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State-of-the-Art Review

Drug-Related Mitochondrial Optic Neuropathies

Wang, Michelle Y. MD; Sadun, Alfredo A. MD, PhD

Editor(s): Liu, Grant T. MD; Kardon, Randy H. MD, PhD

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Journal of Neuro-Ophthalmology: June 2013 - Volume 33 - Issue 2 - p 172-178
doi: 10.1097/WNO.0b013e3182901969
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Mitochondrial optic neuropathy (MON) is increasingly recognized as a major spectrum of optic neuropathies resulting from different genetic and acquired etiologies (1).

Clinical Features

The clinical presentation of MON is characterized by slowly progressive bilateral loss of central vision, dyschromatopsia, central or cecocentral scotomas, and loss of high spatial frequency contrast sensitivity (2) (Table 1). Patients often describe the visual loss as a central haze or dark cloud. Pain is not a feature of MON. Ophthalmoscopic features during the acute/subacute stage often reveal a hyperemic optic disc and peripapillary retinal nerve fiber layer (PRNFL) swelling (3). With time, temporal pallor of the optic disc develops. There is no relative afferent pupillary defect due in part to symmetric optic nerve involvement.

Clinical features of mitochondrial optic neuropathy

Clinical findings such as poor visual acuity, dyschromatopsia, and central visual field loss can be explained by selective damage to the papillomacular bundle (PMB). The fibers of the PMB are most susceptible due to their long unmyelinated segment in the retina and their small caliber. Preferential involvement of the PMB is a feature common to a wide range of acquired and genetic mitochondrial optic neuropathies (4,5).

Figure 1 summarizes the spectrum of MON. Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) are 2 well-documented examples due to mitochondrial or somatic DNA mutations. Other examples include nutritional deficiencies, such as lack of folic acid and vitamin B12, and combinations of nutritional deficiency and toxicity causing tobacco–alcohol and Cuban epidemic optic neuropathies. In all instances, MON begins with dysfunction of mitochondrial oxidative phosphorylation (6) and results in impaired function of the PMB.

FIG. 1
FIG. 1:
Mitochondrial dysfunction plays a central role in the pathogenesis of many optic nerve diseases, either inherited or acquired. Instead of classifying them as separate entities, mitochondrial optic neuropathies have now been recognized as a spectrum of conditions leading to optic atrophy by a similar pathway. CEON, Cuban epidemic of mitochondrial optic neuropathy; TAA, tobacco-alcohol amblyopia.

Common Pathway

Mitochondria provide the majority of cellular energy by oxidative phosphorylation. During the process, electrons are transferred down a chain of complexes. When electrons do not complete the process, reactive oxygen species are generated as a byproduct. The combination of energy depletion and oxidative stress results in the opening of the mitochondrial permeability transition pore, allowing for leakage of cytochrome c, a key activator for apoptosis (Fig. 2).

FIG. 2
FIG. 2:
Accumulation of reactive oxygen species (ROS) leads to a decrease in the electrical potential across the mitochondrial membrane, which allows for an opening of the mitochondrial permeability transition pore (MPTP), allowing for leakage of cytochrome c (Cyt c) into the cytosol. Cyt c then binds to apoptosis activating factor-1 (APAF-1), which activates procaspase-9, triggering the caspase cascade and apoptosis.

The axons of retinal ganglion cells (RGCs) converge toward the optic nerve head and pass through the lamina cribrosa. Myelination of axons begins only posterior to the lamina cribrosa.

The fibers of the PMB are anatomically distinct in 2 regards. First, like all axons emanating from RGCs, they run an unmyelinated course through the retinal nerve fiber layer (RNFL). Second, they are narrow in caliber. Membrane potential must be recharged at each node of Ranvier and along any other unmyelinated segment. A number of factors probably lead to selective vulnerability of the PMB axons. These include high energy needs coupled with low energy production, a high surface area to volume ratio, and absence of saltatory conduction due their unmyelinated structure (7).

As a part of a compensatory mechanism, mitochondria accumulate within RGC axons. These axonal changes can be detected by optical coherence tomography (OCT) (8,9). Appearance of optic disc pallor usually occurs in later stages, indicating irreversible axonal loss. With cessation of triggering factors, improvement in visual fields and corresponding reduction in the nerve fiber layer thickness can be observed in some acquired cases with resolution of axonal engorgement.

Workup and Ancillary Testing

The best screening tests for MON are those that measure the functions subserved by the PMB, including visual acuity, color vision, contrast sensitivity at high spatial frequencies, central visual field testing and, possibly, pattern visual-evoked potentials. The extent of visual loss varies widely; however, visual acuity of hand motions, light perception, or no light perception is very rare as non-PMB retinal nerve fibers usually are spared. Color vision loss sometimes may be more profound than visual acuity loss. Contrast sensitivity may be effective in detecting subclinical toxic optic neuropathy (10). Central or cecocentral scotomas are the hallmark visual field defects. The red Amsler grid is a particularly useful screening test. OCT is a useful ancillary test in the subacute and chronic stages by measuring the RNFL thickness and confirming thinning involving the PMB beginning in the inferotemporal sector (11–14). In the later stages, OCT demonstrates thinning of RNFL thickness in all quadrants (9).


A number of drugs injure the optic nerve by interfering with mitochondrial oxidative phosphorylation, thereby producing a classic clinical picture of MON.

Drugs proven to cause MON by blocking oxidative phosphorylation include ethambutol, chloramphenicol, linezolid, erythromycin, streptomycin, and antiretroviral drugs (15–17). A number of other drugs that can cause optic neuropathy but less strongly associated with mitochondrial dysfunction are amiodarone, infliximab, clioquinol, dapsone, quinine, pheniprazine, suramin, and isoniazid (16,18).


Worldwide, there are approximately 9.2 million new cases of tuberculosis (TB) each year, and about 55% of these patients take ethambutol to prevent or delay the emergence of drug resistance (19). As a consequence, ethambutol is the most common cause of toxic optic neuropathy accounting for 100,000 new cases each year (20).

Ethambutol is a metal chelator, destroying bacteria by inhibiting arabinosyltransferase, an important enzyme in mycobacterial cell wall synthesis. Due to the similarity between mammalian mitochondrial DNA (mtDNA) and bacterial ribosomes, ethambutol also disrupts oxidative phosphorylation and mitochondrial function by interfering with iron-containing complex I and copper-containing complex IV (17). Copper is a required cofactor for cytochrome c oxidase, an essential component in the electron transport chain. Ethambutol may reduce the level of copper, thereby interfering with oxidative phosphorylation. Replacing copper leads to improved RGC survivability in in vivo models of ethambutol optic neuropathy (21). It is interesting that copper deficiency due to malabsorption from bariatric surgery also has been associated with visual loss from optic neuropathy (22,23). Other studies suggest that zinc also might play a role in ethambutol toxicity (21,24), and individuals with reduced serum zinc level may be more susceptible to ethambutol ocular toxicity (25,26). A study using cell cultures demonstrated that the chelating effect of ethambutol may inhibit lysosomal activation, resulting in accumulation of zinc in lysosomes with increased lysosomal membrane permeability and cell death (27).

Ethambutol ocular toxicity has been well documented in the literature shortly after its introduction in 1960s (28–44). The frequency of vision impairment has been reported in 50% of patients at a dose of 60–100 mg/kg/d, 5%–6% at 25 mg/kg/d, and 1% at ≤15 mg/kg/d (45). Visual loss is typically insidious and symmetrical, occurring typically 2–8 months after the initiation of therapy. Central field loss usually is detected (38,39) (Fig. 3) but other patterns such as bitemporal defects have been described (46–48), and neuroimaging may be required because these findings suggest chiasmal involvement. Age, hypertension, and renal disease have been reported as risk factors (49). The standard treatment regimen for newly diagnosed cases of TB consists of an initial phase lasting 2 months, followed by a continuation phase of 4–6 months. The initial phase usually includes isoniazid, rifampicin, pyrazinamide, and ethambutol. Ethambutol toxicity is duration dependent and dose dependent. The recommended single daily dose for the initial phase in adults is 15–20 mg/kg body weight for 2 months or 20–35 mg/kg body weight 3 times a week (50). The dose is as efficacious when given 3 times weekly as when given daily with the potential advantage of better compliance, reduced cost, and less ocular toxicity (51). Typically, toxic levels of ethambutol occur when dosage is not adjusted according to the patients’ weight or renal function. However, vision loss has been reported in 1% of patients taking even the recommended dose (52,53).

FIG. 3
FIG. 3:
Ethambutol optic neuropathy. A. A 65-year-old woman developed vision of 20/400, right eye, and 20/800, left eye, after beginning ethambutol at a dose of 26.5 mg/kg/d for Mycobacterium avium. Automated visual fields show bilateral cecocentral scotomas with temporal field depression. B. Three months after cessation of ethambutol, visual acuity was 20/60, right eye, and 20/80, left eye, with improvement in visual fields. One year later, vision was 20/30 bilaterally.

The Centers for Disease Control has a dosing table for adults based on estimated body weight (54). The World Health Organization has recommended a daily dose of 20 mg/kg (range, 15–25 mg/kg) for children of all ages with drug-susceptible TB (55). A higher range of daily dose (20–30 mg/kg) should be considered only for drug-resistant TB (56).

Optic neuropathy is rare with treatment of less than 2 months and often reversible with early withdrawal. However, irreversible damage may occur especially if treatment exceeds 6 months (57,58). After cessation of ethambutol, visual impairment often worsens over a period of months, followed by stabilization and gradual improvement over the next 6 months. Although vision may improve after cessation of the drug, it is not unusual to have permanent visual deficits (59,60). As ethambutol is renally excreted, patients with impaired renal function are at greater risk for toxicity (61). Most cases of vision loss in patients on recommended doses occur in those with poor renal function (58).

It is important to individualize the treatment regimen and monitor patients closely for early signs of optic neuropathy. Patients should be educated to withdraw the drug at the onset of any visual symptoms. There is no consensus on the standard of treatment for ethambutol ocular toxicity or specific screening and monitoring recommendations for asymptomatic patients. A baseline ophthalmologic examination, including visual acuity, color vision, and visual fields, should be performed before initiation of ethambutol and repeated at the onset of visual symptoms. During the treatment phase, asymptomatic patients taking the recommended doses may be monitored every 1 to 3 months (62). Monthly monitoring may be necessary for patients with increased risks for toxicity, such as diabetes, chronic renal failure, renal TB, alcoholism, old or young age, or coexisting ocular deficits (63). Contrast sensitivity and multifocal ERG also may be helpful tests to detect subclinical changes (64). Pattern visual-evoked responses may demonstrate an increased mean latency of the P100 wave (65), and OCT assists in monitoring RNFL thickness (66).


In the 1970s, chloramphenicol was frequently used as chronic treatment for children with cystic fibrosis (67). Chloramphenicol inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit, thereby inhibiting mitochondrial protein synthesis as well (68). 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. Transmission electron microscopy of bone marrow cells of patients taking chloramphenicol has shown swollen mitochondria with disrupted cristae and an abnormally high level of intramitochondrial iron deposits, confirming the toxic effect of the drug (69). The clinical findings of chloramphenicol optic neuropathy are characterized by hyperemic optic discs with blurred margins, swelling of the PMB, and central scotomas (70).


Linezolid was first introduced in 2000 to treat methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. Linezolid inhibits protein synthesis by binding to 23S ribosomal RNA (rRNA) of the bacterial 50S ribosomal subunit and inhibiting formation of the 70S initiation complex. As mitochondrial ribosomes are similar to those of bacteria, protein synthesis in mitochondria also is disrupted. Linezolid is generally well tolerated when used up to 28 days. Both optic and peripheral neuropathies have been reported in patients taking linezolid for longer periods (71). Linezolid reaches inhibitory concentrations for most gram-positive pathogens within 4 hours after a single oral dose of 600 mg (72). Toxicity has been associated with off label extended therapy of 5–50 months (73–75). Full visual recovery has been reported in some cases after discontinuing the drug (76); however, the peripheral neuropathy is often irreversible. The initial optic disc edema and PRNFL resolves after cessation of the drug (76). In a rat model, linezolid has been shown to induce a dose-dependent and time-dependent decrease in the activity of mitochondrial complex I and complex IV (77).

Other Antibiotics

Erythromycin binds to the 23S rRNA of the 50S ribosomal subunit, impairing protein synthesis. Erythromycin-induced mitochondrial dysfunction has also been noted to be dose dependent (78). Similarly, streptomycin, an aminoglycoside, better known for toxicities involving the eighth cranial nerve and peripheral nerves, also may cause optic neuropathy (79).

Genetic Mitochondrial Dysfunction Predisposes Patients to Greater Toxicity

Pre-existing dysfunction in mitochondrial metabolism from genetic causes such as LHON and ADOA likely makes patients more vulnerable to drug-induced MON.

The nucleoside analog azidothymidine (AZT), also known as zidovudine, is an important component of highly active anti–retroviral therapy (HAART), in the treatment of HIV. 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 used not only by retroviral reverse transcriptase but also by the mtDNA polymerase gamma (80). Therefore, all nucleoside analogue reverse transcriptase inhibitors may induce mitochondrial toxicity by inhibiting mitochondrial polymerase gamma and mtDNA replication (81,82).

Case reports of profound visual loss and color deficiencies in LHON patients harboring either the 11778 or 14484 mutations after initiation of HAART have been reported, suggesting that antiretroviral therapy may be associated with increased risk in genetically predisposed patients (83,84). Ethambutol and erythromycin have also been suggested to trigger LHON (85–87). Similarly, ethambutol has been linked to visual loss in a patient with dominant optic atrophy (DOA) with an OPA1 mutation (88). If possible, these drugs should be avoided in patients harboring genetic mitochondrial defects.


A careful history usually provides key information allowing identification of MON. A complete list of medications may identify the causal agent. Serum vitamin levels of B1, B2, B12, and folic acid as well as red blood cell pyruvate may be helpful in detecting nutritional causes. A 24-hour urine collection for heavy metal screening may help identify particular toxins. A positive family history of optic nerve disease, presence of telangiectatic vessels around the optic disc, and the sequential involvement of both eyes are very suggestive of LHON. This diagnosis may be confirmed by genetic testing. An autosomal dominant family history and slowly progressive optic neuropathy starting in late childhood favors DOA.

Optic neuritis may occasionally occur bilaterally and produce central or cecocentral scotomas. However, a history of multiple sclerosis, presence of white matter defects on magnetic resonance imaging, and recovery of visual acuity over several weeks support the diagnosis of optic neuritis.

Similarly, pituitary tumor or other chiasmal syndromes produce bitemporal visual field loss, which, on occasion, may simulate a cecocentral defect. In such cases, neuroimaging is warranted.

Systemic associations such as combinations of paresthesias, ataxia, or hearing loss suggest multifactorial, mixed nutritional optic neuropathies. These cases do not usually result from toxic exposure or single vitamin deficiency (89).


It is not unusual to find published case reports claiming to describe a new toxic optic neuropathy. Such a collection of anecdotal cases or case series may suggest an association. But establishing an agent to be causal requires a higher standard. We propose the following postulates for establishing toxic optic neuropathy:

  1. There should be a strong scientific rationale to explain why there is an optic neuropathy. Why would RGCs or their axons be vulnerable?
  2. There should be something resembling a clinical dose–response curve. Higher doses should make the optic neuropathy worse and more likely.
  3. Longer duration of exposure is a risk factor. Longer periods of exposure or a higher total dosage should increase the risk.
  4. At least some recovery after discontinuation. Stopping the toxin should help, at least a little.
  5. Asymmetry should be the exception and explicable. Toxins will not preferentially choose one optic nerve over the other.

Generally, the more postulates satisfied, the greater the likelihood of causation.


With MON, there is often a window of reversibility because mitochondrial dysfunction may lead to functional impairment without immediate axonal loss. Axons may undergo compensatory stages of mitochondrial congregation, slowed axonal transport, and axonal swelling before apoptosis. However, if the injury is long standing and the axons have already suffered irreversible damage as reflected by severe optic atrophy, there will be little or no recovery. Therefore, prompt recognition of drug-induced toxicity and cessation of the medication is critical in preventing irreversible vision loss.


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