History
Toxic and nutritional optic neuropathies resemble each other in terms of their clinical presentation in that their presentation is simultaneously bilateral but may vary in congruence. When a patient is suspected of having an optic neuropathy, a thorough history is invaluable and should cover diet (eg, how much and what the patient eats); drug/toxin exposure (eg, heavy metals, fumes, solvents); social history (eg, fixed income, amount of money left to buy food after tobacco and alcohol), including tobacco and alcohol use; and occupational background, with details on whether similar cases exist among coworkers. A history of prior treatment of any chronic disease such as pernicious anemia should always be elucidated.
A family history should be taken. Persons with alcoholism are not always forthcoming with their drinking habits; therefore, obtaining this information, along with dietary details, from friends or relatives may be more reliable. A review of systems should include inquiries about sensory symptoms in the extremities and about gait disturbances because these might reflect a nutritional or toxic peripheral neuropathy and/or a related toxic cerebellar degeneration.
Dimness of vision is the outstanding symptom. Patients gradually become aware of a blur in the center of their reading vision, which continues to slowly progress. This insidious onset often delays early detection, which, in turn, leads to delayed treatment as well. Initially, only one eye may be involved, but the cloud will eventually appear in both eyes, causing the vision to decline. If the visual loss is purely unilateral or if a significant difference in the visual acuity is present between the 2 eyes, other diagnoses should be considered. Some patients may notice that certain colors look faded, or they may experience a general loss of color perception. Dyschromatopsia can be the initial symptom in toxic/nutritional optic neuropathies. Neither of these conditions has orbital pain or pain on ocular movement as one of its symptoms, as opposed to inflammatory of optic neuropathy. For such cases, other diagnoses should be considered in the evaluation of optic neuropathy.
For toxic optic neuropathies, the visual loss may be acute as well as chronic, depending on the insult. Ascertaining whether the onset of the visual symptoms was during or very shortly after exposure to a particular toxin is important. Establishing similar illnesses in coworkers or others exposed to the same drug or chemical also may be helpful.
Ethambutol
The antituberculous drug ethambutol is commonly associated with toxic optic neuropathy (not optic neuritis). This is the drug's most serious adverse effect. The optic neuropathy that occurs is dose dependent and duration related. The chelating properties of ethambutol have been hypothesized to contribute to its neurotoxicity, causing calcium flux into the mitochondria.
Loss of vision does not tend to occur until the patient has been on the drug for at least 2 months, but there are rare reports of early onset of severe, bilateral visual loss even with appropriate dosing of the drug. [1] Symptoms generally appear between 4 months to a year. This onset may be sooner if the patient has concurrent renal disease because this will result in reduced excretion of the drug and, therefore, elevated serum levels. Therefore, proper dosing in patients with renal impairment is critical.
The toxicity that can occur to the anterior visual pathway from this drug is dose related; patients who are receiving dosages of 25 mg/kg/d or greater are most susceptible to vision loss. However, cases of vision loss with even much lower doses have been reported.
The clinical presentation is similar to other toxic optic neuropathies, including dyschromatopsia. Some investigators have reported that patients have, in particular, a red-green dyschromatopsia, but others have found predominantly a blue-yellow one. Therefore, appropriate color vision testing is of particular importance in screening patients on this drug.
Isoniazid
Isoniazid, another antitubercular drug, also can produce toxic optic neuropathy, and patients with concurrent hepatic or renal disease are at higher risk. As with other toxic optic neuropathies, patients present clinically with vision loss, central or cecocentral scotomas, and acquired dyschromatopsias. The color vision deficit tends to be less than that of ethambutol. [2] The drug dosages vary from 200-900 mg/d.
Amiodarone
Amiodarone, a drug very useful in the treatment of life-threatening cardiac arrhythmias, has been implicated as a cause of optic neuropathy, although firm proof of this is still lacking. [3] The mechanism of the neurotoxicity that occurs from the antiarrhythmic amiodarone remains unclear. It is believed that it may relate to a lipidosis that is induced by the drug, which has been supported by histopathologic studies of the optic nerve in these patients.
The most common ocular adverse effect of amiodarone, found in almost all patients on long-term therapy, is a reversible verticillate keratopathy, also called vortex keratopathy. The corneal changes very rarely have any visual significance. [3] Although the optic neuropathy is typically bilateral and symmetric with visual loss and/or field loss, it also may present unilaterally. With this drug, the toxicity to the optic nerve also appears to be dose related, with dosage varying from 200-1200 mg/d. Visual complaints may start 1-72 months after the initiation of treatment and are slowly progressive; the onset of visual loss may also be acute in nature.
The optic neuropathy from amiodarone, as discussed in this article, should not be confused with acute nonarteritic ischemic optic neuropathy – like picture (NAION). Patients with cardiovascular disease being treated with amiodarone and presenting with optic neuropathy may have either drug toxicity or NAION. In amiodarone-induced optic neuropathy, the onset of visual loss is much more insidious and the degree of visual loss is usually less. Bilateral ocular involvement within a short period is common in amiodarone-induced optic neuropathy, while NAION rarely occurs simultaneously in both eyes. Because of the very long half-life of amiodarone, optic nerve edema persists for months, while with NAION, optic disc swelling resolves within weeks.
Tamoxifen
Tamoxifen (Nolvadex), used for both prevention and treatment of breast cancer, has been implicated in the etiology of toxic optic neuropathy, even at low dosage.
Isotretinoin
Isotretinoin (Accutane), used in the treatment of severe acne vulgaris, has been described as rarely causing toxic optic neuropathy, presenting as decreased night vision and loss of color vision.
Other drugs
Other drugs that have been implicated in the toxic optic neuropathies include chloramphenicol, sulfonamides, linezolid, chloroquine, quinine, streptomycin, digitalis, vincristine, and methotrexate.
Other causes
In the workplace, industrial locations, and related to intentional or accidental poisonings, optic nerve toxicity has been reported to result from methanol, ethylene glycol (antifreeze), lead, mercury, thallium, and carbon monoxide.
The most common cause of blindness due to alcohol consumption is the ingestion of methanol, rather than ethyl alcohol. Methanol, otherwise known as methyl alcohol or wood alcohol, can damage the optic nerve and cause death. Historically, methanol was frequently used in the production of "moonshine" during Prohibition, causing countless cases of blindness due to toxic optic neuropathy. As little as 4 mL of methanol has been known to cause blindness.
Physical
In toxic/nutritional optic neuropathy, visual acuity may vary from minimal reduction to no light perception (NLP) in rare cases. Most patients have 20/200 vision or better.
When pupils are assessed, one would not expect to find a relative afferent pupillary defect because the optic neuropathy is virtually always bilateral and symmetric. In most patients, the pupils are bilaterally sluggish to light.
Color vision should be assessed because dyschromatopsia is a constant feature in these conditions.
In nutritional optic neuropathies, the optic disc may be normal or slightly hyperemic in the early stages. In a small group of patients with hyperemic discs, one could find small splinter hemorrhages on or off the disc. Several months to years later in the course of the disease, one might find papillomacular bundle dropout and temporal disc pallor, followed by optic atrophy.
In the early stages of toxic optic neuropathies, most patients also have normal-appearing optic nerves, but disc edema and hyperemia may be seen in some intoxications, especially in acute poisonings. Papillomacular bundle loss and optic atrophy develop after a variable interval depending on the responsible toxin.
In ethambutol toxicity, clinically fundi remain normal initially, thereby rendering early detection challenging. Visible atrophy develops later if the drug is not discontinued.
With isoniazid toxicity, optic nerve swelling has been reported.
Patients on amiodarone typically present with bilateral optic disc swelling, which can be quite marked, along with flame-shaped hemorrhages. However, unilateral presentations of optic neuropathy have also been reported. The impact on vision associated with the optic neuropathy can be nonexistent, mild, [4, 5] or severe. [6]
Causes
Well-documented causes of nutritional optic neuropathy include tobacco, ethanol, thiamine deficiency, and vitamin B-12 deficiency. [7, 8]
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Causes of toxic optic neuropathy include chemicals and drugs, such as methanol, ethylene glycol, ethambutol, isoniazid, digitalis, cimetidine, vincristine, cyclosporine, toluene, sildenafil, and amiodarone. [9]
