many cases imaging findings of mass lesions can be so characteristic that a biopsy can be avoided entirely, for instance in many pituitary tumors, sphenoid wing meningiomas, primary optic nerve sheath meningioma or gliomas of the anterior visual pathways [10, 24, 61]. In addition, MRI may provide evidence for embolic stroke in the workup of CRAO, or for demyelinating disease in the workup of optic neuritis [70]. Not uncommonly, patients come to a neuro-ophthalmologist after already having some neuro-imaging performed that may have been interpreted as normal. In those cases, it is imperative to ensure that the appropriate sequences were done, and it is often helpful to review the images in person with a neuroradiologist.

Although MRI is generally the preferred modality for almost all intracranial processes, CT can be superior in delineating the bony anatomy, e.g., in cases of facial trauma or skeletal abnormalities causing compression of the optic nerve at the optic foramen (e.g., osteopetrosis or osteitis deformans). Extraocular muscle enlargement is well seen on orbital CT. CT can also show calcifications well, e.g., in meningiomas. Primary optic nerve sheath meningiomas in particular can have a characteristic “tramtrack” calcification along the optic nerve [7]. Orbital ultrasound has a limited role in the evaluation of optic atrophy, although it can occasionally show optic gliomas well [10].

Traditional MRI sequences can be impeded by high signal from orbital fat. Fat-suppressed sequences and short tau inversion recovery (STIR) sequences improve the quality of orbital imaging [69]. The caliber of the optic nerves is diminished in most cases of optic atrophy, but this is entirely nonspecific. The nerve may be enlarged in intrinsic optic nerve tumors or in infiltrative conditions such as granulomatous optic neuropathy. High T2 signal in the optic nerves is also nonspecific, and usually does not allow distinction between acute inflammation, demyelination, edema and chronic gliosis, although it has not been reported in glaucoma [30, 69]. The addition of contrast can be helpful in delineating masses and their relationship to the optic nerve. Contrast can also reveal areas of blood-brain barrier breakdown due to inflammation, although this may be absent once optic atrophy has occurred. A notable exception to this is sarcoidosis, which can cause either intrinsic contrast enhancement and thickening of the optic nerves or chiasm or meningeal contrast enhancement, which may be generalized, nodular or surrounding the optic nerve (i.e., optic perineuritis).

Vascular sequences can be helpful in delineating the relationship between the optic nerves and the intracranial internal carotid arteries. In ectatic carotid arteries, there may be flattening or deformation of the optic nerve or gyrus rectus [69].

The question of appropriateness of neuroimaging is often raised when patients present with glaucomatous-appearing optic disc cupping and visual field defects but normal intraocular pressure, i.e., normal tension glaucoma (NTG). Several studies have addressed the question whether all patients with NTG should have neuro-imaging and have arrived at the conclusion that the incidence of significant intracranial disease is quite low, although diffuse small vessel ischemic changes occur more commonly in patients with glaucoma, a finding that likely reflects shared vascular risk factors [48]. It has been recommended that the following features should lead to consideration of neuroimaging for disc cupping: age younger than 50, headache or other cranial pain, symptoms of hypothalamic-pituitary dysfunction, visual acuity worse than 20/40, asymmetrical loss of color vision, an afferent pupillary defect, pallor out of proportion to cupping, or a mismatch between the cupping and the visual field loss (especially if the visual field loss has a “neurologic” pattern, e.g., respecting the vertical meridian) [25, 40, 48].

Laboratory Evaluation

Indiscriminate laboratory screening of patients with optic atrophy is likely of low yield, and testing should be guided by the history and physical exam. This was demonstrated by Lee et al. in a retrospective chart review of cases of optic atrophy, where laboratory evaluation was unrevealing for cases where an underlying diagnosis was not suggested by specific historical features or examination findings [6].

A history of optic neuritis that is not clearly associated with imaging evidence of typical demyelinating disease should prompt testing for neuromyelitis optica (NMO, also known as Devic’s disease) with serum aquaporin 4 antibodies, especially if the optic neuritis was severe, bilateral, or associated with significant lasting vision loss. There may additionally be a history of attacks of longitudinally extensive transverse myelitis, unexplained vomiting or hiccupping (area postrema syndrome), narcolepsy, or attacks targeting the brainstem, diencephalon or cerebral cortex [19]. The identification of NMO is of critical importance, as immunomodulation can very effectively calm disease activity, whereas untreated patients remain at risk of further attacks, and disability in this disorder accrues during the relapses only. The aquaporin 4 antibody is believed to be pathogenic in NMO and is highly specific to this disease [71]. Unfortunately, even with newer-generation tests the sensitivity remains imperfect [72], so repeat testing of the serum or testing for CSF aquaporin 4 antibodies may be necessary if the suspicion remains high after a negative result, although a diagnosis of seronegative NMO can also be made based on clinical criteria [73].

Optic neuritis similar to NMO can rarely occur in other autoimmune disorders, especially systemic lupus erythematosus and Sjogren’s syndrome, and these conditions can also cause transverse myelitis. These can be screened for with an antinuclear antibody (ANA) and Sjogren’s serologies (SSA/Ro and SSB/La). If the ANA is positive, more extensive immunological workup may be required.

Anti-MOG (myelin oligodendrocyte glycoprotein) antibodies have been recently found in some patients with atypical optic neuritis and are believed to be probably pathogenic [74]. Acutely, anti-MOG-associated optic neuritis is more likely to be a bilateral, longitudinally extensive involvement of the anterior optic nerves, with severe optic nerve head swelling but less retinal neuronal loss than aquaporin 4-antibody-associated disease [75]. Anti-MOG-positive patients respond rapidly to steroids and plasma change, but have a tendency to relapse rapidly on steroid withdrawal [74]. Cell-based anti-MOG assays are recommended, but are not yet widely available. Similar to aquaporin-4 antibodies, anti-MOG antibodies are present at higher concentrations in the serum than in the CSF, consistent with peripheral production of antibodies [74].

In otherwise unexplained optic neuropathy and in at-risk populations, infection with either syphilis, Lyme or tuberculosis should be considered, and can be ruled out with appropriate testing. Optic atrophy, and in fact any ocular syphilis, is considered neurosyphilis, and requires testing CSF in addition to serology. Serological testing for syphilis traditionally involves a nontreponemal test followed by a treponemal test, but some labs have adopted the reverse sequence of testing; local guidelines should be followed. The diagnosis of neurosyphilis is based on a CSF WBC count of 20 cells/mL or greater, reactive CSF VDRL, or positive CSF intrathecal Treponema pallidum antibody index [76]. Lyme testing involves a two-step process of initial ELISA testing followed by Western blot. Although Lyme testing can be negative during the time of the bull’s eye skin rash (erythema migrans), the sensitivity and specificity approach 100% by the time neurologic complications develop.

Thyroid function tests and autoimmune thyroid labs (thyroid stimulating immunoglobulin, thyroid binding inhibitory immunoglobulin, anti-thyroid peroxidase antibodies, thyroglobulin antibodies) would be appropriate if there are signs of thyroid eye disease, such as proptosis, lid lag or retraction, or restrictive strabismus.

Sarcoidosis can occasionally cause an isolated optic neuropathy or chiasmopathy [11]. It remains a clinicopathologic diagnosis that should not be made without tissue analysis. Unfortunately, serum and CSF ACE and lysozyme levels have poor sensitivity and specificity, particularly for isolated neurosarcoidosis. A chest CT may reveal hilar adenopathy or interstitial lung disease, but greater sensitivity can be achieved with PET-CT of the body (from the skull base to the thighs), which can reveal otherwise unsuspected biopsy targets. Body PET-CT is also the appropriate study to screen for malignancy if an infiltrative neoplastic or paraneoplastic optic neuropathy is suspected.

Paraneoplastic optic neuropathy (PON) is a very rare cause of vision loss with anti-collapsin response mediating protein-5 (CRMP-5) being the most commonly identified cause [77]. PON is usually part of a multifocal neurological syndrome. The most common associated malignancy is small cell lung cancer. Chest and abdominal CT can be performed if PON is suspected. Given the rarity of PON, the diagnosis is generally only considered after the malignancy has been identified. If a paraneoplastic disorder is suspected, testing for antineuronal antibodies in serum and CSF should be done. Given the overlap in clinical presentations between different paraneoplastic antibody syndromes, this should be done as part of a paraneoplastic panel.

A toxic or metabolic cause of neuropathy should be sought especially if there is relatively symmetric reduced central vision gradually progressive over weeks to month, marked dyschromatopsia, and bilateral central or cecocentral scotomas (or sometimes marked constriction of the visual fields). Addressing the nutritional deficiency, metabolic derangement or toxic exposure can be associated with some degree of visual recovery [2]. Vitamin B12 deficiency in particular causes optic neuropathy. It also causes macrocytic anemia, but the vision loss often precedes hematologic changes [22]. When the B12 level itself is in a borderline range, levels of methylmalonic acid or homocysteine should also be assessed, which when elevated suggest functional B12 deficiency. A nearly identical picture of optic neuropathy with or without myeloneuropathy can be caused by copper deficiency, particularly after gastric bypass surgery or with excessive zinc exposure, e.g., due to denture paste or abuse of over-the-counter zinc supplements. Reported cases have low serum copper, but even more sensitive is measurement of 24-h copper excretion. Screening for heavy metal toxicity is likely of very low yield in the absence of a history of particular toxic exposure [6].

A lumbar puncture should probably not be part of the routine workup of optic atrophy, but may be appropriate in select cases when the neuroimaging is negative but an inflammatory etiology is suspected. Fluid should be sent for basic studies such as protein, glucose, cell counts and oligoclonal bands as well as relevant infectious labs and cultures [78]. CSF cytology and flow cytometry are indicated if carcinomatous meningitis is possible, keeping in mind that in the workup of carcinomatous meningitis the yield of a single lumbar puncture is moderate at best, and two or even three punctures may be required. In mitochondrial disease, there may be elevated protein and lactate levels [17].

Genetic Testing

Genetic testing is appropriate when the clinical picture suggests either LHON or DOA. The former would be supported by maternal family history of vision loss, sequential or simultaneous, sudden or rapidly progressive and ultimately severe vision loss, with central or cecocentral scotomas, relative preservation of pupil responses and a characteristic fundus appearance in the acute phase. The latter is typically characterized by a family history of poor vision or vision loss, an early onset of insidiously progressive bilateral vision loss of variable severity, as well as central or cecocentral scotomas, cupping and temporal pallor or pallor of the remaining neuroretinal rim [30]. Prior to genetic testing, patients should be counseled regarding the implications for themselves and their kin.

Molecular genetic testing of blood for LHON should first screen for one of the three primary mtDNA mutations (m11778G > A, m3460G > A, m14484T > C) as these account for the vast majority of cases [15, 17]. If these are negative, testing for additional rare genetic variants can be performed.

The most common mutation causing DOA is in the OPA 1 gene [15, 79]. Ideally, blood should be collected from the proband and relatives. If a mutation is identified, its segregation in the family should be analyzed and its identity compared to a genetic database to establish whether the mutation is already recognized as pathogenic [80]. Targeted analysis for the c.2826delT pathogenic variant can be performed first in individuals of Danish ancestry due to a founder effect [81]. New mutations should be further analyzed via in silico modeling and via expression testing [80]. If no mutation in OPA1 is found, deletion testing of the OPA1 gene should be performed.

If genetic testing for the most common genetic changes is negative, consideration should be given to performing additional genetic screening by testing a panel of genes known to be associated with optic atrophy rather than performing sequential testing of individual genes [82]. Panel testing can be done using selective exon capture for all coding/genomic regions of interest, followed by next generation sequencing and a bioinformatic analysis [82]. More comprehensive genomic testing such as exome sequencing, genome sequencing and sequencing of the entire mitochondrial genome is now commercially available but may reveal multiple abnormalities that may or may not be relevant, and often require expert interpretation [17, 81].

Summary

Optic atrophy is a common clinical problem in neuro-ophthalmology. It represents the final common pathologic result of a multitude of different insults to the ganglion cells in the retina or their axons in the optic nerve, optic chiasm or optic tracts, or rarely transsynaptic degeneration. However, a careful neuro-ophthalmic history and exam can often establish an etiology or at least substantially narrow the differential diagnosis and guide further workup. Discovering the etiology of optic atrophy is important, and may occasionally allow halting or even reversing visual loss.

The key task is to determine whether the patient with optic atrophy, unilateral or bilateral, is stable or whether there is ongoing destruction of ganglion cells. A general ophthalmic exam and at least a focused neurologic exam should always be performed. The optic disc should be assessed in terms of severity and distribution of pallor and the presence or absence of cupping, and examination of the RNFL and retinal vasculature add important information to the examination of the optic nerve. OCT analysis can substantially refine the clinical impression, and in addition may allow quantitative analysis over time.

In the asymptomatic patient, the history should establish the presence of remote trauma or meningitis, major risk factors for neonatal ischemia, or exposure to medications potentially toxic for the optic nerves. Optic neuritis can be unnoticed, especially in children. It is less common but possible for anterior ischemic optic neuropathy (AION) to go unnoticed. MRI should be performed in most cases to rule out either compression or infiltration of the visual pathways, and can also reveal lesions due to prior episodes of inflammation or demyelination. In most cases, there is little reason to perform other specific tests in this situation.

In the symptomatic patient with optic atrophy, a much more extensive personal history should be obtained, which should include medications, substance use (especially tobacco and alcohol), dietary history, and potentially directed questioning regarding sexual habits and a history of prior infectious disorders such as syphilis, Lyme or tuberculosis. OCT has become an important adjunct to the clinical exam, and is especially helpful in mild or borderline cases. Of all diagnostic studies, neuroimaging (typically MRI) with contrast has by far the highest yield, and should be considered mandatory to rule out compressive/infiltrative/inflammatory disorders. Further testing should be performed in a directed fashion, guided by clues obtained in the history and neuro-ophthalmic exam.