Toxic and nutritional deficiency optic neuropathies …

Michelle Y Wang MD

Neuro-Ophthalmology & Neuro-Otology

Updated 11.20.2023
Released 08.04.1997
Expires For CME 11.20.2026

Toxic and nutritional deficiency optic neuropathies

Author: Michelle Y Wang MD

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Editor: Jonathan D Trobe MD

Toxic and nutritional deficiency optic neuropathies

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Introduction

Overview

Toxic and deficiency optic neuropathies are fairly uncommon in the United States. Due to the effects of these conditions on mitochondria and cellular energy production, these entities share many signs and symptoms. Awareness of the hallmark findings as well as an increased index of suspicion in patients with chronic disease will assist the clinician with diagnosis.

Key points

	• Toxic and nutritional optic neuropathies are classically characterized by gradual painless progressive vision loss, bilateral central or cecocentral scotomas, marked dyschromatopsia, loss of high spatial frequency contrast sensitivity, temporal pallor, and the loss of papillomacular bundle.
	• Many toxic and nutritional optic neuropathies selectively affect the papillomacular bundle due to damage to mitochondrial pathway.
	• A thorough history of medication use, toxic exposure, substance abuse, dietary deficiency, past surgeries, family history, and peripheral neurologic symptoms should be documented.
	• The workup for toxic and nutritional optic neuropathies includes visual field testing, optic coherence tomography, and ancillary laboratory testing tailored to the medical history and examination findings. Magnetic resonance imaging of the brain may be necessary to rule out compressive lesions.
	• Early recognition, removal of toxic agents, and supplementation of nutritional deficiencies may sometimes lead to protracted visual recovery.

Historical note and terminology

Toxic and nutritional optic neuropathies are uncommon in the United States. However, in some times and places these types of optic neuropathies have been far more common; they took on epidemic proportions in Cuba in the early 1990s (62). This family of diseases tends to be relegated to the background until such events as famine, new application of pharmaceuticals, or changes in workplace health and living conditions lead to nutritional deficiencies or toxic exposures.

These entities are divided into nutritional (deficiency states) and toxic neuropathies. But many are multi-factorial, a clear etiology cannot be established, and the terms are often used presumptively. There is no doubt, however, that as the number of new drugs and chemicals increases, more toxic and metabolic optic neuropathies will be identified. One example that illustrates that these multi-factorial conditions have been considered either toxic or nutritional deficiencies is "tobacco-alcohol amblyopia." This entity was first well described by Traquair, who emphasized the slowly progressive time course of the bilateral visual field loss (74). The etiologic factors in tobacco-alcohol amblyopia are now better appreciated, even as there has been a marked decrease in the prevalence of the condition in the United States (57). The term "tobacco-alcohol amblyopia" suggests the relative roles of cyanide (from tobacco) and low levels of vitamin B12 due to poor nutrition and poor absorption associated with alcohol consumption. Deficiencies of B12, other B vitamins, and folic acid are known causes of a similar clinical picture (20). Indeed, it is one of the fundamental curiosities that these nutritional deficiency and toxic optic neuropathies can have similar clinical manifestations (51).

Clinical manifestations

Presentation and course

• In most cases, patients with toxic or nutritional optic neuropathy present with slowly progressive bilateral loss of visual acuity, often described as a central haze or cloud.

Patients may describe an inability to read, to see traffic signs, or to see details in the faces of acquaintances. Patients do not complain of pain or positive visual phenomena such as photopsias. Sometimes paresthesias, ataxia, or hearing loss are associated; however, such neurologic symptoms are more characteristic of general nutritional deficiencies sometimes found in clusters in equatorial countries and termed "tropical amblyopias." They are not usually described in single-vitamin deficiency states (43).

Patients generally have bilateral reduction in visual acuity that varies from minimal (20/25) to finger counting. The visual acuity loss in the two eyes is usually symmetrical. Visual acuity rarely falls below 20/400. Loss of color vision is constant and usually more profound than the loss of visual acuity. Patients with minimal dysfunction may present with isolated color vision deficiencies. The hallmark of toxic and nutritional optic neuropathies is the cecocentral scotoma that begins nasal to the blind spot and extends to involve fixation on both sides of the vertical meridian. An area of relative scotoma forms a bridge between the two islands of absolute scotoma at fixation and the blind spot. Complete loss of the perception of red is common, and red perimetry will demonstrate a much larger elliptical cecocentral scotoma than is found with white light stimuli. Bilateral cecocentral scotomas can look like bitemporal hemianopic scotomas on automated perimetry and can lead to the incorrect presumptive diagnosis of a chiasmal lesion. However, diminished foveal thresholds on automated visual field testing are more common in toxic and nutritional optic neuropathy than in chiasmal lesions. Because of the binocular symmetry of toxic and nutritional optic neuropathy, tests of optic nerve function that depend on asymmetry (relative afferent pupillary defect and brightness sense) will be normal.

The fundus may initially appear normal. However, a careful examination may reveal nerve fiber layer loss in the papillomacular bundle sometimes associated with swelling of the nerve fiber layer in the arcuate bundles above and below the denuded area between the fovea and optic nerve head (62; 63). Later in the course of the disease, the temporal optic disc appears mildly pale. The mismatch between relatively mild temporal disc pallor and severe depression of visual acuity, visual field, and color vision may lead to the misconception that the patient is malingering.

If the cause of the toxic or deficiency optic neuropathy can be found and treated early (for example, cessation of smoking and heavy alcohol intake and the administration of vitamins in tobacco-alcohol amblyopia), vision may return to near normal over several months' time. However, visual loss is often permanent in cases of long-standing toxic or nutritional optic neuropathy.

Ethambutol, an antimicrobial agent frequently used against pulmonary tuberculosis, is a frequent cause of toxic optic neuropathy. In the past, when the recommended dose was 50 mg/kg per day, toxic optic neuropathy was common (04; 39).The incidence of ethambutol toxic optic neuropathy has declined as a consequence of a downscaling of dosing guidelines to 25 mg/kg per day for the first six weeks with a further reduction to 15 mg/kg per day thereafter (39). Nonetheless, even with this dosage guideline, the incidence of toxic optic neuropathy among patients on ethambutol has been reported as high as 5% to 6% at 25 mg/kg per day and 0.7% to 1% when no more than 15 mg/kg per day is prescribed (66; 80). Patients with renal failure are at particular risk, owing to reduced excretion of the drug (15). A meta-analysis suggested that renal function be tested in all patients on ethambutol in order to screen for even mild renal dysfunction (73). Patients on dialysis may be at particular risk, as ethambutol is not well dialyzed (67), and therefore, should be prescribed at lower doses. The slowly progressive bilateral loss of visual acuity is first noted a few months after intake of the agent. Together with severe dyschromatopsia, central or cecocentral scotomas are noted on visual field testing. The fundus findings of slight temporal pallor and nerve fiber layer dropout in the papillomacular bundle are subtle and often overlooked. Once the ethambutol is discontinued, visual recovery may begin within six weeks, but recovery may be delayed as long as six months (38). In some cases, there is no recovery. A small study of 16 subjects reported a 50% likelihood of visual improvement at six months after discontinuation. Improvement was noted in the group receiving a daily dose of less than 15 mg/kg (09). The window of reversibility is mostly due to the fact that mitochondrial impairment does not result in immediate neuronal death (65). The mechanism of ethambutol-induced optic neuropathy may be chelation of copper, thereby precluding normal cytochrome c oxidase activity and mitochondrial metabolism in the optic nerve (33). Appropriate dose adjustments should be made in the most vulnerable populations: the underweight, the elderly, and those with renal insufficiency. All patients treated with ethambutol should have a baseline ophthalmological examination, including best-corrected visual acuity, Ishihara color vision, and ophthalmoscopy, and they should be monitored on a regular basis. Humphrey visual field testing may be performed when available, as well as optical coherence tomography (OCT), which has also been utilized by some to detect decreased retinal nerve fiber layer thickness (08).

Disulfiram, another chelating agent, may produce a toxic optic neuropathy with a picture similar to that of ethambutol, but the prognosis is generally better once the drug is discontinued (18). Complete recovery of disulfiram-induced optic neuropathy usually occurs within two months of its discontinuation. However, irreversible toxicity has been reported (34).

Linezolid, an oxazolidinone antimicrobial active against gram-positive infections, has been reported by several authors to cause a reversible optic neuropathy (42; 58; 25). Although linezolid is probably safe for short courses of therapy, it may be toxic if used in a prolonged course of therapy for osteomyelitis and other chronic infections (71). Linezolid inhibits translation of bacterial DNA by binding to bacterial ribosomal RNA subunits (the binding sites differ from those of the macrolides). Therefore, its prolonged use may also inhibit mitochondrial protein synthesis. A study identified a probable linezolid-associated optic neuropathy that presented with abnormal color vision, characteristic optic nerve changes, and central scotomas attributed to toxic damage to mitochondria (75). In most cases, optic neuropathy has only developed after three months or more of continuous use.

Chloramphenicol, used to treat infection resistant to common antibiotics, may cause toxic optic neuropathy by inhibiting mitochondrial protein synthesis. The incidence and severity of optic neuropathy is dose-dependent. Prompt cessation of the drug and treatment with vitamin B complex usually leads to substantial recovery of visual function. Optic discs appear hyperemic with blurred margins and swelling of the papillomacular bundle, and visual field testing displays central or cecocentral scotomas (79).

Isoniazid, another antimicrobial frequently used to treat tuberculosis, is also toxic to the optic nerves but much less so than ethambutol. Optic neuropathies from isoniazid use are associated with severe bilateral optic disc swelling (29; 69) and with peripheral neuropathy (36).

Tacrolimus, a cytotoxic T-cell suppressor used in transplant medicine, has been reported to cause bilateral or unilateral optic neuropathy (23). In one reported case (03), the optic neuropathy was of rapid onset and with features resembling ischemic optic neuropathy, calling into question the etiology. The onset of vision loss was much more insidious in the other two reported cases (37; 30). In one of these cases (30), there was reversal of vision loss after discontinuation of the tacrolimus. Vasoconstriction with tissue ischemia has been hypothesized as the underlying mechanism (83). Given the extremely low number of reported cases, clinicians should remain vigilant but not deterred in the use of this agent.

Amiodarone, a medication used to treat ventricular arrhythmias, has been implicated in cases of toxic optic neuropathy that is said to be similar to that caused by isoniazid. Proceeding on a much more rapid course than ethambutol-induced optic neuropathy, it is characterized by optic disc swelling, profound visual field defects, and often permanent vision loss (50). Ultrastructural changes have also been reported in the optic nerves of patients on long-term amiodarone therapy (41). The incidence was 0.3% in a large retrospective study. Male gender was associated with a nearly 3-fold increased risk of optic neuropathy. Increased cumulative incidence was observed with treatment duration of more than 41 days (10). On the other hand, another study reported an annual incidence of 1.6 per 100,000 patients using the IMS and FDA data from 2008 through 2012 (44). Anterior ischemic optic neuropathy is often encountered in the setting of arteriosclerosis, which is a common feature in patients treated with amiodarone. Thus, the cause-and-effect relationship between amiodarone and optic neuropathy remains uncertain.

Phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil), employed in the treatment of erectile dysfunction and pulmonary hypertension, have also been reported to cause optic neuropathy (02). The clinical picture appears similar to that of nonarteritic anterior ischemic optic neuropathy (NAION), in that the etiology appears to be vascular and not a direct or indirect toxic effect of the medication on the optic nerve. In many of the cases, the dose and frequency of medication use or time between ingestion of medication and onset of vision loss is not fully documented (54), making it difficult to establish a direct causal relationship (49). Because the use of these medications is widespread and the number of patients experiencing visual loss is fewer than 50 reported cases, it is considered an infrequent cause of optic neuropathy. However, in patients who have experienced NAION in one eye, or who have adequate vision in only one eye, it is prudent to discourage use of these medications (26).

Methanol and ethylene glycol are implicated in toxic optic neuropathy. Methanol is found in poorly distilled alcoholic beverages (home brews). Its ingestion produces a metabolic acidosis as a consequence of the accumulation of formate, one of its toxic metabolites. Methanol produces vision loss within hours of exposure and can lead to complete blindness (84). The optic disc is often hyperemic and swollen. Lack of pupillary reactivity to light usually indicates a poor prognosis (21). Ethylene glycol, the main ingredient in antifreeze, may also produce blindness with a time course similar to that of methanol.

An epidemic of nutritional deficiency optic neuropathy affected thousands of severely malnourished patients in Cuba between 1992 and 1993 (63; 61). In these cases, the vitamin deficiencies associated with poor diet appeared to have been compounded by the ingestion of cassava, which may have led to elevated levels of cyanide (12). This epidemic provided an opportunity for the careful analysis of affected patients before and after treatment with vitamin B12 and folic acid (62). The patients had reported a marked weight loss associated with severe deficiencies of protein and vitamin intake. Laboratory testing demonstrated marked deficiencies of B12 and folate. Twenty Cuban patients with this optic neuropathy were carefully examined just before and three months after the administration of cyanocobalamin (3 mg) and folate (250 mg) each day. Their average visual acuity improved from 20/400 to 20/50 and their average color vision from a correct score of 25% to 87% on the American Optical Color test plates. The arcuate nerve fiber axon bundles were swollen before treatment but recovered afterward. The optic disc, which looked normal initially in most cases, went on to show temporal pallor (62). The clearest objective finding was marked thinning of the nerve fiber layer in the region of the papillomacular bundle forming a wedge defect bordered by swollen nerve fiber layers above and below. This finding was the most important aspect of the case definition, which required five signs: (1) bilateral progressive loss of visual acuity, (2) bilateral cecocentral scotomas, (3) bilateral dyschromatopsia, (4) bilateral losses of high spatial frequency contrast sensitivity, and (5) saccadic pursuit eye movements.

In addition to the visual symptoms, over one third of the patients in the Cuban epidemic had neurologic symptoms, consisting mostly of peripheral neuropathy, ataxia, and hearing loss. Malnourished prisoners of war have also been described to have an optic neuropathy that is associated with a peripheral neuropathy (19).

Immune checkpoint inhibitors (ICIs) have become an important class of cancer immunotherapy for various malignancies such as metastatic malignant melanoma and non-small cell lung cancer. Immune checkpoint inhibitors are monoclonal antibodies that block cytotoxic T lymphocyte-antigen-4, programmed cell death protein 1, and programmed cell death ligand 1. Inhibition of immune checkpoint molecules can lead to an unsuppressed immune response in various organ systems, which manifest as autoimmune-like side effects known as immune-related adverse events (irAEs). Ocular immune-related adverse events are rare, occurring in less than 1% of patients and are predominantly uveitis (35). The presentation is usually delayed and prolonged.

Ipilimumab, a human monoclonal antibody, works by blocking the cytotoxic T lymphocyte-antigen-4 (CTLA-4), which normally downregulates activation of T cells and allows tolerance to self-antigens. Ipilimumab thereby stimulates the immune response against tumor cells. Bilateral optic neuropathy was reported in one patient who presented with concurrent uveitis six weeks after the third ipilimumab infusion (82). A case of bilateral optic neuritis was reported 5 months after initiation of ipilimumab at the same time as steroid treatment (78).

The immune checkpoint inhibitors pembrolizumab, nivolumab, and cemiplimab regulate T cell activation by blocking the protein programmed death 1 (PD-1). Bilateral optic neuritis and neuromyelitis optica spectrum disorder have been reported as rare immune-related adverse events of nivolumab (Kartal and Atas 2018; 48). A retrospective chart review of 1474 patients found 1 patient who developed bilateral optic neuritis after 4 cycles of ipilimumab/nivolumab combination therapy followed by a single cycle of nivolumab monotherapy (32).

The immune checkpoint inhibitors atezolizumab, avelumab, and durvalumab are monoclonal antibodies that target programmed cell death ligand 1 (PD-L1). A case of optic neuritis and hypopituitarism during anti-PD-L1 antibody treatment has been reported (45).

A retrospective case series identified 18 eyes with immune checkpoint inhibitor-associated optic neuritis (17). Visual decline tended to be bilateral and painless, often sparing color vision. The authors found that immune-related adverse events typically occur within 4 cycles of immune checkpoint inhibitor therapy but may be delayed in cases maintained on prolonged monotherapy.

Early recognition of immune-related adverse events is important for effective management, which may include discontinuation of the immune checkpoint inhibitor, initiation of immunosuppressive therapy, or both. Immune-related adverse events generally respond to steroids with or without stopping the immune checkpoint inhibitor (72). Cases that are refractory to steroid treatment may require plasmapheresis, IVIG, mycophenolate, or infliximab. A study conducted to evaluate the effect of systemic immunosuppression on survival and time to treatment failure in patients with melanoma receiving ipilimumab found no association between the use of steroids and overall survival or treatment failure (27). The authors concluded that immune-related adverse events requiring systemic immunosuppression should not compromise the therapeutic benefit.

Prognosis and complications

A rapid diagnosis is crucial because the reversibility of visual loss is largely determined by how quickly the toxin can be removed or the deficient vitamin can be replenished. Surprisingly, vision may recover following the discontinuation of a toxin as long as six to 12 months after exposure (especially in the case of ethambutol toxicity). Despite severe losses of the nerve fiber layer and optic disc temporal pallor, patients may show dramatic degrees of visual recovery (62).

Clinical vignette

Case 1. A 68-year-old woman weighing 50 kg presented with a complaint of progressive loss of vision in both eyes over several months. Past medical history included a diagnosis of pulmonary tuberculosis made 8 months earlier and intake of isoniazid (300 mg per day) and ethambutol (24 mg/kg/day, reduced after 6 weeks to 16 mg/kg/day).

Best-corrected visual acuities were 20/400 in both eyes. There was a complete lack of color vision by Ishihara color plates in both eyes. The pupils constricted incompletely to light, but there was no relative afferent pupillary defect and no optic disc pallor. Tangent visual field testing demonstrated large bilateral cecocentral scotomas.

Ethambutol optic neuropathy (fundus photograph)

A 68-year-old patient with a mild cataract had progressive visual loss in both eyes associated with cecocentral scotomas. In this fundus photograph of the left eye, note the temporal pallor associated with loss of the papillomacul...

There was an elevated creatinine level of 1.9. Two months after stopping ethambutol, visual acuity had improved to 20/100 in the right eye and 20/200 in the left eye.

This is a case of ethambutol-induced toxic optic neuropathy. The patient was also using isoniazid, which is known to produce optic neuropathy, but the contribution of isoniazid is uncertain as there have been few reports of optic neuropathy from exposure to isoniazid alone.

Case 2. A 62-year-old woman with a history of Crohn disease and multiple ileostomies had progressive bilateral vision loss. She described the vision as dim and reported that colors appeared less bright and that red objects appeared brown. She had undergone a resection of the distal ileum approximately 13 months prior to presentation. She had been prescribed oral multivitamin supplementation.

On examination, best-corrected visual acuities were 20/400 in both eyes. She was able to identify only 2 of 15 American Optical color plates. Pupils were sluggishly reactive to light, but there was no relative afferent pupillary defect. Humphrey visual field testing revealed bilateral central scotomas. Fundus examination revealed bilateral temporal pallor with loss of the papillomacular bundle. The patient was also found to have mild ataxia and decreased pinprick sensation in the feet. A macrocytic anemia was present.

This is a case of B12 deficiency seen in a patient following ileal resection. The distal ileum is the site of absorption of the vitamin after binding to intrinsic factor produced by the parietal cells of the gastric mucosa. The patients visual acuity eventually improved to 20/80 in both eyes after six weeks of intramuscular injection of cyanocobalamin.

Biological basis

Etiology and pathogenesis

	• The toxins most clearly established as producing an optic neuropathy include ethambutol, disulfiram, linezolid, chloramphenicol, isoniazid, methanol, ethylene glycol, arsacetin, carbon monoxide, clioquinol, cyanide, hexachlorophene, lead, plasmocid, and triethyltin (70).
	• Less clearly established as toxic to the optic nerve are amiodarone, tacrolimus, nucleoside analogue reverse transcriptase inhibitor, phosphodiesterase-5 inhibitors, carbon disulfide, pheniprazine, quinine, and thallium.
	• Other toxins suspected but unproven as causes of optic neuropathy include carbon tetrachloride, dapsone, and suramin (70).
	• Deficiencies of the following vitamins and trace elements are associated with optic neuropathy: vitamin B12 (cobalamin), vitamin B1 (thiamine), vitamin B2 (riboflavin), folic acid, and copper (55).
	• Proteins, particularly those containing the sulfur amino acids, probably are also crucial for efficient oxidative phosphorylation.
	• Reduced vitamin E and vitamin B1 levels have been suggested to play a role in the development of ethambutol optic neuropathy (56).
	• Optic neuropathies due solely to nutritional deficiencies are uncommon in the United States except in the setting of heavy tobacco and alcohol consumption, severe eating disorders, and gastric bypass surgery.

The fact that so many nutritional deficiency and toxic optic neuropathies produce similar clinical pictures relates to shared metabolic pathways (77). Oxidative phosphorylation within the mitochondria involves electron transfer to oxygen near the beginning of the cycle and the production of adenosine triphosphate (ATP) at the end. Vitamins such as B12 and folic acid are crucial to this process, and their deficiency would lead to reductions of ATP. Similarly, agents such as cyanide or formate (a metabolic product of methanol) block this electron transport. The final common product of these deficiencies and toxins is decreased ATP production by mitochondria within all cells of the body. Selective involvement of the papillomacular bundle may owe to reduced compensatory mechanisms. Muscle cells, for example, can deal with decreased mitochondrial deficiency by producing more mitochondria (60). Neurons, with particular long or thin axons, are at a great disadvantage because all neuronal mitochondria are made in the cell body and must be transported via axoplasmic flow down the axon. Axonal transport is highly energy dependent. Furthermore, mitochondria have a relatively limited lifespan and their transport must be rapid and efficient or the terminal end of the axon will suffer ATP insufficiency and degenerate. Hence, such impairments are first seen in the longest axons (leading to a peripheral neuropathy) and the smallest axons (papillomacular bundle) (64). These dynamics involving mitochondrial insufficiency and mitochondrial axonal transport have been explored in an animal model in which rats are maintained on a folate-deficient diet and exposed to methanol such that formate levels rose and led to blocked electron transport (59). Patients in the Cuban epidemic optic neuropathy were found to have increased serum and cerebrospinal fluid concentrations of formate (16).

Nutritional deficiencies after gastric bypass surgeries are well known. Although copper deficiency optic neuropathy is rare, it may occur after bariatric surgery, as with B12 and thiamine deficiency (46). Multiple nutrient deficiencies often occur concurrently. Zinc excess may potentiate copper deficiency (81).

Differential diagnosis

Confusing conditions

The differential diagnosis of toxic and nutritional optic neuropathies includes disorders that cause acute and subacute symmetrical visual acuity and color vision loss.

Leber hereditary optic neuropathy (LHON) is due to point mutations in the DNA and, as such, is inherited through the maternal line. Probably because of the common pathology involving oxidative phosphorylation, the disease can look like toxic and nutritional deficiency optic neuropathies (53). Patients develop acute or subacute loss of vision, first in one eye and later in the other eye within days, weeks, or months. Leber hereditary optic neuropathy most often presents in men in their late teens or early 20s. It can be distinguished from toxic and nutritional optic neuropathies by the presence of a family history, the occasional presence of telangiectatic vessels around the optic disc of the uninvolved eye during the acute phase, consecutive rather than simultaneous involvement of the 2 eyes, and serum detection of the point mitochondrial DNA mutation.

Kjer autosomal dominant optic atrophy is less often confused with toxic and nutritional optic neuropathies. This type of optic neuropathy develops slowly in late childhood and follows an autosomal dominant inheritance pattern. The gene for this condition codes for a mitochondrial regulatory protein (13).

Although less commonly confused with toxic and nutritional optic neuropathies, chiasmal lesions must also be ruled out. Pituitary adenomas or other lesions that compress the optic chiasm generally present with bitemporal visual field loss. However, in the early stages, bitemporal field losses may look like cecocentral scotomas. Chiasmal lesions are generally masses that are readily discovered on standard imaging studies.

Optic neuritis can occur in both eyes simultaneously. Almost any type of visual field defect can be encountered, including central scotomas that resemble the cecocentral defects of toxic and nutritional optic neuropathies. If the patient has multiple sclerosis, scattered high signal abnormalities may be detected on T2-weighted MRI. Fortunately, patients with optic neuritis usually show dramatic recovery of visual acuity over the ensuing two months.

Finally, psychogenic visual loss must be considered in the differential diagnosis given that objective abnormalities may be subtle or absent in toxic and deficiency optic neuropathies. Visual evoked potentials may be useful to document the increased signal latency that should be present in any organic cause of bilateral optic neuropathy but not in psychogenic visual loss.

Associated or underlying disorders

Preexisting dysfunction in mitochondrial metabolism from genetic causes such as Leber hereditary optic neuropathy and autosomal dominant optic atrophy likely renders patients more vulnerable to drug-induced mitochondrial optic neuropathy.

The nucleoside analog azidothymidine (AZT), also known as zidovudine, is an important component of highly active antiretroviral therapy (HAART) in the treatment of human immunodeficiency virus. It belongs to a class of drugs known as nucleoside reverse transcriptase inhibitors that function by interfering with viral DNA replication. This class of drugs is utilized not only by retroviral reverse transcriptase, but also by the mitochondrial DNA polymerase gamma. Therefore, all nucleoside analogue reverse transcriptase inhibitors may induce mitochondrial toxicity by inhibiting mitochondrial polymerase gamma and mitochondrial DNA (mtDNA) replication.

Patients who develop profound visual loss and color deficiencies after initiation of highly active antiretroviral therapy have been found to the 11778 or 14484 mutations of Leber hereditary optic neuropathy, suggesting that antiretroviral therapy may be associated with increased risk in genetically predisposed patients (40). Ethambutol has also been suggested to trigger Leber hereditary optic neuropathy (68). Similarly, ethambutol has been linked to visual loss in a patient with autosomal dominant optic atrophy with an OPA1 mutation (22). Ethambutol should be avoided in patients with known genetic mitochondrial defects.

Concurrent use of ethambutol and nucleoside analogue reverse transcriptase inhibitors may similarly further increase the risk of mitochondrial toxicity (47).

Diagnostic workup

• A good history of exposure is a far more effective means of establishing the diagnosis than any laboratory test.

Suspected toxicities can be confirmed through serum and urine analysis. A 24-hour urine collection for heavy metal screening may yield positive results. In addition to serum vitamin levels for B1, B2, B12, and folic acid, red blood cell folate is a useful measure of folate levels over the past 100 days. Methylmalonic acid and homocysteine levels are markedly elevated in the majority of cases of B12 deficiency, but false positive high levels are common in elderly patients. The usefulness of serum pyruvate remains to be determined, but it has been shown to be elevated in some cases of Wernicke encephalopathy (14).

Optical coherence tomography can be useful as a means of charting progressive retinal nerve fiber layer loss in patients with established diagnoses (01). However, in early phases of nutritional and toxic disease, the OCT macular thickness analysis may lag behind by a period of several months and will not reliably diagnose disease or predict visual outcomes (85; 11). Thinning of the perifoveal ganglion cell-inner plexiform layer thickness at the onset of visual symptoms may be an early diagnostic marker (24; 76).

Humphrey visual field is an important diagnostic test. Visual field defects in toxic and nutritional optic neuropathies are usually symmetric central or cecocentral scotomas. Bitemporal hemianopia has been reported, with or without overlapping cecocentral scotomas, which may mimic chiasmal compression (31).

In toxic and nutritional optic neuropathies, magnetic resonance imaging (MRI) may demonstrate an increased T2 signal within in the optic chiasm without restricted diffusion, suggesting toxicity at the level of optic chiasm (52). Bitemporal hemianopic visual field defects may be seen in those cases.

Management

• The only effective management is removal of the toxins or supplementation of the deficient vitamin.

In terms of prevention, the most important role for the physician is to have an appropriately high index of suspicion and a sufficient knowledge of pharmacokinetics to identify patients at high risk. In the case of ethambutol, those with high serum levels of ethambutol have the greatest risk of developing permanent visual loss (65). For example, patients with renal impairments are far more likely to develop ethambutol-induced toxic optic neuropathy because of reduced excretion. They should be maintained at lower doses than specified in the usual guidelines. Similarly, patients on dialysis should be prescribed lower doses asbecause excretion of ethambutol is reduced in those cases.

Once a deficiency has been identified, rapid supplementation is important. Table 1 lists common nutrients often implicated in metabolic optic neuropathy, the USDA recommended daily allowance (RDA) for adults, and the dosages commonly given for repletion.

Nutrient	USDA RDA	Repletion dose
B1	1.5 mg	Mild deficiency: 10 mg by mouth daily for a week followed by 3 to 5 mg by mouth for at least 6 weeks Severe deficiency: 50 to 100 mg intravenously, followed by 10 mg intramuscularly daily for one week and 3 to 5 mg by mouth daily for at least 6 weeks
B2	1.7 mg	30 mg by mouth daily
B12	6 mcg	1000 mcg intramuscularly once per week until deficiency is corrected, then once per month. Alternatively, 2000 mcg by mouth daily followed by 1000 mcg by mouth daily as long as malabsorption exists
Folate	400 mcg	1 mg po daily
Copper	2 mg	3 mg po daily

Vitamin and mineral supplementation may be beneficial (63). For example, in the case of the Cuban optic neuropathy, despite mild deficiencies in folate and B12, supplementation of these vitamins helped reverse the effects of the neuropathy.

Outcomes

Visual prognosis is dependent on early diagnosis. Immediate discontinuation of toxin and adequate vitamin supplementation may lead to some visual recovery.

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All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Michelle Y Wang MD

Dr. Wang of the Southern California Permanente Medical Group and Department of Ophthalmology has no relevant financial relationships to disclose.
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Editor

Jonathan D Trobe MD

Dr. Trobe of the University of Michigan has no relevant financial relationships to disclose.
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Former Authors

Alfredo A Sadun MD PhD (original author) and Peter A Quiros MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: Male=female
Heredity: none
Population groups selectively affected: elderly
Occupation groups selectively affected: none selectively affected

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Toxic and nutritional deficiency optic neuropathies

Differential Diagnosis

Leber hereditary optic neuropathy
Kjer autosomal dominant optic atrophy
chiasmal syndromes
pituitary adenoma
optic neuritis
- functional visual loss
- fictitious visual loss

Also Relevant

Alcohol abuse and its neurologic complications
Alcoholic myopathy
Drug-induced neuropathies
Eating disorders: neurologic manifestations
Leber hereditary optic neuropathy
- Nutrition and the brain
- Nutrition-related peripheral neuropathies
- Toxic peripheral neuropathies
- Vitamin B12 deficiency

Toxic and nutritional deficiency optic neuropathies …

Toxic and nutritional deficiency optic neuropathies

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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to access the full version.

Questions or Comment?

Also in This Category

Brain death/death by neurologic criteria

Hepatic encephalopathy

Bowel dysfunction in neurologic disorders

Coma due to primary brainstem and diencephalic lesions

Giant cell arteritis

Ischemic optic neuropathy

Transient visual loss

Vestibular schwannoma

Toxic and nutritional deficiency optic neuropathies

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Brain death/death by neurologic criteria

Hepatic encephalopathy

Bowel dysfunction in neurologic disorders

Coma due to primary brainstem and diencephalic lesions

Giant cell arteritis

Ischemic optic neuropathy

Transient visual loss

Vestibular schwannoma

This is an article preview.
Start a Free Account
to access the full version.