Toxic/Nutritional Optic Neuropathy

Updated: Feb 21, 2023
Author: Andrew A Dahl, MD, FACS; Chief Editor: Hampton Roy, Sr, MD 



The anterior visual pathway is susceptible to damage from toxins or nutritional deficiency. These disorders tend to be classified under the heading toxic/nutritional optic neuropathy, a syndrome characterized by papillomacular bundle damage within the optic nerves, central or cecocentral scotoma, and reduction of color vision. Both toxicity and malnutrition, acting either independently or together, have been implicated in the pathogenesis of these disorders. Although these problems have been classified as optic neuropathies, in most of these entities, the primary lesion has not actually been localized to the optic nerve and may possibly originate in the retinal ganglion cells or nerve fiber layers, chiasm, or even the optic tracts.


The exact mechanism by which nutritional deficits damage the optic nerve has not been elucidated. Although the etiology is likely multifactorial, most clinicians agree that in patients who abuse ethanol and tobacco, malnourishment often is present, and undernutrition, rather than direct toxicity, is the principal cause of the visual loss. Specific deficiencies of vitamin B-12 (cyanocobalamin), thiamine (vitamin B-1), other B-complex vitamins (riboflavin, niacin, and pyridoxine), and folic acid, as well as reduced systemic levels of other proteins with sulfur-containing amino acids, may play a role.

Whether tobacco or ethanol has a direct toxic effect on the optic nerve remains unclear. Why certain other agents are toxic to the optic nerve, particularly the portion that comprises the papillomacular bundle, also remains largely unestablished. Whether an unusual configuration of the vascular supply of the optic nerve head in certain individuals predisposes them to the accumulation of toxic agents has been questioned.

Ethyl alcohol, like tobacco, produces its toxic effects through metabolic means. Extended high-dosage exposure may lead to folate or vitamin B-12 deficiency, resulting in accumulation of formic acid, inhibiting the electron transport chain and mitochondrial function, ultimately resulting in impairment of adenosine triphosphate (ATP)–mediated axonal transport within nerves, including the optic nerve.

The toxin methyl alcohol (methanol) causes focal delamination of the optic nerve in animal experiments and in humans.

All of these deficiencies or toxicities affect mitochondrial oxidative phosphorylation. In essence, the toxic and nutritional optic neuropathies actually are acquired mitochondrial optic neuropathies, similar in clinical picture to congenital mitochondrial optic neuropathies.

It has been hypothesized that the chelating properties of ethambutol are what contribute to its neurotoxicity, but this has yet to be proven. The mechanism of the neurotoxicity that occurs from the cardiac antiarrhythmic amiodarone also remains unclear, with researchers believing that it may relate to lipid accumulation in optic nerve axons, with subsequent impedance of axoplasmic flow.



United States

Toxic and nutritional optic neuropathies are not common in the United States. In the general population, nutritional amblyopia is more common among tobacco and alcohol abusers and those who are undernourished. Toxic optic neuropathies usually are associated with exposure of employees in a workplace, ingestion of materials/foods containing toxic substances, or systemic medications.


Nutritional optic neuropathy is definitely more prevalent in regions of famine, such as in Africa, where it may take on epidemic proportions.


Morbidity of these disorders depends on risk factors, the underlying etiology, and the duration of symptoms before the institution of treatment. A patient with advanced optic atrophy is less likely to recover visual function than a patient who does not have such pathologic changes.


These disorders have no racial predilection. All races are susceptible.


These disorders are found equally in both males and females.


Any age may be affected by toxic optic neuropathies, but nutritional optic neuropathies are very rare in children, perhaps since drinking and smoking are much less frequent in this age group. Historically, toxic optic neuropathy was formerly seen in children with chronic pulmonary conditions, such as cystic fibrosis, when treated with chloramphenicol.


If patients with nutritional optic neuropathy are compliant with the treatment regimen, and unless the loss of vision is already far advanced, the prospect for recovery or at least improvement is excellent, except for the most chronic cases. However, the rate of recovery varies from a few weeks to several months. The prognosis is also better if treatment is initiated in the first few months after the onset of symptoms. Visual acuity tends to recover before color vision. When recovery has been complete, recurrences are unusual. Although extremely rare, cases of spontaneous improvement of vision have been reported without patient cooperation.

For toxic optic neuropathies, when the responsible toxin is discontinued, vision usually recovers to normal over several days to weeks. However, this does depend in large part on the nature of the offending agent and on its total exposure before it was removed.

Patient Education

Patients must be alerted to report any visual problems to their ophthalmologist immediately if they are taking ethambutol, isoniazid, or amiodarone.




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.


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, 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, 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 (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 (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.


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]


Well-documented causes of nutritional optic neuropathy include tobacco, ethanol, thiamine deficiency, and vitamin B-12 deficiency.[7, 8]

  • 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]






Laboratory Studies

In any patient with bilateral central scotomas, serum B-12 (pernicious anemia) and red cell folate levels (marker of general nutritional status) need to be obtained. Other tests that could support the diagnosis of nutritional optic neuropathy are direct or indirect vitamin assays, serum protein concentrations, and antioxidant levels. Serologic testing for syphilis also should be completed.

Patients suspected of having a toxic optic neuropathy should have a CBC count, blood chemistries, urinalysis, and a serum lead level, particularly in those who have a coexisting peripheral neuropathy. The blood and urine also may be screened for other toxins if exposure to a particular one is not identified on history. On the other hand, if a specific intoxicant is suspected, one would try to identify it or its metabolites in the patient's tissues or fluids.

Imaging Studies

Although imaging studies yield normal results in toxic/nutritional optic neuropathy, they almost always are indicated, unless one is absolutely certain of the diagnosis. The most appropriate imaging study is an MRI of the optic nerves and chiasm with and without gadolinium enhancement.[10]

Other Tests

Formal visual field evaluation

Formal visual field evaluation, whether it is a static (Humphrey) or kinetic (Goldmann) field, is absolutely essential in the evaluation of any patient suspected of having toxic/nutritional optic neuropathy.

Central or cecocentral scotomata with preservation of the peripheral field are characteristic visual field defects of these optic neuropathies and are actually most prevalent in patients with these disorders. Rarely, patients may present with other defects, as mentioned below. Although the field defects do tend to be relatively symmetric, early on in a patient's presentation, the defect is usually more developed in one field than in the other field. Soft margins are another characteristic of these defects, which are easier to define/plot for colored targets, such as red, than for white stimuli. The anatomic basis of the cecocentral scotoma has yet to be established.

In ethambutol toxicity, central scotomas are the common visual field defect, but bitemporal defects[1] and peripheral field constriction have been reported. The field defect in amiodarone toxicity may be simply a generalized constriction of fields or cecocentral scotomas.

Optical coherence tomography

Optical coherence tomography (OCT), which is now commonly used to measure nerve fiber layer thickness in patients with glaucoma, can also be used to quantify such changes in patients with other optic neuropathies, like the one caused by ethambutol.[11, 12] As discussed above, early changes are not clinically apparent in patients on ethambutol. With OCT, one can clearly quantify the loss of retinal nerve fibers from the optic nerves of these patients as a sign of early toxicity from the drug, which might not yet be apparent on funduscopy. Therefore, in conjunction with visual field testing, it is an additional objective test available to monitor patients on ethambutol.



Medical Care

Based on the literature, one standard treatment for patients who have nutritional optic neuropathy is not apparent, as various authors have had success with a variety of regimens.

Improved nutrition clearly is the key, as dietary deficiency is the common denominator in these patients. A well-balanced diet, which is high in protein, also should be supplemented with B-complex vitamins. Others believe that thiamine may contribute to recovery, even in patients who continue to abuse alcohol or tobacco.

Injections of hydroxycobalamin have been successful in treating patients with tobacco amblyopia, even when smoking continues.

It cannot be overemphasized to patients that stopping, or at least reducing, their smoking or consumption of alcohol is critical to their recovery. The latter, combined with an improved diet (green leafy vegetables and fruit daily) and vitamin supplementation, are the mainstay of therapy in nutritional optic neuropathy. Therefore, specific therapy includes thiamine 100 mg PO bid, folate 1 mg PO qd, a multivitamin tablet daily, and the elimination of any causative agent (eg, tobacco, alcohol).

Vitamin B-12 injections are reserved for patients with pernicious anemia. If pronounced nerve fiber layer dropout is present, treatment is futile.

Toxic optic neuropathies

For cases of toxic optic neuropathies, the treatment is more definitive; the goal is to identify and remove the offending substance.

Other than stopping the causative drug or substance, no specific treatment is available for the optic neuropathy caused by ethambutol. Once this is accomplished, most patients will recover, and this may take weeks to months. However, there are reports that vision may still decline or fail to recover even when the drug is stopped[13] if damage is severe enough.

For isoniazid, vision also improves when administration of the drug is ceased. In some patients, the administration of pyridoxine has been used to help reverse the toxicity of isoniazid, but this improvement may be simply related to stopping it and not the pyridoxine. Because these drugs may be given concurrently in the treatment of tuberculosis, and both may produce a toxic optic neuropathy, physicians should remember that if stopping one does not result in the improvement of a patient's vision, then the other drug also should be stopped.

If an optic neuropathy is diagnosed in a patient taking both isoniazid and ethambutol, the latter drug should be discontinued first. If visual symptoms persist, then the isoniazid must also be discontinued.[2]

Prompt discontinuation of amiodarone (in consultation with the patient's cardiologist) is essential if compelling evidence exists of toxic optic neuropathy from the drug. The visual symptoms, along with the disk swelling, can improve[5] gradually over the next several months, rather than immediately. Conversely, visual loss or associated field defects reportedly can be permanent despite discontinuation of the drug,[14, 6] with the disc swelling progressing to optic nerve pallor. Of note, some patients have developed disc edema and subsequent optic neuropathy even after cessation of the drug.[5, 6]


When considering a nutritional optic neuropathy in a patient, especially elderly patients, one must always consider that folate or vitamin B-12 deficiencies may be responsible. In such cases, a hematologic consultation is warranted before treatment is undertaken, especially in the presence of a normal hematocrit.

A neurologist may be consulted to look for neurologic manifestations of nutritional deficiencies, neurological consequences of pernicious anemia, or toxicities from systemic medications and to determine whether further tests, such as cerebrospinal fluid studies, are indicated.

With respect to patients on amiodarone, it is strongly recommended to consult with the patient's cardiologist before discontinuing the drug. The ophthalmologist, in conjunction with the cardiologist, should determine whether the less established visual complications of the drug outweigh its highly proven cardiac clinical benefits.


See Medical Care.


No complications are associated with the aforementioned therapy. The only complication of not seeking or complying with therapy is profound bilateral visual loss but never total blindness.


Patients in whom ethambutol or isoniazid is indicated for tuberculosis need to have a baseline ophthalmologic examination before treatment is instituted and should be monitored by their ophthalmologist periodically as long as they are on the drug to detect any optic nerve toxicity as soon as possible. Patients should also be made aware of the potential ocular adverse effects of these drugs and should be encouraged to seek medical attention as soon as visual symptoms become apparent.

Any patient for whom amiodarone is being considered for treatment requires a baseline ophthalmic examination before the drug is initiated. Furthermore, once on the drug, patients should be evaluated at least every 6 months. Even if a patient presents with corneal changes associated with the drug, their decreased vision should never be attributed to this until any pathology of the optic nerve has been excluded.

Patients should seek assistance from their primary physician on methods to stop or reduce their smoking and/or alcohol intake.

Long-Term Monitoring

Patients with toxic/nutritional optic neuropathy should be observed initially every 4-6 weeks and then, depending on their recovery, every 6-12 months. At each visit, the patient's visual acuity, color vision, visual fields, pupils, and optic nerves should be assessed. Optical coherence tomography may be used to quantify nerve fiber layer or ganglion cell structure.



Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Vitamin supplements

Class Summary

Given to those patients who are deficient in a particular vitamin or those who are suspected of having a particular vitamin deficiency.

Folic acid (Folvite)

Important cofactor for enzymes used in production of red blood cells.

Thiamine (Thiamilate)

Essential coenzyme that combines with ATP to form thiamine pyrophosphate.