Toxic and nutritional optic neuropathies both present clinically with symmetric progressive bilateral vision loss, decreased color vision, central or cecocentral scotomas on formal visual field testing, and no relative afferent pupillary defect because of the symmetric nature of optic nerve involvement. [1][2] 

In most cases, vision loss progresses over months rather than days to weeks, and vision decreases slowly. 

A thorough history is crucial to make a diagnosis. Specifically, exposure to drugs, alcohol and tobacco use, dietary intake, and occupational background should be investigated in any patient presenting with the bilateral symmetric slow visual loss.

Early in the disease, optic nerves usually appear normal or, on occasion, slightly hyperemic. Continued exposure to a toxic substance or nutrient deficiency would cause the slow appearance of bilateral temporal optic disc pallor due to the injury of ganglion cell axons specifically in the papillomacular nerve fiber bundle. This would eventually lead to the diffuse pallor of the optic disc. If an obvious visual field defect is not shown on routine 30-2 perimetry, central 10-2 perimetry will demonstrate central or cecocentral scotomas.[3][4][5]

Nutritional Optic Neuropathy

Nutritional optic neuropathy is usually sporadic; however, it has been described as epidemic during the times of war and/or famine.  [6][7][8] 

The role of vitamin B12,  folic acid, and copper deficiencies in nutritional optic neuropathy is well established. Although multivitamin supplementation in malnourished people is paramount, there is no clear evidence that deficiencies of thiamine, niacin, riboflavin, and pyridoxine are the primary causes of nutritional optic neuropathy.

B12-deficiencies (probably the most common culprit of nutritional optic neuropathies) result from the following:

• Pernicious anemia
• Advanced age due to the presence of atrophic gastritis and food-cobalamin malabsorption
• Gastric acid reduction therapy used commonly for the treatment of gastroesophageal reflux disease
• History of gastric surgery, gastrointestinal diseases such as celiac disease
• Parasitic infestation by tapeworms
• Alcoholism with its resultant nutrient deficiencies and gastic malabsorption
• Nitrous oxide toxicity
• Rarely, strict vegetarianism

Folate deficiency can result from:

• Decreased uptake (it is quite rare and associated with very poor diet) 
• Increased demand (pregnancy and diseases associated with rapid cell proliferation such as hemolysis and leukemia)
• Malabsorption (alcoholism and its associated nutritional malabsorption, gastrointestinal (GI) diseases which also result in reduced absorption of dietary folic acids such as jejunal diseases and short bowel syndrome)
• Treatment with folate antagonists (such as methotrexate and trimethoprim sulfa).

Copper deficiency is usually caused by gastric surgery and its resultant malabsorption syndromes, GI disease, total parenteral nutrition and enteral feeding, and rarely it may be secondary to acquired dietary deficiency. Zinc toxicity can also result in copper deficiency and can be result from the inadvertant injestion of denture cream.

Toxic Optic Neuropathy

Use of toxic mediacations as well as injestion or inhalation of toxic substances can both cause toxic optic neuropathy.

Clinical suspicion of toxin injection should prompt investigation for the presence and levels of specific toxins in the blood, urine and sometimes hair.

Below, toxicities secondary to specific medications and substances are discussed. 

Ethambutol

Ethambutol is an antimycobacterial drug and is the cause of the most commonly encountered toxic optic neuropathy with a globally-estimated incidence of at least 100,000 patients.

It is essential that all patients with suspected ethambutol toxicity be assessed for the secondary invasion of optic nerves by tuberculosis with an MRI of brain and orbits with contrast administration as well as lumbar puncture before ethambutol is held responsible for visual loss, although in cases with infiltrative optic neuropathy visual loss would rarely be very symmetric.

Ethambutol toxicity is both dose-dependent (usually occurring in patients using at least 35 mg/kg per dose of the drug) and duration-dependent (almost never occurring less than 2 months after initiating drug therapy with the mean onset of duration being 7 months after the start of treatment).

Risk of ocular ethambutol toxicity is higher in patients older than 65 years of age, low body mass index (BMI), abnormally increased glomerular filtration rate (for example, patients with renal tuberculosis), and HIV positive patients.

As in other patients with toxic-nutritional optic neuropathies, the most common visual field defect on formal perimetry tesitng is central or ceco-central scotomas; although, any nerve fiber bundle defect and rarely, bitemporal defects can be seen.

Again, the fundoscopy is usually normal even in the presence of decreased central vision but bilateral optic nerve pallor would eventually develop if the injection of the medication continues. 

Importantly, in patients with optic neuropathy secondary to ethambutol prompt discontinuation of medication after toxicity has been recognized often leads to eventual visual improvement that can continue for up to 6 months after the cessation of the drug therapy.  

Methanol

The clinical picture of methanol optic neuropathy, unlike that of other toxins, is acute in nature with development of central visual loss soon after methanol injection.

Both in epidemic and sporadic settings, usually the patient inadvertently ingests the toxin that is often present in home-distilled alcoholic beverages. Other sources of methanol intoxication include intake of paint solvents, gasoline additives, antifreeze, windshield fluid, and copy machine fluid. Methanol is also sometimes injected in suicide attempts.

The first manifestations of methanol injection are GI symptoms such as nausea and vomiting. Subsequently, the patient experiences headache, shortness of breath, abdominal pain, confusion, and visual loss of any degree. Coma and death may ensue. In patients with severe visual impairment the pupils may be dilated and non-reactive to light.

In the acute stage the funduscopic examination reveals hyperemic optic disc with edema. Supporting biochemical evidence of acute methanol toxicity is high anion gap metabolic acidosis due to accumulation of formate, a metabolite of methanol. Serum level of methanol greater 20 mg/dL establishes a diagnosis.

The main drug used for treatment of acute methanol toxicity is fomepizole which is an inhibitor of alcohol dehydrogenase, the enzyme that oxidizes methanol to formate. Folate supplementation, hyperventilation if the patient is intubated, sodium bicarbonate administration for patients with serum pH lesser than 7.3, and hemodialysis for patients with renal failure or pH lesser than 7.3 should also be utilized.

Amiodarone

Amiodarone, an antiarrhythmic drug, has been arguably associated with sequential or bilateral anterior optic neuropathy simulating non-arteritic anterior ischemic optic neuropathy (NAION).

Clinical characteristics of amiodaron-associated optic neuropathy are gradually progressive unilateral or bilateral vision loss, prolonged bilateral optic disc swelling, and sometimes, the halt of visual loss when amiodarone is stopped.

In patients who develop optic neuropathy while receiving amiodarone and in those patients that other treatable causes have been excluded, cardiology consultation regarding discontinuation of the drug should be sought since there is a potential for some vision recovery if the drug is discontinued.

Currently, there is no sufficient evidence to recommend regular screening of all patients receiving amiodarone for the presence of optic neuropathy.  

Tobacco and Alcohol

Alcohol is no longer considered to cause toxic optic neuropathy, but alcoholism is associated with much higher incidence of nutritional deficiencies, some of which can cause optic neuropathy.

Toxic optic neuropathy attributed to smoking (especially cigar or pipe smoking) is a diagnosis of exclusion, and other etiologies including mitochondrial optic neuropathies, for example, Leber’s hereditary optic neuropathy (LHON), should be explored.

In the early 1990s, there was an epidemic of optic and peripheral neuropathy in Cuba associated with famine. Patients presented with features typical of toxic/nutritional optic neuropathies: symmetric visual loss, decreased color vision, cecal and cecocentral scotomas on visual field testing and resultant optic nerve pallor, and nerve fiber layer thinning. Over 51,000 people were affected, and the prevailing theory was that these patients harbored mitochondrial mutations which prediscposed them to the optic and peripheral neuroapthy which was brought on by the nutritional deficiencies. However, the majority of the affected patients did not have one of the LHON mutations. It was concluded that Cuban epidemic optic neuropathy (CEON) may have been secondary to another yet undiscovered mitochondrial DVA multation or be an aquired variety of mitochondrial dysfunction brought on by severe nutritional deficiencis in patients with undelying yet unidentified mitochondrial DNA mutations.

Nutritional optic neuropathy is more prevalent during the time of war and famine and is more prevalent in patients who are at risk of having poor nutritional intake, for example, alcoholics and patients who are socially marginalized.

Toxic optic neuropathy prevalence varies depending on the toxic substance. For instance, in a large retrospective study of 857 patients taking ethambutol, 1.5% were found to have ethambutol toxic optic neuropathy. In another large prospective study of 837 patients taking amiodarone, the maximum annual incidence rate of bilateral visual loss which was attributed to amiodarone was 0.13%.

The pathophysiology of toxic and nutritional optic neuropathies have been thought to be secondary to the involvement of ganglion cell axons in the papillomacular bundle resulting in central and cecocentral defects on formal visual field testing. Specific pathophysiology varies depending on the toxic substance and is discussed briefly below.