Original Article
Frequency of Dry Eyes in Type 1 Diabetics at Sindh
Institute of Ophthalmology and Visual Sciences
Shehnilla Shujaat, Bibi Rafeen
Talpur, Syed Muhammad Faisal, Fariha Sher Wali, Khalid Iqbal Talpur, Anees
Fatima
Pak J Ophthalmol 2019, Vol. 35, No. 2
. . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . .. . .. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . .
See
end of article for authors
affiliations …..……………………….. Correspondence
to: Shehnilla Shujaat Department
of Ophthalmology, Sindh Institute of
Ophthalmology and Visual Sciences Hyderabad, Pakistan. Email: m.shehnila@gmail.com |
Purpose: To Determine
the Frequency of Dry Eyes in Type 1 Diabetics at Sindh Institute of
Ophthalmology and Visual Sciences. Study
Design: Cross sectional study. Place
and Durational of Study: At Sindh institute of Ophthalmology
and visual sciences and for six months 1st January 2017 to 30th June 2017. Material and Methods: Type 1 diabetics who were 30 to 70 years old with duration of
disease less than 5 years were registered and sampling was done by non-probability
convenience sampling. Schrimer test and tear film breakup time were performed
to analyse dry eyes in type 1 diabetes. Data was recorded in proforma and
results were assessed by using Statistical Program for Social Sciences (SPSS,
version 16.0). The percentages, frequencies were collected and t test was
applied. Results:
Out of one hundred diabetic patients, 71 (71%) had dry eye disease (P < 0.001).
The mean age of the patients in this research was 50.97 years (range 30 – 70
years). Old aged Diabetics were having the high risk of dry eyes (P < 0.001).
Gender was not found to be a risk factor of dry eyes in diabetics. Evaporative type dry eye disease was more
prevalent than non-evaporative type due to ocular surface diseases. Conclusion: Diabetics
are at high risk for having dry eyes, so they should be directed to have
periodic ocular examination to prevent severe ocular surface complications
leading to visual morbidity. Keywords: Dry
Eyes, Type 1 Diabetes Mellitus, Tear Film. |
Diabetes mellitus is identified as an important risk factor for
dry eyes. The reported prevalence of dry eye disease in diabetics is up to
54.3%1. Dry eye disease is also known as KCS. Kerato-Conjunctivitis-Sicca
is a Latin word and it means dry conjunctiva and cornea. Dry eye disease can be
caused by various factors2. Dry eye disease is almost always
progressive and chronic. Dry eye disease also increases the risk of corneal
infections, epithelial erosions and corneal vascularization in most of cases.
There is very strong association between diabetes and dry eye disease. Severe form of dry eye disease can lead to
superficial corneal punctate erosions, corneal epithelial defects and even
infective keratitis that can cause corneal opacification to permanent corneal
scaring. Diabetes is a well-known cause of visual morbidity in 20-74 years old
patients characterized by hyperglycemia leading to associated micro and
macrovascular complications. Worldwide more than 285 million people are
affected by diabetes mellitus3. Dry eye syndrome is comparatively
higher in patients, who have long standing diabetes4. Recently dry
eyes are found to be very commonly reported problem in approximately 10-30% of
population older than 30-40 years4. Such diabetic patients suffer
from many complications of cornea which include superficial corneal punctate
erosions, corneal ulceration and persistent infections. Diabetes can cause
pathological events in the blood glucose that is ordinarily converted in to
energy to fuel for various body functions5. Long duration and uncontrolled
diabetes permits unusually abnormal levels of blood sugar to be accumulated in small
and large blood vessels leading to pathology in macro and micro vessels that hampers
flow of blood to different body organs6. This study was done to
evaluate the correlation between glycated haemoglobin (HbA1C) and occurrence of
dry eye syndrome. Increased glycated haemoglobin (HbA1C) values causes increased
rate of dry eyes disease. Diabetic patients usually present with foreign body
sensation and have below normal schrimer test results. Long duration and
uncontrolled diabetes leads to pathological crisis in the microvasculature of
the lacrimal gland that cause abnormal lubrication of eyes7.
Diabetics also have decreased sensation of the cornea that is another factor
for initiating ocular surface problems. Early diagnosis of dry eye syndrome in
diabetics should be made to protect the diabetics from corneal complications7,8.
The objective of the present study was to Assess and Determine the Frequency of
Dry Eyes in Type 1 Diabetics at Sindh Institute of Ophthalmology and Visual
Sciences Hyderabad.
MATERIAL
& METHODS
This was a Cross sectional study that was performed at the Sindh
Institute of Ophthalmology and Visual Sciences. There were 100 Diabetic
patients and 200 eyes included in the sample size in this study and the duration was six months.
Rao software was used to
calculate the sample size. The confidence interval was 95% and response
distribution was 50%. Sampling technique was non-probability convenience
sampling. Patients included in the study had Insulin dependent diabetes
mellitus, were 30 and 70 years old and duration of disease was not less than 5
years. The following patients were excluded from the study: Those who had used
of topical medication within the past 6 months, had history of laser treatment
on the cornea or other ocular surgical procedures, patients having any lid
abnormality or previous ocular trauma and patients having corneal opacity.
There were 100 type 1 diabetic
patients who were analysed for dry eye disease in the study having the age of ≥30
years visiting the outpatient department of SIOVS for various eye problems.
Age, gender and duration of the diabetes were recorded for all the patients. The
history of other diseases was reviewed by checking previous medical records and
patient interview. Patients having type 1 diabetes were examined and analysed
for dry eyes. Diabetics under-went a thorough ocular examination by the author.
Two test were performed on each of these patients, they were Tear Film Break up
Time (TBUT) and schrimer test. These patients were assessed for having mild (Grade
1), moderate (Grade 2) and severe (Grade 3) dry eye disease. All the data was
recorded in a specific pro forma. Slit lamp examination was performed in all
these patients. Dry eye disease was suspected in patients having history of
foreign body sensation, redness and excessive tearing. The condition was
diagnosed by schrimer test and TBUT. Informed consent form was collected from
all of the patients. In TBUT test, a break up time of tear film less than 10
sec with local anaesthetic was considered below normal. In schrimer test less
than 06 mm of filter paper wetting after 5 minutes with local anaesthetic was
considered below normal.
This Observational study was
analysed by using SPSS version 16. P-value < 0.05 was reported significant
using the t-test.
RESULTS
Dry eye disease was examined in
right eyes of 100 patients in 30 – 40 year age group. Higher frequency of
moderate and severe dry eye disease was found in
41 – 50 year age group. In 61 – 70 year age group more frequency of moderate
dry eye disease found.
We examined dry eye disease in
left eyes of 100 patients in 31-40 year age group. Higher frequency of moderate and severe dry
eye disease was found in 41-50 year age group. In 51-60 year age group mild and
moderate dry eye disease was more common. In 61-70 year age group mild dry eye
disease was found to be more common. We found greater number of normal eyes in
51-60 years age group.
Table 1: Association of Age and grading of evaporative dry eyes in the
right eye.
|
|
|
Tear film break up time in R/E |
|
|||
|
|
|
|
|
|
Total |
|
|
|
Mild |
Moderate |
Severe |
Normal |
|
|
|
|
|
|
|
|
|
|
|
30-40y |
1 |
4 |
4 |
8 |
17 |
|
|
|
|
|
|
|
|
|
|
41-50y |
13 |
12 |
9 |
5 |
39 |
|
Age |
|
|
|
|
|
|
|
|
51-60y |
12 |
5 |
3 |
16 |
36 |
|
|
|
|
|
|
|
|
|
|
61-70y |
2 |
4 |
2 |
0 |
8 |
|
|
|
|
|
|
|
|
|
Total |
28 |
25 |
18 |
29 |
100 |
||
P < 0.001
Table 2: Association of Age and grading of evaporative dry eyes in
the left eye.
|
Tear film break up time in L/E |
Total |
||||
Mild |
Moderate |
Severe |
Normal |
|||
Age |
30 – 40 |
2 |
3 |
6 |
6 |
17 |
41 – 50 |
13 |
12 |
8 |
6 |
39 |
|
51 – 60 |
7 |
7 |
2 |
20 |
36 |
|
61 – 70 |
4 |
0 |
3 |
1 |
8 |
|
Total |
26 |
22 |
19 |
33 |
100 |
P.00
Table 3: Results of non-evaporative dry eye disease (schirmer) in
right eye.
|
|
Frequency |
Percent |
Valid Percent |
Cumulative Percent |
|
0-5mm |
27 |
27.0 |
27.0 |
27.0 |
Schirmer in R/E |
|
|
|
|
|
|
6-30mm |
73 |
73.0 |
73.0 |
100.0 |
|
|
|
|
|
|
|
Total |
100 |
100.0 |
100.0 |
|
Table 4: of non-evaporative (schirmer) dry eye disease in left eye.
|
|
Frequency |
Percent |
Valid Percent |
Cumulative Percent |
|
0-5mm |
29 |
29.0 |
29.0 |
29.0 |
Schirmer |
6-30 |
|
|
|
|
|
|
71 |
71.0 |
71.0 |
100.0 |
In L/E |
mm |
|
|
|
|
|
Total |
100 |
100.0 |
100.0 |
|
Schirmer
test checked in left eyes of 100 diabetics. Abnormal readings were found in the
29% of patients and normal schirmer test values were found in the 71% of
patients. This indicates the higher prevalence of dry eye disease.
Table 5: Descriptive statistics of duration and TBUT in R/E.
|
N |
Mean |
Std. Deviation |
Std. Error Mean |
Duration |
100 |
16.24 |
5.091 |
.509 |
TBUTR/E |
100 |
7.20 |
5.512 |
.551 |
We
compared the duration of type 1 diabetes with results of TBUT in right eyes. We
found P value < 0.001.
Table 6: Descriptive statistics of duration and TBUT in L/E.
|
N |
Mean |
Std. Deviation |
Std. Error Mean |
Duration |
100 |
16.24 |
5.091 |
.509 |
TBUTL/E |
100 |
7.68 |
5.128 |
.513 |
We
compared the duration of type 1 diabetes with values of TBUT in left eyes. We
found P value < 0.001.
Table 7: Descriptive statistics of duration and schirmer test in R/E.
|
N |
Mean |
Std. Deviation |
Std. Error Mean |
Duration |
100 |
16.24 |
5.091 |
.509 |
Schirmer R/E |
100 |
12.21 |
6.812 |
.681 |
We
compared the duration of type 1 diabetes with values of schirmer test in right
eyes. We found P value < 0.001.
Table 8: Descriptive statistics of duration and schirmer test in L/E.
|
N |
Mean |
Std. Deviation |
Std. Error Mean |
Duration |
`` |
16.24 |
5.091 |
.509 |
Schirmer |
|
|
|
|
|
100 |
11.84 |
7.212 |
.721 |
L/E |
|
|
|
|
When
we compared duration of diabetes with schirmer test readings of left eyes in type
1 diabetes p value was < 0.001.
Table 9: Sex and TBUT in B/E.
|
|
TBUT B/E |
|
|||
|
|
Mild |
Moderate |
Severe |
Normal |
Total |
Sex |
Male |
15 |
18 |
7 |
12 |
52 |
Female |
13 |
7 |
11 |
17 |
48 |
|
Total |
|
28 |
25 |
18 |
29 |
100 |
P
< 0.001
In
our study 40% males and 31% females had evaporative dry eye disease in both
eyes.
DISCUSSION
Diabetes mellitus is a very common generalized disorder affecting
a multi systems of the body9,10. There is a strong association
between dry eye disease and diabetes mellitus11.
Very few studies are performed to see the association with type 1
diabetes. As this eye problem is very common and can trigger severe eye
morbidity, dry eye disease should be checked in each diabetic patient coming in
outpatient department to decrease the advanced complications that leads to
blindness12 Dry eyes is also a very common ocular surface pathology.
It usually triggers and aggravates various eye diseases that leads to severe
corneal complications and then finally to blindness13.
Dry eye is classified into hyposecretory and evaporative dry eyes. Ocular surface diseases and meibomian gland dysfunction14
Leads to evaporative dry eye disease non evaporative dry eye disease is well
known disorder in female gender due to higher prevalence of autoimmune related
pathology and old aged patients associated with age related lacrimal gland malfunction15.
Analysis and treatment of
dry eyes is not only for the examination of dry eyes but to decrease the almost
all eye morbidities that lead several corneal complications. This research was
performed to analyse the frequency of dry eyes in type 1 diabetics. There are
several tests to analyse dry eye disease but and schirmer test and tear film
breakup time are very important tests16. Evaporative dry eye disease
is detected by below normal TBUT results and non-evaporative detected by below normal
schrimer test values17. Evaporative dry eye disease is a most
prevalent classification of dry eye disease.
In this research total 200 eyes of 100 type 1 diabetics were seen, out
of these patients 48 (48%) females 52 (52%) were males. In our diabetics,
minimum age seen was 32y, maximum age recorded 70 year and mean age seen was
50.97 year. Two important tests performed on type 1 diabetics, these were
schrimer test and TBUT and then their results were analysed to asses that how
many number of diabetics were having dry eye disease. Analysis of over study
described that minimum tear film break up time noticed 0Seconds, maximum was 19
seconds and Mean TBUT was 7.68 seconds in left eyes. The results of left eyes
were comparable with right eyes. Minimum
tear film break up time noticed 0s maximum observed 19s and Mean tear film
break up time value observed noticed
7.68s in left eyes. Values of
TBUT showed that a very large number of diabetics had below normal values. It
shows many diabetics were having dry eye disease. These diabetics were also
suffering from ocular surface diseases of eyes and poor hygiene of eye lids18,
so hygiene of eyelid should be regarded a cause of ocular surface problems and
then leading to dry eyes. Other test performed was schirmer test denoting the
secretions of accessory lacrimal glands. If the secretions of accessory
lacrimal glands are disturbed then patient experience non evaporative dry eyes.
Non-evaporative dry eye disease is prevalent in old aged diabetics due to age
related malfunction of accessory lacrimal glands and female gender due to
autoimmune multi system pathologies. This test is also considered as pillar of
examination of dry eye disease. When
schrimer test results were analysed they showed that minimum result was 0mm,
maximum found 30mm and mean checked 12.21mm in right eyes. Again the results of
left eyes were comparable with right eyes. Minimum value was 0mm, maximum value
was 28mm and mean schirmer test value was 11.84mm in left eyes. Abnormal
schirmer test readings were found in the right eyes of 27% patients and normal
schirmer test values were found in the right eyes of 73% patients. Abnormal
schirmer test readings were found in the left eyes of 29% patients and normal
schirmer test values were found in the left eyes of 71% patients. In our study 71%
patients had dry eye disease, seen by TBUT and schirmer test. This indicates
the higher pre-valence of evaporative type of dry eyes than non-evaporative dry
eyes.
Eyelid hygiene and ocular surface diseases are main culprits of
evaporative type of dry eye disease. Prevention of evaporative type of dry eye
disease can be done by taking some safe measures like face washing twice a
day. In a study conducted by Marten
Goebbels, on dysfunction of tear film in type 1 diabetes mellitus, mean TBUT
was 10 seconds and 11 seconds in non-diabetic. They compared the results of dry
eye tests done on diabetics and non-diabetics. They found significant lower
schirmer test values in diabetics than in non-diabetics. They thought that
decreased amount of reflex tearing in diabetics can be the cause of decreased
schirmer test values. In their study the amount of aqueous tear secretion was
measured by fluorophotometry and there was insignificant difference in-between
the values of dry eyes in diabetics and non-diabetics. [19] So according to
them there is no difference in the secretion of tear film in diabetics and in
patients without diabetes.
Old age was found to be strongly associated with occurrence of dry
eye disease. Abnormal tear film break up time was maximal in 40 to 50 year age
group. Age of our patients was divided into four groups and prevalence of dry
eyes was seen in these groups. Almost all patients were having bilateral
disease with little asymmetry, but both eyes of all patients were analysed. Dry
eye disease was found in 9% right eyes of 31-40 y age group, 34% right eyes of
41-50 y age group, 20% right eyes of 51-60 y age group and 8% right eyes of
61-70 y age group. Then Left eyes of 100 patients were seen. DED was found in
11% of 31-40 year age group, in 33% of 41-50 year age group, in 16% of 51-60
year age group and in 7% of 61-70 year age group. P value was significant (P <
.001) when association of dry eyes and age was analysed.
In a study conducted by paiShobha G on tear film function and tear
secretion among diabetics20, TBUT was found to be significantly
reduced in diabetic group. Tear film break time was less then10 seconds in 30%
of patience. The overall mean TBUT in diabetics was 9.8 ± 7.01 seconds they
also found lower schirmer test values in diabetic group. The mean schirmer test
result was 7.7 + 3.9 mm in diabetic group. According to them tear film break-up
time is very valuable test when performed accurately.
Diabetics should be checked for occult ocular surface disturbance
with detailed retina examination. In a study performed by Masoud Raza manaviat,
it was noticed that, there was not a marked correlation between gender and
prevalence of dry eye disease. There was percentage was 66.7% in 65-85 year old
age and decreased prevalence in 27-41
year aged patients . Long history of diabetes is strongly associated with
prevalence of dry eye disease. In this research the minimum duration of
diabetes was 6y, maximum 30year and Mean duration was 16.24year.When
association of dry eye disease and duration was assessed P value was found
significant (P < 0.001).
As we have little discussed earlier about the relation of gender
with dry eye disease21. In this research 48 females were included.
We did not observe high prevalence of dry eyes in females than males. It was
almost equal prevalence of dry eyes in females and males. So dry eye disease
was not gender related.
In another cohort study performed on 3722 patients, having age
range from 49-91 year, the frequency of dry eye disease was 14.4% in diabetic
patients they found 8.4% in patients less than 60 years of age and 19% in
patients having age older than 80 year. So the dry eyes and old age were
strongly associated.
Saifart et al assessed 92 patients having both types of diabetes,
having age from 7year-69year with a healthy subjects they observed dry eyes in
52.8% diabetics. In other research done on 140 diabetic patients, age range
from 20-93 year, having dry eye disease were examined. They found the more
prevalence of dry eye syndrome in these patients. 80% females were affected
from dry eye disease. In a study
conducted on 100 patients of type two diabetes. He compared the diabetics with
normal subjects he found significant lower values of tear film break up time in
diabetics.
In a research performed on 2414
patients, 322 subjects developed dry eye disease in a period of 5 year. Dry eye
syndrome was studied in 30 Pakistani subjects, 10 females and 20 males having
age range of 20 to 60 years. The visual acuity at the time of examination was
6/60 or less in 21 (70%) patients and 6/18 or above in nine (30%). Fifteen
(50%) subjects were almost blind and other six (20%) patients were having poor
prognosis. Only nine (30%) subjects had a chance of visual improvement.
CONCLUSION
Old age and longer duration of
type 1 diabetes mellitus are common risk factors in occurrence of dry eye
disease. Gender is not a risk factor in progression of dry eyes. We observed
high no of abnormal results in TBUT and less no of below normal results in
schirmer test. So evaporative type of dry eye disease was more common due to
ocular surface diseases than non-evaporative in our study.
Author’s
Affiliation
Dr. Shehnilla Shujaat
MS (Ophthalmology) Senior Registrar
Department of Ophthalmology, Sindh Institute of Ophthalmology and Visual Sciences Hyderabad, Pakistan.
Dr. Bibi Rafeen Talpur
FCPS, Assistant professor
Department of Ophthalmology, Sindh Institute of Ophthalmology and Visual Sciences Hyderabad, Pakistan.
Dr. Syed Muhammad Faisal
FCPS, FRCS, Assistant professor
Department of Ophthalmology, Sindh Institute of Ophthalmology and Visual Sciences Hyderabad, Pakistan.
Dr. Fariha Sher Wali
FCPS, Assistant professor
Department of Ophthalmology, Sindh Institute of Ophthalmology and Visual Sciences Hyderabad, Pakistan.
Dr. Khalid Iqbal Talpur
Ph.D Biochemistry and Molecular biology
Assistant professor
Scientific ophthalmic research and pathology laboratory, Sindh
Institute of Ophthalmology and Visual Sciences Hyderabad, Pakistan.
Dr. Anees Fatima
MS (Ophthalmology) Senior Registrar
Department of Ophthalmology, Sindh Institute of Ophthalmology and Visual Sciences Hyderabad, Pakistan.
Role of
Authors
Dr. Shehnilla Shujaat
Primary Investigator, Corresponding author
Dr. Rafeen Talpur
Co- Investigator
Dr. Syed Muhammad Faisal
Co- Investigator
Dr. Fariha S. Wali
Co- Investigator
Dr. Khalid Iqbal Talpur
Co- Investigator
Dr. Anees Fatima
Co- Investigator
REFERENCES
1. Man,
R.E.K., et al. Incidence and risk
factors of symptomatic dry eye disease in Asian Malays from the Singapore Malay
Eye Study. The Ocular Surface, 2017; 15
(4): 742-748.
2. The Definition and Classification of Dry Eye Disease: Report of the
Definition and Classification Subcommittee of the International Dry Eye
Workshop. The Ocular Surface, 2007; 5
(2): 75-92.
3. McGill, M., et al. The
interdisciplinary team in type 2 diabetes management: Challenges and best practice
solutions from real-world scenarios. Journal of Clinical &
Translational Endocrinology, 2017; 7:
21-27.
4. Vehof, J., et al. Predictors
of Discordance between Symptoms and Signs in Dry Eye Disease.
Ophthalmology, 2017; 124 (3): 280-286.
5. Wolf, M., et al. Effects of
MMP12 on cell motility and inflammation during corneal epithelial repair.
Experimental Eye Research, 2017; 160:
11-20.
6. Kandarakis, S.A., et al. Emerging
role of advanced glycation-end products (AGEs) in the pathobiology of eye
diseases. Progress in Retinal and Eye Research, 2014; 42 : 85-102.
7. McDougall, AJ, McLeod JG. Autonomic neuropathy, II: Specific
peripheral neuropathies. Journal of the Neurological Sciences, 1996; 138 (1): 1-13.
8. de França CF,
Fernandes AP, Carvalho DP, de Mesquita Xavier SS, Júnior MA, Botarelli FR,
Vitor AF. Evidence of interventions for the risk of dry eye in critically ill
patients: An integrative review. Appl Nurs Res. 2016; 29: e14-7.
9. Tao Z, Shi A, Zhao J.
Epidemiological Perspectives of Diabetes. Cell Biochem Biophys. 2015
Sep;73(1):181-5.
10. Nawaz, M.S., et al. Evaluation
of current trends and recent development in insulin therapy for management of
diabetes mellitus. Diabetes & Metabolic Syndrome: Clinical Research
& Reviews, 2017; 11 (Supp 2): S833-S839.
11. van der Vaart, R., et al. The
Association Between Dry Eye Disease and Depression and Anxiety in a Large
Population-Based Study. American Journal of Ophthalmology, 2015; 159 (3): 470-474.
12. Vehof J, Hysi PG, Hammond CJ. A
Metabolome-Wide Study of Dry Eye Disease Reveals Serum Androgens
as Biomarkers. Ophthalmology, 2017; 124 (4): 505-511.
13. Markoulli, M, et al. The
impact of diabetes on corneal nerve morphology and ocular surface integrity.
The Ocular Surface, 2017.
14. Barabino S, Horwath-Winter
J, Messmer EM, Rolando M, Aragona P, Kinoshita S. The role of systemic and
topical fatty acids for dry eye treatment. Prog Retin Eye Res. 2017
Nov;61:23-34.
15. Hampel U, Garreis F. The
human meibomian gland epithelial cell line as a model to study meibomian gland
dysfunction. Experimental Eye Research, 2017; 163: 46-52.
16. Zhang, J, et al. A link
between tear breakup and symptoms of ocular irritation. The Ocular Surface,
2017; 15 (4) 696-703.
17. Wang J, Palakuru JR, Aquavella JV. Correlations Among Upper and Lower Tear Menisci, Noninvasive Tear
Break-up Time, and the Schirmer Test. American Journal of Ophthalmology,
2008; 145 (5): 795-800.e1.
18. Trubilin, V.N., et al. PHS14
- Clinical and Economic Analysis of Eyelid Hygiene Complex for Patients with Meibomian
Glands Dysfunction in Russia. Value in Health, 2016; 19 (7): A606.
19. Waltman, S., et al. Vitreous
Fluorophotometry and Blood-Sugar Control in Diabetics. The Lancet, 1979; 314 (8151): 1068.
20. Abstracts of Paper Presentation during 58th National
Conference of Anatomical Society of India 2010 held at Dr. D. Y. Patil Medical
College, Pune. Journal of Anatomical Society of India, 2011; 60( 1): 65-144.
21. Chao, W, et al. Report of the
Inaugural Meeting of the
TFOS i2 = initiating innovation Series: Targeting the Unmet Need for Dry Eye
Treatment. The Ocular Surface, 2016; 14
(2): 264-316.