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 The latter was eventually withdrawn from the market so that EMB is now only available in the D-form.7 Since the very first published report in ethambutol-related ocular toxicity came out in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.
Significance of the Study
As we have a lot of tuberculosis (TB) cases, will we have increase rate of Ethambutol Toxic Optic Neuropathy (ETON)?
1. To see if Ethambutol Toxic Optic Neuropathy (ETON) is frequent in Southern Philippines Medical Center (SPMC);
2. To see if there are variables that increases the likelihood of Ethambutol Toxic Optic Neuropathy (ETON);
3. Information gathered can increase awareness and recognition of Ethambutol Toxic Optic Neuropathy (ETON).
OBJECTIVES
General objective
The study would like to determine the factors that affect the occurrence of Ethambutol Toxic Optic Neuropathy (ETON).
Specific Objectives
To describe the demographic profile of the patients treated with ethambutol;
To describe the clinical profile of the patients both medically and ophthalmologically;
To determine the rate of ETON among patients who are into ethambutol medication;
To determine the factors associated with the occurrence of ETON.
METHODOLOGY
Research Design
The research will make use of a prospective cross-sectional study design. The rate of Ethambutol Toxic Optic Neuropathy (ETON) will be determined and at the same time determine the factors of occurrence of ETON.
Setting
This will be done at the Ophthalmology Out-patient clinic in Southern Philippines Medical Center (SPMC) from the period February 2011 to July 2011.
Participants
A prospective study of patients who will be referred to the Department of Ophthalmology Out-patient clinic in Southern Philippines Medical Center (SPMC) for treatment with Ethambutol (EMB) for tuberculosis.
Data Gathering
An interview schedule shall be used to gather the data. The following processes are to be done accordingly: (See Complete Baseline Examination Chart, Appendix 1).
1. Get the baseline data on all patients referred to the Department of Ophthalmology which includes:
 Patient's General data: name, age, sex, status, address, contact number & occupation;
 Chief complaint and Present illness;
 Descriptions of patient's past medical history and medications which includes: hypertension (HPN), diabetes mellitus (DM), stroke, bronchial asthma (BA), renal problem, glaucoma, trauma, optic neuritis/neuropathy, tuberculosis (TB) and others;
Patient's vital signs specifically blood pressure and weight; and
 Complete ophthalmologic examinations: determination of visual acuity (VA), pinhole (PH), corrected vision with glasses (cc), best-corrected visual acuity (BCVA) using Snellen chart; color discrimination with Ishihara chart; Tangent test for visual field defects; Slit lamp evaluation; Intraocular pressure (IOP) measurement with Applanation tonometer, and fundus examination using the ocular lens or indirect ophthalmoscope.
2. Patient will be referred to ophthalmology sub-specialty clinics when necessary, especially when there is already an existing significant ocular findings during the baseline ophthalmologic examination.
3. Follow-up all patients periodically from first visit up to the last visit, on a monthly interval and do ophthalmologic examinations for 6 months, and compare each results.
Variables
The dependent variable will be the occurrence of Ethambutol-Toxic Optic Neuropathy (ETON).
The independent variables will be the following:
Hypertension
Diabetes mellitus
Stroke
Bronchial Asthma
Renal problem
Glaucoma
Trauma
Optic neuritis/neuropathy
Tuberculosis
Alcohol
Smoking
Sample Size Estimation
There will be a total of 120 patients to be included in the study (See Sample Size Estimation, Appendix 2). The assumption of the sample size is based on the rate of 5.0% with ETON among Filipinos in the data available at the Department of Health, where 6,000 patients developed ETON out of 134,000 during the year.37-39 The maximum permissible error is set at 5% with 95% confidence interval.
Data Handling and analysis
Data gathered will be encoded into the computer using the data entry program of Epi Info version 6 statistical software. The same software shall be used to analyze the data.
Data analysis will include descriptive statistics and analytical statistics. The descriptive statistics like the means and standard deviation for the qualitative variable and proportions for the qualitative variables shall be generated. In order to analyze the factors of the occurrence of ETON, the Odds Ratio (OR) shall be computed. The 95% confidence interval of OR and the p-values shall also be derived.
Ethical Consideration
Permission to conduct study
The author will send letters to the different clinics of the Out-Patient Department of Southern Philippines Medical Center (SPMC) asking for referrals of all patients recently diagnosed with Tuberculosis (TB) should be referred to the Department of Ophthalmology for baseline ophthalmologic examination prior to starting the anti-TB regimen which includes Ethambutol (See Letter, Appendix 3). As soon as patients were seen, permission from the participating individuals will be sought. An informed consent will be used for this purpose (See Informed Consent, Appendix 4)
Data management
The data will be encoded into the computer. All identifying information shall not be stored into the computer so that the information cannot be traced back to the person concerned. The interview schedule shall be kept and archived for a period of 5 years. Only the authors shall have access to the interview schedule. After 5 years, the interview schedules shall be disposed of by shredding.
Data Analysis Plan
Below are the dummy tables that will be used to analyze the data.
Table 1. Distribution of Study Participants According to Demographic Profile
Demographic Profile
Freq
%
Age
<10
10 - 19
20 - 29
30 - 39
40 - 49
50 - 59
60 and above
Sex
Male
Female
Marital status
Single
Married
Separated
Widow/er
Address
Davao City
Outside Davao City
Table 2. Distribution of Study Participants According to Past Medical Hisotry
Medical history
Freq
%
Hypertension
Diabetes mellitus
Stroke
BA
Renal problem
Glaucoma
Trauma
Optic neuritis/neuropathy
Tuberculosis
Alcohol
Table 3. Factors of ETON
Factors
With ETON
Without ETON
Odds Ratio
95% Confidence Interval
p-value
Hypertension
Diabetes mellitus
Stroke
BA
Renal problem
Glaucoma
Trauma
Optic neuritis
Tuberculosis
Alcohol
