Ethambutol Optic Neuropathy

Paul D. Chamberlain; Ama Sadaka; Shauna Berry; Andrew G. Lee

Disclosures

Curr Opin Ophthalmol. 2017;28(6):545-551. 

In This Article

Screening for Subclinical Ethambutol-induced Optic Neuropathy

Of significant interest to prescribing physicians and ophthalmologists are methods to screen for preclinical signs of EON so as to stop ethambutol before vision loss occurs. Visually evoked potentials and optical coherence tomography (OCT) have been used to assess subclinical visual impairment in patients with optic neuritis and multiple sclerosis,[33–35] and are under investigation for their potential role in detecting subclinical EON. In addition, multifocal electroretinogram (MfERG) has been used to successfully detect retinopathies due to toxicity from medications such as chloroquine,[36] and may be able to detect retinal damage secondary to ethambutol toxicity.

Visual Evoked Potentials

Visual evoked potentials or visual evoked responses are small electrical signals generated in the occipital cortex following a brief visual stimulus. The p100 wave is a positive deflection that occurs on an average 100 ms after the visual stimulus. An increased latency of the p100 is a well-established tool in the diagnosis of optic nerve disease such as optic neuritis,[37] though the exact amount that constitutes an abnormality varies by machine. The utility of VEP for detecting subclinical abnormalities in patients taking ethambutol is less well established.

Several studies have found increased p100 wave latency in patients diagnosed with EON.[4,7,22,32] In 2008, a study of 857 patients showed that increased latency (mean 127.7 ms) was found in 65.4% of the eyes in patients diagnosed with EON. In a 2015 study[7] five of nine patients with EON on whom VEP was conducted had increased latency. In this study, the amount of latency was not specified and VEP was not conducted on 53 of the 62 patients with EON. Other studies have also evaluated the effect of ethambutol therapy on p100 latency regardless of EON status.[30,38–41] A study of 31 patients in 2016[30] reported data showing that the mean p100 latency increased from 101 to 106.4 and 115.1 ms at 2 and 4 months, respectively. Another study reported changes in VEP p100 latency in terms of the percentage of patients who had increased latency beyond a given cut-off value derived from the VEP p100 of study controls.[41] They found that 34.8% of patients taking ethambutol had increased latency beyond 107 ms, 2 SD beyond the control mean of 97 ms. Other studies have produced similar results.[38,39]

Taken together these results show promise for the utility of VEP for EON screening, but more research is needed to better understand its usefulness for this purpose clinically. At this time, the use of VEP for EON screening must be done with a word of caution. Although a finding of increased p100 latency may indicate decreased function of the optic nerve, it is not yet clear how many of these patients will go on to develop clinical EON. In addition, VEP testing is not readily available to all clinicians and patients. Any decision to discontinue ethambutol or change the dosing should be made by the prescribing physician following a discussion in which risk of possible EON is weighed against the risk of potentially suboptimal antituberculosis treatment.

Optical Coherence Tomography

OCT and measurement of the retinal nerve fiber layer (RNFL) has also proven an effective tool in the evaluation of optic neuritis and other optic neuropathies,[42] although its sensitivity in detecting subclinical disease has not been as high as VEP.[33,35] Like VEP, OCT has only been evaluated as a tool for detecting EON in a handful of small studies to date.[30,39,43,44,45–47,48*] Several studies used OCT to detect changes in the RNFL of patients with clinically significant vision loss from EON.[44,45–47] These studies demonstrated a decrease in RNFL thickness of 20–79%.[45,47] However, the value of OCT depends on its ability to reliably detect subclinical EON so that ethambutol therapy may be adjusted before vision loss occurs. In studies aimed at detecting subclinical EON, the findings have not been validated.[30,39,43,48,49] Two studies representing 68 patients taking ethambutol actually found an increase in RNFL thickness overall or in select quadrants.[30,43] Another study detected temporal RNFL thinning in 3/104 (2.88%) of 104 eyes in patients taking ethambutol,[39] but no patient developed subsequent EON. Yet another reported aggregate RNFL thinning of approximately 5 μm[48] over 2 months, though data on individual patients was not reported. In addition to damage to the RNFL, experiments in animal models have demonstrated toxicity of the retinal ganglion cell layer.[50,51] One study in 37 patients treated with ethambutol examined changes in the ganglion cell-inner plexiform layer (GCIPL) thickness on OCT.[43] One patient developed EON and OCT revealed GCIPL layer thinning whereas patients without EON had no significant changes GCIPL thickness. Taken together, these findings suggest that although OCT is likely to be able to detect significant RNFL and possibly GCIPL thickness changes in patients with clinical EON, it may or may not be useful in screening patients for subclinical disease while on ethambutol therapy. More research is needed to adjudicate this question and establish OCT screening guidelines for EON.

Multifocal Electroretinography

While damage to the optic nerve is likely important in the mechanism of visual loss in many patients taking ethambutol, evidence also suggests that ethambutol may produce visual symptoms through toxicity to retinal cell layers as well.[36,43,50,51] Multifocal electroretinogram is a test especially useful in the detection of retinopathies[36] and produces a waveform with two negative deflections (N1 and N2) and one positive deflection [P1]. Abnormalities in MfERG provide early and reliable detection of retinopathies due to chloroquine and hydroxychloroquine,[36] but relatively few studies have examined its utility in detecting EON. Four case series representing nine patients[52–55] have shown decreased amplitude of MfERG waves in central and nasal macular regions in patients with vision loss while taking ethambutol. In two larger studies of 17[56] and 44[57] patients taking ethambutol the researchers found decreased P1 amplitude and delayed P1 latency. None of the patients in these studies developed visual symptoms, suggesting the ability of MfERG to detect subclinical disease. More research is needed to understand the role MfERG should play in the detection of subclinical retinal toxicity in patients taking ethambutol.

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