Abstract

Ethambutol is a commonly used antimycobacterial agent used in the treatment of tuberculosis (TB) and known for its potential to cause optic neuropathy. It typically presents as bilateral, painless visual loss and incidence can range between 0.5% and 18% depending on factors such as duration of treatment and dosage [1,2]. We report the case of a 35-year-old female presenting with bilateral optic neuritis suggestive of toxic optic neuropathy secondary to ethambutol with associated central nervous system (CNS) imaging abnormalities on the MRI. In clinical practice, ethambutol optic neuropathy (EON) is often under-recognised, but the condition is potentially reversible if detected early, making diagnosis crucial.

Case Presentation

A young female in her mid-thirties presented with a three-week history of worsening blurry vision. She complained initially of blurred vision in both eyes that first occurred on waking. It gradually progressed over three weeks, and she developed what she described as a large central white spot in both eyes, worse on the left. Eye movements were not painful. Occasionally, she saw colourful spots around the periphery of her vision, but these were transient. Changes in her vision became stagnant after three weeks and did not deteriorate further.

She was known to have hypothyroidism on levothyroxine and had recently moved to the UK one month prior to her hospital admission. She denied that she smoked, drank alcohol or used drugs and she lived with her husband and children. Her sister suffers from systemic lupus erythematosus but there was no other significant family history. She was started on treatment for possible tuberculosis after developing a chest infection with features suspicious of TB while still in India. She received a course of anti-tuberculosis treatment comprising of isoniazid, rifampicin, pyrazinamide, and ethambutol, which was started in India six months prior to admission. The exact duration and regime of treatment is not known as it was not initiated in the UK.

She was referred to neurology from the ophthalmology department after being found to have bilateral optic neuritis on examination. Her ophthalmological assessment revealed reduced visual acuity – Right 6/60 with glasses (6/36 with pinhole), Left 1/60 with glasses, Intraocular pressure (IOP) Right 13 mmHg and Left 13 mmHg.  An Ishihara exam was attempted but the patient struggled due to poor vision; however, colour vision was notably worse. There was no relative afferent pupillary defect (RAPD) and no conjunctival abnormalities.  The rest of the neurological exam was normal – Power was 5/5 globally, reflexes were present and symmetrical and plantars were downgoing. Sensation to fine touch and pin prick was preserved in all dermatomes.

Investigations and differential diagnoses

The patient subsequently underwent a CT head scan with contrast, which revealed no acute abnormalities – no evidence of leptomeningeal or pachymeningeal enhancement. This was followed by an MRI of the brain and orbits which demonstrated subtle increased bulk of the pre-chiasmatic optic nerves within the intra-conal segments, at the orbital apex and back to the chiasm with subtle symmetrical central T2 signal change on Short Tau Inversion Recovery (STIR) sequences, without significant neural or perineural enhancement on fat-saturated T1 sequences post gadolinium as highlighted in Figure 1. No additional intracranial abnormalities were identified, and the visualised cervical spinal cord up to the C4 level appeared normal on the non-dedicated imaging. The main differential for these findings was inflammatory, and given the symmetrical change and involvement of the chiasm, neuromyelitis optica (NMO) spectrum disorder would have been the radiologically favoured differential. Importantly, an extensive workup for inflammatory aetiologies was unremarkable. Negative testing for cerebrospinal fluid (CSF) specific oligoclonal bands, aquaporin-4 (AQP4), and myelin oligodendrocyte glycoprotein (MOG) antibodies made demyelinating disorders less likely. MRI changes, while not universally present in EON, can support the diagnosis and help differentiate from demyelinating or compressive optic neuropathies.

Figure 1: Neuroimaging findings at presentation: MRI demonstrated bilateral T2 signal hyperintensity on coronal Short Tau Inversion Recovery (STIR) within the pre-chiasmatic, intraconal optic nerves (A, yellow arrows). Symmetrical signal extended back to the level of the chiasm (B, red arrow heads). Axial and coronal T1 fat-saturated sequences post gadolinium demonstrated no enhancement (C and D, blue arrows).

On the OCT, the disc and macula were unremarkable with normal retinal nerve fibre layer (RNFL) thickness.

Nutritional deficiencies, particularly of B-complex vitamins, were also excluded as vitamin levels A, B, and E were all within normal range. There was no family history of hereditary optic neuropathy, such as Leber’s hereditary optic neuropathy. Bloods, including serum angiotensin converting enzyme (ACE), QuantiFERON, HIV, syphilis, and hepatitis B, C, were negative which made infiltrative diseases like sarcoidosis, active tuberculosis and infectious causes less likely. Normal inflammatory markers also supported this. Viral CSR PCR was also negative. Thyroid function tests were in the normal range.  CSF was tested, and results are shown in Table 1 below. Normal CSF opening pressure ruled out idiopathic intracranial hypertension as a potential cause.

ANA was positive, with positive Anti-Ro antibody for which she was referred to rheumatology. Anti-double-stranded DNA (anti-dsDNA) and the rest of ANA antibody profile were negative. Rheumatology opinion was that, given she had no symptoms of systemic lupus erythematosus or Sjogren’s disease and normal inflammatory markers, this positive antibody was likely drug-induced secondary to her TB treatment.

CSF Results Table

Opening pressure (OP)17 cm H20
Albumin100 mg/L (<300)
IgG21 mg/L (<34)
WCC1 (lymph – 0)
RBC0
MicroscopyNo growth
Viral PCRnegative
Total Protein0.27g/L
Glucose3.31 mmol/L
Table 1. Table showing results of CSF investigations.

Treatment and Patient Outcome

Ethambutol was stopped, and the patient was treated with five days of oral methylprednisolone 500mg once daily, followed by vitamin C, zinc, iron, and copper supplementation.

Initially, there was not much improvement in her vision, and she was discharged with close outpatient follow-up. Her first ophthalmological assessment one month later did not show much improvement. However, at her second review three months later, there was improvement in visual acuity (VA): right eye 6/12 with correction (improving to 6/9 with pinhole) and left eye 6/12 with correction (6/9 with pinhole). Intraocular pressures were within normal limits—18 mmHg in the right eye and 16 mmHg in the left. There was excellent improvement in visual acuity ten months later with VA 6/6 in both eyes. She has not developed any further complications to date.

Discussion

Ethambutol-induced optic neuropathy (EON) is a well-documented but potentially under-recognised adverse effect of ethambutol therapy. Most cases present during active treatment; however, toxicity can manifest weeks to months after discontinuation, likely due to cumulative effects and individual susceptibility [3]. This patient’s subacute progression of bilateral blurry vision over 3–4 weeks is characteristic of EON, which typically presents as bilateral, symmetric, painless visual decline with central or cecocentral scotomas and colour vision deficits [4,5].

EON is a well-established adverse effect of ethambutol that correlates strongly with both the dose and duration of therapy. The risk increases significantly with higher daily doses, with some papers suggesting that it can occur in approximately 15% of patients on 50 mg/kg/day, 5% on 25 mg/kg/day, and less than 1% on the standard 15 mg/kg/day regimen [3,6]. Despite standard dosing, some individuals remain vulnerable to toxicity, underscoring the role of individual susceptibility.

The mechanism behind ethambutol-induced optic neuropathy is not fully understood, but several theories have been proposed. One hypothesis suggests that ethambutol and its metabolites chelate essential trace metals, particularly zinc, disrupting retinal and optic nerve homeostasis [7]. Additionally, ethambutol may impair mitochondrial function by interfering with iron and copper-dependent complexes in the electron transport chain, which may increase reactive oxygen species production, leading to oxidative stress and retinal ganglion cell injury [1,6,7]. Supplementation with trace elements and multivitamins has been suggested as a potential supportive strategy to reduce the risk or severity of EON, although evidence remains limited [7]. There is evidence for treatment with copper, zinc, vitamin C and hydroxocobalamin, given the previous mechanism of injury as supplementation may reduce these risks [8]. While the diagnosis is largely clinical, imaging findings are rarely described in the literature, making radiologic documentation of EON particularly valuable. Our case highlights distinctive MRI findings in ethambutol toxicity, demonstrating a subtle increase in the bulk of the pre-chiasmatic optic nerves within the intraorbital segments, extending to the orbital apex and back to the optic chiasm. Additionally, there was a subtle symmetrical central T2 hyperintensity and a slight increase in signal intensity on post-contrast imaging at the level of the orbital apex, with no large volume neural or perineural enhancement as shown in Figure 1.  These imaging characteristics are infrequently reported, and the presence of such correlating MRI findings shows the uniqueness and clinical significance of our case in expanding the radiologic spectrum of ethambutol-induced optic neuropathy. There are a few other reports of similar MRI findings supporting the diagnosis, as in the Journal of Neuro-Ophthalmology showing hyperintense signal within the optic chiasm and a small amount of hyperintensity within the optic chiasm anterior to the infundibulum [9], and a case report in the Taiwan Journal of Ophthalmology [1].

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The patient received empiric treatment with corticosteroids and a regimen including zinc, vitamin C and copper, along with cessation of the drug [4]. A short course of methylprednisolone was given, as there is no known treatment regime for ethambutol-induced optic neuropathy. A small Korean study showed that steroids did have a positive therapeutic effect on EON [10]. The aquaporin-4 and anti-MOG antibodies had also just been sent, and though it was felt to be less likely inflammatory in nature, a decision was made to cover with steroids at this time. There was not much change to her symptoms initially however, substantial improvement in visual acuity was noted over the next few months. This improvement in visual acuity after cessation of the drug and treatment outlined above supports the diagnosis of ethambutol toxicity. One study reports up to 77% of patients show significant improvement in vision however, outcomes vary with recovery time ranging from 1 month to 12 months [11,12]. Notably, the cornerstone of management in EON remains prompt discontinuation of ethambutol [2,3].

In conclusion, this case highlights the importance of swift recognition and management of ethambutol-induced optic neuropathy. Early diagnosis, immediate discontinuation of the drug, timely treatment, and ongoing ophthalmological monitoring can significantly improve visual outcomes. While magnetic resonance imaging may reveal optic nerve abnormalities in ethambutol-induced optic neuropathy, these findings are often subtle and non-specific, underscoring the need for acute diagnostic consideration by physician to guide targeted interpretation. Educating patients about the early signs of visual impairment and encouraging them to report symptoms promptly is essential [13]. Ultimately, this case emphasises the critical value of reviewing a patient’s medical history and medication exposure when evaluating vision loss, as well as the need for thorough counselling regarding visual side effects when initiating ethambutol therapy. Given the widespread global use of ethambutol in tuberculosis treatment, clinicians must maintain a high index of suspicion for this condition.

References

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