Purpose
To classify subtypes of meibomian gland dysfunction (MGD) and evaluate the dependency of dry eye signs, symptoms, and parameters on MGD subtype.
Design
Cross-sectional study. Study Population: the right eyes of 447 patients with MGD of various subtypes and 20 healthy volunteers.
Methods
Patients were divided into 4 subtypes of MGD based on meibum expression, meibum quality, and MG loss on meibography images (meibograde of 0–6). Subtypes were patients with high meibum delivery (hypersecretory and nonobvious MGD) and those with low meibum delivery (hyposecretory and obstructive MGD). Additional clinical tests included tear film break-up time (TFBUT), ocular staining, osmolarity, Schirmer I, blink interval timing and the Ocular Surface Disease Index (OSDI) questionnaire.
Results
A total of 78 eyes had hypersecretory MGD; 49 eyes had nonobvious MGD; 66 eyes had hyposecretory MGD; and 254 eyes had obstructive MGD. Increased tear film osmolarity and lower TFBUT were found in the low-delivery groups; hyposecretory ( P = 0.006, P = 0.016) and obstructive MGD ( P = 0.008, P = 0.006) relative to high-delivery MGD (hypersecretory and nonobvious groups, respectively). Worse ocular symptoms and ocular staining were also found in low-delivery MGD groups than the high delivery MGD groups ( P < 0.01 and P < 0.006, respectively).
Conclusions
Patients with low-delivery MGD had worse dry eye parameters and ocular symptoms than those with high meibum delivery, indicating the pivotal role of meibum secretion in ocular surface health that should be targeted in MGD therapy. Furthermore, nonobvious MGD cannot be diagnosed using conventional dry eye tests and requires morphologic assessment of meibography images to confirm MG loss.
Meibomian gland (MG) function is essential in maintaining ocular surface health and stability. MG functional abnormalities lead to reduced meibum secretion and/or altered lipid composition, consequently resulting in evaporative dry eye disease (DED). There is no precise definition of MG dysfunction (MGD) in published papers. MGD is associated with multiple pathological mechanisms, and various subtypes have been described based on anatomic changes, pathophysiological alterations, or the severity of disease. The International Workshop on MGD classifies MGD as low- and high-delivery status, based on the degree of meibum secretion.
Clinically, hypersecretory (high-delivery) MGD is characterized by the release of large amounts of meibum at the lid margin. It is arguable whether there is a true hypersecretion from MG or the presence of mild obstruction where meibum releases after forceful pressure of the eyelid. Nonetheless, no remarkable changes in gland structure were noted by meibography in this subtype. Conversely, a decreased lipid secretion due to either hyposecretion or obstruction indicates low-delivery MGD. Primary hyposecretion of MG is associated with gland atrophy without signs of gland obstruction. In contrast, obstructive MGD presents with reduced lipid secretion combined with highly viscous meibum due to duct orifice inflammation and hyperkeritinization.
The consequence of MGD is tear film instability resulting in dry eye symptoms. Currently, it is unclear how different subtypes of MGD affect the characteristics of the tear film. Thus, the clinical implications of classifying MGD subtypes are not obvious. In the present study, MGD was divided into proposed subtypes, and the question of how various clinical ocular surface parameters differed among the subgroups of MGD and healthy controls was investigated.
Methods
The right eyes of 447 patients with MGD diagnoses according to the guidelines from 2011 at the Norwegian Dry Eye Clinic were included in this cross-sectional study. The study was conducted in accordance with the Declaration of Helsinki. The Regional Committee for Medical and Health Research Ethics, Section C, South East Norway (REC) reviewed the use of the data in this study. The REC found the research project “ Evaluation of Data from the Norwegian Dry Eye Clinic ” to be outside the remit of the Act on Medical and Health Research (2008) and therefore could be implemented without specific approval. Written informed consent was obtained from all participants’ prior data collection.
Study patients were randomly selected from all patients seeking consultation due to various ocular symptoms of discomfort consistent with dry eye. All patients were examined at their initial consultation at the clinic by using a standardized protocol including the Ocular Surface Disease Index (OSDI) symptom questionnaire and supplementary clinical tests such as ocular surface staining, tear film break-up time (TFBUT), blink rate, tear film osmolarity, meibography, Schirmer I test, and meibum expressibility and quality. The clinical tests were performed by independent clinicians who were blinded to the classification criteria of MGD subgroups applied in this study. MGD was diagnosed after first diagnosing evaporative DED based on symptoms assessment and tear film parameters. To distinguish MGD from other subtypes of DED, specific assessments were made of meibum expressibility and quality and were evaluated by gland dropout on meibography images. In addition, 20 healthy volunteers without any systemic diseases or pre-existing ocular conditions or symptoms were recruited from the general population through the National Centre for Optics, Vision, and Eye Care as a control group.
Clinical Examinations
All patients first completed a symptom questionnaire to obtain an OSDI score between 0 (no symptoms) and 100. The ability of 5 MGs in the central area of the lower eyelid was tested for meibum secretion after firm digital pressure was applied. The results were scored from 0 to 3 depending on the number of expressible glands found among the 5 central glands, where 0 = all glands expressible; 1 = 3–4 glands expressible; 2 = 1–2 glands expressible; and 3 = no glands expressible ( Table 1 ). The quality of expressed meibum was scored from 0 to 3, where 0 = clear fluid; 1 = cloudy fluid; 2 = cloudy and particulate fluid; and 3 = opaque, toothpaste-like meibum. The final meibum quality score was the sum of all 8 central MGs in the lower eyelid ( Table 1 ). MGs that were not able to express meibum could affect the results, and this was noted in the patient’s journal.
| Examination | Evaluation |
|---|---|
| Ocular surface disease index questionnaire | Score from 0 (no dry eye symptoms) to 100 (severe symptoms) |
| Tear film break-up time | Less than 5 seconds: decreased |
| Ocular staining score | Nasal conjunctiva (0–3), cornea (0–3), temporal conjunctiva (0–3) |
| Blinking interval | Less than 10 seconds: decreased |
| Tear film osmolarity | Higher than 308 mOsmol/L: increased |
| Meibograde | Grade 0: 0–25% MG loss Grade 1: 26–50% MG loss Grade 2: 51–75% MG loss Grade 3: >75% MG loss Total meibograde (0–6): upper eyelid + lower eyelid |
| Schirmer’s test | Less than 5 mm: decreased |
| Meibum expressibility | Score 0: all glands expressible Score 1: 3–4 glands expressible Score 2: 1–2 glands expressible Score 3: no glands expressible |
The Schirmer I test was performed without anesthesia by inserting the test strip in the lateral third of the lower eyelid for 5 minutes. The TFBUT for each eye was measured for 30 seconds after instillation of 5 μl of 2% fluorescein to the conjunctival sac. Ocular fluorescein staining was analyzed in similar fashion and graded using the Oxford grading system. , Blink interval timing was recorded, and tear film osmolarity were evaluated using the TearLab system (TearLab Corp., San Diego, California). The dry eye severity level was graded from 1 to 4 according to the guidelines proposed by the 2007 International Dry Eye Workshop ( Table 2 ).
| Dry Eye Severity Level | 1 | 2 | 3 | 4 ∗ |
|---|---|---|---|---|
| Discomfort, severity and frequency | Mild and/or episodic | Moderate episodic or chronic | Severe frequent or constant | Severe and/or disabling and constant |
| Conjunctival staining | None to mild | Variable | Moderate to marked | Marked |
| Corneal staining (severity/location) | None to mild | Variable | Marked central | Severe punctate erosions |
| TFBUT, s | Variable | ≤10 | ≤5 | Immediate |
| Schirmer I score (mm/5 min) | Variable | ≤10 | ≤5 | ≤2 |
Meibography images were acquired using the Oculus Keratograph 5 (Oculus, Wezlar, Germany). Images were analyzed by an independent expert and according to our previously described method ( Table 1 ). Briefly, loss of the MG was graded using the 4-point meibograde 0 to 3. Meibogrades of upper and lower lids were combined to give 1 score from 0 to 6. Additional measurements of MG length, thickness, density (i.e., the space between 2 adjacent MGs) and number of distorted glands was performed using ImageJ version 2.0.0 software (National Institutes of Health, Bethesda, Maryland). Computerized analyses were performed of the 3 most representative glands in the upper eyelid only.
After the clinical examination, patients were divided into 4 groups by using a novel classification with basis on a combination of previously proposed diagnostic criteria ( Figure 1 ). , , The obstructive MGD group included subjects who fulfilled the previously proposed diagnostic criteria, as follows : they had 1) poor meibum secretion (meibum expressibility score ≥1) and 2) altered meibum quality (score >5). Subjects with poor meibum expression (meibum expressibility score ≥1) and minimally altered meibum quality (score ≤5) were then divided into the hyposecretory MGD group. The hypersecretory MGD group consisted of patients with high meibum expression (meibum expressibility score = 0) and subtle MG loss (meibograde ≤2) ( Figure 2 ). The remaining patients with high meibum secretion (meibum expressiblity score = 0) and moderate to severe MG loss (meibograde >2) formed a separate, undefined MGD group ( Figure 2 ).
Statistical Analysis
Data were analyzed using SPSS version 25.0 software (IBM, Armonk, New York). The data were tested for normal distribution using the Shapiro-Wilk test. Results from the MGD subtype groups and the control group were compared by using pair-wise comparisons and Kruskall-Wallis test with Dunn-Bonferroni post hoc test. The results for all parameters are presented as mean ± standard deviation. A P value of <0.05 was considered statistically significant.
Results
Seventy-eight eyes (50 women and 28 men; mean age of 42.1 ± 15.1 years old) had hypersecretory MGD; 49 eyes (28 women and 21 men; mean age: 50.7 ± 15.8 years old) had undefined MGD; 66 eyes (55 women and 11 men; mean age: 51.1 ± 17.2 years old) had hyposecretory MGD; and 254 eyes (199 women and 55 men; mean age: 53.4 ± 15.7 years old) had obstructive MGD. The controls were 20 eyes of 20 healthy volunteers (11 women and 9 men; mean age: 31.7 ± 14 years old).
The clinical parameters in each group of study subjects are presented in Table 3 , and the P value for pairwise comparisons of clinical parameter and MG parameters are presented in Table 4 and 5 , respectively. Compared to the control group, all MGD subgroups had significantly shorter TFBUT and blink intervals ( P < 0.001 and P < 0.001, respectively). The hypersecretory, undefined, and obstructive MGD groups had poorer meibum quality ( P < 0.001) than the control group. Tear film hyperosmolarity (>308 mOsmol/L) was found in low-delivery MGD groups only ( P = 0.006 for hyposecretory and P = 0.008 for obstructive MGD).
| Clinical Parameters | Normal Control | Hypersecretory MGD | Undefined MGD | Hyposecretory MGD | Obstructive MGD |
|---|---|---|---|---|---|
| Eyes, n | 20 | 78 | 49 | 66 | 254 |
| Age, years | 31.7 ± 14.0 | 42.1 ± 15.1 | 50.7 ± 15.8 | 51.1 ± 17.2 | 53.4 ± 15.7 |
| OSDI score | 30.3 ± 19.7 | 28.7 ± 18.1 | 41.1 ± 24.1 | 38.7 ± 22.2 | |
| Meibum expression | 0.8 ± 0.8 | 0.0 ± 0.0 | 0.0 ± 0.0 | 2.1 ± 0.7 | 1.7 ± 0.6 |
| Meibum quality | 0.03 ± 0.2 | 8.1 ± 4.1 | 8.9 ± 4.5 | 2.6 ± 1.6 | 10.6 ± 4.4 |
| Ocular staining score | 0.9 ± 0.6 | 1.12 ± 1.4 | 1.1 ± 1.5 | 2.0 ± 2.2 | 1.8 ± 2.1 |
| Tear-film break-up time, s | 9.6 ± 9.9 | 4.6 ± 3.2 | 4.0 ± 2.7 | 3.2 ± 1.9 | 3.4 ± 2.4 |
| Schirmer’s test value | 16.5 ± 11.9 | 14.3 ± 8.5 | 16.2 ± 9.7 | 15.7 ± 9.8 | 14.7 ± 9.7 |
| Blink interval, s | 19.5 ± 10.0 | 3.6 ± 2.4 | 3.1 ± 2.3 | 3.1 ± 2.2 | 3.3 ± 4.4 |
| Osmolarity | 305.0 ± 10.5 | 307.7 ± 13.2 | 307.5 ± 15.6 | 314.0 ± 13.5 | 313.2 ± 14.8 |
| Meibograde | 0.4 ± 0.5 | 1.4 ± 0.7 | 3.9 ± 0.9 | 3.7 ± 1.7 | 2.9 ± 1.6 |
| Number of distorted glands | 2.7 ± 1.5 | 1.2 ± 1.3 | 0.9 ± 1.4 | 0.8 ± 1.3 | 0.9 ± 1.3 |
| MG thickness (ImageJ unit) | 20.9 ± 3.7 | 19.7 ± 3.2 | 19.9 ± 3.9 | 19.3 ± 4.8 | 19.1 ± 3.6 |
| MG density (ImageJ unit) | 20.2 ± 16.3 | 15.7 ± 2.7 | 16.3 ± 3.4 | 14.8 ± 3.0 | 15.4 ± 3.1 |
| MG length (ImageJ unit) | 298.5 ± 49.2 | 306 ± 58.4 | 234.7 ± 85.5 | 216.6 ± 81.1 | 254.3 ± 73.6 |
| MG dropout, % | 12.6 ± 5,1 | 18.3 ± 6.8 | 36.4 ± 15.2 | 41.3 ± 19.6 | 32.9 ± 16.7 |
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