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Figure 1.
Overall Percentage Without Spontaneous Resolution Over Time Using Kaplan-Meier Methods in 1958 Infants
Overall Percentage Without Spontaneous Resolution Over Time Using Kaplan-Meier Methods in 1958 Infants
Figure 2.
Percentage of Children Whose Obstruction Eventually Spontaneously Resolved at Any Time After Specified Age
Percentage of Children Whose Obstruction Eventually Spontaneously Resolved at Any Time After Specified Age
Table.  
Associations Between Probing Age and CNLDO Resolution Using Multivariable Logistic Regression
Associations Between Probing Age and CNLDO Resolution Using Multivariable Logistic Regression
1.
Sathiamoorthi  S, Frank  RD, Mohney  BG.  Incidence and Clinical Characteristics of Congenital Nasolacrimal Duct Obstruction.  Br J Ophthalmol. doi:10.1136/bjophthalmol-2018-312074Google Scholar
2.
Nelson  LR, Calhoun  JH, Menduke  H.  Medical management of congenital nasolacrimal duct obstruction.  Ophthalmology. 1985;92(9):1187-1190.PubMedGoogle ScholarCrossref
3.
MacEwen  CJ, Young  JDH.  Epiphora during the first year of life.  Eye (Lond). 1991;5(pt 5):596-600.PubMedGoogle ScholarCrossref
4.
Nucci  P, Capoferri  C, Alfarano  R, Brancato  R.  Conservative management of congenital nasolacrimal duct obstruction.  J Pediatr Ophthalmol Strabismus. 1989;26(1):39-43.PubMedGoogle Scholar
5.
Price  HW.  Dacryostenosis.  J Pediatr. 1947;30(3):302-305.PubMedGoogle ScholarCrossref
6.
Paul  TO, Shepherd  R.  Congenital nasolacrimal duct obstruction: natural history and the timing of optimal intervention.  J Pediatr Ophthalmol Strabismus. 1994;31(6):362-367.PubMedGoogle Scholar
7.
Petersen  RA, Robb  RM.  The natural course of congenital obstruction of the nasolacrimal duct.  J Pediatr Ophthalmol Strabismus. 1978;15(4):246-250.PubMedGoogle Scholar
8.
Robb  RM.  Success rates of nasolacrimal duct probing at time intervals after 1 year of age.  Ophthalmology. 1998;105(7):1307-1309.PubMedGoogle ScholarCrossref
9.
Ffooks  OO.  Dacryocystitis in infancy.  Br J Ophthalmol. 1962;46(7):422-434.PubMedGoogle ScholarCrossref
10.
Weil  BA. Dacryocystitis. In: Viers ER, ed.  The Lacrimal System, Proceedings of the First International Symposium. St. Louis, MO: CV Mosby Co; 1971: 118.
11.
Melton  LJ  III.  History of the Rochester Epidemiology Project.  Mayo Clin Proc. 1996;71(3):266-274.PubMedGoogle ScholarCrossref
12.
Therneau  T, Grambsch  P.  Modeling Survival Data: Extending the Cox Model. Berlin, Germany: Springer-Verlag; 2000.
13.
Katowitz  JA, Welsh  MG.  Timing of initial probing and irrigation in congenital nasolacrimal duct obstruction.  Ophthalmology. 1987;94(6):698-705.PubMedGoogle ScholarCrossref
14.
Janssen  AG, Mansour  K, Bos  JJ, Castelijns  JA.  Diameter of the bony lacrimal canal: normal values and values related to nasolacrimal duct obstruction: assessment with CT.  AJNR Am J Neuroradiol. 2001;22(5):845-850.PubMedGoogle Scholar
15.
Mannor  GE, Rose  GE, Frimpong-Ansah  K, Ezra  E.  Factors affecting the success of nasolacrimal duct probing for congenital nasolacrimal duct obstruction.  Am J Ophthalmol. 1999;127(5):616-617.PubMedGoogle ScholarCrossref
16.
Kashkouli  MB, Beigi  B, Parvaresh  MM, Kassaee  A, Tabatabaee  Z.  Late and very late initial probing for congenital nasolacrimal duct obstruction: what is the cause of failure?  Br J Ophthalmol. 2003;87(9):1151-1153.PubMedGoogle ScholarCrossref
17.
Repka  MX, Chandler  DL, Beck  RW,  et al; Pediatric Eye Disease Investigator Group.  Primary treatment of nasolacrimal duct obstruction with probing in children younger than 4 years.  Ophthalmology. 2008;115(3):577-584.e3.PubMedGoogle ScholarCrossref
18.
Ciftçi  F, Akman  A, Sönmez  M, Unal  M, Güngör  A, Yaylali  V.  Systematic, combined treatment approach to nasolacrimal duct obstruction in different age groups.  Eur J Ophthalmol. 2000;10(4):324-329.PubMedGoogle ScholarCrossref
19.
Kushner  BJ.  The management of nasolacrimal duct obstruction in children between 18 months and 4 years old.  J AAPOS. 1998;2(1):57-60.PubMedGoogle ScholarCrossref
20.
Flick  RP, Katusic  SK, Colligan  RC,  et al.  Cognitive and behavioral outcomes after early exposure to anesthesia and surgery.  Pediatrics. 2011;128(5):e1053-e1061.PubMedGoogle ScholarCrossref
21.
Sun  LS, Li  G, Miller  TLK,  et al.  Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood.  JAMA. 2016;315(21):2312-2320.PubMedGoogle ScholarCrossref
Original Investigation
November 2018

Spontaneous Resolution and Timing of Intervention in Congenital Nasolacrimal Duct Obstruction

Author Affiliations
  • 1Mayo Clinic School of Medicine, Rochester, Minnesota
  • 2Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
  • 3Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota
JAMA Ophthalmol. 2018;136(11):1281-1286. doi:10.1001/jamaophthalmol.2018.3841
Key Points

Question  What are the trends for spontaneous resolution in congenital nasolacrimal duct obstruction, and when is an appropriate time to intervene?

Findings  In this large population-based study of 1998 infants with congenital nasolacrimal duct obstruction, the rate of spontaneous resolution of congenital nasolacrimal duct obstruction plateaued after age 9 months, and the success rate of the initial probing declined after age 15 months.

Meaning  These findings suggest that surgical intervention may be appropriate during a new time frame, between 9 and 15 months, capitalizing on the condition’s changing rate of resolution as well as the declining success rate of the initial probing.

Abstract

Importance  Although the overall rate of spontaneous resolution in congenital nasolacrimal duct obstruction (CNLDO) and efficacy of probing have been documented in the literature, the optimal timing of intervention has not been established.

Objective  To report new findings regarding spontaneous resolution in a large cohort of children with CNLDO.

Design, Setting, and Participants  The medical records of 1998 consecutive infants diagnosed with CNLDO from January 1, 1995, through December 31, 2004, while residing in Olmsted County, Minnesota, were retrospectively reviewed. Data were analyzed between January 1, 2015, and January 2017.

Main Outcomes and Measures  Rate of spontaneous resolution over time and by sex.

Results  The cohort, diagnosed at a median age of 1.2 months (interquartile range, 0.4-3.6), was 48% girls (n = 959) and 89% white (n = 1626; 173 were unreported). Among the 1998 cases, 1669 (83.5%) spontaneously resolved, 289 (14.5%) underwent treatment, and the remaining 40 (2.0%) were lost to follow-up. Of the 1958 infants followed up, CNLDO in 925 (47.3%) spontaneously resolved by age 3 months, in 1300 (66.4%) by 6 months, in 1472 (75.7%) by 9 months, and in 1516 (78.4%) by 12 months. The rate of resolution was 35% faster (95% CI, 23%-47%; P < .001) at less than 1 month vs 3 months, 43% faster (95% CI, 27%-64%; P < .001) at 3 months vs 6 months, 39% faster (95% CI, 16%-64%; P < .001) at 6 months vs 9 months, and 1% slower at 9 months vs 12 months (hazard ratio, 0.99; 95% CI, 0.80-1.22; P = .78). Congenital nasolacrimal duct obstruction resolved in boys 0.5 months (95% CI, 0.2-0.8; P < .001) faster than girls (median, 2.9 vs 3.4 months), and unilateral obstructions resolved 0.2 months (95% CI, 0.1-0.4; P = .002) faster than bilateral (median, 3.1 vs 3.3 months) ones. Children probed at 15 months or older had decreased odds of resolution after probing (odds ratio, 0.11; 95% CI, 0.01-0.89; P = .04) compared with children probed at age 12 to 14 months.

Conclusions and Relevance  Based on this large cohort of children with CNLDO, probing between age 9 and 15 months may be reasonable given that the rate of spontaneous resolution plateaued after 9 months and initial probing success declined after 15 months. This time frame supports both an earlier and narrower range of ages for intervention compared with the current practice of probing after age 1 year.

Introduction

Congenital nasolacrimal duct obstruction (CNLDO) occurs in 1 in 9 newborns1 and is characterized by persistent tearing and intermittent mucopurulent discharge from 1 or both eyes. Standard early treatment includes hydrostatic nasolacrimal massage and topical antibiotics. While the obstruction will spontaneously resolve in most infants, it does not in up to 25% of affected children.2-8 Mechanical probing of the nasolacrimal duct has been accepted as a first-line treatment for persistent CNLDO; however, a consensus on the optimal timing for this intervention has not been established. To capitalize on the condition’s high frequency of spontaneous resolution,3-7 some authors propose waiting until the child is aged 12 or 13 months to probe. Others contend that delaying probing can increase the risk of inflammation and fibrosis, which may decrease the success rates of subsequent probings.8-10 The purpose of this study is to describe the natural course of spontaneous resolution in a cohort of 1998 infants diagnosed as having CNLDO and to suggest a reasonable time frame for surgical intervention.

Methods

Quiz Ref IDThe medical records of 1998 consecutive patients younger than 5 years diagnosed as having CNLDO while residing in Olmsted County, Minnesota, from January 1, 1995, through December 31, 2004, were retrospectively reviewed. The inclusion criteria and demographic data of the 1998 patients have been previously reported.1 Institutional review board approval was obtained from Mayo Clinic and Olmsted Medical Group, and written informed consent was obtained from the patients’ families. The population of Olmsted County is relatively isolated from other urban areas and virtually all medical care is provided to its residents by Mayo Clinic, Olmsted Medical Group, and their affiliated hospitals. All patient-physician encounters in the county, including summary information on demographics, clinical examinations, diagnoses, and surgical interventions, are collected through the Rochester Epidemiology Project (REP), a computerized medical record linkage system used in this study.11

Data regarding sex, laterality, natural history, and treatment were recorded for each patient. The date on which the symptoms of dacryostenosis resolved was established by parental history. If the date was not documented, resolution was calculated to occur between the last documentation of CNLDO and the subsequent infant evaluation negative for the condition. For example, if a child, when examined at age 2 months, was found to have dacryostenosis that was absent at the examination at age 4 months, the calculated date of resolution was the midpoint between the 2 examinations, or at 3 months of age. Most infants had well-child examinations at age 2 days, 2 weeks, 1 month, 2 months, 4 months, 6 months, 9 months, and 12 months. Any additional sick child visits provided increased surveillance during relatively short intervals of time. Multiple examinations over the years, in both primary and subspecialty care, were reviewed to confirm full resolution of symptoms.

Categorical and continuous variables were descriptively summarized using frequencies and percentages and medians and ranges, respectively. The rates of spontaneous resolution, beginning at age 12 months vs 9 months, were compared by first left-truncating follow-up for all patients still being followed up at age 9 months and 12 months (ie, beginning follow-up at 9 months and 12 months, respectively). A marginal Cox regression model clustered on each patient was then used to estimate the relative risk of spontaneous resolution beginning at 12 months compared with 9 months.12 Similar methods were used to compare 3 months and 0 months, 6 months and 3 months, and 9 months and 6 months. Kaplan-Meier curves were used to summarize overall unresolved over time for the entire cohort and to compare time with resolution by sex and laterality. Distribution of variables across the need for surgical treatment were compared using χ2/Fisher exact tests (where appropriate) for categorical variables and 2-sample t tests for continuous variables. Associations between successful probing intervention and probing age were examined using multivariable logistic regression. A successful probing was defined as the absence of epiphora postoperatively, whether the condition was unilateral or bilateral preoperatively. Other variables included in the model were diagnosis age (categorized as <1 month, 1-2 months, 3-5 months, and 6 months or older), sex, and presence of bilateral CNLDO. All analyses were performed using SAS, version 9.4 (SAS Institute Inc). All tests were 2-sided.

Results

Among the 1998 infants who received a diagnosis during the 10-year period, CNLDO in 1669 (83.5%) spontaneously resolved, 289 (14.5%) required surgical treatment, and 40 (2.0%) were lost to follow-up. The principal cohort of this study is the 1958 infants followed up, which includes the 1669 whose obstruction spontaneously resolved and the 289 who required surgical intervention. The 1669 whose obstruction spontaneously resolved were diagnosed at a median age of 1.0 months compared with 6.0 months for the 289 who required treatment (P < .001). Figure 1 illustrates graphically the number and percentage of the 1958 observed infants whose obstruction had not yet spontaneously resolved by age in months. The median age at resolution was 2.4 months (interquartile range, 1.3-5.3 months; range, 0-87 months) for the 1669 whose obstruction spontaneously resolved, while the 289 surgically treated patients underwent their first procedure at median age of 14.0 months (interquartile range, 9.5-21.1 months; range, 1-248 months).

The rate of spontaneous resolution was highest in the first few months of life, declining until age 9 months, when the rate flattened thereafter as shown in Figure 2. The rate of resolution was 35% faster (95% CI, 23%-47%; P < .001) at younger than 1 month vs 3 months; 43% faster (95% CI, 27%-64%; P < .001) at 3 months vs 6 months; 39% faster (95% CI, 16%-64%; P < .001) at 6 months vs 9 months; and 1% slower at 9 vs 12 months (HR, 0.99; 95% CI, 0.80-1.22; P = .78). Boys’ obstruction resolved 0.5 months faster (95% CI, 0.2-0.8; P < .001) than girls’ (median, 2.9 vs 3.4 months) (eFigure 1 in the Supplement), and unilateral obstructions resolved 0.2 months faster (95% CI, 0.1-0.4; P = .002) than bilateral (median, 3.1 vs 3.3 months) ones (eFigure 2 in the Supplement).

Two hundred seventy-two (94.1%) of the 289 surgically treated patients eventually underwent a probing, of which 242 (89%) had obstruction resolve without additional treatment. After adjusting for the effects of age at diagnosis, sex, and laterality, children probed at 15 months or older had decreased odds of resolution after probing (OR, 0.11; 95% CI, 0.01-0.89; P = .04) relative to children probed at age 12 to 14 months (Table). When patients younger than 9 months (OR, 0.16; 95% CI, 0.02-1.35; P = .09) and aged 9 to 11 months (OR, 0.41; 95% CI, 0.04-4.10; P = .45) were compared with probed patients aged 12 to 14 months, there was no difference in their success rates. The success rate of probing was 89.5% (n = 68 of 76) in children younger than 9 months, 94.5% (n = 52 of 55) in children aged 9 to 11 months, 97.8% (n = 45 of 46) in children aged 12 to 14 months, and 81.1% (n = 77 of 95) in children months or older. When segregated by 6-month age groups, a successful initial surgical intervention was 90.2%, 83.1%, 71.4%, and 64.7% at ages 6 to 12 months, 12 to 18 months, 18 to 24 months, and older than 24 months, respectively.

Discussion

Quiz Ref IDIn this population-based cohort of 1958 followed-up infants, complete resolution of CNLDO with nonsurgical treatment was achieved in 1516 patients (78.4%) by the first year of life. The rate of resolution was highest in the first months of life, decreasing until 9 months of age, after which the rate changed minimally. The obstruction resolved faster in boys than girls and in unilateral disease compared with bilateral disease. Patients probed at 15 months or older had lower odds of resolution without additional treatment compared with those probed at age 12 to 14 months, with no difference in the success rates between patients younger than 9 months and aged 9 to 11 months.

Quiz Ref IDSpontaneous resolution has been reported to occur in more than 90% of infants treated conservatively by several clinical studies.2-4,7,13 However, most of these studies were of selected populations, with less than 200 patients. Their small sample sizes and associated biases may have provided imprecise and unrepresentative estimates. While our study corroborates the tendency of CNLDO to resolve without surgical treatment as suggested in the literature, it does so with a relatively lower 1-year resolution rate. In this cohort diagnosed over a 10-year period, 78.4% of the observed infants spontaneously resolved by 12 months, and among the 1669 who never required surgical treatment, 1516 (90.8%) had resolved by the first year of life.

The rate of resolution decreases with increasing age, as observed by other investigators3,6 and confirmed in this cohort. Beginning at soon after birth, the spontaneous resolution rate declines by approximately 30% every 3 months until age 9 months, at which time the rate plateaus. Although the rate of resolution is no better at age 9 months compared with 12 months, there are fewer patients at age 1 year who have the potential to resolve. In this study, nearly 9 of 10 patients whose obstruction spontaneously resolved did so by age 9 months.

The condition resolved faster in boys than in girls, which, to our knowledge, has not been previously demonstrated. Although the rate of resolution between the sexes was small and is likely to be clinically irrelevant, any differences could be owing, at least in part, to the observation that the nasolacrimal canal and fossa of girls is a mean of 0.35 mm smaller than boys.14 Resolution of CNLDO also occurred faster in unilateral disease than bilateral disease, consistent with prior reports.15-17

Several studies have described an age-dependent decrease in success rates of initial probings from greater than 90% when done before age 12 months to 50% to 70% of those done after.13-16,18 One group noted a similar decline when comparing the success of probings before age 6 months with those between age 6 months and 12 months.19 However, the Pediatric Eye Disease Investigator Group, reporting on a prospective cohort of 718 children, did not find an association between age at surgery and surgical success up to age 36 months.17 The findings of this cohort confirm a negative association between increasing age after 15 months and a successful initial surgical intervention. The poorer results in older children have been attributed to the development of more complicated obstructions from chronic infections and scarring.20 Moreover, because the median age at CNLDO diagnosis was 6.0 months in the group who received surgical treatment compared with 1.0 months in those who spontaneously resolved, the decreasing success of probings in older children is likely owing to natural selection. Presumably, later-presenting children may have more complicated obstructions that reduce successful outcomes.

The optimal timing of the first probing remains controversial. A number of studies advocate delaying surgical procedures until after the first year of life, citing CNLDO’s high rate of spontaneous resolution.3-7 However, others favor early probing, citing the decline in favorable outcomes with increasing age as well as the previous reports of morbidities associated with persistent CNLDO.8-10 Conflicting conclusions based on underpowered studies, case series, and expert opinions promote the ongoing controversy. Given that the overall resolution rate changes minimally after age 9 months, it may be reasonable to consider intervening earlier than the current practice of probing at 12 months or older. However, probing beyond 12 months, as demonstrated by this study and others, appears to be less successful than when performed before age 1 year.

While probing with general anesthesia is recommended for better procedural control and completion, studies in the past several years on the association of childhood anesthesia and the development of cognitive impairment have questioned whether some procedures, including probings under anesthesia, is worth the risk. However, these studies suggest that multiple, not single, exposures to anesthetics and cumulative exposure greater than 120 minutes were associated with increased learning disabilities.20 Neurotoxicity risk stratified by being younger than 18 months is nonexistent in the literature; that is, there is no calculated difference in anesthesia risk for a 9-month-old child compared with a 1-year-old child. Findings from the landmark Pediatric Anesthesia Neurodevelopment Assessment study also demonstrated that 1 brief anesthetic, of a duration less than 80 minutes, was not associated with cognitive or behavioral abnormalities in exposed children when compared with their unexposed sibling.21 A probing typically involves less than 20 minutes of anesthetic exposure, and 80% to 90% of children require only one procedure.17 An argument for earlier probing, other than a higher success rate, is that by delaying procedures, older children could develop more complicated obstructions and ultimately require additional surgical procedures and increased exposure to general anesthesia.

Limitations

Quiz Ref IDThere are a number of limitations to the findings in this study. Its retrospective design is limited by nonstandardized and incomplete documentation. Accurately determining the age at resolution, for example, was problematic. Although most infants experienced 8 to 9 well-child examinations by age 18 months, both parental observation and the calculated date of resolution could have been calculated imprecisely if they were not. However, underestimations of the age at resolution would be expected to be balanced by overestimations with no systemic bias and no effect on the observations regarding sex, laterality, and the total number of resolutions. Although the REP system is uniquely designed to capture all of a patient’s medical visits in Olmsted County, some residents may have sought care outside of the county, leading to an overestimation of spontaneous resolution rate in this population. Finally, our ability to generalize these findings to other populations is limited by the demographics of Olmsted County, a relatively homogeneous semiurban white population.

Conclusions

Given that the rate of spontaneous resolution appears to plateau after age 9 months and a successful probing outcome declines beyond age 15 months, surgical intervention between these time intervals appears to be a reasonable treatment strategy for infants with nasolacrimal duct obstruction. This time frame establishes both an earlier and narrower range of ages for intervention compared with the current general practice of probing after age 1 year. Further prospective investigation is needed to definitively determine the most appropriate age for surgical intervention in children with CNLDO.

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Article Information

Corresponding Author: Brian G. Mohney, MD, Department of Ophthalmology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (mohney@mayo.edu).

Accepted for Publication: July 12, 2018.

Published Online: August 30, 2018. doi:10.1001/jamaophthalmol.2018.3841

Author Contributions: Drs Sathiamoorthi and Mohney had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Sathiamoorthi, Mohney.

Statistical analysis: Sathiamoorthi, Frank.

Obtained funding: Mohney.

Administrative, technical, or material support: Sathiamoorthi, Mohney.

Supervision: Mohney.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: The study was supported by Research to Prevent Blindness Inc and the Rochester Epidemiology Project (grant R01-AG034676 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Sathiamoorthi  S, Frank  RD, Mohney  BG.  Incidence and Clinical Characteristics of Congenital Nasolacrimal Duct Obstruction.  Br J Ophthalmol. doi:10.1136/bjophthalmol-2018-312074Google Scholar
2.
Nelson  LR, Calhoun  JH, Menduke  H.  Medical management of congenital nasolacrimal duct obstruction.  Ophthalmology. 1985;92(9):1187-1190.PubMedGoogle ScholarCrossref
3.
MacEwen  CJ, Young  JDH.  Epiphora during the first year of life.  Eye (Lond). 1991;5(pt 5):596-600.PubMedGoogle ScholarCrossref
4.
Nucci  P, Capoferri  C, Alfarano  R, Brancato  R.  Conservative management of congenital nasolacrimal duct obstruction.  J Pediatr Ophthalmol Strabismus. 1989;26(1):39-43.PubMedGoogle Scholar
5.
Price  HW.  Dacryostenosis.  J Pediatr. 1947;30(3):302-305.PubMedGoogle ScholarCrossref
6.
Paul  TO, Shepherd  R.  Congenital nasolacrimal duct obstruction: natural history and the timing of optimal intervention.  J Pediatr Ophthalmol Strabismus. 1994;31(6):362-367.PubMedGoogle Scholar
7.
Petersen  RA, Robb  RM.  The natural course of congenital obstruction of the nasolacrimal duct.  J Pediatr Ophthalmol Strabismus. 1978;15(4):246-250.PubMedGoogle Scholar
8.
Robb  RM.  Success rates of nasolacrimal duct probing at time intervals after 1 year of age.  Ophthalmology. 1998;105(7):1307-1309.PubMedGoogle ScholarCrossref
9.
Ffooks  OO.  Dacryocystitis in infancy.  Br J Ophthalmol. 1962;46(7):422-434.PubMedGoogle ScholarCrossref
10.
Weil  BA. Dacryocystitis. In: Viers ER, ed.  The Lacrimal System, Proceedings of the First International Symposium. St. Louis, MO: CV Mosby Co; 1971: 118.
11.
Melton  LJ  III.  History of the Rochester Epidemiology Project.  Mayo Clin Proc. 1996;71(3):266-274.PubMedGoogle ScholarCrossref
12.
Therneau  T, Grambsch  P.  Modeling Survival Data: Extending the Cox Model. Berlin, Germany: Springer-Verlag; 2000.
13.
Katowitz  JA, Welsh  MG.  Timing of initial probing and irrigation in congenital nasolacrimal duct obstruction.  Ophthalmology. 1987;94(6):698-705.PubMedGoogle ScholarCrossref
14.
Janssen  AG, Mansour  K, Bos  JJ, Castelijns  JA.  Diameter of the bony lacrimal canal: normal values and values related to nasolacrimal duct obstruction: assessment with CT.  AJNR Am J Neuroradiol. 2001;22(5):845-850.PubMedGoogle Scholar
15.
Mannor  GE, Rose  GE, Frimpong-Ansah  K, Ezra  E.  Factors affecting the success of nasolacrimal duct probing for congenital nasolacrimal duct obstruction.  Am J Ophthalmol. 1999;127(5):616-617.PubMedGoogle ScholarCrossref
16.
Kashkouli  MB, Beigi  B, Parvaresh  MM, Kassaee  A, Tabatabaee  Z.  Late and very late initial probing for congenital nasolacrimal duct obstruction: what is the cause of failure?  Br J Ophthalmol. 2003;87(9):1151-1153.PubMedGoogle ScholarCrossref
17.
Repka  MX, Chandler  DL, Beck  RW,  et al; Pediatric Eye Disease Investigator Group.  Primary treatment of nasolacrimal duct obstruction with probing in children younger than 4 years.  Ophthalmology. 2008;115(3):577-584.e3.PubMedGoogle ScholarCrossref
18.
Ciftçi  F, Akman  A, Sönmez  M, Unal  M, Güngör  A, Yaylali  V.  Systematic, combined treatment approach to nasolacrimal duct obstruction in different age groups.  Eur J Ophthalmol. 2000;10(4):324-329.PubMedGoogle ScholarCrossref
19.
Kushner  BJ.  The management of nasolacrimal duct obstruction in children between 18 months and 4 years old.  J AAPOS. 1998;2(1):57-60.PubMedGoogle ScholarCrossref
20.
Flick  RP, Katusic  SK, Colligan  RC,  et al.  Cognitive and behavioral outcomes after early exposure to anesthesia and surgery.  Pediatrics. 2011;128(5):e1053-e1061.PubMedGoogle ScholarCrossref
21.
Sun  LS, Li  G, Miller  TLK,  et al.  Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood.  JAMA. 2016;315(21):2312-2320.PubMedGoogle ScholarCrossref
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