Toxic and Nutritional Optic Neuropathy

Etiology

Nutritional Optic Neuropathy

Nutritional optic neuropathy is usually sporadic; however, it has been described as an epidemic during 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 gastric malabsorption
• Nitrous oxide toxicity
• Rarely, strict veganism

Folate deficiency can result from:

• Decreased uptake (it is quite rare and associated with a 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 result from the inadvertent ingestion of denture cream.

Toxic Optic Neuropathy

The use of toxic medications as well as ingestion 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.

All patients with suspected ethambutol toxicity must be assessed for the secondary invasion of optic nerves by tuberculosis with an MRI of the 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 two months after initiating drug therapy, with the mean onset of duration being seven months after the start of treatment).

The risk of ocular ethambutol toxicity is higher in patients older than 65 years of age, with 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 testing is central or ceco-central scotomas; although, any nerve fiber bundle defect and rarely, bitemporal defects can be seen.

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

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

In epidemic and sporadic settings, the patient usually inadvertently ingests the toxin that is often present in home-distilled alcoholic beverages. Other sources of methanol intoxication include the 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.

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

The primary drug used to treat acute methanol toxicity is fomepizole, 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 a 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, 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 predisposed them to the optic and peripheral neuropathy brought on by the nutritional deficiencies. However, most 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 mutation or be an acquired variety of mitochondrial dysfunction brought on by severe nutritional deficiencies in patients with underlying yet unidentified mitochondrial DNA mutations.

Epidemiology

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%.

Pathophysiology

The pathophysiology of toxic and nutritional optic neuropathies has been thought to be secondary to the damage 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.

History and Physical

Patients with toxic and nutritional optic neuropathies typically present with slow and insidious bilateral and very symmetric visual loss. The exception to this is methanol-related optic neuropathy, where the visual loss follows methanol injection. Patients may report decreased vision, visual field defects, difficulty seeing in low-light conditions, and decreased visualization of colors. Early in the disease process, The optic disc often appears normal on the fundus exam. Late in the disease process, there is diffuse pallor of the optic disc and thinning of the retinal nerve fiber layer.[9]

Evaluation

When a patient with bilateral and symmetric optic neuropathy is encountered, it is recommended that the following tests be routinely performed:

• Blood tests for vitamin B12 levels and serum cobalamin levels
• Levels of vitamin B12 metabolites (serum methylmalonic acid and plasma total homocysteine)
• Complete blood count (CBC) with smear analysis to rule out anemia, macrocytosis, and neutrophil hypersegmentation
• Levels of intrinsic factor and parietal cell antibodies to rule out pernicious anemia
• Red blood cell folate levels are a more reliable indicator of tissue stores than serum folate levels)
• Plasma total homocysteine level

To investigate the presence of copper deficiency, serum, and urinary copper levels, as well as various hematologic parameters like anemia, and neutropenia, the presence of vacuolated myeloid precursors and ringed sideroblasts should be checked. Levels of niacin, riboflavin, pyridoxine, and thiamine should also be tested in all patients to assess for vitamin deficiencies.[10][9]

Treatment / Management

Treatment of the nutritional or toxic optic neuropathy is based on the cause. Nutritional supplements will need to be given in cases of nutritional optic neuropathy. If the supplement cannot be absorbed in an oral form, then it may have to be administered parentally. Medications causing optic nerve toxicity should be discontinued unless the benefits of continuing the medication outway the risk of further optic nerve damage. The specialist prescribing the medication should be consulted to provide recommendations for alternate therapies. Patients should be encouraged to limit or discontinue the use of alcohol and tobacco products to reduce the risk of worsening optic neuropathy.

Differential Diagnosis

All patients presenting with a bilateral low progressive symmetric visual loss should be investigated for the presence of maculopathies, which can usually be excluded by performing intravenous fluorescence angiography and multifocal electroretinogram (ERG).

Hereditary optic neuropathies such as dominant optic atrophy and Leber's hereditary optic neuropathy can also present similarly to toxic or nutritional optic neuropathies; thus, the genetic tests to exclude these conditions should be performed in all patients suspected of having toxic/nutritional optic neuropathies.

Depending on a patient's clinical presentation and if demyelination, compression, infiltration, and ischemia are suspected to be the causes of visual loss, an MRI of the brain and orbits with contrast administration, targeted serological testing, and occasionally, lumbar puncture should be performed. Note that the visual loss is usually acute and not symmetric in these etiologies.

In patients with normal-appearing optic nerves, no thinning of the peripapillary retinal nerve fiber layer and normal ganglion cell analysis on ocular coherence tomography, the presence of decreased central acuities with no relative afferent pupillary defect, and constricted visual fields likely indicate a nonorganic visual loss.

Prognosis

The visual prognosis of toxic and nutritional optic neuropathy is variable and is dependent on the cause and severity of the initial optic nerve insult. One systematic review found that in patients with B12 deficiency optic neuropathy, there was improved visual acuity after oral B12 supplementation in greater than 50% of patients with the diagnosis. However, a small percentage of patients progressed to blindness.[11] 

Methanol-induced toxic optic neuropathy shows resolution of visual disturbances in two to three weeks after intoxication in most patients. However, around a third or more of patients develop permanent visual defects.[12] Nutritional optic neuropathy associated with folate deficiency has a good visual prognosis if treated within a few months after symptoms develop.[13] The prognosis of tobacco and alcohol-induced optic neuropathy is variable, with milder symptoms and duration portending a better prognosis.[14]