Global issues
Ethambutol-induced optic neuropathy: a nationwide
1 Aim To investigate the risk factors and comorbidities
Graduate Institute of Clinical
Medical Science, China
Medical University, Taichung,
Taiwan
2
Department of Ophthalmology,
China Medical University
Hospital, Taichung, Taiwan
3
School of Medicine, China
Medical University, Taichung,
Taiwan
4
Department of Family
Medicine, China Medical
University Hospital, Taichung,
Taiwan
5
Management Office for Health
Data, China Medical University
and Hospital, Taichung, Taiwan
6
Graduate Institute of
Epidemiology and Preventive
Medicine, National Taiwan
University College of Public
Health, Taipei, Taiwan
7 elevated risk compared with those whose prescription
Department of Ophthalmology,
National Taiwan University
Hospital, Taipei, Taiwan
Correspondence to
Dr Pei-Chun Chen, Graduate
Institute of Epidemiology and
Preventive Medicine, National
Taiwan University College of
Public Health, Taipei 100,
Taiwan; peichunchen@ntu.edu.
tw, Dr I-Jong Wang,
Department of Ophthalmology,
National Taiwan University
Hospital, 7, Chung-Shan South
Road, Taipei 100, Taiwan;
ijong@ms8.hinet.net
Accepted 18 August 2012
Published Online First
8 September 2012
1368
population-based study from Taiwan
Hsin-Yi Chen,1,2 Shi-Wei Lai,3,4 Chih-Hsin Muo,5 Pei-Chun Chen,5,6 I-Jong Wang1,7
ABSTRACT
associated with ethambutol-induced optic neuropathy
(EON).
Method Using the Taiwan Longitudinal Health Insurance
Database, we conducted a study within a nationwide
representative cohort of patients treated with EMB. We
identified 231 patients newly diagnosed with EON
between 2000 and 2008, and 924 control subjects.
Adjusted OR by estimating the risk of EON in relation to
comorbidities and EMB prescription protocol was
determined.
Results Compared with the control group, EON patients
were at risk with older age, hypertension (adjusted
OR=1.62, 95% CI 1.16 to 2.26) and renal diseases
(without end-stage renal diseases (ESRD), adjusted
OR=2.11, 95% CI 1.02 to 4.35; with ESRD, adjusted
OR=3.73, 95% CI 1.79 to 7.74). Patients with an EMB
prescription duration longer than 3 months were not at
less than 3 months (OR=1.35, 95% CI 0.99 to 1.83,
adjusted for age, sex, hypertension and renal diseases).
Patients whose average daily dose was greater than
1200 mg, compared with the other two groups
(800∼1199 mg, less than 800 mg) were not at increased
risk for EON.
Conclusions Age, hypertension and renal diseases are
risk factors for EON in the Taiwanese population.
INTRODUCTION
Although ethambutol (EMB) is well known to be
the most common cause of toxic optic neur-
opathy,1 2 it is still commonly used in medical
practice due to increasing drug resistance in tuber-
culosis treatment.1 3 The incidence of
ethambutol-induced optic neuropathy (EON), its
clinical characteristics and risks factors and its
dosage information, have been poorly described
and characterised in many previous studies.2–6
However, the causes of EON and its risk factors
remain to be determined. Some previous studies
showed that EON is dose-related and reversible,7
but others revealed a controversial result.8–12
Because of these ambiguities, the reported inci-
dence of the toxicity varies widely across studies,
ranging from 0.5% to more than 35%.4 13–15
Unfortunately, with the increase in the number of
cases reporting irreversible EON,,4–6 an urgency
exists to identify the potential risk factors asso-
ciated with EMB. To better understand the risk
factors related to EON in our population, we con-
ducted this study using an 8-year population-based
dataset from the Taiwan National Health
Insurance (NHI) Programme.
Br J Ophthalmol 2012;96:1368–1371. doi:10.1136/bjophthalmol-2012-301870
METHODS
The NHI programme offers healthcare coverage to
more than 99% of the 23 million people.
Electronically submitted reimbursement claims data
have been available since 1996, and are sent to the
National Health Research Institute which collabo-
rates with the NHI to construct the NHI Research
Database.16 The Longitudinal Health Insurance
Database was established for research purposes. This
dataset, comprising one million beneficiaries ran-
domly selected from all people enrolled in the NHI
between 1996 and 2000, includes files of registration,
ambulatory care claims, inpatient claims and pre-
scription drugs, and provides information on health-
care utilisation.
Cases and controls
This study consists of 11 753 subjects who were
dispensed EMB between 1996 and 2008. The
cohort was comprised of patients who were
20 years of age or older and who were diagnosed
with EON between 2000 and 2008 on either an
inpatient or an outpatient basis. All cohort partici-
pants were identified using International
Classification of Diseases, Ninth Revision, Clinical
Modification (ICD-9) code 377. A control group
was randomly selected from the remaining sub-
jects who did not experience EON but were on
EMB during the specified time period. This
resulted in a case-to-control ratio of 1 : 4. The
index date of the case subject was the date of their
EON diagnosis. For each control subject, we
assigned an index date frequency matching the
index year and the month associated with each of
the case subjects. Study subjects with missing
information on sex and birth date were excluded.
Finally, a total of 231 patients with EON (cumula-
tive incidence, 2% (231/6369); incidence density:
36.3 per 1000 person-years) and 924 control group
subjects were included.
Variables
We scanned diagnosis information on outpatient
and inpatient claims before the index date to iden-
tify some comorbidities, including diabetes melli-
tus (ICD-9 250.XX), obesity (ICD-9 278.0, 278.00,
and 278.01), hypertriglyceridaemia (ICD-9 272.1),
alcoholism (ICD-9 303, 305.00, 305.01, 305.02,
305.03, and v11.3), gallstones (ICD-9 574.00,
574.01, 547.10, 574.11, 574.20, and 574.21), hepa-
titis B (ICD-9 V02.61, 070.20, 070.22, 070.30, and
070.32), hepatitis C (ICD-9 V02.62, 070.41,
070.44, 070.51, and 070.54), hypertension (ICD-9
401–405), renal diseases (ICD-9 585, 586, 588.8,
and 588.9), systemic lupus erythematosus (ICD-9
710.xx), Reiter’s syndrome (ICD-9 711.1x),
 Global issues

rheumatoid arthritis and other inflammatory polyarthopathies Table 1 Characteristics of optic neuropathy cases and control
(ICD-9 714.xx), palindromic rheumatism (ICD-9 719.3x), poly- subjects selected from ethambutol (EMB)-treated patients
myalgia rheumatica (ICD-9 725), and malignant illness (ICD-9 Controls Optic neuropathy
140–208). To assess whether the risk of EON increases in (n=924) cases (n=231)
patients with advanced-stage renal diseases, we further classi- n (%) n (%) p Value
fied this group into two subgroups (end-stage renal diseases,
ESRD and non-ESRD). Patients with ESRD were identified Sex 0.80
using the Catastrophic Illness Registry. In the NHI programme, Female 316 (34.2) 77 (33.3)
patients with ESRD were eligible to apply for a catastrophic Male 608 (65.8) 154 (66.7)
illness certification, which allows for the waiver of copayments Age group (in years) 0.001
for medical care related to ESRD. In both the EON case group 20–39 169 (18.3) 21 (9.1)
and the controls, prescription duration and average daily dosage 40–64 318 (34.4) 77 (33.3)
of EMB were calculated from the date of the participant’s first ≥65 437 (47.3) 133 (57.6)
prescription until the index date. Average daily dose was calcu- Mean (SD) 60.3 (19.6) 65.4 (15.9) <0.0001
lated by dividing total number of milligrams prescribed by total Diabetes mellitus 150 (16.2) 31 (13.4) 0.29
number of days supplied during the year before the index date. Obesity 3 (0.3) 0 (0.0) 0.39
According to the standard prescription guideline for EMB,17 we Hypertriglyceridaemia 9 (1.0) 0 (0.0) 0.13
stratified the average daily dosage into three categories: (1) less Alcoholism 6 (0.7) 1 (0.4) 0.70
than 800 mg, (2) 800–1199 mg, (3) greater than 1200 mg. The Gallstones 30 (3.3) 7 (3.0) 0.87
compliance in these patients is assessed under directly observed Hepatitis B 16 (1.7) 6 (2.6) 0.39
therapy by healthcare personnel. Hepatitis C 17 (1.8) 6 (2.6) 0.46
Hypertension 357 (38.6) 126 (54.6) <0.0001
Statistical analysis Renal diseases <0.0001
We compared the differences in sex, age and comorbidities Non-ESRD 23 (2.5) 13 (5.6)
between case group and control group using Pearson’s χ2 test. ESRD 16 (1.7) 16 (6.9)
The logistic regression model, which estimated the OR and a Systemic lupus erythematous 8 (0.9) 2 (0.9) 1.00
95% CI, was used to evaluate the association between age, sex, Reiter’s syndrome 1 (0.1) 0 (0.0) 0.62
comorbid disease and the risk of EON. The logistic regression Rheumatoid arthritis and other 109 (11.8) 29 (12.6) 0.75
inflammatory polyarthopathies
analyses did not include the comorbidities in which the preva-
Palindromic Rheumatism 0 (0.0) 1 (0.4) 0.045
lence rates were similar between case group and the controls,
Polymyalgia Rheumatica 5 (0.5) 1 (0.4) 0.84
or the comorbidities in which the prevalence rates were very
Malignant illness 87 (9.4) 15 (6.5) 0.16
low in both groups. We did not select the comorbidities for
Duration of EMB prescription, 162.0 (250.0) 168.3 (192.9) 0.67
inclusion relying on p values due to the small number of cases
mean (median) days
with comorbidities. We further examined whether patients
with coexisting hypertension, diabetes and renal diseases were ESRD refers to end-stage renal diseases.
at a greater risk of EON. ORs for optic neuropathy in relation
to duration of EMB prescription and average daily dosage were
calculated as well. All analyses were performed using SAS stat- adjustment was made for other comorbidities (Model 2,
istical software (V.9.1 for Windows; SAS Institute, Inc, Cary, OR=0.58).
North Carolina, USA). We used a two-tailed test for all analyses Table 3 indicates the adjusted ORs of EON in patients with
and the significance level was set at a p value <0.05. coexisting diabetes, hypertension and renal diseases compared
with those without these diseases. The OR for patients with
RESULTS hypertension alone was 1.79 and increased to 3.84 for hyper-
In both the EON group (case) and the non-EON group tensive patients with renal diseases. The OR for patients
(control), patients taking EMB were more likely to be male having all three of these comorbidities was 3.94. For renal dis-
(table 1). The patients in the EON group (65.4±15.9 years) eases alone, the OR was 2.42, but it was not statistically
were older than the controls (60.3±19.6 years). Compared with significant.
the control group, the EON group was more likely to have Table 4 presents the OR of EON in relation to duration of
hypertension (54.6% vs 38.6%) and renal diseases (non-ESRD, the EMB prescription. Patients whose EMB prescription dur-
5.6% vs 2.5%; ESRD, 6.9% vs 1.7%, p<0.0001). ation was longer than 3 months were found to be at a mild ele-
In the logistic regression models adjusted for age, sex, diabetes, vated risk of EON compared with those less than 3 months
hypertension, renal diseases and malignant illness, the OR for (OR=1.38, 95% CI 1.02 to 1.86, Model 1, adjusted for age and
EON in patients aged 40–64 years, compared with patients in sex). However, when additionally adjusted for hypertension
the 20–39-year age range, was 1.76 (table 2, Model 2). The and renal diseases, there is no increased risk (OR=1.35, 95% CI
adjusted OR increased to 1.93 for patients aged 65 years and 0.99 to 1.83).
older. Hypertension was associated with an increased risk of Table 5 shows the result of OR for optic neuropathy in rela-
EON (OR=1.62). Additionally, patients with renal diseases also tion to average daily dosage of EMB prescription. For all cases
showed an elevated risk for EON compared with subjects treated with EMB, relative to the group whose average daily
without renal diseases. For patients who had renal diseases but dose was less than 800 mg, the other two groups were not
without ESRD, the adjusted OR was 2.11; the adjusted OR rose with increased risk for EON. The same result was noted in the
to 3.73 for patients with ESRD. However, diabetes was asso- cases with renal diseases. Mild increased risk for EON was only
ciated with a decreased risk of EON. The risk was not statistic- noted in the group whose average daily dose was between 800
ally significant in the age-adjusted and sex-adjusted model and 1199 mg in the cases without renal diseases (OR=1.46,
(Model 1, OR=0.71), but the risk became significant after an 95% CI 1.04 to 2.06).

Br J Ophthalmol 2012;96:1368–1371. doi:10.1136/bjophthalmol-2012-301870 1369

 Global issues

Table 2 Adjusted ORs for optic neuropathy in relation to medical Table 4 ORs for optic neuropathy in relation to duration of ethambutol
comorbidities prescription
Model 1 Model 2 OR (95% CI)
Variable OR (95% CI) OR (95% CI) Optic
neuropathy
Sex Controls cases
Female 1.00 (reference) 1.00 (reference) (n=924) % (n=231) % Model 1 Model 2
Male 0.94 (0.69 to 1.29) 0.96 (0.70 to 1.32)
Age Duration of prescription, months
20–39 years 1.00 (reference) 1.00 (reference) ≤3 months 436 (47.2) 88 (38.1) 1.00 1.00
40–64 years 1.96 (1.17 to 3.30) 1.76 (1.03 to 3.01) >3 months 488 (52.8) 143 (61.9) 1.38 (1.02–1.86) 1.35 (0.99–1.83)
≥65 years 2.48 (1.51 to 4.08) 1.93 (1.12 to 3.32) Model 1 was adjusted for age and sex.
Diabetes mellitus Model 2 was additionally adjusted for hypertension and renal diseases.
No 1.00 (reference) 1.00 (reference)
Yes 0.71 (0.46 to 1.08) 0.58 (0.37 to 0.90)
Hypertension
decreased with increasing age after peaking in the 25–44 age
No 1.00 (reference) 1.00 (reference)
group.3 They postulated that age was an independent risk
Yes 1.64 (1.19 to 2.26) 1.62 (1.16 to 2.26)
factor for EON based on the thought that renal function
Renal diseases
decreases related to aging.3,18 Although renal tubular function
No 1.00 (reference) 1.00 (reference)
is known to decrease with age,18 the aging effect of EMB clear-
Non-ESRD 2.17 (1.07 to 4.40) 2.11 (1.02 to 4.35)
ance is not yet known. Compared with that study, our current
ESRD 4.00 (1.96 to 8.17) 3.73 (1.79 to 7.74)
logistic analysis model could explain why age should be a
Malignant Illness
strong risk factor for EON.
No 1.00 (reference) 1.00 (reference)
Furthermore, our analysis identified some other interesting
Yes 0.58 (0.33 to 1.03) 0.63 (0.35 to 1.13)
findings. First, hypertension was associated with an increased risk
ESRD refers to end-stage renal diseases. of EON (OR=1.62), which has seldom been reported.2–6 13 14
Model 1 was adjusted for age and sex.
Second, diabetes was associated with non-statistically significant
Model 2 was additionally adjusted for variables listed in this table.
reduction in risk of EON in the age- and sex-adjusted model, and
the association became statistically significant after further
DISCUSSION adjusting hypertension and renal disease. The role that diabetes
This study used population-based data to understand the plays in EON needs to be further elucidated in a future study.
comorbidities associated with EON in Taiwan, which is one of Third, patients with renal diseases were also at an elevated risk
the few studies investigating the roles of multiple systemic for EON compared with subjects without renal diseases. The
factors in EON in a large Chinese cohort. Our results show adjusted OR for patients with renal diseases, but without ESRD,
that patients with EON were found to be older and to have was 2.11, and this rose to 3.73 for patients with ESRD. This
hypertension and renal diseases compared with the controls. important result confirms the previous belief that poor renal func-
Our result is in agreement with the general belief that tion is an important risk factor for EON.2–6 13 14
advanced age and renal diseases are the two most common risk
factors for EON.2–6 13 14 In one recent meta-analysis of 70
EON cases, the authors noted that the majority of patients
were over 40 years of age, and 40% of them were over Table 5 ORs for optic neuropathy in relation to average daily dosage
65 years,3 which is consistent with our result (57.6%, over of ethambutol (EMB) prescription
65 years old). However, when the authors further considered OR (95% CI)
the CDC’s statistics on the age distribution of tuberculosis
Optic
cases, they found that the number of cases of tuberculosis neuropathy Average
Controls cases daily
(n=924) % (n=231) % dose, mg Model 1 Model 2

Table 3 Adjusted ORs for optic neuropathy in relation to hypertension, All EMB-treated cases
diabetes and renal diseases <800 439 (47.5) 115 (49.8) 1.00 1.00
800–1199 290 (31.4) 88 (38.1) 1.28 (0.93 to 1.76) 1.36 (0.98 to 1.89)
Optic
neuropathy ≧1200 195 (21.1) 28 (12.1) 0.68 (0.43 to 1.09) 0.72 (0.45 to 1.16)
Renal Controls cases With renal diseases
Hypertension Diabetes diseases (n=924) % (n=231) % OR (95% CI) <800 24 (61.5) 21 (72.4) 1.00 1.00
800–1199 13 (33.3) 7 (24.1) 0.39 (0.11 to 1.36) 0.40 (0.11 to 1.40)
− − − 517 (56.0) 94 (40.7) 1.00
≧1200 2 (5.13) 1 (3.45) 0.41 (0.03 to 5.36) 0.37 (0.03 to 4.91)
+ − − 231 (25.0) 87 (37.7) 1.79 (1.23 to 2.58)
Without renal diseases
− + − 42 (4.55) 7 (3.03) 0.86 (0.37 to 1.98)
<800 415 (46.9) 94 (46.5) 1.00 1.00
− − + 6 (0.65) 3 (1.30) 2.42 (0.59 to 9.98)
800–1199 277 (31.3) 81 (40.1) 1.44 (1.02 to 2.03) 1.46 (1.04 to 2.06)*
+ + − 95 (10.3) 14 (6.06) 0.72 (0.39 to 1.33)
≧1200 193 (21.8) 27 (13.4) 0.79 (0.49 to 1.28) 0.78 (0.48 to 1.26)
+ − + 20 (2.16) 16 (6.93) 3.84 (1.88 to 7.83)
− + + 2 (0.22) 1 (0.43) 2.38 (0.21 to 26.83) Model 1 was adjusted for age and sex.
Model 2 was additionally adjusted for hypertension and renal diseases.
+ + + 11 (1.19) 9 (3.90) 3.94 (1.57 to 9.90)
Average daily dose was calculated by dividing total number of milligrams prescribed
Adjusted for age and sex. by total number of days supplied during the year before the index date.

1370 Br J Ophthalmol 2012;96:1368–1371. doi:10.1136/bjophthalmol-2012-301870


Because hypertension and renal disease are both risk factors
of EON, we further examine the joint effects of these
comorbidities on EON risk. To assess the influence of diabetes
on the associations, the analysis was also stratified by diabetes.
The adjusted OR for patients with hypertension only was 1.79,
and for patients with renal diseases only it was 2.42 (not statis-
tically significant). The adjusted OR for patients with hyper-
tension only was 1.79 and increased to 3.84 for those with
coexisting renal disease. The OR was at similar strength for
patients who were also comorbid for diabetes. This study is the
first to notice that hypertension is a potential aggravating
factors for EON in patients with renal diseases.3 5
Conflicting results about the treatment protocol of EMB on
EON were noted.12 13 One recent meta-analysis study has
reported that the duration and dose of EMB were positively cor-
related with risk of EON.13 In another study in Korea,12 they
reported that renal dysfunction and daily dose of EMB, but not
duration of EMB treatment, seem to be related to development
of EON. To clarify this important issue in our population, we
further analysed the EMB dosing regimen, including the pre-
scription duration and average daily dosage. Interestingly, our
result reveals that both prescription duration and average daily
dosage do not have significant association with the risk of EON.
We believe this most likely represents an idiosyncratic reaction
of EMB in our Chinese population. Furthermore, we found the
majority of EMB-treated cases (about 88%) were, on average,
less than 1200 mg/per day. According to the treatment guideline
of tuberculosis,17 recommended dose was standardised for three
or four body weight bands. It is a great pity that the body
weight data were not available in our dataset; therefore, we
failed to understand the real daily dose based on weight. This is
a major limitation in this study compared with others, and con-
strains a direct comparison with previous studies because of dif-
ferent study design and statistical method. However, this result
could be a good basis for future prospective studies in EON.
Although the results are quite meaningful, some limitation
should be mentioned. First, the EON diagnoses were totally
reliant upon claims data (ICD-9 coding from clinicians), which
may be less accurate than diagnoses carried out individually
through a standardised procedure. Second, other selection biases
also inherit in this kind of retrospective study. Because the
vision and body weight data were not available in our health
insurance database, we were unable to understand the real dose
effect on the severity of vision impairment in each patient based
on body weight. Even so, this dataset has good sample random-
isation.19 Third, to avoid misdiagnosis for the case group, we
ensured that all study cohorts should have EON diagnoses in
consensus with concurrent and continuous intake of EMB.
Fourth, because we could not determine compliance in this
retrospective study, however, comments on how compliance is
assessed in these patients (directly observed therapy, etc) would
be useful to have. Additionally, we excluded any tuberculosis
case coded with any optic neuropathy before EMB use.
In summary, age factor, hypertension and renal diseases were
found to be important risk factors for EON. The important
Br J Ophthalmol 2012;96:1368–1371. doi:10.1136/bjophthalmol-2012-301870
Global issues
issue of dosing regimen of EMB on EON should be clarified in
future studies. We hope that our current work would help
patients avoid this vision-threatening disease.
Contributors Dr CH-Y: conception and design, acquisition of data, analysis and
interpretation of data, drafting of the manuscript, critical revision of the manuscript
for important intellectual content, obtaining funding. Dr S-WL: conception and design,
analysis and interpretation of data, critical revision of the manuscript for important
intellectual content. C-HM: statistical expertise, conception and design, critical
revision of the manuscript for important intellectual content. Dr P-CC: statistical
expertise, conception and design, critical revision of the manuscript for important
intellectual content, obtaining funding. Dr I-JW: critical revision of the manuscript for
important intellectual content, supervision.
Financial disclosure(s) The authors have no commercial or proprietary interest in
any of the materials discussed in this article. This work was supported by Taiwan
National Sciences Council (NSC 98-2621-M-039-001), Department of Health Clinical
Trial and Research Center of Excellence (DOH100-TD-B-111-004), and the China
Medical University Hospital (1MS1).
Competing interests None.
Ethics approval This kind of database study, provided by our health insurance
research unit, does not need the IRB evaluation in our school.
Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES
1. Sadun AA, Wang MY. Ethambutol optic neuropathy: how we can prevent 100,000
new cases of blindness each year. J Neuroophthalmol 2008;28:265–8.
2. Choi SY, Hwang JM. Optic neuropathy associated with ethambutol in Koreans.
Korean J Ophthalmol 1997;11:106–10.
3. Talbert Estlin KA, Sadun AA. Risk factors for ethambutol optic toxicity. Int
Ophthalmol 2010;30:63–72.
4. Melamud A, Kosmorsky GS, Lee MS. Ocular ethambutol toxicity. Mayo Clin Proc
2003;78:1409–11.
5. Lee EJ, Kim SJ, Choung HK, et al. Incidence and clinical features of
ethambutol-induced optic neuropathy in Korea. J Neuroophthalmol 2008;28:269–77.
6. Lim SA. Ethambutol-associated optic neuropathy. Ann Acad Med Singapore
2006;35:274–8.
7. Leibold JE. The ocular toxicity of ethambutol and its relation to dose. Ann N Y
Acad Sci 1966;135:904–9.
8. Tsai RK, Lee YH. Reversibility of ethambutol optic neuropathy. J Ocul Pharmacol
Ther 1997;13:473–7.
9. Kumar A, Sandramouli S, Verma L, et al. Ocular ethambutol toxicity: is it
reversible?. J Clin Neuroophthalmol 1993;13:15–7.
10. Woung LC, Jou JR, Liaw SL. Visual function in recovered ethambutol optic
neuropathy. J Ocul Pharmacol Ther 1995;11:411–19.
11. Chan RY, Kwok AK. Ocular toxicity of ethambutol. Hong Kong Med J
2006;12:56–60.
12. Zoumalan CI, Sadun AA. Optical coherence tomography can monitor reversible
nerve-fibre layer changes in a patient with ethambutol-induced optic neuropathy.
Br J Ophthalmol 2007;91:839–40.
13. Fraunfelder FW, Sadun AA, Wood T. Update on ethambutol optic neuropathy.
Expert Opin Drug Saf 2006;5:615–18.
14. Sadun AA, Win PH, Ross-Cisneros FN, et al. Leber’s hereditary optic neuropathy
differentially affects smaller axons in the optic nerve. Trans Am Ophthalmol Soc
2000;98:223–32; discussion 32-5.
15. Menon V, Jain D, Saxena R, et al. Prospective evaluation of visual function for early
detection of ethambutol toxicity. Br J Ophthalmol 2009;93:1251–4.
16. National Health Insurance Research Database. http://w3.nhri.org.tw/nhird//en/
index.htm. Taiwan, 2011.
17. World Health Organization. Treatment of tuberculosis: guidelines 4th ed. Geneva,
Switzerland: WHO, 2010.
18. Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in
renal function with age. J Am Geriatr Soc 1985;33:278–85.
19. Ho JD, Hu CC, Lin HC. Open-angle glaucoma and the risk of stroke development: a
5-year population-based follow-up study. Stroke 2009;40:2685–90.
1371
Copyright of British Journal of Ophthalmology is the property of BMJ Publishing Group and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.