AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

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, 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 retina, chiasm, or even the optic tracts.

Pathophysiology

The exact mechanism(s) 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, undernutrition is the principal cause of the amblyopia. Others believe that specific deficiencies in vitamin B-12, thiamine, folic acid, proteins with sulfur-containing amino acids, or any combination of these also play a role. Whether tobacco or ethanol has a direct effect on the optic nerve remains unclear. Why certain agents are toxic to the optic nerve, particularly the portion that comprises the papillomacular bundle, also remains largely unestablished. Whether the unusual configuration of the vascular supply of the optic nerve head predisposes it to the accumulation of toxic agents has been questioned.

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 antiarrhythmic amiodarone remains unclear. Researchers believe that it may relate to a lipidosis that is induced by the drug.

Frequency

United States

Toxic and nutritional optic neuropathies are not common in this country. 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.

International

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

Mortality/Morbidity

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.

Race

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

Sex

These disorders are found equally in both males and females.

Age

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

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

Toxic and nutritional optic neuropathies resemble each other in terms of their clinical presentation and to most of the optic neuropathies that present simultaneously and bilaterally. When a patient is suspected of having an optic neuropathy, a thorough history is invaluable and should cover diet (eg, how much and what 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. Treatment of any chronic disease or illness should always be elucidated.

A family history also should be taken. Persons with alcoholism are not always forthcoming with their drinking habits; therefore, obtaining these details, along with diet details, from friends or relatives may be more reliable. Review of systems should inquire about sensory symptoms in the extremities and about gait disturbances because these might reflect a nutritional or toxic peripheral neuropathy and/or toxic effect upon the cerebellum.

• 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. Initially, only one eye may be involved, but eventually the cloud will appear in both eyes, causing the vision to decline. If the visual loss is 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 neuropathy. Neither of these conditions has pain as one of its symptoms. For such cases, other diagnoses should be considered.
• 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 is one drug that commonly is associated with toxic optic neuropathy. The optic neuropathy that occurs is dose dependent and duration related. Loss of vision does not tend to occur until the patient has been on the drug for at least 2 months, but 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. 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, even with much lower doses, have been reported.
  • The clinical presentation is similar to toxic optic neuropathies in general, 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, scotomas, and acquired dyschromatopsias. The drug dosages vary from 200-900 mg/d.
  • Amiodarone, a drug very useful in the treatment of life-threatening arrhythmias, has been implicated as a cause an optic neuropathy, although proof of this is still lacking. Its most common ocular side effect, found in more than two thirds of patients, is a reversible verticillate keratopathy. The corneal changes have absolutely no visual significance. 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 optic neuropathy from amiodarone, as discussed in this article, should not be confused with the acute nonarteritic ischemic optic neuropathy-like picture also reported with this drug.

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. However, 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, fundi remain normal initially; 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. If appropriate action is not taken, this may be complicated by permanent visual loss and bilateral optic atrophy.

Causes

• Causes of nutritional optic neuropathy include tobacco, ethanol, thiamine, and vitamin B-12.
• Causes of toxic optic neuropathy include chemicals and drugs, such as methanol, ethylene glycol, ethambutol, isoniazid, digitalis, cimetidine, vincristine, cyclosporine, toluene, and amiodarone.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Certain maculopathies/macular dystrophies
Dominantly inherited (Kjer) optic neuropathy
Mitochondrially inherited (Leber) optic neuropathy
Compressive or infiltrative lesion of optic chiasm
Bilateral inflammatory or demyelinative optic neuropathy
Syphilitic optic neuritis
Graves disease
Radiation optic neuropathy
Diabetic papillopathy
Nonphysiologic visual loss – Hysteria/malingering

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab 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, 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.

Other Tests

• 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 or peripheral field constriction have been reported. The field defect in amiodarone toxicity may be simply a generalized constriction of fields or cecocentral scotomas.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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 hydroxocobalamin 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 at this institution 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.
• For cases of toxic optic neuropathies, the treatment is more definitive; the goal is to identify and to remove the offending substance.
  • Other than stopping the drug, no specific treatment is available for the optic neuropathy caused by ethambutol. Once this is accomplished, recovery may take weeks to months. However, there are reports that vision may still decline or fail to recover even when the drug is stopped.
  • 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.
  • Prompt discontinuation of amiodarone is essential if evidence exists of toxic optic neuropathy from the drug. The visual symptoms, along with the disk swelling, will improve gradually over the next several months, rather than immediately. However, visual loss or associated field defects reportedly can be permanent despite discontinuation of the drug.

Consultations

• 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 or toxicities from systemic medications and to determine whether further tests, such as cerebrospinal fluid studies, are indicated.

Diet

See Medical Care.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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

Drug Category: Vitamin supplements

Given to those patients who are deficient in

a particular vitamin or those who are suspected of having a particular vitamin deficiency.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Outpatient Care

• Patients with nutritional/toxic 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.

In/Out Patient Meds

• See Medication.

Deterrence/Prevention

• Patients in whom ethambutol or isoniazid is indicated 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.
• Any patient for which 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.

Complications

• 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.

Prognosis

• 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.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• For both medical and legal reasons, physicians need to be aware of how toxins or nutritional deficiencies can be factors responsible for sporadic cases of visual loss. One should not assume that cecocentral scotomas are caused by toxic/nutritional optic neuropathy because there are many examples of bilateral cecocentral scotomas from compressive or infiltrative lesions of the optic chiasm. Therefore, even if one is very confident of the diagnosis of toxic/nutritional optic neuropathy, neuroimaging should be obtained.
• Physicians need to be aware of underlying litigating circumstances when it comes to the diagnosis of toxic optic neuropathy. Such issues include medical malpractice, workers' compensation, and product liability and recall. For these reasons, clinicians should have compelling evidence before establishing that a toxin is the cause of an optic neuropathy, although making the diagnosis could assist in preventing visual loss in other people (eg, coworkers) exposed to the same toxin.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Robert C Sergott, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

• Danesh-Meyer H, Kubis KC, Wolf MA. Chiasmopathy?. Surv Ophthalmol. Jan-Feb 2000;44(4):329-35. [Medline].
• Glaser JS. Nutritional and toxic optic neuropathies. In: Glaser JS, ed. Neuro-ophthalmology. 3rd ed. Philadelphia:. Lippincott;1999.
• Grant WM, Schuman JS. Toxicology of the Eye. 4th ed. Springfield, Ill:. Charles C Thomas Publisher;1993.
• Johnson LN, Krohel GB, Thomas ER. The clinical spectrum of amiodarone-associated optic neuropathy. J Natl Med Assoc. Nov 2004;96(11):1477-91. [Medline].
• Kerrison JB. Optic neuropathies caused by toxins and adverse drug reactions. Ophthalmol Clin North Am. Sep 2004;17(3):481-8; viii. [Medline].
• Lessell S. Nutritional deficiency and toxic optic neuropathies. In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology. 2nd ed. Philadelphia:. WB Saunders Co;2000.
• Macaluso DC, Shults WT, Fraunfelder FT. Features of amiodarone-induced optic neuropathy. Am J Ophthalmol. May 1999;127(5):610-2. [Medline].
• Mantyjarvi M, Tuppurainen K, Ikaheimo K. Ocular side effects of amiodarone. Surv Ophthalmol. Jan-Feb 1998;42(4):360-6. [Medline].
• Melamud A, Kosmorsky GS, Lee MS. Ocular ethambutol toxicity. Mayo Clin Proc. Nov 2003;78(11):1409-11. [Medline].
• Miller NR. Anterior toxic optic neuropathies. In: Walsh and Hoyt's Clinical Neuro-Ophthalmology. 4th ed. Baltimore:. Lippincott Williams & Wilkins;1982: 254-260.
• Miller NR. Retrobulbar toxic and deficiency optic neuropathies. In: Walsh and Hoyt's Clinical Neuro-ophthalmology. 4th ed. Baltimore:. Lippincott Williams & Wilkins;1982: 289-307.
• Nagra PK, Foroozan R, Savino PJ. Amiodarone induced optic neuropathy. Br J Ophthalmol. Apr 2003;87(4):420-2. [Medline].
• Nazarian SM, Jay WM. Bilateral optic neuropathy associated with amiodarone therapy. J Clin Neuroophthalmol. Mar 1988;8(1):25-8. [Medline].
• Phillips PH. Toxic and deficiency optic neuropathies. In: Miller NR, Newman NJ, eds. Walsh and Hoyt's Clinical Neuro-ophthalmology. 6th ed. Baltimore:. Lippincott Williams & Wilkins;2005: 447-463.
• Rizzo JF 3rd, Lessell S. Tobacco amblyopia. Am J Ophthalmol. Jul 15 1993;116(1):84-7. [Medline].
• Sadun AA. Metabolic optic neuropathies. Semin Ophthalmol. Mar 2002;17(1):29-32. [Medline].
• Woon C, Tang RA, Pardo G. Nutrition and optic nerve disease. Semin Ophthalmol. Sep 1995;10(3):195-202. [Medline].

Article Last Updated: Aug 5, 2005