TOXIC/NUTRITIONAL OPTIC NEUROPATHY

Signs and Symptoms

Due to myriad potential causes, toxic/nutritional optic neuropathy has no clearly identifiable racial, gender or age-dependent predilection.1,2 The condition presents as a painless, often progressive, bilateral, symmetric visual disturbance with variable optic nerve pallor. Temporal pallor tends to be the classic rule. This may manifest as a reduction of visual acuity, which may range from minimal to total amaurosis in some cases.2 There will be attendant loss of central visual field (usually relative cecocentral scotoma) and dyschromatopsia. Relative afferent pupillary defects are not usually present, as the condition is typically bilateral and symmetrical. Initially, most patients will present with visual symptoms in the setting of normal-looking optic discs, which may become edematous before progressing to optic atrophy with temporal disc pallor.2

Due to similarities in appearance and pathophysiologic responses, toxic optic neuropathy and nutritional optic neuropathy cannot be distinguished clinically from one another; consequently, both are typically discussed together. The differentiating factors are elicited in patient history. Patients suffering from toxic optic neuropathy will present with a history of exposure to or ingestion of a toxic substance. Well-known toxins causing this neuropathy include ethambutol, linezoilid, isoniazid, dapsone, ciprofloxacin, vigabatrin, disulfifram, methotrexate, cisplatin, cyclosporine, tamoxifen, sildenafil, infliximab, ethanol, ethylene glycol, thallium, lead, mercury, digitalis, chloroquine, streptomycin, carbon monoxide and amiodarone, to name a few of the more common causes.2-9

In the absence of toxic exposure, a similar clinical appearance occurs in nutritional optic neuropathy. In this instance, patients will have nutritional deficits of B vitamins such as thiamine (B1), riboflavin (B2), niacin (B3), pyridoxine (B6) or cobalamine (B12), as well as vitamin D, vitamin E, copper and folic acid.2,10-12 In these patients, there may also be a pronounced history of alcohol ingestion and tobacco use. “Tobacco optic neuropathy” has historically been described as optic nerve dysfunction related to the toxic effects of the constituents in tobacco. It has been considered to be an entity distinct from that often described as “tobacco-alcohol amblyopia,” a disorder better described as a nutritional optic neuropathy, as it is not truly amblyopia.13,14 More recently, nutritional optic neuropathy has been associated with special diets, anorexia, malnutrition and bariatric surgery.15-17

Pathophysiology

Toxic optic neuropathy may result from passive exposures to neuro–poisonous substances in the environment, ingestion of certain foods, intentional or unintentional ingestion of other materials containing toxic substances or from elevated serum therapeutic drug levels occurring in the treatment of other diseases, such as tuberculosis. The origin of toxic neuropathy is not limited to direct toxin exposure and may occur as a result of deficiencies of essential nutrients in the diet or from metabolic disease.18 In some cases, the substance or agent causing the toxic neuropathy impairs the tissue’s vascular supply or metabolism.

The common offender, tobacco, produces metabolic deficiencies as part of the systemic nicotine cascade. The historical term tobacco-alcohol amblyopia is outdated, as tobacco and alcohol abuse—with its attendant nutritional deficiencies—produces organic pathology within the nerve. Today, the condition is more accurately called toxic/nutritional optic neuropathy. Its pathophysiology is poorly understood, but it is generally attributed to toxic effects of cyanide and B12 deficiency.18 While nicotine has not been indicted to directly cause optic nerve damage, the cyanide in the smoke cannot be detoxified and causes neurotoxicity.19

Ethanol (consumable alcohol), like tobacco smoke, produces its toxic effects metabolically. Chronic exposures typically lead to vitamin B12 deficiency, folate deficiency or both. Over time, these deficiencies cause accumulations of formic acid. Both formic acid and cyanide inhibit the electron transport chain and mitochondrial function, resulting in disruption of ATP production and, ultimately, impairment of the ATP–dependent axonal transport system.2

The pathophysiologic relationship is unknown for many of the agents identified to date as causes of toxic optic neuropathy. Mitochondria of the retinal ganglion cells and damage to the papillomacular bundle in particular seem to be a common target of toxic optic neuropathy. OCT has identified decreased retinal nerve fiber layer thickness, especially in the temporal papillomacular quadrant, in eyes of patients that have had ethambutol-induced optic neuropathy.20 Research suggests toxic agents or their metabolic byproducts interfere with the oxidative phosphorylation in mitochondria, causing a buildup of reactive oxygen species, energy depletion, oxidative stress and activation of apoptosis.21

Management

The management for confirmed toxic/nutritional optic neuropathy includes immediate removal of the offending agent. Patients with suspected toxic optic neuropathy require a complete ocular evaluation with formal color vision testing and automated threshold visual field testing. They should also be referred for complete physical and laboratory studies such as a complete blood count with differential, serum B vitamin, copper and folate levels, a heavy metal screening (lead, thallium) and possibly testing for the Leber’s mitochondrial DNA mutation.5 In some cases, the toxic process may be reversible, with both signs and symptoms, demonstrating some progress toward recovery following removal of the offending agent or the addition of nutritional supplementation.5

Deficits associated with nutritional optic neuropathy are most commonly seen with deficiencies in vitamins B1, B12, D and E; folate; and copper. It is important that patients with toxic/nutritional optic neuropathy who also have undergone bariatric surgery be evaluated for adequate levels of vitamin B1, copper, vitamin B12, folate, methylmalonic acid and homocystine. Obtaining levels of vitamin A, C, D, K and E, as well as iron, zinc, selenium and magnesium, is advisable. Evaluating total protein, albumin and cholesterol also gives a sense of general nutritional status.15,17

Supplements frequently recommend-ed include a multivitamin, iron, vitamin D, folic acid, calcium citrate and vitamin B12. Although vitamin B1 is typically included in a multivitamin, the amount is fairly small. It is recommended to add an additional 100mg daily for at least the first year. In severe vitamin B12 deficiencies, a week of daily intramuscular injections (1,000 units per day) can greatly elevate serum levels of B12.16

Clinical Pearls

Toxic/nutritional optic neuropathy should be considered in cases of bilateral, progressive vision loss and in patients presenting with bilateral, temporal optic disc pallor.

An extensive history may be the best method of uncovering circumstances and situations that involve toxic and nutritional optic neuropathy.

Differential diagnoses in these cases may be challenging. It is essential to exclude other conditions such as Leber’s optic neuropathy, dominant optic neuropathy, infiltrative optic neuropathy secondary to sarcoidosis, infectious optic neuropathy and compressive optic neuropathies secondary to space occupying lesion.

Should prescriptive drugs or workplace exposure result in toxic optic neuropathy, clinicians should remain aware of potential underlying litigation issues such as worker’s compensation, product liability, product recall and medical malpractice.

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2. Grzybowski A, Zülsdorff M, Wilhelm H, Tonagel F. Toxic optic neuropathies: an updated review. Acta Ophthalmol. 2014 Aug 27. doi: 10.1111/aos.12515. [Epub ahead of print].

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10. Miléa D. Nutritional, toxic and drug-induced optic neuropathies. Rev Prat. 2001;51(20):2215-9. (article in French)

11. Gratton SM, Lam BL. Visual loss and optic nerve head swelling in thiamine deficiency without prolonged dietary deficiency. Clin Ophthalmol. 2014;8:1021-4.

12. Hsu CT, Miller NR, Wray ML. Optic neuropathy from folic acid deficiency without alcohol abuse. Ophthalmologica. 2002;216(1):65-7.

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14. Orssaud C, Roche O, Dufier JL. Nutritional optic neuropathies. J Neurol Sci. 2007;262(1-2):158-64.

15. Sawicka-Pierko A, Obuchowska I, Hady RH, et al. Nutritional optic neuropathy following bariatric surgery. Wideochir Inne Tech Malo Inwazyjne. 2014;9(4):662-6.

16. Sawicka-Pierko A, Obuchowska I, Mariak Z. Nutritional optic neuropathy. Klin Oczna. 2014;116(2):104-10.

17. Becker DA, Balcer LJ, Galetta SL. The Neurological Complications of Nutritional Deficiency following Bariatric Surgery. J Obes. 2012;2012:608534.

18. Santiesteban-Freixas R, Mendoza-Santiesteban CE, Columbie-Garbey Y, et al. Cuban epidemic optic neuropathy and its relationship to toxic and hereditary optic neuropathy. Semin Ophthalmol. 2010;25(4):112-22.

19. Syed S, Lioutas V. Tobacco-alcohol amblyopia: a diagnostic dilemma. J Neurol Sci. 2013;327(1-2):41-5.

20. Chai SJ, Foroozan R. Decreased retinal nerve fibre layer thickness detected by optical coherence tomography in patients with ethambutol-induced optic neuropathy. Br J Ophthalmol. 2007;91(7):895-7.

21. Altiparmak UE. Toxic optic neuropathies. Curr Opin Ophthalmol. 2013;24(6):534-9.