As we have a lot of tuberculosis (TB) cases here in Southern Philippines Medical Center (SPMC), this study would like to know if there will be an increase rate and frequency of Ethambutol Toxic Optic Neuropathy (ETON) in this institution. This will also find out if there will be variables that will increase the likelihood of Ethambutol Toxic Optic Neuropathy (ETON), and lastly, the informations that will be gathered in this study will help increase the awareness and recognition of Ethambutol Toxic Optic Neuropathy (ETON) in this institution.
Tuberculosis (TB) has been present since prehistoric times. Around 460 BC, Hippocrates identified phthisis, which is the Greek term for consumption (TB seemed to consume people from within with its symptoms of bloody cough, fever, pallor and long relentless wasting) as the most widespread disease of the times, which was almost always fatal. Today, centuries later, TB is still the most common infectious disease, infecting millions of people worldwide.1 It has been a major public health problem in the Philippines for the past several decades. In the late 1990's, the Philippines was fourth in the world for the number of cases of tuberculosis, and had the highest number of cases per head in South East Asia.2 In 2002, TB was the sixth among the 10 leading causes of death and the 10 leading causes of illness in the country. While the mortality rate from TB has decreased in the past 20 years (from 206 deaths per 100,000 population in 1982 to 36 deaths per 100,0000 in 2002), still around 75 Filipinos die of TB everyday. By 2008, the country reached a TB case detection rate of 77% (exceeding the national and global target of 70%). Currently, the national TB treatment success rate is at 89% (above the national target of 85%). Globally, based on 2010 statistical record, the Philippines is one of the 22 countries identified by the World Health Organization (WHO) as having a high burden of TB, ranking at ninth worldwide. 2-4
Ethambutol hydrochloride (EMB) is one of the first-line agents employed in the treatment of tuberculosis,5 which was first introduced in 1961.6 Its original formulation was a racemic mixture, with the D-isomer providing most of the therapeutic effect and the L-isomer providing much of the toxic effect. The latter was eventually withdrawn from the market so that EMB is now only available in the D-form.7 Since the very first published report in ethambutol-related ocular toxicity came out in 1962,8 EMB is now the most widely implicated drug causing toxic optic neuropathy in man.9
The chelating property of EMB is the main culprit behind its toxicity. It may alter the Cytochrome-C oxidase activity and mitochondrial metabolism in optic nerves.10 Studies have shown that there is an association with decreased serum zinc and copper levels.11-12 There is also evidence in the literature showing that ocular toxicity is dose and duration-dependent.13-18 Renal disease is an important risk factor for the development of ocular toxicity.19 It was stated in a 1974 report of Barron et al. that 25mg/kg/day (locally-available commercial preparations contain less dosage) for 60 days followed by 15mg/kg/day for an indefinite period is exceedingly safe.20 However, toxicity has been reported to occur even at safe doses.21-22 Some authors believe that in the elderly, there is no such thing as a "safe dose".23
Ethambutol Toxic Optic Neuropathy (ETON) is a diagnosis of exclusion. It should always be considered in a patient with a history of taking anti-TB drugs presenting with bilateral near symmetric visual impairment.24-26 Ocular signs and symptoms can appear as early as 1-2 months after the initial treatment of anti-TB regimen containing EMB (average 2-8 months).25,33-34 Bilateral, insidious, and symmetrical impairment of vision is the usual manifestation. Fundus findings are unremarkable and optic discs are initially normal but may eventually undergo atrophy. Common visual field defects are central or cecocentral scotoma, bitemporal hemianopsia and sometimes, peripheral constriction. Color vision defects may occur as an early sign of ETON even with normal visual acuity. It usually manifests as red or green color vision deficiencies which could be due to the involvement of the central fibers of the optic nerve.35-36
Since tuberculosis (TB) is a worldwide public health problem and, our country is classified as one of the "high TB burden countries" by the World Health Organization (WHO), the occurrence of ETON is also becoming a burden, similar to other countries. That is why this must be closely monitored. It is estimated that ETON have an incidence of 1 to 5% among EMB users, even at the "safe dose" of 15 mg/kg/day which was recommended by WHO.8,13,20-23,34,37 The incidence in the Philippines can be calculated at 6,000 per year based on 134,000 cases under directly observed therapy short-course (DOTS) program of the Department of Health in our country.37-39 Because of the continuous use of EMB as part of the anti-TB regimen, the risk of visual impairment from ETON remains to ensue.
In 1999, Inocencio and Castillo presented 34 patients diagnosed with ETON seen at the Neuro-ophthalmology clinic of the Department of Ophthalmology at the Philippine General Hospital (PGH).33 To date, it remains the largest local case series on ETON ever published in our country. Even at the "standard dosage" of anti-TB drugs, ocular toxicity was quite evident, as 26 of 34 patients ended up with best-corrected visual (BCVA) of 20/200 or worse after one year of treatment. Only 3 patients improved 20/20 vision after EMB has been stopped for 1 year, and only four patients by the 2nd year. From the clinical profiles, the authors concluded that discontinuation of EMB intake does not assure reversal of visual impairment and recommended careful monitoring of patients on EMB treatment for early detection and prevention of visual loss.34
There was an unpublished local study in Davao City last 1999 conducted by Pineda, Galera-Pineda and Torno which was a retrospective, case series study which reviewed 7 cases of Ethambutol-induced optic neuritis encountered by the authors in their clinical practice. All these patients were complaining of blurring of vision after taking Ethambutol treatment for tuberculosis for at least 4 months in duration. The authors noted that on subsequent follow-ups, all 7 patients seemed to have a decreased over-all visual function weeks, months, or years after withdrawal of the drug. They reviewed the cases and set some parameters such as visual acuity, color vision, afferent pupillary defect and visual field acuity to test the patient's over-all visual function, including their predisposing illnesses. The review revealed that 4 out of 7 (57%) patients didn't fully recover theri visual acuity, 5 out of 7 (71%) had defects in color vision, 4 out of 7 (57%) had persistence of afferent pupillary defects and all patients had visual field defects weeks, months or years after initial diagnoses. The authors were also able to single out some common factors such as old age, low weight, duration and dosage of Ethambutol can predispose patients to the illness. 54
Also in the same year of 1999, Chen and Liang at the Beihai People's Hospital, Guangxi Autonomous Region, Beihai published this Chinese article were they investigated the clinical manifestations, treatment and prevention of optic nerve damage by EMB toxicity on 17 patients with tuberculosis. Changes in visual acuity, fundal appearance, visual field and color sensation were major abnormal findings. According to the neural damage, the patients were diagnosed as axial neuritis in 7 cases, periaxial neuritis in 2 cases, mixed type in 3 cases and there were no significant changes on fundus, color sensation or visual field in 5 cases. All of the 17 patients did not show appearance of retinitis. The visual acuity impairment and the duration of damage were related to the daily dosage significantly. The optic nerve function was recovered after the cessation of EMB and after vasodilators or neurotrophic drugs were given. Hence, they recommended appropriate small dosage of EMB, regular examination and monitoring of visual function is necessary in order to prevent optic nerve damage. They also added that physicians should be fully aware of the diagnosis and clinical manifestations of ocular toxicity of EMB, and as soon as the diagnosis is made, EMB should be stopped immediately and appropriate therapy should be given accordingly.42
In 2002, Tamesis et al. reported 14 patients aged 27-82 years who developed ETON while on standard dosage of anti-TB treatment.43 The time period from start of anti-TB intake to onset of visual symptoms stretched from 2 to 12 months, and visual acuity ranged anywhere from 20/60 to hand motions. This report was significant in being the first to highlight the local issues and controversies surrounding ETON. It contained the random survey and the very first local paper that proposed recommendatory guidelines on the monitoring of patients under TB treatment.
In 2004, several studies have been reported. Fang et al. studied Ethambutol-induced optic neuritis in 2 patients with end-stage renal disease on hemodialysis and it was found out that renal disease is an important risk factor for the development of ocular toxicity.19
Another local case series was reported in the same year of 2004 from the Cebu City Medical Center during the Philippine Academy of Ophthalmology (PAO) Annual Meeting. They investigated 100 patients enrolled in the national TB program and found 11% of these patients manifested either visual acuity or color perception deficits.44 Once more, in the same meeting, another large case series seen at a private clinic was reported. With 39 diagnosed case of ETON, the report looked at the patient demographic risk profile and found that pre-existing co-morbidity in the eye predisposed patients to the development of ETON.45
The following year, a new local case series was presented during the 2005 Joint Meeting of the Philippine Academy of Ophthalmology and American Academy of Ophthalmology (PAO-AAO) in Manila.25 In 19 patients diagnosed with ETON at a private clinic over a period of 1 year, the time from intake of anti-TB drugs to onset of visual symptoms ranged from 4-12 months. Best-corrected visual acuity (BCVA) at the time of diagnosis showed 20/70 to 20/200 in 6 patients, and 20/400 or worse in 13 patients. Fifteen patients eventually developed mild pallor (usually temporal sector) of the optic nerves.25,34
In 2006, a review article was presented by Chan and Kwok in Hong Kong Medical Journal about Ocular toxicity of ethambutol.5 Classically, the characteristics of its toxicity is described as dose- and duration-related. The reported dose-related incidence of ethambutol-related retrobulbar neuritis varies between 18% in patients receiving more than 35 mg/kg/day, 5% to 6% with 25 mg/kg/day, and less than 1% with 15 mg/kg/day of ethambutol HCL for more than 2 months.15,27 No 'safe dose' of ethambutol has been reported,23 with toxicity observed at doses as low as 12.3 mg/kg/day.22 In Hong Kong, the usual daily dose is 15 mg/kg for adults and children. As such, ethambutol-related ocular toxicity is not commonly seen in Hong Kong. As the major excretion pathway of ethambutol is via the kidneys, patients with poor renal function are at higher risk of ocular toxicities. Other factors that predispose subjects to toxicity include diabetes and optic neuritis related to tobacco and alcohol consumption.46-47 In duration-related, the manifestation of ocular toxicity is usually delayed, and generally does not develop until at least 1.5 months after treatment.48 The mean interval between onset of therapy and toxic effects has been reported to be 3 to 5 months.23,27,49 Manifestations of toxicity as late as 12 months after therapy initiation have also been reported.13,39 It should be pointed out that these reports concerned small numbers of patients with unknown external validity. Although classically described as reversible on discontinuation of ethambutol (with visual acuity recovery over a period of weeks to months), permanent visual impairment without recovery has been reported within a follow-up period ranging from 6 months to 3 years in some patients in whom where was prompt ethambutol discontinuation.23,39,47-49 No risk factor was identified for the poor visual recovery, although another study23 showed a statistically significant difference in visual recovery between groups of patients aged older than 60 years and those aged younger than 60 years. Visual improvement was reported by 20% and 80%, respectively. Even in patients who report visual improvement after therapy discontinuation, complete recovery is not always achieved.23,39 Progressive worsening of vision after ethambutol discontinuation has also been documented.39 These series of reports are once again small-scale with unknown external validity, and only patients with severe visual deficits were recruited. Furthermore, queries were made on the possible contribution of isoniazid-induced ocular toxicity to the observed irreversibility, as isoniazid was not also withdrawn in the affected individuals.39 Authors recommended that ethambutol must be immediately discontinued when ethambutol-induced ocular toxicity is recognized and the patient referred to an ophthalmologist for further evaluation. Therapy discontinuation is only effective management that can halt the progression of vision loss and allow recovery of vision. They also added that when severe ocular toxicity occurs, both isoniazid and ethambutol should be stopped immediately and other additional antituberculosis agents considered. If isoniazid is not stopped immediately, it should in any event be stopped 6 weeks later if ocular toxicity is not severe and there is no improvement in vision.39
Likewise, back in 2006 at the Joint Meeting of the Asian Neuro-ophthalmology Society and International Neuro-ophthalmology Society in Tokyo, Japan, a paper was presented describing histopathologic changes in the retinal ganglion cell layer and optic nerve of adult albino rats fed with so called safe dose of Ethambutol.50 No observable changes in the retinal ganglion cell layer nor the proximal 2 mm of the optic nerve were observed among the treatment groups. However, changes in the outer nuclear layer of the retina were noted among rats given ethambutol at doses as low as 15mg/kg/day.
Another published report in 2006 by Su-Ann Lim that there were 3 cases of ethambutol-associated optic neuropathy (ETON).1 Two with little or no recovery and recommend that ethambutol be used with caution, proper patient education, and proper ophthalmologic monitoring. This consists of baseline (pre-treatment) best-corrected visual acuity (BCVA), color vision, and Humphrey visual field (HVF). Subsequent monitoring in asymptomatic patients is also important. She concluded that ETON is an established "ocular" drug complication. In her reported cases, we are reminded that ethambutol usage is associated with a real risk of toxic optic neuropathy and permanent visual loss. The incidence of this is approximately 1%.20,27 Although isoniazid may also be responsible, its adverse effect is from a long-term ingestion. 55 It was previously reported from the Department of Health in Hong Kong that apart from ethambutol, isoniazid, though to a lesser extent and as a rare complication, has also implicated in the development of visually related side effects.40,41,58 In limited reported literatures, the well known complication of isoniazid is peripheral neuritis (peripheral neuropathy).56-57,59 Nevertheless, ethambutol-associated optic neuropathy is more widely recognized. In addition, ethambutol toxicitiy has frequently been reported to present with central or centroceacal scotomas. However, bitemporal field defects have occasionally been reported.28 This disorder has been studied in several animal models. Monkey experiments using the racemic mixture demonstrated that ethambutol first affects the optic chiasm.29-30 Studies in rats using the D-isomer confirmed the special susceptibility of the optic chiasm31. In rabbits, however, the damaged was in the optic nerves32. All physicians prescribing the drug should be aware of this and the drug should be used with proper patient education and ophthalmological monitoring.
