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It is difficult to assess the degree of optic nerve damage in patients with ethambutol‐induced optic neuropathy, especially just after the onset of visual loss, when the optic disc typically looks normal.
To evaluate changes in retinal nerve fibre layer thickness (RNFLT) using optical coherence tomography (OCT) in patients with optic neuropathy within 3 months of cessation of ethambutol treatment.
A retrospective observational case series from a single neuro‐ophthalmology practice.
8 patients with a history of ethambutol‐induced optic neuropathy were examined within 3 months after stopping ethambutol treatment. All patients underwent a neuro‐ophthalmologic examination, including visual acuity, colour vision, visual fields and funduscopy. OCT was performed on both eyes of each patient using the retinal nerve fibre layer analysis protocol.
The interval between cessation of ethambutol treatment and the initial visit ranged from 1 week to 3 months. All patients had visual deficits characteristic of ethambutol‐induced optic neuropathy at their initial visit, and the follow‐up examination was performed within 12 months. Compared with the initial RNFLT, there was a statistically significant decrease in the mean RNFLT of the temporal, superior and nasal quadrants (p=0.009, 0.019 and 0.025, respectively), with the greatest decrease in the temporal quadrant (mean decrease 26.5 μm).
A decrease in RNFLT is observed in all quadrants in patients with ethambutol‐induced optic neuropathy who have recently discontinued the medication. This decrease is most pronounced in the temporal quadrant of the optic disc.
Since its introduction in 1961, ethambutol has been widely used to treat infections caused by Mycobacterium tuberculosis and Mycobacterium avium complex. Side effects of ethambutol have been well documented since its original use, with the most serious one being optic neuropathy, which has been reported to occur in 1–5% of patients.1 Ocular manifestations usually develop months after initiation of treatment, but ocular symptoms occurring a few days after the onset of drug use have been reported in patients prescribed standard dosages of ethambutol (15–25 mg/kg/day).2,3 Clinical features of ethambutol‐induced optic neuropathy resemble those of a compressive optic neuropathy with a subacute clinical course with painless loss of central vision, cecocentral scotomas and dyschromatopsia. Funduscopy is typically normal, especially at the initial stages of the disease; therefore, other tests that can be performed to serially monitor disease progression may be useful.
Because it is difficult to assess the degree of optic nerve damage in patients with ethambutol‐induced optic neuropathy, especially just after the onset of visual loss, we used optical coherence tomography (OCT) to evaluate changes in retinal nerve fibre layer thickness (RNFLT) in patients with optic neuropathy who have recently discontinued ethambutol. Zoumalan et al4 previously used OCT to measure RNFLT in patients with ethambutol‐induced optic neuropathy, but their series reviewed three subjects who had various visual outcomes and were at different clinical stages, with the longest time elapsed being 5 years after cessation of ethambutol. To our knowledge, this is the first investigation using OCT to quantify a change in RNFLT in ethambutol‐induced optic neuropathy with relatively recent discontinuation (within 3 months) of antibiotic treatment.
After obtaining Institutional Review Board approval, the records of 10 patients with ethambutol‐induced optic neuropathy, seen over a period of 3 years (from October 2003 to May 2006) in a single neuro‐ophthalmology practice, were identified. Two patients were excluded from the study because they were seen only once. Thus, eight patients were included in the study and were examined within 3 months after stopping ethambutol treatment. All eight patients underwent at least two neuro‐ophthalmologic examinations and OCTs.
Each examination included an assessment of visual acuity using the Snellen Visual Acuity Chart, and of colour vision using the 11‐plate Ishihara Color Vision Test. Humphrey 24‐2 standard automated perimetry using the Swedish Interactive Test Algorithm strategy (Carl Zeiss Meditec, Dublin, California, USA) was performed at each visit. Funduscopy was performed by a single neuro‐ophthalmologist, and the appearance of optic disc was classified as normal, slightly pale or pale. OCT (OCT 3000, Humphrey‐Zeiss, Dublin, California, USA) was performed on both eyes of each patient using the retinal nerve fibre layer analysis protocol, as has been described elsewhere.4 Statistical analysis of the RNFLT was performed using the Student's t test. A p value of <0.05 was considered significant.
The mean (SD) age of the eight patients was 69.5 (11.1) years. The interval between cessation of ethambutol treatment to the initial evaluation ranged from 1 week to 3 months (mean (SD) 6.1 (4.2) weeks). The duration of symptoms ranged from 2 weeks to 3 months before the initial neuro‐ophthalmic presentation (mean (SD) 6.3 (3.8) weeks). The total duration of ethambutol treatment ranged from 3 to 22 months (mean (SD) 8.9 (6.7) months). The follow‐up examination, including an OCT, was performed between 2 months and 12 months (mean (SD) 8.1 (4.3) months) after the initial visit.
Table 11 summarises the clinical characteristics of the eight patients with ethambutol‐induced optic neuropathy. Comparing the data from the initial examination with that during the follow‐up examination showed that visual acuity in both eyes improved in six patients, remained the same in one patient and worsened in one patient. Colour vision was abnormal in both eyes in all patients at the initial visit, with three patients showing an improvement at the follow‐up visit. In the seven patients in whom automated perimetry could be done, three patients showed an improvement in mean deviation in both eyes, three patients showed a worsening in both eyes, and in one patient one eye had improved while the other eye had worsened. Five of eight patients had normal‐appearing optic discs at their initial visit, and in three of these patients optic disc pallor developed during the follow‐up period.
Comparing the mean RNFLT of both eyes of each patient at the initial visit with that of the follow‐up visit, 12 eyes showed a decrease in the mean RNFLT, 3 eyes showed no change, whereas only one eye showed a slight increase. There was a trend towards decreased RNFLT in all patients when comparing data from the initial with that from the follow‐up visit (mean 18.8 μm). This decrease was most pronounced in the temporal quadrant of the optic disc (mean –26.5 μm). The decrease in RNFLT of the temporal, superior and nasal quadrants was significant (p values 0.009, 0.019 and 0.025, respectively; table 22).
The optic disc typically looks normal in the early stages of ethambutol‐induced optic neuropathy, and it has been difficult to objectively measure a change in optic disc appearance in these patients. OCT is now a well‐recognised technique used to image the cross‐sectional microstructure of the retina, and has been used to measure the nerve fibre layer thickness in other optic neuropathies such as glaucoma.5 In our study, we used OCT to quantify the change in RNFLT in order to provide an objective means of measuring clinical progress in addition to traditional examination methods. The temporal quadrant of the optic disc and the corresponding retinal nerve fibres were most affected in our study, even though there was a statistically significant decrease in the superior and nasal quadrants as well. The greatest decrease in RNFLT in the temporal quadrant was also found in the study by Zoumalan et al.4 A selective loss of fibres in the papillomacular bundle has been suggested in toxic and hereditary forms of optic neuropathies, and this may explain their more prominent decrease in the temporal quadrant in our patients.
Toxicity from ethambutol is traditionally described as reversible on discontinuation of the drug, and vision is believed to recover gradually over weeks to months. However, permanent visual impairment has been described even with timely cessation of ethambutol in up to 3 years of follow‐up.1,6,7,8 During our follow‐up period ranging from 2 to 12 months, we observed improved vision in both eyes of six patients. Interestingly, even though there was some improvement in vision in these patients, we observed either a decrease or no change in RNFLT in all of these patients.
It is important to note that recovery is often not complete even in patients who report visual improvement after cessation of ethambutol treatment.1,6 Continued worsening of vision after cessation of ethambutol has also been described.1 In our series, two of the eight patients showed no improvement in vision, whereas the remaining six patients experienced some improvement. Of the two patients whose vision did not improve, one patient's vision remained stable in both eyes, whereas the other patient had progressive loss of vision even after stopping the medication.
OCT may serve as a useful tool to objectively quantify changes in RNFLT and to serially monitor the progression of the disease in patients with ethambutol‐induced optic neuropathy. In our study, a decrease in RNFLT, especially in the temporal quadrant, was seen in patients with ethambutol‐induced optic neuropathy who had recently discontinued the medication.
OCT - optical coherence tomography
RNFLT - retinal nerve fibre layer thickness
Competing interests: None declared.