Toxic optic neuropathy is damage to the anterior visual pathway due to exposure to chemical substances. Well-known causes include tobacco, alcohol, and paint thinner, and among medications, ethambutol is representative. It is characterized by nearly simultaneous and similar visual impairment in both eyes, and unlike optic neuritis, it is painless.
Causative substances of toxic optic neuropathy are broadly divided into drug-induced and chemical-induced.
| Category | Main causative substances |
|---|---|
| Antituberculosis drugs | Ethambutol (Ebutol®, Esambutol®), isoniazid (Iscotin®) |
| Antibiotics | Chloramphenicol (Chloromycetin®), streptomycin, linezolid (Zyvox®) |
| Antiarrhythmic drugs | Amiodarone (Ancaron®) |
| Anticancer drugs | Cisplatin (Randa®), carboplatin, vincristine (Oncovin®), 5-FU |
| Immunosuppressants | Cyclosporine (Neoral®), tacrolimus (Prograf®) |
| Other drugs | Interferon preparations, tamoxifen (Nolvadex®), infliximab (Remicade®), sildenafil (Viagra®) |
| Chemical substances | Methanol, carbon monoxide, carbon disulfide, toluene (paint thinner), carbon tetrachloride, styrene, quinine |
Ethambutol is a first-line drug used against Mycobacterium species, particularly Mycobacterium tuberculosis and nontuberculous mycobacteria such as Mycobacterium avium complex (MAC). Ethambutol optic neuropathy (EON) is its most significant adverse effect and consistently ranks among the most frequent causes of drug-induced optic neuropathy.
The prevalence of EON in patients receiving tuberculosis treatment is estimated at 1–2%. According to the World Health Organization (WHO), approximately 9.2 million new tuberculosis cases are reported annually, potentially resulting in up to 100,000 new cases of EON per year.
The risk of EON is highly dose-dependent. The estimated prevalence by EMB dose is shown below.
| EMB dose | Estimated prevalence |
|---|---|
| <15 mg/kg/day | <1% |
| 25 mg/kg/day | 5–6% |
| >35 mg/kg/day | 18–33% |
However, EON has been reported even at low doses (<15 mg/kg). In a Japanese nationwide survey, 52.2% of EON cases occurred at low doses, indicating that there is no truly “safe” dose 3).
In 2009, the WHO revised its guidelines to include EMB in the maintenance phase of tuberculosis treatment, extending the duration of administration. This change has raised concerns about an increased risk of developing EON 1).
It is broadly divided into drug-induced and chemical-induced causes. Among drugs, the antituberculosis agents ethambutol and isoniazid are the most common, followed by amiodarone, linezolid, cisplatin, interferon, infliximab, and others. Representative chemical substances include methanol, carbon monoxide, and toluene (paint thinner). All share the common features of bilateral, painless vision loss and color vision abnormalities.
Common features of toxic optic neuropathy include the following:
Unlike other toxic optic neuropathies, EON can occur relatively soon after starting treatment. The onset time ranges from 1 month to 36 months after starting medication, but it is unlikely within 2 months, with an average of 7 months.
The main subjective symptoms are as follows.
Color vision abnormalities may be the first sign. A subjective awareness that red does not appear as vivid as before can be a clue. Since bilateral visual loss progresses insidiously, regular visual acuity and color vision checks are important for early detection.
The exact mechanism of EMB neurotoxicity is unknown, but metal chelation is considered the main cause. Both EMB and its metabolite 2,2-ethylenediaminodibutyric acid (EDBA) are chelating agents and are thought to induce optic neuropathy through the following pathways2).
Animal studies have shown that zinc deficiency is associated with myelin destruction and glial cell proliferation. In humans, long-term use of EMB may worsen optic neuropathy due to vitamin E and B1 deficiency.
Optic neuropathy caused by ethambutol, linezolid, mesalazine, etc., is thought to be an acquired mitochondrial dysfunction, and similar to Leber hereditary optic neuropathy, optic disc hyperemia and thickening of the nerve fiber layer above and below the optic disc may be observed.
High-dose and long-term use, age 65 or older, renal impairment, hypertension, diabetes, smoking, and concurrent use of isoniazid are known risk factors. For details, see the “Causes and Risk Factors” section.
Isoniazid (Iscotin®) is a major anti-tuberculosis drug alongside EMB. Since isoniazid consumes vitamin B6 during metabolism, supplementation of vitamin B6 is important during treatment with this drug. Concurrent use with EMB may further increase the frequency of optic neuropathy.
The following drugs have also been reported to cause toxic optic neuropathy. The risk varies depending on dosage, duration of administration, and individual susceptibility.
Optic neuropathy due to tobacco and alcohol overlaps with nutritional optic neuropathy. It is thought to involve a mechanism in which retinal ganglion cells with high ATP consumption, specifically P cells, are preferentially damaged, which corresponds to the formation of central scotomas.
The diagnosis of toxic optic neuropathy is made clinically. First, the history of ingestion or exposure to causative substances (especially antituberculosis drugs such as EMB) is confirmed through interview. Furthermore, MRI and blood tests are performed to rule out optic neuritis and other optic neuropathies.
As screening, it is desirable to perform visual acuity, visual field, critical flicker frequency, and color vision tests before administration of antituberculosis drugs such as EMB, and to check once every 1 to 2 months during administration.
VEP
Visual evoked potential (VEP): Considered the most sensitive test for monitoring. In toxic optic neuropathy, a decrease in amplitude is characteristic, and delay in P100 latency is generally not observed. However, there are reports that P100 is prolonged to 107 ms or more in patients taking ethambutol 2). It is useful for detecting potential optic nerve damage but is not specific to EON.
OCT
Optical coherence tomography (OCT): Detects thinning of the peripapillary retinal nerve fiber layer (pRNFL) and changes in the ganglion cell layer-inner plexiform layer (GCIPL). Temporal-dominant changes are characteristic, with reductions of 20-79% reported 2). It is also useful for evaluating visual prognosis.
The following should be considered in the differential diagnosis of toxic optic neuropathy:
| Disease | Key Differentiating Features |
|---|---|
| Leber hereditary optic neuropathy | Early stage is easily misdiagnosed as toxic (smoking also involved). Mitochondrial gene mutation testing is required. |
| Autosomal dominant optic atrophy | Slow progression, early onset of optic atrophy. |
| Compressive/infiltrative optic neuropathy | Treatable diseases that should be ruled out by neuroimaging. |
| Bilateral optic neuritis (inflammatory) | Presence or absence of eye movement pain is an important differentiating point. |
| Nutritional optic neuropathy | Optic neuropathy due to vitamin B12/B1 deficiency. Often overlaps with tobacco-alcohol dependence. |
| Maculopathy | Decreased central vision. Differentiated by fluorescein angiography and focal electroretinography. |
The principle of treatment for toxic optic neuropathy is discontinuation of the toxic substance. There is no specific antidote. No treatment is superior to drug cessation. For early detection, it is important to evaluate visual function before administration and to regularly monitor visual acuity, color vision, and visual fields during treatment.
There is no established treatment for EON. When EON is suspected, the most important action is to promptly discontinue EMB. The ophthalmologist should contact the prescribing physician directly before stopping EMB.
After stopping EMB, visual acuity and visual field defects may continue to progress for 2–3 months. Thereafter, gradual recovery occurs, but recovery is slow, taking from six months to two years.
Since vitamin B6 is consumed during the metabolism of isoniazid, supplementation with vitamin B6 is important during isoniazid therapy. In cases complicated by EON, discontinuation of isoniazid should also be considered.
Smoking should be discontinued because it has additive adverse effects in toluene (thinner) poisoning and EON. If underlying diseases that affect blood flow, such as hypertension or diabetes, are present, treatment should be coordinated with an internist.
| Prognostic factor | Impact |
|---|---|
| Early detection and early discontinuation | Visual improvement in 30–64% |
| Age < 60 years | Recovery rate approximately 80% |
| Age ≥ 60 years | Recovery rate approximately 20% |
In patients whose vision recovers, an average improvement of 2 lines on the Snellen visual acuity chart is observed 2). Some patients experience complete recovery of vision, while others have permanent visual impairment. The presence of optic disc pallor at onset is associated with a poor prognosis.
There are reports that RNFL thickness continues to decrease even after discontinuation of EMB, and irreversible vision loss can occur despite close monitoring and prompt drug discontinuation 2). In cases of severe optic atrophy, visual function may not improve.
If EMB is discontinued before irreversible optic atrophy occurs, visual function improves in 30–64% of patients. However, complete recovery is rare, and the average improvement is 2 Snellen lines. Symptoms may continue to progress for 2–3 months after discontinuation, so continuous follow-up is necessary. For details, see the section on “Standard Treatment.”
Retrobulbar optic neuropathy is the most common form of EON, and the optic disc appears normal at onset.
Drug-induced optic neuropathies caused by ethambutol, linezolid, mesalamine, etc., are thought to result from acquired mitochondrial dysfunction. The pathophysiology is similar to hereditary Leber hereditary optic neuropathy, and optic disc hyperemia and thickening of the nerve fiber layer above and below the disc may be observed.
Both EMB and its metabolite EDBA act as metal chelators. EDBA has lower intraocular clearance than ethambutol itself, leading to higher local concentrations, and is thought to contribute more to toxicity 2).
The main pathways of damage are as follows:
Parvo-cellular axons (p-cell axons) that constitute the papillomacular bundle have particularly high ATP consumption and mitochondrial energy demand. Therefore, in toxic and nutritional optic neuropathies, these axons are preferentially damaged 2). This is consistent with the mechanism of central scotoma formation.
In tobacco-alcohol optic neuropathy, p-cells with high ATP consumption are also thought to be predominantly damaged. In contrast, gamma cells involved in the pupillary light reflex are preserved, so the pupillary light reflex is relatively maintained.
Animal experiments suggest that EMB-induced axonal neuropathy tends to occur at the optic chiasm, which is consistent with the existence of clinical cases presenting with bitemporal hemianopia.
Sabhapandit et al. (2023) conducted a systematic review of 12 studies published between 2010 and 2021 (5818 individuals, 309 with EON) and reported that extended use of EMB beyond 2 months leads to significant optic neurotoxicity 1). Visual improvement after EMB discontinuation was statistically significant (P = 0.035). Improvements in color vision and visual field defects did not reach statistical significance.
Matsumoto et al. (2021) reported a case of an 85-year-old man who, despite low-dose EMB (12 mg/kg) and short duration (2.5 months), experienced rapid visual deterioration after EMB discontinuation, leading to irreversible vision loss 3). Corrected visual acuity, which was 20/17 before discontinuation, dropped to 20/330 (right eye) and 20/1000 (left eye) within 3 weeks. This demonstrates that even low doses can cause catastrophic vision loss.
Peterson & Hawy (2022) reported a case of late-onset EON in an 82-year-old man who took <15 mg/kg/day of EMB for 3 years during MAC treatment 4). Visual acuity improved after EMB discontinuation, and the improvement persisted at 10 months. Although the median onset is reported as 9 months, this case shows that onset can occur after more than 3 years.
Konana et al. (2024) reported three cases of cone dysfunction due to ethambutol toxicity 5). The main complaints were photophobia and decreased visual acuity, and electroretinography showed delayed latency of flicker responses. This suggests that ethambutol toxicity affects not only the optic nerve but also retinal cell layers.
With the introduction of fixed-dose combination tablets (FDC: containing isoniazid, rifampicin, pyrazinamide, and ethambutol per tablet) and extended treatment duration, an increase in EON incidence is anticipated 2). Important future research topics include establishing screening systems, verifying the utility of OCT and VEP in detecting subclinical EON, elucidating the pathogenesis of EON, and identifying risk factors.
