Prof Bron lecture. The A-Z of MGD

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  • Function is disturbed
    Alteration of these functions leads to:
    Decreased tear film stability
    Symptoms
    Result of:
    Anatomical abnormalities
    Abnormalities in secretion
    Diffuse
    Involves most of the meibomian glands
    Localized involvement of meibomian glands
    Does not cause abnormalities in the tear film or ocular surface epithelia
    Not considered within the context of MGD.
    Obstruction
    Obstruction of the meibomian gland orifice and terminal duct is identified as the most prominent aspect of MGD.
  • Function is disturbed
    Alteration of these functions leads to:
    Decreased tear film stability
    Symptoms
    Result of:
    Anatomical abnormalities
    Abnormalities in secretion
    Diffuse
    Involves most of the meibomian glands
    Localized involvement of meibomian glands
    Does not cause abnormalities in the tear film or ocular surface epithelia
    Not considered within the context of MGD.
    Obstruction
    Obstruction of the meibomian gland orifice and terminal duct is identified as the most prominent aspect of MGD.
  • Function is disturbed
    Alteration of these functions leads to:
    Decreased tear film stability
    Symptoms
    Result of:
    Anatomical abnormalities
    Abnormalities in secretion
    Diffuse
    Involves most of the meibomian glands
    Localized involvement of meibomian glands
    Does not cause abnormalities in the tear film or ocular surface epithelia
    Not considered within the context of MGD.
    Obstruction
    Obstruction of the meibomian gland orifice and terminal duct is identified as the most prominent aspect of MGD.
  • Function is disturbed
    Alteration of these functions leads to:
    Decreased tear film stability
    Symptoms
    Result of:
    Anatomical abnormalities
    Abnormalities in secretion
    Diffuse
    Involves most of the meibomian glands
    Localized involvement of meibomian glands
    Does not cause abnormalities in the tear film or ocular surface epithelia
    Not considered within the context of MGD.
    Obstruction
    Obstruction of the meibomian gland orifice and terminal duct is identified as the most prominent aspect of MGD.
  • TFLL cools as it spreads over the cornea
  • The glands are under neural and endocrine control.
  • TFLL spreads aand stabilises in about 1 second
    Which retards evaporation from the ocular surface.
  • TFLL spreads aand stabilises in about 1 second
    Which retards evaporation from the ocular surface.
  • Spreading of the TFLL is much slower than the blink.
    The blink is over in about 0.2 seconds, whereas the TFLL spreads over about one second.
  • MGD is an extremely common form of posterior blepharitis, with frequency of 40-65 % reported in Asian studies and a lower frequency in studies from USA, Australia
  • NON-CICATRICIAL
    Orifices
    In lid skin
     plugged
    Margins
    thick
    hyperaemic
    Expressed Lipid
    cloudy
  • Blackie 2008 FIGURE 6. A, NOMGD with recalcitrant obstruction despite forceful expression. The lower eyelid is compressed between a swab on the palpebral conjunctival surface and the thumb on the outer eyelid surface. Despite the use of maximum force approaching 275 g/mm2 (approximately 80 psi), the glands do not yield significant secretion. Before the application of forceful expression, the lids, eyelid margins, and meibomian gland orifices appeared normal. However, with forceful expression, the orifices evidenced elevated whitish plugs. B, NOMGD yielding secretion with forceful expression. The lower eyelid is compressed between 2 swabs on the surface of the palpebral conjunctiva and on the outer eyelid surface. Before expression, the lids, eyelid margins, and orifices appeared normal; however, standardized diagnostic expression failed to express secretion. The application of forceful expression almost immediately produced copious secretion on the form of filaments, indicating narrowing of the distal portion of the ducts, near the orifice. The color of the secretion varied from white to semipurulent.
  • We have proposed that Marx’s line may provide a route by which inflammatory mediators gain access to the terminal duct and stimulate the production of cornified envelope proteins that are a part of the keratinization process.
  • A similar mechanism may explain the forward movement of Marx’s line and the MCJ with age and its relation to MGD
  • In the Clegg 2010 proteomic study the presence of Clagranulin A and B correlated with MGD severity. These are cornified envelope proteins which could have a role in the keratinising process that is the basis of duct obstruction in MGD. They also correlated with signs or redness and visual blur. Calgranulin A correlated with the occurrence of a gritty feeling
    These proteins also have a role in innate immunity, barrier functions and stress signalling.
  • Bacterial lid commensal load is increased in anterior blepharitis. P epidermidis, P acnes S aureus
    Likely but less certain in MGD
  • S.aureus and other lid commensals produce esterases and lipases which can release irritant FAs and glycerides and contribute to symptoms.
    Organisms may contribute to symptoms even in the absence of direct infection
  • Background: Norn found that 46% of lower lid glands were active = expressible, and expressibility fell with age
     
    A method for recording the grading of Meibomian gland function is proposed and a modification to the recruitment criteria. This is modified from that proposed in a letter to JS in May 18 2009.
     
    At recruitment and during study visits, assessment of Meibomian gland function will be based on the quality and expressibility of expressed Meibomian secretions from the central 5 glands of the lower lids.
    Assessments are made during expression from the lower central 5 Meibomian glands with moderate digital pressure:
     
    1. Quality of expressed secretion is assessed according to a modified Bron et al. (1991) scale:
    The quality of expressed secretion for each gland will be recorded on the scale:
     
    0= clear;
    1 = cloudy;
    2 = cloudy particulate;
    3 = inspissated, like toothpaste. To this could be added:
    4 = plugging
    5 = pathological occlusion
    Where no oil is expressible a dashed line [-] is placed in the box if it is thought to be physiological.
    .
    The highest grade recorded from any gland is entered in the final box.
    [Because there is a variable expressibility of normal glands it will not possible to sum the scores to achieve a total score until studies have been done to confirm both precision and accuracry. Accuracy would be achievable if ‘pathologically inexpressible glands’ were confirmed to be abnormal on the basis of Meibography.
     
    In a clinical record this would be recorded as:
     
    Quality of expressed Meiboinan gland excretion.
     
    Gland 1
    Gland 2
    Gland 3
    Gland 4
    Gland 5
    Highest grade
    Grade
     
     
     
     
     
     
     
    In a study in which there is a risk of a toxic action on the Meibomian glands (eg systemic use of retinoids) a highest entry grade of  1 is allowable; a grade of  2 is excluded.
     
    2. Expressibility is assessed according to the Pflugfelder 1998 scale:
     
    0 = all 5 glands are expressible with clear fluid;
    1 = 3-4 glands out of 5 are expressible;
    2 = 1-2 glands are expressible and
    3 = No glands are expressible.
     
    In a CRF this would be recorded as:
    Expressibility of Meibomian glands
    Grade
     
     
    At entry, there will be no expressibility inclusion criterion.
    [This is because there is variability in expressibility of normal glands at the central part of the lower lid (Korb and Blackie 2008; Blackie and Korb 2009.]
     
     
     
    Bron AJ, Benjamin L, Snibson GR. Meibomian gland disease. Classification and grading of lid changes. Eye 1991; 5 ( Pt 4): 395-411.
     
    Blackie CA, Korb DR. Recovery time of an optimally secreting meibomian gland. Cornea 2009; 28: 293-7.
     
    Korb DR, Blackie CA. Meibomian gland diagnostic expressibility: correlation with dry eye symptoms and gland location. Cornea 2008; 27: 1142-7.
     
    Pflugfelder SC, Tseng SC, Sanabria O, et al. Evaluation of subjective assessments and objective diagnostic tests for diagnosing tear-film disorders known to cause ocular irritation. Cornea 1998; 17: 38-56
  • Casual levels are reduced in MGD:
    Slightly increased in aqueous-deficient dry eye
  • Cyclical activity ?? Role of EDAR??
    Figure 1. Photograph demonstrating the meibography system, which is composed of a slit lamp equipped with an infrared transmitting filter and an infrared charge-coupled device (CCD) video camera. Images of meibomian glands can be observed on the monitor.
    Figure 2. Images demonstrating representative cases of each grade of the meibomian gland changes. The upper and lower eyelids were turned over and meibomian glands were observed using an infrared transmitting filter and an infrared charge-coupled device video camera. Changes in meibomian glands were scored using the following grades in each eyelid (meiboscore): grade 0, no loss of meibomian glands; grade 1, area loss was less than one third of the total meibomian gland area; grade 2, area loss was between one third and two thirds; grade 3, area loss was more than two thirds.
    Figure 3. Bar graph showing the average meibomian gland change score (meiboscore) stratified by age group or gender in each age group. There was a significant positive correlation between age and meiboscore in the entire subject population (R = 0.428; P<0.0001), in males (R = 0.462; P<0.0001), and in females (R = 0.418; P<0.0001).
    Figure 4. Bar graph showing the average lid margin abnormality score. Four lid margin abnormalities (irregular lid margin, vascular engorgement, plugging of meibomian gland orifices, and anterior or posterior replacement of the mucocutaneous junction) were scored from 0 to 4 according to the number of these abnormalities present in each eye. There was a significant positive correlation between age and the lid margin abnormality score (R = 0.538; P<0.0001).
  • Blackie 2010
    Heat measures:
    Infra red heat- Goto 2002
    warm moist air – Mitra 2005; Matsumoto 2006
    infrared and hot air sources; [Blackie 2008][Matsumoto 2006][Olson 2003][Mitra 2005]
    Orghexa masks – Ishida 2008
    Hot towel at 40-45C for 5 min/day increased TFLL thickness in MGD subjects [Olsen 2003][Blackie 2008] Infrared source [Mori 1999; Goto 2002], or a disposable eye warmer [Mori 2003] for 5 minutes, once or twice a day in different studies, has improved tear stability and reduced symptoms in MGD patients.
    Warm, moist air 10 min bd improved symptoms and tear stability and reduced ocular surface damage in patients with MGD [Matsumoto 2006]
    Maskin SL. Intraductal meibomian gland probing relieves symptoms of obstructive meibomian gland dysfunction. Cornea 2010; 29: 1145-52.
  • The Spiteri study uses the Fuller latent heat [Blephasteam?] device in an observer-masked study of SS and non-SS dry eye. The earlier, Mitra 2005, study showed an increase in TFLL and comfort in normal subjects
    Nagahiliy 2004 Increased meibometry reading after heating with LED. Lid surface temp increased about 5 degrees C. Decreased after colloing with compress.
    Goto did not find improvements if ADE was also present.
    Forcible blinking## or expression also increases TFLL thickness and
  • These two studies shows the effect of lid warming alone. [were they both unblinded?]
    Mori 2003: Unblinded study.
    Eyelid warmer. 5 min daily for 2 weeks 34 eyes of 17 MGD patients
    On activation, mask temperature the temperature rises to 45 degrees in 2 minutes at stays above 40 degrees for 15 min. Measurements were made 2 weeks after treatment. Lid temp rose by about 6 °C Corneal temp rose to around 37.4 °C BUT and dry-eye symptoms significantly improved after the treatment in the therapeutic study (P .01). The incidence of meibomian gland obstruction was significantly decreased after treatment (14 eyes [41.2%]) compared to before treatment (26 eyes [76.5%]) (P .006). The incidence of normal tear lipid layer in the treated group was significantly higher after treatment (28 eyes [82.4%]) than before (19 eyes [55.9%]) (P .036). No comment on the difference between groups
    Olson 2003: 20 MGD dry eye patients treated with warm or RT wet compresses to one or other eye. Found a significant increase in mean TFLLT in the experimental eye after 5 minutes (P < 0.001), 15 minutes (P < 0.001), and 30 minutes (P < 0.001) of treatment, and after 5 minutes following the 30-minute treatment period (P < 0.001) when compared to baseline TFLLT
    Goto et al. 2002 showed improved TF stability after warm compresses
    Goto 2002 –37 refractory non-inflam MGD -17 with ADE: infrared warm compression device (IWCD, Eye Hot, Cept Co,
    Tokyo, Japan. subjective face scores improved significantly, from 12.3 (SD 5.9) to 8.4 (6.1), and from 7.0 (1.7) to 5.3 (2.0) (both p <0.0001). The results for tear evaporation rates during forced blinking (p = 0.002), fluorescein staining (p = 0.03), rose bengal staining (p = 0.03), BUT (p <0.0001), and meibomian gland orifice obstruction score (p <0.0001) had also improved significantly at the end of the 2 week period
  • Spiteri A, Mitra M, Menon G, et al. Tear lipid layer thickness and ocular comfort with a novel device in dry eye patients with and without Sjogren's syndrome. J Fr Ophtalmol 2007; 30: 357-64. [###check this is the precursor of the Blephasteam device]
     
    BACKGROUND: To measure changes in tear-film lipid-layer thickness (LLT) and symptoms in patients with dry eye symptoms with and without Sjogren's syndrome after using a novel device. The device is designed to promote release of meibomian sebum into the tear film by delivering latent heat to the eyelids. STUDY DESIGN: Two prospective, controlled, randomised, observer-masked, single-intervention studies. METHODS: Two independent studies were conducted in a major university hospital in the South West of England. The first study involved 24 patients with dry eye symptoms without Sjogren's [the PDE study] and the second study involved 31 patients with dry eye symptoms and Sjogren's syndrome (the SS study). The PDE study was randomised into two groups. Group I (12 patients) underwent 10 min of treatment with the activated device and Group II (12 patients) had no treatment. The SS study was similarly randomised into Group I (17 patients) and Group II (14 patients). The LLT and subjective alterations in ocular comfort of each subject were assessed prior and immediately after 5 and 30 min subsequent to the 10-min period. In the SS study, a further assessment was carried out at 60 min. RESULTS: In the PDE study, treated patients exhibited a at bilateral increase of LLT 5 min (right eyes, 1.2 levels, p<0.0005; left eyes, 1.0 levels, p<0.0005, Mann-Whitney) and at 30 min (right eyes, 0.7 levels, p<0.005; left eyes, 0.6 levels, p<0.005). Mean symptom scores improved in the treated group compared with the control group at 5 min (treatment group, +2.0; control group, +0.2; p<0.05) and 30 min (treatment group, +2.8; control group, +0.4; p<0.015). In the SS study, treated patients exhibited a bilateral increase of LLT, 5 min (right eyes, 0.5 levels, p<0.009; left eyes, 0.5 levels, p<0.005, Monte Carlo 2-tailed), 30 min (right eyes, 0.5 levels, p<0.007; left eyes 0.5 levels, p<0.002) and 60 min (right eyes, 0.3 levels, p<0.1; left eyes, 0.3 levels, p<0.05). There was no change in any of the control patients in any of the assessments. With regard to symptom scores, the mean change at 5 min measured +0.8 in the treatment group and remained relatively unchanged at +0.1 in the control group (p<0.1). At 30 min, this change measured +1.3 in the treatment group and +0.1 in the control group (p<0.03) and at 60 min, the change measured +1.5 in the treatment group and remained at +0.1 in the control group (p<0.02). CONCLUSION: Meibomian therapy with this novel device increases LLT and ocular comfort in patients with dry eye symptoms with and without Sjogren's syndrome.
    Pearce 2006: In 20 patients with dry eye, treatment for 10 minutes reduced raised eyelid temperature, improved tear lipid film spreadability and reduced tear evaporation rate from 40gm/m2/h to 27g/m”/h (32%).
    Pearce 2007: In a further study, [subjects? TFOS] an increase in the BUT and VA was reported. ##
    Thirty one symptomatic dry eye subjects (2+ symptoms by McMonnies questionnaire4,5) 23 female, 8 male, mean age 25 SD ± 7.7 years were recruited. Each subject was treated with the EyeCalm goggles at 50 ̊C for 10 min. [Note the higher temperature – using the EyeCalm]
    A significant improvement in median low contrast VA of 0.1 log units was observed following treatment (p=0.029)
    • Mean NITBUT improved significantly from 11.3 to 17.2 sec (p=0.000) • Lipid layer appearance was not found to change (p=0.496)
    • Aberrometry showed a significant reduction in overall Zernike RMS values (p=0.020) for a 5mm pupil
  • Thermodynamic treatment of MGD: Friedland et al 2011 was effective, in this feasibility study, in treating obstructive MG dysfunction and dry eye signs and symptoms for the 3-month study period [The mean MG secretion score, tear break-up time, corneal staining score, number of MGs yielding liquid secretion and symptom scores all improved significantly from baseline to 1 week. This was maintained through the 3-month follow-up. There was no further improvement in a fellow eye treated additionally with another device to apply manual, heated expression]
    The melting temperature of meibum is increased in MGD [Mc Culley and Shine 1998]]
    MG expression increases TFLL thickness [Korb##]
    Arciniega 2011 MG expression reduces evaporation in both normals and KCS with MGD.
    In an earlier study by Blackie et al. 2008 – they found that the inner surface of the lids could be raised 38.8 degrees with a 45 degree warm compress source, in 4 mins. Thise was increased by more prolonged exposure. It took longer to achieve in the upper lid.
    To optimize WC efficiency, patients should (1) heat the WC to approximately 45 degrees C, (2) optimize contact between the WC and outer eyelid surfaces, (3) reheat the WC frequently and have a replacement heated WC on hand for exchange, and (4) perform the activity for at least 4 min in order to achieve an inner lower eyelid temperature > or = 40 degrees C. Longer therapy may be necessary for more severe obstructions. These data suggest that precise, customized, labor-intensive WC procedure is necessary to optimize treating meibomian gland dysfunction and obstruction using WCs.
  • McCann 2011 found improved tear stability, BUT, (HA too), osmolarity and staining (not HA or HPMC)
    In the Goto 2006 study a small dab of ointment containing 0.3 % ofloxacin both polar and non-polar lipids was applied along the length of the lower lid in 30 office workers with refractory dry eye. There were no controls and of course, no masking. They found improved symptoms, a thicker TFLL and a reduced BUT after 2 weeks treatment 3 times a day.
  • -Tears Again / Actimist 
    Craig 2010: Effect of liposomal spray compared with saline in normals. Masked, RCT. Improved comfort. ?
    Results: Treated and control eyes were not significantly different at baseline (p > 0.05). Post-application,
    LLG increased significantly from baseline, at 30 and 60 min, only in the treated eyes (p = 0.005). NIBUT also increased significantly in the treated eyes only (p < 0.001), at 30, 60 and 90 min. TMH did not alter significantly (p > 0.05). Comfort improved relative to baseline in 46% of treated and 18% of control eyes, at 30 min post-application. Of those expressing a preference in comfort between the eyes, 68% preferred the liposomal spray.
    Improvements in symptomatology, visual acuity, eyelid margin inflammation, tear production and lid parallel conjunctival folds have been documentedwith use of the lipid spray in patientswith dry eye [16–18], in contact lens wear [19] and following cataract surgery [20].
    McKeen et al. in 1998 reported the transfer material the tear film after application of a calcium carbonate ointment to the skin of the lids. This was confirmed by Tsubota 1999.
    Liposomal spray: Dausch 2006; Khaireddin Schmidt 2009; Purslow?
    Dausch et al. 2006 compared the efficacy of a phospholipid containing liposomal preparation, sprayed onto the closed lids on the symptoms and signs of evaporative dry eye. After the initial 6 weeks period of treatment, the BUT, Schirmer, visual acuity and inflammation of the lid margin and LIPCOF score was significantly better in the spray group than in the comparative, LIPISIC, triglyceride-containing, eye gel group. The same result was obtained in the crossover study. This was an RCT, presumably not masked. The preparation is TEARS AGAIN, Optima Pharmaceutical GmbH, Germany.
    In an earlier study by Lee et al. 2004, similar significant efficacy was shown for symptoms and signs when comparing the spray with a saline spray.
    In a related study of 216 patients with EDE, Khaireddin and Schmidt showed that TEARS AGAIN spray was more effective than a hyaluronic acid drop in reducing LIPCOF grade (p < 0.02) and the grade of inflammation of the lid margin (p < 0.002). With respect to the tear film break-up time (NIBUT) there was a significant difference between the results of both groups (p < 0.003). The improvement of the break-up time in patients of the eye spray group turned out to be more than twice as high as that in the artificial tears group.
    [16] Dausch D, Lee S, Dausch S, Kim JC, Schwert G, Michelson W. Comparative study
    of treatment of the dry eye syndrome due to disturbances of the tear film lipid
    layer with lipid-containing tear substitutes. Klin Monatsbl Augenheilkd
    2006;223:974–83.
    [17] Khaireddin R, Schmidt KG. Comparative investigation of treatments for evaporative
    dry eye. Klin Monatsbl Augenheilkd 2009. September 15 [Epub ahead
    of print].
    [18] Lee S, Dausch S, Maierhofer G, Dausch D. A new therapy concept for the
    treatment of dry eye—the usefulness of phospholipid liposomes. Klin Monatsbl
    Augenheilkd 2004;221:825–36.
  • Topical Fucidic acid: Seal 1995: 1% gel improved symptoms in 75% of patients with rosaceal blepharitis, compared to 50% in those treated with oral oxytetracycline. Patients with non-rosaceal blepharitis did not respond fusidic acid alone, although 25% of them responded to oral oxytetracycline [Seal 1995]. Fusidic acid is bactericidal to gram positive organisms.
    Topical azithromycin:
    Anti-inflammatory: inhibits cytokine release (IL6, IL-8, TNF ), of PMN chemotaxis and phagocytosis, and of inflammatory cell adhesion [Beigelman 2009][Prescott 2005].
    In open label studies:
    1% drops were reported to be effective in the treatment of the symptoms and signs of blepharitis, including MGD, [Foulks 2010][Haque 2010].
    Treatment with azithromycin and hot compresses was more effective than compresses alone and there was an improvement in the chemistry of expressed meibum [Foulks 2010]. [Drug used bd for 2 days and then od for 12 days]
    Opitz 2011: Open label 26 of 33 completed 30 day study. Twenty-six of 33 patients completed the study. Tear break-up time and Schirmer score increased by 52.7 per cent (p < 0.0001) and 24 per cent (p < 0.05), respectively. There was a reduction in corneal and conjunctival staining by 83.2 and 67.9 per cent, respectively (p < 0.0001). Lid margin scores were reduced by 33.9 per cent (p < 0.0001). The patient's symptom score improved from 2.73 at baseline to 2.21 after 30 days of treatment (p < 0.01). The mean OSDI at baseline was 34.44. After two weeks and 30 days of treatment, the ODSI was 14.51 and 13.15 respectively (p < 0.0001).
    Topical tetracyclines for ocular rosacea since 1966 [Roper-Hall 1966].
    Restasis: Perry 2006. At 3-months, several findings were statistically significantly (P < 0.05) in the tCsA group compared with the placebo group. These differences included lid margin vascular injection, tarsal telangiectasis, and fluorescein staining. The most significant finding (P = 0.001) was the greater decrease in the number of meibomian gland inclusions in the tCsA group compared with the placebo group.
    Metronidazole : In a study of 10 patients with ocular rosacea and blepharitis by Barnhorst et al. [Barnhorst 1996], treatment with topical metronidazole gel 1 %, applied to the lid margin for 12 weeks and combined with lid hygiene, was more effective than lid hygiene alone in improving eyelid and ocular surface scores.
    gel 1% in ocular rosacea. Barnhorst 1996
    Azithromycin % drop bd : Luchs 2008 MGD
    Add: Tea Tree Oil 50% with TTO shampoo – for demodex Tseng
  • This example from a rabbit study by Akpek shows the extended residence time for Azythromycin, over several days, achieved with a polymeric vehicle after a single instillation.
    Azithromycin is detectable in the tears for 7 days after the instillation of a single drop and the level is greater when the vehicle contains the polyacrylic polymer, polycarbophil, a component of the durasite drop.
  • High cellular retention determines that tissue levels are even greater in the conjunctiva and cornea, again, over days.
    AKPEK 2009 FIG. 1. Pharmacokinetic profi le of azithromycin in ocular tissues after a single instillation of 1% azithromycin. Formulations
    with (●) and without (○) polycarbophil were measured in the tear fi lm (A), conjunctiva (B), cornea (C), and aqueous humor
    (D). Concentration profi les for each tissue were generated from 60 rabbits per treatment; each time point shown is the mean
    FIG. 2. Pharmacokinetic profi le of 1% azithromycin with
    polycarbophil following the FDA-approved multiple administration
    regimen (1 drop twice a day for the fi rst 2 days, followed
    by 1 drop once a day for 5 days). The concentration
    of azithromycin in conjunctiva (A), cornea (B), and eyelids
    (C) were evaluated at the indicated times during the drug
    administration period and during the 6 days following the
    last drug instillation. Discontinuation of the treatment is
    indicated by the arrowhead in the X-axis. Concentration
    profi les for each tissue were generated from 156 rabbits,
    using 4 rabbits per time point. Data shown are the mean

  • And on multiple dosing with a standard regime over 7 days, [b.d. 2 days; o.d. 5days], tissue levels rise steadily in conjunctiva, cornea and, importantly lids minus conjunctiva. Levels decline slowly post-treatment, remaining at an effective antimicrobial level for at least 6 days.
    AKPEK 2009 FIG. 1. Pharmacokinetic profi le of azithromycin in ocular tissues after a single instillation of 1% azithromycin. Formulations
    with (●) and without (○) polycarbophil were measured in the tear fi lm (A), conjunctiva (B), cornea (C), and aqueous humor
    (D). Concentration profi les for each tissue were generated from 60 rabbits per treatment; each time point shown is the mean
    FIG. 2. Pharmacokinetic profi le of 1% azithromycin with
    polycarbophil following the FDA-approved multiple administration
    regimen (1 drop twice a day for the fi rst 2 days, followed
    by 1 drop once a day for 5 days). The concentration
    of azithromycin in conjunctiva (A), cornea (B), and eyelids
    (C) were evaluated at the indicated times during the drug
    administration period and during the 6 days following the
    last drug instillation. Discontinuation of the treatment is
    indicated by the arrowhead in the X-axis. Concentration
    profi les for each tissue were generated from 156 rabbits,
    using 4 rabbits per time point. Data shown are the mean

  • Check refs
    1, Frucht Perry 1993; Frucht-Pery et al compared the use of tetracycline chloride (250 mg four times daily) with a semisynthetic tetracycline, doxycycline (100 mg daily).17 Both medications were efficient, but although tetracyclines made the patients recover faster, more gastrointestinal complications occurred
    Zengin 1995;
    Seal ea 1995
    Bartholomew 1982 et al noted 54% remission with repeated courses or continuous administration of tetracycline (250 mg twice daily) for ocular rosacea. 8
    2. McCulley & Shine 2000;
    3. Meisler e a 2000
    4. Marks & Davies;
    5. McCulley 1984;
    6. Miyachi 1986;
    7. Li e a 2001;
    8. Pruzanski 1992;
    9. Hassin e a 1971; Mc Culley 1984; Dougherty ea 1991
    Shine ea 2003: Minocycline decreases meibum Fas and diglycerides
    Minocycline 50 mg bd plus lid hygiene with warm compreses v lid hygiene alone, 8 weeks n = 10 + 10.
    The study was not randomised or masked. This study showed better tear film stability [BUT] from baseline after minocycline treatment and a decrease in meibum branched chain FAs. in MGD patients. MGD quality 0-3 and stain were not affected. Hygiene had none of thses effects. Minocycline was more effective than lid hygiene alone. [note use of 50 mL drop of 0.5% fluorescein]. It is not clear that they checked for a sig diff between groups. [Souchier 2008]
  • From Tabbara, we see that a single, iG dose of azytrhomycin gives effective antimicrobial levels in the conjunctiva for at least a couple of week
    From Tabbara, Arch Ophthal1998;116:1625-1628 Azythromycin levels in tissues after a single oral dose
    Objective: To assess azithromycin levels in human serum, aqueous humor, tear fluid, and conjunctival tissue specimens after administration of a single 1-g oral dose of azithromycin.
    Methods: Sixty patients undergoing cataract surgery were included in this analysis. Serum, aqueous, and tear specimens were collected 3, 6, and 12 hours and 1, 2, 3, and 4 days after azithromycin administration. Conjunctival tissue biopsy specimens were collected 1, 2, 3, 4, 6, 8, 10,
    12, and 14 days after azithromycin administration. All specimens were subjected to analysis by high-performance liquid chromatography–mass spectrometry. Results: Azithromycin concentration ranges during the specified sampling times were as follows: serum, 21 to 974 ng/mL; tear, 82 to 2892 ng/mL; aqueous, 10 to 69 ng/mL; and conjunctival, 0.7 to 32 μg/g. Levels above the 90% minimal inhibitory concentration (MIC90) for Chlamydia trachomatis were detected after 4 days in all tear samples and after 14 days in all conjunctival tissue specimens following oral azithromycin
    administration. Conclusion: We demonstrated prolonged high levels of azithromycin in drug-targeted ocular tissue. Prolonged high concentrations of azithromycin in conjunctival tissue make this drug suitable for treatment of conjunctivitis caused by chlamydiae and other susceptible organisms.
    Arch Ophthalmol. 1998;116:1625-1628
  • Matsumoto 2009 F1: Reduced lid margin injection and periglandular inflammatory cells after treatment. Fig. 1 Anterior segment slitlamp photographs and confocal laser scans of a representative patient with obstructive meibomian
    gland disease receiving antiinflammatory treatment. A,B Note the reduction of lid margin injection, and debris after
    8 weeks of treatment. C Note the numerous periglandular inflammatory cells in the eyelid confocal scan at the initiation of the study. D Note the clearance of the periglandular inflammatory infiltrates at the final follow-up
    Unmasked non RCT
    Controls: 11 pts. ATS np; HA 0.1%; hygiene
    Treated: 16 pts. This plus: Levofloxacin 0.5% qid; FML 0.1% tid; oral minocycline 100mg bd
  • The key features of dry eye, enunciated at the 2007 DEW were hyperosmolarity and inflammation at the ocular surface. of Dry Eye
    Hyperosmolarity
    Inflammation
    - at the ocular surface.
    Tear hyperosmolarity has been defined as the core mechanism of dry eye.
    Importantly this implies hyperosmolarity of the exposed surface cells.
    ADDE / EDE are its major forms.
    This is a practical convenience, since evaporation is the basis of hyperosmolarity in both forms.
    Lid closure or the prevention of evaporation should reverse all those features of DE due to tear hyperosmolarity.
    Other features might not be reversed. Although hyperosmolarity is the core mechanism this does not exclude
    That other mechanisms, occurring in parallel, could contribute to and complicate the disease state.
    Examples could be:
    1. Etiological: Preservative toxicity;
    Preservative toxicity. Preservatives cause surface damage and inflammatory events – surface damage leads to tear film breakup and tear hyperosmolarity. This EDE will add to the existing clinical picture.
    2. Baudouin has stressed that tear hyperosmolarity leads to a vicious circle of inflammatory events so that the disease becomes self-perpetuating. The resulting autonomous state might not respond to the prevention of evaporation and might require other measures to reverse.
  • Dry eye outcomes from various etiologies, are conveniently divided into aqueous-deficient and evaporative according to whether there is an aqueous deficiency, or increased evaporative loss. But both forms are due to the effect of evaporative loss. ie All dry eye is evaporative. I will take MGD as the model cause of EDE.
    Lacrimal T-cell infiltration followed by B-cells and plasma cells. MG terminal duct obstruction
    Inflammatory products of the LG or Lid margin could modify the surface phenotype.
    Osmotic stress (350-500mOsm/L) stimulates signaling cascade in the epithelium (JNK, ERK, MAPK) inducing release of
    Pro-inflammatory mediators (IL-1, IL-8; TNF; MMPs 9, 13, 1, 3)
    Induction of cornified envelope proteins,
    reduced cell viability
    apoptosis via cytochrome C-mediated death pathway.
    Tong 2010 Calgranulin A and B correlate with MGD severity, redness and visual blur; A, with gritty sensation. The calgranulins are cornified envelope proteins which also act in stress signalling, innate immunity and barrier functions. Role in the keratinisation process of MGD? Tsai et al 2006 found the presence of peptides in Meibomian secretions ( interferon regulatory factor =3 and and tyrosine kinase –C) which may have an inflammatory role.
  • Since, in one sense, all dry eye is evaporative there is the expectation that it may be triggered by behaviours or environments that exacerbate evaporation – eg low blink rate, wide lid aperture. Low humidity, high wind velocity and occupatio,
    Thus ocular exposure in thyroid disease, writing, computer work, cycling, driving with an open window, low atmospheric pressure, air-conditioning upgaze and dry windy conditions. Their effects can be usefully avoided.
    Lid closure is a simple but impractical way – though we employ it usefully as a temporary measure using Botox. But we know that simply restoring tear osmolarity is not enough, because the basis of inflammation changes with time.
  • In the waking state aqueous tear flow is maintained by reflex impulses from the ocular surface and nasal passages,
    And this sensory drive can be seen as a regulating lacrimal flow and the blink action.
    Initiate compensatory responses to ocular surface stress.
    Reduced sensory drive a potential cause of dry eye.
    Role:
    Sensory drives and central inputs maintain ocular surface homeostasis
    Initiates compensatory responses to ocular surface stress.
    Dysregulation contributes to dry eye when reflex sensory drive is compromised.
    NOTES:
    Lacrimal Functional Unit (Stern et al. 1994)
    Sensory impulses from the ocular surface regulate lacrimal and conjunctival secretions (possibly meibomian) and blink action, supported by central nervous, sympathetic, endocrine and immunological influences
    Maintain tear film stability corneal transparency and accurate retinal image formation
    Ocular Surface System
    These epithelia and those of the nasolacrimal system are in continuity participate in feedback and share embryological origins.
  • Various causes of hyperosmolarity, lead to a vicious circle of l inflammatory cytokine induction, epithelial damage with glycocalyx and goblet cell loss, tear instability and amplification of tear hyperosmolarity . It is assumed that this leads to a self-perpetuating, autonomous disease state and that removing its proximate will not result in reversal.
  • The aim of therapy is to restore and maintain tissue normality and the ocular surface environment - in order to achieve ocular comfort
    To achieve ocular comfort
    Therapy for the Ocular Surface
    attempts
    To restore and maintain:
    Tissue normality
    Ocular surface environment
    To achieve ocular comfort
  • Drop instillations provide washout and for volume replacement, and non-Newtonian, pseudoplastic agents having a particular attraction. and in some countries, slow delivery is achieved with HPMC inserts.
    Ionic composition and an alkaline pH are reported to achieve some repair to the surface epithelium and tonicity is addressed, either by directly lowering molarity or by arming cells against osmotic damage.
    Punctal plugs an occlusion have an important role in water conservation.
    Add recombinant albumin, mucoadhesion etc
    Substitutes
    Viscous Polymers
    Newtonian & non-Newtonian
    Mucoadhesives
    Carbophil vehicle? Durasite
    Compositional Approaches
    Ionic -Theratears
    pH -BION
    Tonicity - Hypotears
    Gels and Ointments Carbopol 970
    Unit dose – preservative free
    Osmoprotectant Optive
    Suppress osmotically stimulated mediator release eg IL-1
    Surface- modifying agents
    ECABET SODIUM 12-sulfoabietic acid from pine resin – non-absorbable – nonspecific binding
    KLS -0611treat surface damageKissei
    KCT- 0809treat surface damageKissei
    Sea Buckthorne Oildecrease tear osmolarity
    LANCUTOVIDEpromotes hydrationLantibro
    LUBRICINshear stress at ocular surface
    HPGM hydroxypropyl guarmannan 0.25%Alcon
    CMC with stabilised oxychlorocomplex (Purite). Breaks down with light exposure
    Viscous polymers:
    Tamarind seed polysaccharide, larch arabinogalactan.
    AQUALLIOD colloidal nanolipid-emulsifier , gels on contact with ocular surface. Altaire
    Optive
    Soothe
    Dwelle
    ISTA
  • The viscosity Newtonian drops is unchanged by shearing. (HPMC)
    So symptoms of drag may occur with highly viscous drops, during blinking or eye movements.
    The viscosity of non-Newtonian drops falls with increased shear, so that they don’t cause symptoms during the blink and can form a thick, stable tear film. (Hyaluronic acid; Systane)
  • Treatment of dry eye is not the focus of this presentation, but may be summarised briefly;
    Tear Substitutes: eg.
    alkaline pH-BION; balanced electrolytes-Theratears, reduced molarity - Hypotears
    Non-Newtonian drops; gels
    Unit dose preparations which avoid the risk of toxicity
    Tear Conservation
    Punctal occlusion by Plugs, including the ‘Smart Plug’ which expands into place after insertion; permanent occlusion.
    Moisture Conserving spectacles
    Immunomodulation
    Steroids, CsA, autologous serum
    Secretagogues
    M3-agonists used systemically: Pilocarpine Civimeline have been shown to relieve symptoms but dosage must be adjusted carefully to limit systemic side-effects
    P2Y2 agonists, Ecabet sodium;15-HETE are currently under study.
  • Referring to obstructive non-cicatricial MGD
    A distinct disorder – May be occult or non-obvious when symptoms and ocular surface signs unaccompanied by lid signs. It is essential to express the glands in any symptomatic case.
    It also gives rise to ocular surface disease which may be secondary to evaporative dry eye.
    The severity of ocular surface disease is amplified when EDE and ADE occur together.
    The initiating event is terminal duct obstruction presumed to be inflammatory in origin. There is little evidence of a direct role for bacteria but there may be an indirect one.
    Treatment is directed to glandular function and the function of the tear film lipid layer.
    Physical treatments (heat massage, probing) are directed to restoring oil delivery. Antibiotic and anti-inflammatory therapy is directed to suppressing inflammatory events and hence inhibiting progression.
    The possibility of restoring glandular function by stimulating acinar cell proliferation is not excluded (Sullivan).
    Cicatricial disease is irreversible and hence treatment is directed towards suppressing inflammaotry ocular surface changes and perhaps to preventing extension of disease.
  • Treatment of dry eye is not the focus of this presentation, but may be summarised briefly;
    Tear Substitutes: eg.
    alkaline pH-BION; balanced electrolytes-Theratears, reduced molarity - Hypotears
    Non-Newtonian drops; gels
    Unit dose preparations which avoid the risk of toxicity
    Tear Conservation
    Punctal occlusion by Plugs, including the ‘Smart Plug’ which expands into place after insertion; permanent occlusion.
    Moisture Conserving spectacles
    Immunomodulation
    Steroids, CsA, autologous serum
    Secretagogues
    M3-agonists used systemically: Pilocarpine Civimeline have been shown to relieve symptoms but dosage must be adjusted carefully to limit systemic side-effects
    P2Y2 agonists, Ecabet sodium;15-HETE are currently under study.
  • Choice of therapy including the level of invasiveness must be guided by the severity of the dry eye. Some simple rules are:
    General Measures: - patient education: Changes in the home and the work environment to reduce air flow, increase humidity, limit upgaze during computer use, where possible modify systemic medications.
  • Regulation of tear osmolarity is multi- factorial .
    All dry eye is evaporative but it is convenient to maintain the classification into ADDE and EDE.
    Meniscus osmolarity is an important diagnostic test for dry eye, but the measured value may underestimate potential damage to the ocular surface.
    Environmental and local compartmental factors may determine osmolar levels and distribution of damage at the ocular surface, and possibly, different phenotypes.
  • Tetracyclines Inhibit:
    Keratinization 4
    leucocyte migration 5
    N O and ROS formation 6
    MMP formation * 7
    Prostanoid formation 8
    Anti-microbial at dose used  2
    Inhibit bacterial lipases 9
    4. Marks & Davies; 5. McCulley 1984; 6. Miyachi 1986; 7. Li e a
    2001; 8. Pruzanski 1992; 9. Hassin e a 1971; Mc Culley 1984;
    Dougherty ea 1991
    Treatment of dry eye is not the focus of this presentation, but may be summarised briefly;
    Tear Substitutes: eg.
    alkaline pH-BION; balanced electrolytes-Theratears, reduced molarity - Hypotears
    Non-Newtonian drops; gels
    Unit dose preparations which avoid the risk of toxicity
    Tear Conservation
    Punctal occlusion by Plugs, including the ‘Smart Plug’ which expands into place after insertion; permanent occlusion.
    Moisture Conserving spectacles
    Immunomodulation
    Steroids, CsA, autologous serum
    Secretagogues
    M3-agonists used systemically: Pilocarpine Civimeline have been shown to relieve symptoms but dosage must be adjusted carefully to limit systemic side-effects
    P2Y2 agonists, Ecabet sodium;15-HETE are currently under study.
  • If we look at the mechanisms causing dry eye disease, we can focus on the ocular surface and the lacrimal and Meibomian glands as targets.
    Events at the ocular surface are relevant to all forms of dry eye. These are tear hyperosmolarity and the release of inflammatory mediators and proteases (MMPs); mucosal inflammation leading to epithelial apoptosis, glycocalyx changes and goblet cell loss. Corneal nerve damage can lead to loss of sensory drive to the lacrimal gland.
    In SSDE and less, in NSDE, the lacrimal gland is infiltrated by autoreactive T-cells, and, importantly, to the accumulation of hyper-reactive B-cells. There is primary acinar cell loss. In scarring diseases such as Stevens Johnson syndrome the primary event if duct obstruction.
    In MGD-related dry eye I assume that the primary event is terminal duct obstruction due to epithelial keratinization and glandular loss is secondary.
  • MGD-associated Symptoms
    MGD - alone
    MGD –ocular surface disease
    MGD –Evaporative Dry Eye
  • The TFLL is a viscoelastic structure which, in the normal eye, spreads in the upsyroke of the blink, to stabilise in about 1 sec. It is possible to measure the initial rate of spreading by DR-1, video interferometry, by the shift of pattern over time. (Yokoi 2004? 2011 this ARVO)
    In this example, the rate was estimated to be 10.4 mm/sec
    This compares to a rate for the upstroke of the blink of about 60 mm/s and of the downstroke, around 180 mm/s (Nakamura e a 2008)
  • Tear physiology: The healthy eye is bathed continuously with tears and the tear film is refreshed continuously with each blink. The interblink interval is about 5 seconds. Lengthening this interval increases the period over which evaporative loss can occur. It may contribute to the occurrence of dry associated with Parkinson’s disease or when working at a computer terminal.
  • Prostanoids, cytokines, neurokinins, neuromediators - sources of pain
  • Total phospholipid 10.17 %
  • Lissamine green staining seen in a subject after removal of soft contact lens.
    I believe the area indicated by the arrow may be Shiraishi’s LWE-like lesion. However, I wonder if this lesion may in fact be Marx’s line in a diseased state.
  • Grades
    Bron Mathers
    Pflugfelder
    Nichols
  • Blepharitis- Inflammation of Whole Lid
    Marginal Blepharitis- Inflammation of the lid margin
    Anterior blepharitis
    Posterior blepharitis
  • Rmshort –RST
    Ari-Hooked
    30 second rule
    Firefly forest
  • Add: Tea Tree Oil 50% with TTO shampoo – for demodex Tseng
    MGD
    Liposomal spray: Dausch 2006; Khaireddin Schmidt 2009
    Heat measures:
    infra red heat- Goto 2002;
    warm moist air – Mitra 2005; Matsumoto 2006
    Orghexa masks – Ishida 2008
    Fucidic acid: Success in rosacea blepharitis, above tetracycline – but not in non-rosacea blepharitis Seal and Ficker.
    Metronidazole gel 1% in ocular rosacea. Barnhorst 1996
    Azithromycin % drop bd : Luchs 2008 MGD
  • Inflammatory products of the LG or Lid margin could modify the surface phenotype.
    Osmotic stress (350-500mOsm/L) stimulates signaling cascade in the epithelium (JNK, ERK, MAPK) inducing release of
    Pro-inflammatory mediators (IL-1, IL-8; TNF; MMPs 9, 13, 1, 3)
    Induction of cornified envelope proteins,
    reduced cell viability
    apoptosis via cytochrome C-mediated death pathway.
    Tong 2010 Calgranulin A and B correlate with MGD severity, redness and visual blur; A, with gritty sensation. The calgranulins are cornified envelope proteins which also act in stress signalling, innate immunity and barrier functions. Role in the keratinisation process of MGD? Tsai et al 2006 found the presence of peptides in Meibomian secretions ( interferon regulatory factor =3 and and tyrosine kinase –C) which may have an inflammatory role.
  • Lymphoedema Distichiasis syndrome if a familial disorder now know to be caused by mutations, deletions and insertions in the transcription factor gene, FOXC2 (Fang et al 2000. At least some mutations affect the DNA recognition helix which therefore is presumed to affect DNA binding and transcription (Berry 2005. One mutation also influences nuclear localisation in the cell. References to the phenotype may be found in Erickson 2001; Brice 2002; Traboulsi 2002 and Brooks 2003. FOXC2 is expressed in lymphatic tissues and other tissues involved in the syndrome (Dagenais 2004).
    Conditions associated with the disorder include: cleft palate (Baluau); extradural arachnoid cysts (Yabuchi); Type I extraspinal cysts (Kanagu) and renal disease with diabetes mellitus. (Yldrum-Turruner 2005)
    Fig, 1. Lower eyelids. A, Normal monkey eyelid. The Meibomian glands (G) and hair follicles
    (H) are well developed. F, Follicle of cilium; S, skin; M, muscle; C, palpebral conjunctiva. B,
    Eyelid of monkey fed 86.6 mg of PCB in 1 month. The Meibomian glands have atrophied. The
    ducts of the glands (D) are filled with hyperkeratotic cell debris. Although the follicle of the
    cilium appears intact, no hair follicle is seen. (x34.)
    EFFECT OF POLYCHLORINATED BIPHENYLS AND POLYCHLORINATED QUATERPHENYLS IN CYNOMOLGUS MONKEY (MACACA FASCICULARIS) SINJIRO HORI a, HIROTAKA OBANA a, TAKASHI KASHIMOTO a, TORU OTAKE a,HIROSHI NISHIMURA a, NOBUKO IKEGAMI a, NOBUHARU KUNITA a and HIROTSUGU UDA b
    aosaka Prefectural Institute of Public Health, 1-3-39, Nakamichi, Higashinari-ku, Osaka,
    and bSecond Department of Pathology, Faculty of Medicine, Osaka University 4-3-57,
    Nakanoshima, Kita-ku, Osaka (Japan)
    SUMMARY 1982
    Female Cynomolgus monkeys (Macaca fascicularis) with P-KC-400,
    Y-PCB, PY-PCB or polychlorinated quaterphenyls (PCQ) received a daily dose
    of 5 mg for 20 weeks, and some monkeys received a daffy dose of 10 mg of
    Y-PCB or 0.5 mg of PCQ.
    The chemical compositions of the polychlorobiphenyls (PCB) used for
    the oral administration were as follows: P-KC-400, PCB from which polychlorodibenzofurans
    (PCDF) have been removed from Kanecklor 400,
    largely contains tri- and tetrachlorobiphenyls and no PCDF. Whereas, Y-PCB
    and PY-PCB, PCB with constituents similar to PCB ingested by Yusho
    patients, largely contain penta- and hexachlorobiphenyls, in addition,
    PCDF of 400 ppm was present only in Y-PCB, but not in PY-PCB.
    There were immunosuppression, enlargement and histopathological
    changes of the liver (such as interstitial inflammation, and proliferation of
    epithelial cells of biliary duct, etc.) in the groups fed P-KC-400 and PY-PCB
    (free of PCDF). In the group fed Y-PCB (with PCDF), there were more
    apparent decreases in body weight, immunosuppression, fatty liver and
    histopathological changes than in the groups P-KC-400 and PY-PCB. In
    addition, there were hair loss, acneform eruptions, edema of the eyelid,
    congestion and abscess of the Meibomian gland, and cornifications of the
    skin, characteristic dermatological findings of Yusho disease.
    Abbreviations: PCB, polychlorinated biphenyls; PCDF, polychlorodibenzofurans; PCQ,
    polychlorinated quaterphenyls; RER, rough endoplasmic reticulum; SER, smooth endoplasmic
    reticulum.
  • Lymphoedema Distichiasis syndrome if a familial disorder now know to be caused by mutations, deletions and insertions in the transcription factor gene, FOXC2 (Fang et al 2000. At least some mutations affect the DNA recognition helix which therefore is presumed to affect DNA binding and transcription (Berry 2005. One mutation also influences nuclear localisation in the cell. References to the phenotype may be found in Erickson 2001; Brice 2002; Traboulsi 2002 and Brooks 2003. FOXC2 is expressed in lymphatic tissues and other tissues involved in the syndrome (Dagenais 2004).
    Conditions associated with the disorder include: cleft palate (Baluau); extradural arachnoid cysts (Yabuchi); Type I extraspinal cysts (Kanagu) and renal disease with diabetes mellitus. (Yldrum-Turruner 2005)
    Fig, 1. Lower eyelids. A, Normal monkey eyelid. The Meibomian glands (G) and hair follicles
    (H) are well developed. F, Follicle of cilium; S, skin; M, muscle; C, palpebral conjunctiva. B,
    Eyelid of monkey fed 86.6 mg of PCB in 1 month. The Meibomian glands have atrophied. The
    ducts of the glands (D) are filled with hyperkeratotic cell debris. Although the follicle of the
    cilium appears intact, no hair follicle is seen. (x34.)
    EFFECT OF POLYCHLORINATED BIPHENYLS AND POLYCHLORINATED QUATERPHENYLS IN CYNOMOLGUS MONKEY (MACACA FASCICULARIS) SINJIRO HORI a, HIROTAKA OBANA a, TAKASHI KASHIMOTO a, TORU OTAKE a,HIROSHI NISHIMURA a, NOBUKO IKEGAMI a, NOBUHARU KUNITA a and HIROTSUGU UDA b
    aosaka Prefectural Institute of Public Health, 1-3-39, Nakamichi, Higashinari-ku, Osaka,
    and bSecond Department of Pathology, Faculty of Medicine, Osaka University 4-3-57,
    Nakanoshima, Kita-ku, Osaka (Japan)
    SUMMARY 1982
    Female Cynomolgus monkeys (Macaca fascicularis) with P-KC-400,
    Y-PCB, PY-PCB or polychlorinated quaterphenyls (PCQ) received a daily dose
    of 5 mg for 20 weeks, and some monkeys received a daffy dose of 10 mg of
    Y-PCB or 0.5 mg of PCQ.
    The chemical compositions of the polychlorobiphenyls (PCB) used for
    the oral administration were as follows: P-KC-400, PCB from which polychlorodibenzofurans
    (PCDF) have been removed from Kanecklor 400,
    largely contains tri- and tetrachlorobiphenyls and no PCDF. Whereas, Y-PCB
    and PY-PCB, PCB with constituents similar to PCB ingested by Yusho
    patients, largely contain penta- and hexachlorobiphenyls, in addition,
    PCDF of 400 ppm was present only in Y-PCB, but not in PY-PCB.
    There were immunosuppression, enlargement and histopathological
    changes of the liver (such as interstitial inflammation, and proliferation of
    epithelial cells of biliary duct, etc.) in the groups fed P-KC-400 and PY-PCB
    (free of PCDF). In the group fed Y-PCB (with PCDF), there were more
    apparent decreases in body weight, immunosuppression, fatty liver and
    histopathological changes than in the groups P-KC-400 and PY-PCB. In
    addition, there were hair loss, acneform eruptions, edema of the eyelid,
    congestion and abscess of the Meibomian gland, and cornifications of the
    skin, characteristic dermatological findings of Yusho disease.
    Abbreviations: PCB, polychlorinated biphenyls; PCDF, polychlorodibenzofurans; PCQ,
    polychlorinated quaterphenyls; RER, rough endoplasmic reticulum; SER, smooth endoplasmic
    reticulum.
  • Jester et al. IOVS 1988Rhino Mouse
    Fig. 2. Light micrographs of meibomian glands from normal (A) and rhino mouse at 3 months (B), 6 months (C) and 1 year (D) of age. In
    the normal lid the meibomian glands are prominent glandular structures with saccular acini connected to a common duct (arrow) by an
    arborescent ductal network. At 3 (B) and 6 (C) months of age the keratinized epithelium of the epidermis and meibomian gland (arrow)
    appear markedly thickened and hyperkeratinized. Keratinized cells or horny cells appear to fill both the pilary canals of the skin, forming
    utriculi (open arrows), and the common duct of the meibomian gland leading to plugging of the orifice (C, arrowhead). By one year of age, the
    meibomian gland is markedly atrophic and distorted by the presence of large dermal cysts (D, open arrow) (hematoxylin and eosin; A, X80; B,
    X80; C, X80; D, X54).
    Fig. 3. Immunoperoxidase staining of keratin proteins present in lids from rhino mice at 3 months (A) and 1 year (B) of age. Although
    meibomian glands remain prominent structures at 3 months of age (A, arrow), at 1 year of age there is a marked loss of meibomian gland
    tissue. Large dermal cysts noted by histology (D, open arrow) are stained with antikeratin antibodies suggesting an epithelial origin (B, open
    arrow) (A, X80; B, X54).
  • Add: Tea Tree Oil 50% with TTO shampoo – for demodex Tseng
    MGD
    Liposomal spray: Dausch 2006; Khaireddin Schmidt 2009
    Heat measures:
    infra red heat- Goto 2002;
    warm moist air – Mitra 2005; Matsumoto 2006
    Orghexa masks – Ishida 2008
    Fucidic acid: Success in rosacea blepharitis, above tetracycline – but not in non-rosacea blepharitis Seal and Ficker.
    Metronidazole gel 1% in ocular rosacea. Barnhorst 1996
    Azithromycin % drop bd : Luchs 2008 MGD
  • Arita
  • Combined anterior
    blepharitis and MGD
  • Matsumoto 2008 MolVis : Confocal imaging of MGD
  • We do not know about secretory rates, only about accumulation rates after recovery from lid margin cleansing
  • From MGD workshop Knop
    Inset from Knop 2009 Ophthmologe
  • Anterior blepharitis is an inflammation of the lid margin anterior to the gray linea and concentrated around the lashes.1 It may be accompanied by squamous debris or collars around the lashes and inflammation may spill onto the posterior lid margin.
    Posterior blepharitis is an inflammation of the posterior lid margin,b which may have different causes, including MGD, conjunctival inflammation (allergic or infective) and or other conditions, such as acne rosacea.2-6
    Meibomian gland dysfunction (MGD) is a term used to describe a common, symptomatic, progressive disorder of the meibomian glands affecting their secretion and leading to functional obstruction.
     
     
     
  • Anterior blepharitis is an inflammation of the lid margin anterior to the gray linea and concentrated around the lashes.1 It may be accompanied by squamous debris or collars around the lashes and inflammation may spill onto the posterior lid margin.
    Posterior blepharitis is an inflammation of the posterior lid margin,b which may have different causes, including MGD, conjunctival inflammation (allergic or infective) and or other conditions, such as acne rosacea.2-6
    Meibomian gland dysfunction (MGD) is a term used to describe a common, symptomatic, progressive disorder of the meibomian glands affecting their secretion and leading to functional obstruction.
     
     
     
  • Prof Bron lecture. The A-Z of MGD

    1. 1. The A to Zee of MGD reflections on the 2011 Workshop A J Bron Nuffield Department of Clinical NeuroSciences ,Oxford OXFORDSHIRE LOC Oct 23rd 2012
    2. 2. Definition of MGD Meibomian gland dysfunction (MGD) is a chronic, diffuse abnormality of the meibomian glands, commonly characterized by terminal duct obstruction and/or qualitative/quantitative changes in the glandular secretion. This may result in alteration of the tear film, symptoms of eye irritation, clinically apparent inflammation, and ocular surface disease.
    3. 3. Definition of MGD Meibomian gland dysfunction (MGD) is a chronic, diffuse abnormality of the meibomian glands, commonly characterized by terminal duct obstruction and/or qualitative/quantitative changes in the glandular secretion. This may result in alteration of the tear film, symptoms of eye irritation, clinically apparent inflammation, and ocular surface disease.
    4. 4. Definition of MGD Meibomian gland dysfunction (MGD) is a chronic, diffuse abnormality of the meibomian glands, commonly characterized by terminal duct obstruction and/or qualitative/quantitative changes in the glandular secretion. This may result in alteration of the tear film, symptoms of eye irritation, clinically apparent inflammation, and ocular surface disease.
    5. 5. Definition of MGD Meibomian gland dysfunction (MGD) is a chronic, diffuse abnormality of the meibomian glands, commonly characterized by terminal duct obstruction and/or qualitative/quantitative changes in the glandular secretion. This may result in alteration of the tear film, symptoms of eye irritation, clinically apparent inflammation, and ocular surface disease.
    6. 6. Summary • Meibomian Physiology • MGD and MGD-associated disease • Diagnosis • Therapy
    7. 7. Physiology: Tear composition Lacrimal Gland lysozyme, lactoferrin, sIgA EGF, HGF, retinol lipocalin Salivary agglutinin Collectin SPD Ocular surface mucins (MUC 1, 2, 4, 5AC) sIgA Oil Glands 90% non-polar lipids 10% polar, phospholipids Plasma albumin, ceruloplasmin Lacrimal LIPID LAYER Melting range: 20-45 °C Corneal Temp: ≅ 32 °C < 100 nm thick
    8. 8. The normal meibomian glands Men Women • Meibum delivered to the marginal reservoir • Gives rise to the oily layer of the tear film.
    9. 9. Spreads to form a stable Lipid Layer in ≅ 1second
    10. 10. Spreads to form a stable Lipid Layer in ≅ 1second
    11. 11. Blink: Blink Cycle: Tsubota et al. 1998 Cycle: Divisions: 17 ms Interblink period: Particle stabilisation time Owens and Phillips 2002
    12. 12. Prevalence of MGD 100.00% 90.00% 80.00% 70.00% 60.00% * † ‡ § 50.00% 40.00% 30.00% ¶ 20.00% £ 10.00% 0.00% Shihpai Eye Study Beijing Eye Study Japanese Bangkok Study* * Telangiectasia or Meibomian gland orifice plugging † Telangiectasia ‡ Gland dropout, expressibility and nature of Meibum secretion § Telangiectasia or Meibomian gland orifice plugging OR collarettes ¶ Tear break up time < 1SD (10 sec) £ Meibomian gland plugging OR collarettes (grade 2-3) International MGD Workshop IOVS 2011 - Schaumberg Melbourne study Salisbury Eye Evaluation
    13. 13. Meibomian Gland – PATHOLOGY • Orifice Obstruction by • Hyperkeratinization of terminal duct epithelium and • Increased meibum lipid viscocity normal gland MGD Workshop Knop et al. 2011 obstructed gland
    14. 14. NON-CICATRICIAL MGD NON-CIC. MGD NON-CICATRICIAL •Orifices • In lid skin • ± plugged •Expressed Lipid • cloudy / opaque NORMAL MEIBOMIAN ORIFICES
    15. 15. Bimanual expression of opaque meibum in Non-Obvious MGD Blackie Korb et al. 2010
    16. 16. Tear film Black line Tear Meniscus occlusal conjunctiva TFLL Marx’s line apex occlusal conjunctiva Meibomian orifices Marx’ s Line Route for inflammatory occlusal skin mediators to terminal duct? Bron et al. 2011 MG
    17. 17. Forward movement of Marx’s Line with Age Yamaguchi 2010
    18. 18. Cicatricial MGD
    19. 19. 6 7 Cicatricial MGD 8
    20. 20. Two Kinds of MGD
    21. 21. • Bacterial load is increased in anterior blepharitis • Likely but less certain in MGD Courtesy of N Yokoi 2003
    22. 22. Action of commensal esterases • FAs and glycerides released by bacterial esterases may contribute to MGD symptoms. triglyceride wax ester • Cholesterol released Cholesterol from cholesterol ester may stimulate S. aureus growthCholesterol ester Shine & McCulley 1991; 1993a,b
    23. 23. Evaluation of the Meibomian Glands Evaporimetry Interferometry Meibography Meibometry Morphology Expression Lipid chemistry
    24. 24. Interferometry • Lipid layer thin • Spread slow • Pattern vertical Goto, E. and Tseng. Arch Ophth. 2003 Norm Pattrn Hor A. Normal LTD MGD Vert Copyright restrictions may apply. 53.8 ± 20 Spread 0.36 Time ± seconds 0.22 B. LTD/MGD 79.1 ±13 3.54 ± 1.86 Thick nm
    25. 25. Clinical Measurement in MGD • Lid signs 1 • Expressed meibum 2, 3 2 – Margin vascularity – Alterred mucocut junction – Orifices- plugged/ retroplaced – Ducts exposed/retroplaced – Marx’s Line Displaced • • • • 0= clear 1= cloudy 2= cloudy; particulate 3= toothpaste • Meibography: • Gland Dropout 3, 4 • • • • 0 = nil 1 ≤ 33% loss 2 > 33% ≤66% 3 ≥67% 1. Foulks and Bron 2003; 2. Bron et al 1991; 3. Mathers and Billborough ; 4.Pflugfelder et al.
    26. 26. Meibomian Glands Yielding Liquid Secretion Korb and Blackie 2008. Controlled force applied over 8 glands of lower lid The MGYLS score is the number of meibomian glands yielding liquid secretion out of 8 expressed glands MGYLS score / 8 % ‘Active’ 4.3% Central = 2.46 31 % Nasal = 3.45 STANDARDISED EXPRESSION Temporal = 0.35 43% Total = 6.25 26%
    27. 27. Meibometry • Oil is blotted from the lid onto a loop of tape • The change in transparency is read in the meibometer • A peak reading is taken from the centre of the blot Chew et al 1993; Versura
    28. 28. Meibometry Chew et al 1993; Versura • Oil is blotted from the lid onto a loop of tape • The change in transparency is read in the meibometer • A peak reading is taken from the centre of the blot Yokoi et al 1999
    29. 29. Non-Invasive Meibography Arita et al 2008 Arita et al 2008
    30. 30. Therapeutic Strategy • • Relieve Symptoms • • Re-establish and • Maintain Ocular • Health • • Unblock glands, Restore oil delivery, Restore tear lipid layer, Maintain Patency Reduce lid commensals, Reverse lid and surface inflammation. • Treat dry eye if present International MGD Workshop IOVS 2011
    31. 31. Therapeutic Tactics Heat: Physical measures – Heat and massage • Hot compresses 1 • Proprietary Devices – Duct dilatation 7 – Orgahexa mask 2 – Lid Cleansing – Infrared LED 3, rice bag – Iron oxide eye warmer 4 – Warm moist air 5; Blephasteam 6 – Lipiflow 1 Olson 2003 ; 2. Ishida 2008 ; 3. Goto 2003; 4. Mori 2003 ; 5. Mitra 2005; 6. Pearce 2006, 2007; Matsumoto 2006; 7. Maskin 2010
    32. 32. Heat application in MGD Source Lipid Layer Evaporatn Infrared ↑ ↑ ↓ Mori 1999 Iron oxide warmer ↑ ↑ ↓ Mori 2003 ↓ Goto 2002 ↓ Infrared Warm compresses ↑ Stain ↓ ↑ Sympt ↑ Moist warm Stability BUT Moist warm Ref Olson 2003 ↓ ↑ ↓ Spiteri 2007 Matsumoto 2006
    33. 33. Iron oxide eyelid warmer BUT FATIGUE DRYNESS Also improved MGD obstruction score • 17 MGD pts • Five min daily for 2 weeks • Mask temp. > 40 °C Mori et al 2003
    34. 34. Blephasteam • Eyes open, • See-through goggles • 10 minutes exposure to warm, moist air (42° C). Eye Calm: 50°C 10 min DE pts ↑Lipid spread ↓Evaporation ↑BUT and VA Pearce 2006, 2007
    35. 35. Lipiflow • An insulated conformer heats the inner surface of the lids. • An inflatable pad applies a pulsatile pressure to the glands through the tarsal plate • • • • Improved: Symptoms BUT Stain Meibum expression (MGYLS) Friedland et al 2011
    36. 36. Restoring tear film stability • Oils, emulsions • Castor oil 1.25% 1; • Refresh • Emustil, unidose (SIFI) 2 • Soothe 3,4 • Low dose ofloxacin 0.3% ointment 5 2. Khanal 2007 3. McCann 2011, 4. Korb 2005 5. Scaffidi 6. Goto et al 2006 Goto et al 2006 Symptom score Lipid Layer Thickness
    37. 37. Restoring tear film stability Lipid Layer Thickness Liposomal Spray • Increased TFLL and BUT for 40-90 min in normals 1. • In dry eye – improved 2,3,4 : – Symptoms, – Lid margin inflam – LIPCOF 1. Craig 2010; 2. Lee 2004; 2. Dausch 2006; 3. Khaireddin 2009; Tear Stability NIBUT
    38. 38. MGD -Topical Therapy • Antibiotic • • • Fusidic acid 1% 1 Azithromycin 1% 8 Doxycycline 1 • Glucocorticoids NSAIDS – FML1 • Immunomodulatory – Restasis Perry 2006 • Other – – – – Metronidazole gel 1% Barnhorst 1996 1 Standard dry eye therapies Androgen 7 1.Seal e a 1995 2. Smith and Flowers 1995; Barnhorst et al 1996; 3. Mayer e a 2001 Azythromycin Tetracyclines: •Inhibit: spectrum • broad •Keratinization 4 • Excellent penetration / •leucocyte retention migration 5 •NO and ROS formation 6 • Anti-inflammatory action •MMP formation * 7 – Inhibits: •Prostanoid formation 8 – IL6, IL-8, TNF α release •Anti-microbial at dose used  2 – PMN chemotaxis / •Inhibit bacterial lipases 9 phagocytosis – Inflammatory cell ahesion 4. Romero ea 2004; 5. Olsen 2003; 6. Mori 2003; 7. RCTs testosterone; 8. Luchs 2008 9. Perry 2006, Rubin 2006
    39. 39. Topical Azithromycin 30μl 1% tears polycarbophil vehicle Study in rabbits Akpek et al. 2009
    40. 40. Topical Azithromycin single dose conjunctiva cornea Study in rabbits Akpek et al. 2009
    41. 41. Topical Azithromycin Multiple dosing b.d. 2 days; o.d. 5days single dose Azithromycin ( µ g/g) conjunctiva Conjunctiva A 200 conjunctiva 150 100 50 0 1 2 3 4 5 6 7 8 Day 9 10 11 12 cornea Azithromycin ( µ g/g) Cornea B 400 300 cornea 200 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Study in rabbits µ Azithromycin ( g/g) Day Eyelids 250 C 200 Lid 150 100 50 0 Akpek et al. 2009 1 2 3 4 5 6 7 Day 8 9 10 11 12 13 13
    42. 42. MGD - Systemic Therapy Antibiotics: – Tetracyclines 1 • Tetracycline 250 bd • Doxycycline* 50-100 od • Minocycline 2 50-100od – Erythromycin 3 – Azythromycin 1, Frucht Perry 1993; Zengin 1995; Seal ea 1995 2. McCulley & Shine 2000; 3. Meisler e a 2000 Tetracyclines: •Inhibit: •Keratinization 4 •leucocyte migration 5 •NO and ROS formation 6 •MMP formation * 7 •Prostanoid formation 8 •Anti-microbial at dose used  2 •Inhibit bacterial lipases 9 4. Marks & Davies; 5. McCulley 1984; 6. Miyachi 1986; 7. Li e a 2001; 8. Pruzanski 1992; 9. Hassin e a 1971; Mc Culley 1984; Dougherty ea 1991
    43. 43. Azythromycin levels in tissues after a single, 1 G oral dose Tabbara, Arch Ophthal1998 Conjunctiva Tears Serum Aqueous
    44. 44. Before therapy After active therapy Non-preserved ATS + HA + lid hygiene versus the same plus Levofloxacin, FML 0.1% and oral minocycline.
    45. 45. Omega-3-essential fatty acids? • • • • • • EPA – fish oils; flax seed, sea buckthorne oil DHA – oil of evening primrose; blackcurrent seed EPA blocks TNFα; IL-1; PG synthesis: blocks PLA2; COX2 Dietary EPA/DHA modifies 1 meibomian polar lipids. PUFAs – theoretical reduction in meibomian oil viscosity. Dietary EPAflax seed – Dermatitis – MGD 2 Gilbard 1.Sullivan ea 2000; Bremer 2000
    46. 46. Key Features of Dry Eye • Hyperosmolarity • Inflammation DEWS 2007  A multifactorial disease of the tears and ocular surface that results in  Symptoms of discomfort, visual disturbance and tear film instability  And damage to the ocular surface. It is accompanied by  Inflammation of the ocular surface  Increased osmolarity of the tear film and
    47. 47. Various Aetiologies Key Mechanisms Fujihara 1999 Lacrimal Gland inflammation Disease Outcomes Hyperosmolarity Aqueous Deficient DE Lid margin Oil gland blockade - MGD Evaporative DE
    48. 48. These triggers can be avoided
    49. 49. Lacrimal Functional Unit (Stern et al. 1994) Tear Homeostasis • In the waking state aqueous tear flow is maintained reflexly by sensory impulses from the ocular surface and nasal passages, • Regulating aqueous lacrimal and conjunctival • Active sensory drive and central flow and the inputs maintain ocular surface • Blink action. This is homeostasis • Supported by central • Initiate compensatory responses to nervous, sympathetic, endocrine and immunoocular surface stress. logical influences • Reduced sensory drive is a Dry Eye and Ocular Surface Disorders Stern, Beuerman, Pflugfelder 2004 potential cause of dry eye.
    50. 50. The Evolution of Dry Eye Disease Causes TEAR HYPEROSMOLARITY INFLAM MOLECULES VICIOUS CIRCLE EARLY BREAK-UP SURFACE DAMAGE It is likely that with time the disease becomes self-perpetuating
    51. 51. Therapy for the Ocular Surface To restore and maintain: •Tissue normality •Ocular surface environment •To achieve ocular comfort
    52. 52. Tear Substitutes LG •Volume: Viscous Polymers – Newtonian & non-Newtonian – HPMC insert - Lacrisert •Composition – Ionic balance - Theratears – pH - BION – Tonicity – Hypotears, Ialurex Restoring the Environment – Osmoprotection - Optive •Gels and Ointments •Conserving plugs and specs MG
    53. 53. Polymers Viscosity →  The viscosity Newtonian drops is unchanged by shearing. (HPMC)  So choice of concentration is limited by symptoms of viscous drag. Newtonian nonNewtonian Shear rate →  The viscosity of non-Newtonian drops falls with increased shear, which minimises viscous drag during blinking or eye movement. (Hyaluronic acid; Systane)
    54. 54. Treatment of Dry eye: ADDE • Substitutes pH-BION; electrolytesTheratears, Non-Newtonian drops- HA; gels - Systane Unit dose • Conservation Plugs, occlusion –’Smart Plug’ Conserving spectacles • Immunomodulation • Steroids, CsA, autologous serum • Secretagogues • • • P2Y2 agonists, Ecabet sodium; M3-agonists: Pilocarpine Civimeline Osmoprotectant - Optive Stern et al
    55. 55. Conclusions • • • • • MGD is common Look for it in any adult > 40 years Diagnosis is simple Examine the lid margins Express the glands – MGD may be non obvious.
    56. 56. Conclusions • MGD gives rise to symptoms in 3 ways. – Directly – due to lid inflammation – By the release of inflammatory mediators into the tear film – By causing evaporative dry eye. • Intial treatment involves simple measures. • More advanced treatments are available
    57. 57. Thank You for your Attention
    58. 58. Declaration of Interests: A.J.Bron • Within the past 5 years, Professor Bron has either consulted for or advised, the following companies. • • • • Acucela Alcon Allergan Bausch and Lomb • Canfite • Clinact • Dompe March 2010 F2G Kowa Lux Bio Merck Ocusense Pfizer Santen Senju Takeda Tear Lab
    59. 59. Non-cicatricial MGD Cictricial MGD
    60. 60. Thank you
    61. 61. Treatment of Dry eye: General Measures • Personal and Environmental ↑ Relative humidity ↓ Air Conditioning / wind speed – VDU positioning – Smoke and chemical fume exposure
    62. 62. Staging Treatment for Dry Eye Treatment of dry eye is based on the severity of symptoms. General Measures: - patient education • Changes in the home and the work environment. • Modification of systemic medications. • • • • Stage I – For mild dry eye a low cost preserved drop two to four times daily, may be suitable. Stage II – Moderate dry eye: Increase instillation frequency. Initial response poor, switch to – alternative tear substitute with a different formulation – pres free? or – A Pseudoplastic agent could be more effective than a Newtonian preparation – Gel preparation to increase residence time and reduce frequency of instillation. – Ointment at night. • • • • Stage III – Severe dry eye frequent, preservative-free agent and, Punctal plugs or permanent occlusion to conserve fluid. – ± short course of topical steroids prior to plugging, to damp down inflammation before drainage is obstructed. Moisture may be further conserved by conserving spectacles.
    63. 63. Equipping Your Clinic to Diagnose Dry Eye • Validated Questionnaires • A quiet environment – McMonnies CANDEES • A defined test sequence – Schein • A Battery of Tests – WHS-PHS – – – – – – – – Validated questionnaire – OSDI (Ocular Surface Record blink interval Disease Index) Tear sampling eg. Osmometry – DEQ – IDEEL Fluorescein BUT Calculate Ocular Protection Index Grade staining - fluorescein (Lissamine Green) Meibomian morphology and expression. – Other tests
    64. 64. Conclusions • All dry eye is evaporative but classification into ADDE and EDE is still convenient. • Evaporative loss is governed by local and environmental factors. • Meniscus osmolarity is an important diagnostic test for dry eye, but the measured value may underestimate TF osmolarity and the potential damage to the ocular surface. • Progression of DE disease may generate hybrid phenotypes with diagnostic and therapeutic implications.
    65. 65. Treatment of Evaporative Dry eye EDE ( - MGD) • Systemic Therapy • Hygienic Measures : 4 – Heat – compress / LCD/ IR /Chem – Massage 5 6 • • Pharmacological: – antibiotic – steroid ? – other • • • • Metronidazole FK 506 – atopic blepharitis Cyclosporin A - Restasis Androgen 7 • Antibiotics: – Tetracyclines 1 • Tetracycline • Doxycycline* • Minocycline 2 – Erythromycin – Azythromycin Omega-3 Fatty Acid • General Measures • dry eye therapies 4. Romero ea 2004; 5. Olsen 2003; 6. Mori 2003; 7. Current RCTs of topical testosterone 1, Frucht Perry 1993; Zengin 1995; Seal ea 1995 2. McCulley & Shine 2000; 3. Meisler e a 2000
    66. 66. Severity Grading and Treatment of MGD-related ocular surface disease and dry eye SEVERITY LEVEL Disease Stage Level 1 Level 2 Level 3 Level 4 Level 5 Subclinical Symptomatic Minimal Symptomatic Mild Symptomatic Moderate Symptomatic Severe None Asymptomatic or occasional symptoms Some of the time. Precipitated by environmental factors Half of the time Some limitation of activity Most of the time Frequent limitation of activity All of the time Severe/disabling/con stant OSDI Range (0-100) 0 0-12 0-12 13-22 23-32 33-100 TFBUT seconds ≥ 10s < 10 - ≥ 7s < 7 - ≥ 5s < 5 - ≥3 < 3 - ≥1 < 1 or instant breakup Tear Osmolarity mOsm/L < 308 < 308 < 308 Mildly increased > 308 - ≤ 313 Moderately Increased > 314 - ≤ 317 Markedly increased > 317 Nil minimal mild moderate marked Nil Nil CCLRU 1 CCLRU 2 CCLRU 3 CCLRU 4 Ocular Surface Staining Scale (0-15) NEI Industry (0-33) 0 Nil Minimal Mild Moderate Severe 0 Nil 0-3 4-6 7-10 11-15 0 Nil 0-7 8-14 15-23 24-33 Schirmer Score mm ≥ 10 mm ≥ 10 mm < 10 - ≥ 7 mm < 7 - ≥ 5 mm < 5 - ≥ 3 mm < 3 mm TREATMENT OF No MGD –RELATED treatment OCULAR SURFACE DISEASE No treatment + artificial tear substitutes + simple viscosity agents (preservatives allowable at low frequency of use) Symptom frequency & severity Conjunctival Hyperaemia CCLRU Level Zero + alternative AT selection + immune modulation + alternative AT selection + gels and ointments ± punctal plugs ± moisture conserving spectacles + alternative AT selection + autologous serum + conserving spectacles + surgical procedures
    67. 67. Mechanisms of Disease - Targets of Therapy EDE Terminal duct obstruction 2° acinar loss Ocular surface Loss of Compensatory Feedback ADDE ↑ microbial load Tear Hyperosmolarity Inflammatory Mediators & proteases Mucosal Inflammation and Goblet Gell Ioss Lacrimal Gland Lymphoid infiltration 1° acinar loss
    68. 68. MGD-associated Symptoms MGD - alone MGD –ocular surface disease MGD –Evaporative Dry Eye
    69. 69. Initial rate of spread (H’(0) ) Tear Film Lipid Layer Based on shift of pattern over time 8.0 7.0 H’(0)=10.4 mm/sec 6.0 5.0 4.0 2.0 Actual value Voigt model 1.0 (R2=0.982) 3.0 0.0 0.2 0.4 0.6 0.8 1.0 1. 1.4 1.6 1.8 2. 2.2 2.4 2.6 2.8 2 0 Time (sec.) Left eye: J M Yokoi et al 2011
    70. 70. Pathological Mechanisms • Gland blockade • Oil deficiency and chemical change • Local lid margin inflammation • Release of inflamm mediators from lid International MGD Workshop IOVS 2011 • Ocular surface inflammation • Tear film instability • Evaporative dry eye • Amplified surface inflammation
    71. 71. Tear Physiology Tears secreted continuously Each blink refreshes tear film Blink rate: 12/min Each blink:0.2-0.3 s Interblink interval:5 s
    72. 72. inflammatory mediators free FAs glycerides
    73. 73. Omega-3-essential fatty acids? Gilbard
    74. 74. Yokoi
    75. 75. Conceptual diagram of the TFLL Butovich et a
    76. 76. Normal Meibum Composition • • • • • • • • • • • Wax and sterol esters (WESE)-- [63.0%] Triglycerides (TG)----------------- [14.8%] Cerebrosides (CB) -----------------[9.9%] Trihexosides (TX)------------------ [0.18%] Ceramides (CER) ------------------ [0.18%] Monoglycerides (MG)------------- [1.5%] Free fatty acids (FFA)--------------[0.15%] Phosphatidylcholine (PC)--------- [5.8%] Phosphatidylserine (PS)----------- [0.07%] Phosphatidylethanolamine (PE)- [1.8%] Sphingomyelin (SM)--------------- [2.5%] McCulley and Shine 2004
    77. 77. Thickness of the Tear Film Lipid Layer Method Reference Thickness (nm) Specular microscopy McDonald, 1968, 1969 100 Specular microscopy Norn, 1979 100 Specular microscopy Norn corrected by Olsen (1985) 65 Differential interferometry Hamano and Mitsunaga, 1980 100 Specular reflectometry * Guillon, 1982 Photometric reflectometry Olsen, 1985 * Calculated for subject showing the marmoreal pattern - ca. 70% of normals. 13-70 32-46
    78. 78. The Melting Range of Human Meibomian Lipid Reference °C Linton, Curnow and Riley, 1961 35-40 Nicolaides, 1965 30-45 Brown and Dervichian, 1969 35-40 Ong and Larke, 1990 32-40 Tiffany and Marsden, 1986 19.5-32.9 Corneal temperature is about 32 °C
    79. 79. Yokoi 04 02 10
    80. 80. Diagnosis of Evaporative dry eye - EDE • Not easy: • “Yes”-if MGD +dry eye symptoms, and typical surface staining but no signs of aqueous-deficient dry eye.(-ve Schirmer) • “No”-if MGD and no dry eye symptoms or signs. • “Maybe”-if aqueous-deficient dry eye has been diagnosed but MGD is also present.
    81. 81. Practical MGD diagnosis • Clues: – Morphological lid margin change – Vertical streaking of TF Lipid Layer • Asymptomatic – routine diagnostic expression – MGD less likely <40-50 y – More likely if skin disease present • Symptomatic – Same approach, but – Carry out a systematic assessment for ocular surface disease • Morphology – Plugging – Orifice metaplasia – Displacement/extension of Marx’s line – Lid Margin hyperaemia • Gland expression (LL - 8gl) Oil Quality (0-3) – 0 =clear; 1=cloudy; 2 = particles; – 3=paste-like • Gland expressibility (0- 4) (LL - 5gl) – 0 = all expr; 1 = 4 expr – 2 = 3 expr; 3 = 2 expr; 4 = none expr. • Meibography (1-4) (LL 15 gl) – 1 = no partial gl; 2 = ≤ 25% partial gl; – 3=25-50% partial gl; 4 = > 75%
    82. 82. Practical MGD diagnosis • Clues: – Morphological lid margin change – Vertical streaking of TF Lipid Layer • Asymptomatic – routine diagnostic expression – MGD less likely <40-59 y – More likely if skin disease present • Symptomatic – Same approach, but – Carry out a systematic assessment for ocular surface disease • Investigating Ocular Surface Disease Sequence of tests • Symptom questionnaire • (Blink rate) • Meniscus height (or radius) • Tear osmolarity • Fluorescein Break up Time (BUT) • Corneal and Conjunctival stain • Schirmer Test • (MGD Grade)
    83. 83. Blepharitis • Blepharitis: inflammation of the whole lid • Marginal blepharitis Anterior Posterior
    84. 84. Dry Eye Questionnaires Name Number of questions Author Womens Health Study 3 Schaumberg et al. 2003 Internat. Sjögren Classificn 3 Vitali et al. 2002 Schein 6 Schein et al. 1997 McMonnies 12 McMonnies and Ho 1986 OSDI 12 Schiffman et al. 2000 SPEED 12 Korb et al. 2005 CANDEES 13 Doughty et al. 1997 DEQ 21 Begley et al. 2002 NEI-VFQ 25 OCULAR COMFORT INDEX 31 Johnson Murphy 2007 IDEEL 57 Rajagopalan et al. 2005
    85. 85. Development • Normal – Sebaceous primordium – Control of keratinization • Disease – Congenital aplasia – Dystichiasis – Dystichiasis lymphoedema syndrome • Animal Models – Rhino mouse
    86. 86. Physiology Secretion • Regulation – – – – Neural VIP Chol. NO; Cr V Reflex secretion? Hormonal Continuous 24/7? • sleep? • Role of blink Excretion • Via skin?
    87. 87. Evolution – Natural History of MGD • Key Aspects – Acinar atrophy – Duct obstruction – Cicatricial change • Short term human models – Chemical burns – Erythema multiforme – Graft v Host disease • Mid-term – Atopic dermatitis • Longterm
    88. 88. MGD CF Key lipids/ lipid change Bugs Inflammatory mediators Symptoms: Specific:itch; rub;other Non-specific: Evolution Progressive drop out Progressive lipid change Dose response? EDE drop out↑ Reservoir ↓ Film thickness ↓ Film quality ↓ Evaporation ↓ MKC XS Inflamm ± EDE
    89. 89. Immunomodulators- CsA • CsA binds to cyclophilin • Complexes with calcineurin • Prevents transcription of the IL-2 gene via NF-AT • Inhibits T-cell proliferation, activation of Tcell-dependent Bcells; cytotoxic lymphocytes • eg 2.0% in olive oil qds/bd • 0.05% Restasis® Roitt and Delves 2001
    90. 90. In the awake subject blinking spontaneously: • We assume that: Secretion = Excretion • Excretion is most likely via the lashes and surface of the skin.
    91. 91. Steady State or Casual Levels • Roughly normal distribution • Repeatable • Similar between eyes • Greater temporally • Rise with age in both sexes • Lower in women from puberty to sixth decade • Highest in the first hour after waking Men Women
    92. 92. Men Women
    93. 93. Steady state levels and delivery rate Steady state level: meibometry units
    94. 94. The Functions of Meibomian Oil In the lid margin reservoirs: • to maintain lid skin in a hydrophobic state, and prevent tear • to resist contamination with skin oil • to prevent maceration of the lid skin by the tears On the tear film lipid layer: • to spread over the aqueous layer, lower free energy and impart stability to the tear film • to thicken the aqueous layer (Marangoni effect) • to provide a smooth optical surface for the cornea • to provide a barrier against foreign particles • to provide some anti-microbial activity • to seal the lid margins during prolonged closure • to reduce evaporation overspill
    95. 95. Blink 1 2 4 5 3
    96. 96. Blink 1 2 3 4 5 6
    97. 97. On lid closure the oil film folds like a concertina (- the pleated drape effect) • Its structural integrity is due to: – Higher viscosity at low corneal temperature – Stabilising effect of lipocalins and collectin D? • Gradual pattern-change with blinking implies mixing within the lipid film. • Sudden pattern change implies mixing with the lid reservoir • In this way the lipid of the film is gradually turned over.
    98. 98. Diagnostic Pinwheel
    99. 99. Conclusions • The meibomian glands make an important contribution to ocular health. • MGD is a common form of blepharitis which is often overlooked. • Many techniques are available to study normal and disordered gland function. • They can be adapted for diagnosis of MGD and used in clinical trials of new therapies.
    100. 100. Evaluation of Meibomian Gland Function Evaporimetry Interferometry Meibography Meibometry Morphology Expression Lipid chemistry
    101. 101. Interferometry Yokoi
    102. 102. 1 2 3 4 5 6
    103. 103. 1 2 3 4 5 6
    104. 104. 1 2 4 5 3
    105. 105. 1 2 3 4 5 6
    106. 106. Method:(integrated meibometry) • The full length of the blot is scanned • The change in optical density is integrated along the length of the blot
    107. 107. 4 5
    108. 108. 12 14 13 15
    109. 109. Conversion of meibometer readings to lipid values ( µg/mm2 ) • Calibration – arachis oil units • Estimation of pick-up (19%) • Extrapolation to a standard lid (35x2x1 mm2 )
    110. 110. Passive defences • Blink Reflex • Reflex tearing • Tear film Lipid Layer • Tear Film Mucin Layer – Blocks bacterial adhesion (Fleiszig et al 2002) – Entrains antimicrobials and anti-proteases • Epithelial integrity – surface tight junctions • Compact Bowman’s layer
    111. 111. The Ocular Flora • Colonisation begins at birth • Gram Positive Organisms Commonest – CoNS – S. aureus – Corynybacteria • Gram negative organisms infrequent – – – – H.influenzae Moraxella sp. Neisseria sp. E.coli • Lid cultures more often positive than conjunctiva
    112. 112. Risks for Infection • Disease – – – – Blepharitis Atopy Dry Eye Diabetes • Drugs – Antibiotics – Steroids – Retinoids • Contact Lens-Associated Keratitis – EWCL 1:500 – DWCL 1:2,500 (Poggio et al 1989)
    113. 113. Evaporation depends on composition and thickness • Composition • Polar Lipids (13%) – phosholipids – sphingomyelin • Non-Polar Lipids 1-3 – cholesterol – cholesterol ester – wax esters Spreading • Biphasic Concept 4,5 1.Andrews 1973; 2. Tiffany 1978; 3. Nicolaides 1981; 4. Holly 1971; 5. McCulley and Shine 1997; 2002,
    114. 114. Tear Distribution • Tears are contained in the conjunctival sacs, menisci and tear film • The film consists of 3 layers. – Surface oil layer – Aqueous sub-phase – Deep mucin layer |
    115. 115. Topical Treatment • Anterior Blepharitis • Hygienic Measures: – Gentle lid scrubs – Bicarbonate / baby lotion • Pharmacological: – antibiotic • Fusidic acid 1% 1 – steroid • hydrocortisone ½% • Loteprednol – other • Metronidazole 1% gel 2 • FK 506 – atopic blepharitis 3 • Cyclosporin A - Restasis 1.Seal e a 1995 2. Smith and Flowers 1995; Barnhorst et al 1996; 3. Mayer e a 2001 • MGD • Hygienic Measures 4 : – Heat – compress 5/LCD/IR 6 /Chem – Massage – ‘Thermodynamic’ Lipiflow • Pharmacological: – Antibiotic: Azithromycin 8 – steroid ? – other • Metronidazole • Cyclosporin A - Restasis 9 • Androgen 7 • dry eye therapies 4. Romero ea 2004; 5. Olsen 2003; 6. Mori 2003; 7. RCTs testosterone; 8. Luchs 2008 9. Perry 2006, Rubin 2006
    116. 116. Overlap of DED Symptoms and Clinical Signs of MGD Study Shihpai Eye Study (Lin, 2003) Bangkok Study (Lekhanont, 2006)* Symptoms Assessed (all frequency) Eye dryness Gritty/sandy Burning Sticky Watery/tearing Redness Lash crusting Eyes stuck shut (am) Eye dryness Foreign body sensation Burning Discomfort Sticky Tearing Clinical Evaluations/ MGD Definition Telangiectasis or gland plugging ≥ G1 Telangiectasis, Collarettes, and Plugging % with Dry Eye Symptoms who also had MGD 61.7% (p = NR) 63.6% (p = 0.006)
    117. 117. Systemic Factors • Androgen deficiency • Complete androgen insensitivity syndrome • Menopause • Aging • Sjogren syndrome • Stevens-Johnson syndrome • Toxic epidermal necrolysis • Haematopoietic stem cell transplantation • Ectodermal dysplasia syndrome • Pemphigoid • • • • • • • • • • • Psoriasis vulgaris Parkinson’s disease Psoriasis Atopy Rosacea Cicatrical pemphigoid Polycyctic ovary syndrome Discoid lupus erythematosus Turner syndrome Benign prostatic hyperplasia Hypertension
    118. 118. Medications • • • • • • • Postmenopausal hormone therapy Anti-androgens Medications used to treat BPH Antihistamines Antidepressants Omega-3 fatty acids (possibly protective) Accutane (isotretinoin)
    119. 119. E fficacy in differential diagnosis Test measure Symptoms questions Test efficacy in diagnosissummary from Tear stability reviews N v DE: Cut-off (Sens%/Spec %) FBUT< 10s27 (82/86 ) Tear secretion Schirmer I Schirmer II <5.5mm/5min15 (85/83) PRT<12mm 14 (56/69) PRT< 20mm 17 (86/83) Ocular surface damage Evidence based approach EDE v ADDE: Cut-off (Sens%/Spec %) DE > 14.5-McMon1 (82/36-v RB,SCH,TBUT) DE >15- OSDI 4 (80/79- v Lissamine,Sch, Symp) (60/83- Dr diagnosis) Index of tear volume- PRT Sens/Spec )>70% N v EDE: Cut-off (Sens%/Spec %) RB Stain >3.512 RB Stain >413 (95% v 96%) (63/84) Lid (meibomian morphology) MG expression- Expressibility/ Volume/ Quality NA Expression grade>1.019 86/73 EDE >= 3 (83.0 / 90.0)8 Expression grade>1.019 Alcinar unit density/diameter 86/73 Meibography EDE >= 3 (83.0 / 90.0)8 Unit density <70/mm 2, 16 ( 81/81) Long diameter <65um (90/81) Short diameter<25um (86/96) Meibometry Interferometry Evaporation rate NA NA DE<22 29(51.1/89.9) EDE>22.3(61.2/90.6) Meibomian physiochemistry Tear secretion- Fluorimetry Fluorescein clearance DE<12.9 (74.5/73.6)29 EDE<15.1(80.2/58.7) ADDE<9.6(69.5/96.8) EDE>27.5(45.5/79.8) Tear volume- Fluorimetry Tear meniscus height, radius/volume NA DE<0.25 7(74.5/73.6)-R DE<0.189 (72.8/66.6)-TMH DE<9.62 (93.3/66.7) Tear Osmolarity DE>31611 (69%/92.8%) EDE>31510 (73%/72%/) ADDE> 32510 (60%/39%) Tear Dynamics- IndicesEvap/Total flow DE>1529 (na) EDE>1529 (na) EDE> na (NA) Tear Dynamics- IndicesEvap/TTR DE>2029 (na) EDE>2029 (na) EDE>na (na) Tear Dynamics- Indices- TFI DE<96 3 (64.7/60) DE<240 6 (83%/40%) NA
    120. 120. Recommended tests for evaluation and diagnosis of MGD Area SYMPTOMS McMonnies; Schein; OSDI; DEQ; OCI;SPEEDetc McMonnies; Schein; OSDI; DEQ; OCI; SPEED etc Lid morphology Slit-lamp microscopy Slit-lamp Confocal microscopy - Meibomian gland mass MG expressibility Expressed oilquality,volume? quality, Lid margin reservoir Evaporative loss Specialised unit Questionnaires SIGNS - MGD Meibomian Function General clinic Tests Intererferometry Slit-lamp Slit-lamp microscopy Slit-lamp microscopy Tear Film Lipid Layer Thickness Spread time/rate Evaporimetry Meibography - Meibometry - Interferometry SL.Video interferometry Evaporimetry - Tears Osmolarity Stability Osmolarity Tear film TFLL TearLab device, other TFBUT; OPI Spread time TearLab device, other TFBUT; OPI Interferometry; spread rate; pattern Indices Tear secretion Tear volume Tear volume Schirmer 1 Meniscus height Not available Fluorophotometry/FCR Volume by fluorophotometry Meniscus radius of curvaturemeniscometry Tear clearance TFI Ocular Surface Inflammation Ocular surface staining Biomarkers Oxford scheme; NEI/Industry scheme - Flow cytometry; bead arrays; cytokines; interleukins; MMPs
    121. 121. Severity Grading and Treatment of MGD SEVERITY LEVEL Level Zero MGD Level 1 Level 2 Level 3 Level 4 Level 5 Subclinical Symptomatic Minimal Symptomatic Mild Symptomatic Moderate Symptomatic Severe
    122. 122. Severity Grading and Treatment of MGD SEVERITY LEVEL Level Zero MGD Symptom frequency & severity OSDI grade Range (0-100) MGD Grade Quality of expressed meibum – grade range 0-3, LL, 8 glands * Range (0-24) Level 1 Level 2 Subclinical Symptomatic Minimal No Asymptomatic or Some of the time. symp occasional Precipitated by toms symptoms environmental factors 0 0-12 0-12 clear Subclinical, non-obvious MGD; Altered quality, only on expression; No gland loss Minimally altered quality of expressed meibum from scattered glands; None to minor gland loss 0 1-5 6-10 Level 3 Level 4 Level 5 Symptomatic Mild Half of the time Some limitation of activity Symptomatic Moderate Most of the time Frequent limitation of activity Symptomatic Severe All of the time Severe/disabling/ constant 13-22 23-32 33-100 Moderately increased opacity and viscosity of meibum, Plugging; increased marginal vascularity; Loss of orifice definition; Moderate gland loss Marked, diffuse MGD: cicatricial or non-cicatricial. Multiple lid margin signs. Lid deformity and marked lid margin hyperaemia; Severe gland loss Mildly altered meibum quality. Occasional lid margin signs; Mild gland loss 11-15 16-20 21-24
    123. 123. Severity Grading and Treatment of MGD SEVERITY LEVEL Level Zero MGD Symptom frequency & severity OSDI grade Range (0-100) MGD Grade Quality of expressed meibum – grade range 0-3, LL, 8 glands * Range (0-24) TREATMENT OF MGD Based on symptom and gland status. Level 1 Level 2 Subclinical Symptomatic Minimal No Asymptomatic or Some of the time. symp occasional Precipitated by toms symptoms environmental factors Level 3 Level 4 Level 5 Symptomatic Mild Half of the time Some limitation of activity Symptomatic Moderate Most of the time Frequent limitation of activity Symptomatic Severe All of the time Severe/disabling/ constant 13-22 23-32 33-100 Moderately increased opacity and viscosity of meibum, Plugging; increased marginal vascularity; Loss of orifice definition; Moderate gland loss Marked, diffuse MGD: cicatricial or non-cicatricial. Multiple lid margin signs. Lid deformity and marked lid margin hyperaemia; Severe gland loss 0 0-12 0-12 clear Subclinical, non-obvious MGD; Altered quality, only on expression; No gland loss Minimally altered quality of expressed meibum from scattered glands; None to minor gland loss 0 1-5 6-10 11-15 16-20 21-24 + general advice about MGD, the potential influence of diet, home and work environment ± hygienic measures + hygienic measures, heat and massage ± topical ATs ± emollient lubricant or liposomal spray ± topical azithromycin ± oral tetracycline derivatives + oral tetracycline derivatives ± antiinflammatories Mildly altered meibum quality. Occasional lid margin signs; Mild gland loss
    124. 124. Severity Grading and Treatment of MGD-related ocular surface disease and dry eye SEVERITY LEVEL Disease Stage Level Zero Level 1 Level 2 Level 3 Level 4 Level 5 Subclinical Symptomatic Minimal Symptomatic Mild Symptomatic Moderate Symptomatic Severe
    125. 125. Severity Grading and Treatment of MGD-related ocular surface disease and dry eye SEVERITY LEVEL Disease Stage Level 1 Level 2 Level 3 Level 4 Level 5 Subclinical Symptomatic Minimal Symptomatic Mild Symptomatic Moderate Symptomatic Severe None Asymptomatic or occasional symptoms Some of the time. Precipitated by environmental factors Half of the time Some limitation of activity Most of the time Frequent limitation of activity All of the time Severe/disabling/con stant OSDI Range (0-100) 0 0-12 0-12 13-22 23-32 33-100 TFBUT seconds ≥ 10s < 10 - ≥ 7s < 7 - ≥ 5s < 5 - ≥3 < 3 - ≥1 < 1 or instant breakup Tear Osmolarity mOsm/L < 308 < 308 < 308 Mildly increased > 308 - ≤ 313 Moderately Increased > 314 - ≤ 317 Markedly increased > 317 Nil minimal mild moderate marked Nil Nil CCLRU 1 CCLRU 2 CCLRU 3 CCLRU 4 Ocular Surface Staining Scale (0-15) NEI Industry (0-33) 0 Nil Minimal Mild Moderate Severe 0 Nil 0-3 4-6 7-10 11-15 0 Nil 0-7 8-14 15-23 24-33 Schirmer Score mm ≥ 10 mm ≥ 10 mm < 10 - ≥ 7 mm < 7 - ≥ 5 mm < 5 - ≥ 3 mm < 3 mm Symptom frequency & severity Conjunctival Hyperaemia CCLRU Level Zero
    126. 126. Severity Grading and Treatment of MGD-related ocular surface disease and dry eye SEVERITY LEVEL Disease Stage Level 1 Level 2 Level 3 Level 4 Level 5 Subclinical Symptomatic Minimal Symptomatic Mild Symptomatic Moderate Symptomatic Severe None Asymptomatic or occasional symptoms Some of the time. Precipitated by environmental factors Half of the time Some limitation of activity Most of the time Frequent limitation of activity All of the time Severe/disabling/con stant OSDI Range (0-100) 0 0-12 0-12 13-22 23-32 33-100 TFBUT seconds ≥ 10s < 10 - ≥ 7s < 7 - ≥ 5s < 5 - ≥3 < 3 - ≥1 < 1 or instant breakup Tear Osmolarity mOsm/L < 308 < 308 < 308 Mildly increased > 308 - ≤ 313 Moderately Increased > 314 - ≤ 317 Markedly increased > 317 Nil minimal mild moderate marked Nil Nil CCLRU 1 CCLRU 2 CCLRU 3 CCLRU 4 Ocular Surface Staining Scale (0-15) NEI Industry (0-33) 0 Nil Minimal Mild Moderate Severe 0 Nil 0-3 4-6 7-10 11-15 0 Nil 0-7 8-14 15-23 24-33 Schirmer Score mm ≥ 10 mm ≥ 10 mm < 10 - ≥ 7 mm < 7 - ≥ 5 mm < 5 - ≥ 3 mm < 3 mm TREATMENT OF No MGD –RELATED treatmen OCULAR t SURFACE DISEASE No treatment + artificial tear substitutes + simple viscosity agents (preservatives allowable at low frequency of use) Symptom frequency & severity Conjunctival Hyperaemia CCLRU Level Zero + alternative AT selection + immune modulation + alternative AT selection + gels and ointments ± punctal plugs ± moisture conserving spectacles + alternative AT selection + autologous serum + conserving spectacles + surgical procedures
    127. 127. Etiologies Mechanisms Fujihara 1999 LG in SS Outcomes Lid margin Severe MGD Hyperosmolarity ADDE EDE
    128. 128. McCully 1970s
    129. 129. Classification of Chronic Blepharitis ANTERIOR • Seborrhoeic • Non-seborrhoeic • (± S aureus) (± S aureus) With:crusting, collarettes, ulceration, folliculitis,enhanced cellmediated immunity Meibomian Gland Dysfunction) • Hypersecretory – meibomian seborrhoea • Hyposecretory – Retinoid toxicity – Obstructive
    130. 130. S. aureus on the lid margin % Normals 1 8 Normals 2 6 Mixed Blepharitis 3 11 “Staph.” blepharitis 2 40 Atopic blepharitis 4 76 Retinoid toxicity 5 79 1. Badiani e a 1988; 2. Dougherty McCulley 1984; 3. Groden e a 1988; 4. Huber-Spitzy e a 1992; Tufts e a 1992 5. Blackman ea 1975
    131. 131. Surgical Risks • Cataract Surgery – – – – IOL contamination 26% (Vafides et al 1984) Aqueous contamination 29-43% (Sherwood et al 1989; Dickey et al 1991) Post-extraction endophthalmitis 0.022 –1.42% (Jenkins et al 1990; Norregard et al 1997) • LASIK Surgery – 62 articles – Organisms including: S. aureus; MRSA; Streptococcus pyogenes, pneumoniae; Nocardia; Mycobacteria including M. chelonae;
    132. 132. Anterior Blepharitis • Lash-bearing region: – inflammation – lid swelling – crusting – collarettes • Symptoms: – irritation – itching • Primary • Secondary to: • Skin Disease – Acne rosacea – Seborrheic dermatitis – Atopic dermatitis – Candida –ulcerative blepharitis – Demodex ?
    133. 133. Models of MGD Ditichiasis Lymphoedma • Mouse herpes simplex 1 • Mouse SLE 2 • Rabbit:epinephrine 3 • PCBs - Primate 4 • Hamster retinoids 5 deletions / insertions in FOXC2 gene • The "rhino" mouse 6 • Meibomian occlusion 7 • Distichiasis lymphoedema syndrome. 8 1. Kintner, Brandt 1995; Dennis et al. 1995; 2. Chan et al. 1995; 3. Jester et al. 1981, 1989; 4. Ohnishi, Kohno 1979; 5. Lambert, Smith 1989 6. Jester et al 1988; 7. Gilbard et al. 1989 8. Kriederman 2003
    134. 134. Models of MGD PCBs Ohnishi 1979 • Mouse herpes simplex 1 • Mouse SLE 2 • Rabbit:epinephrine 3 • PCBs - Primate 4 • Hamster retinoids 5 • The "rhino" mouse 6 • Meibomian occlusion 7 • Distichiasis lymphoedema syndrome .8 1. Kintner, Brandt 1995; Dennis et al. 1995; 2. Chan et al. 1995; 3. Jester et al. 1981, 1989; 4. Ohnishi, Kohno 1979; 5. Lambert, Smith 1989 6. Jester et al 1988; 7. Gilbard et al. 1989 8. Kriederman 2003
    135. 135. Rhino Mouse - Jester et al.1988 Hyperkeratinized duct duct Normal Rhino 3 m Hyperkeratinized duct Rhino 12 m Rhino 6 m MG loss MG still present Rhino 3 m Rhino 12 m
    136. 136. Topical Treatment • MGD • Hygienic Measures 4 : – Heat – compress 5/LCD/IR 6 /Chem – Massage – ‘Thermodynamic’ Lipiflow 1.Seal e a 1995 2. Smith and Flowers 1995; Barnhorst et al 1996; 3. Mayer e a 2001 4. Romero ea 2004; 5. Olsen 2003; 6. Mori 2003; 7. RCTs testosterone; 8. Luchs 2008 9. Perry 2006, Rubin 2006
    137. 137. Spreading of the lipid layer
    138. 138. Yokoi 2003 Combined anterior and posterior blepharitis. Simple MGD
    139. 139. Thickness of the Tear Film Lipid Layer Method Reference Thickness (nm) Specular microscopy McDonald, 1968, 1969 100 Specular microscopy Norn, 1979 100 Specular microscopy Norn corrected by Olsen (1985) 65 Differential interferometry* Hamano and Mitsunaga, 1980 100 Specular reflectometry Guillon, 1982 13-70 Photometric reflectometry Olsen, 1985 32-46 * Calculated for subject showing the marmoreal pattern - ca. 70% of normals.
    140. 140. Blink 1 4 2 5 3
    141. 141. Summary: Meibomian secretion and delivery •Basal secretion •Blink-assisted delivery •Ductal retention and/or reduced excretion in sleep? •Wide variation in casual levels and ‘secretory rates’ •Those with low lacrimal and oil secretion may be at greater risk for dry eye
    142. 142. Data from Owens and Phillips (2001) Tear film kinetics
    143. 143. CICATRICIAL MGD 10 Plugging Opacity; ductal exposure; 7 retroplacement; hyperaemia Diagnosis Tests Expression of cloudy oil 11 Ductal exposure 13 retroplacement
    144. 144. Meibomian Gland - PHYSIOLOGY • Delivery • occurs with muscular contraction during lid movement • Riolans muscle • Orbicularis • Secretion • generates a secretory force by a constant cell biological process of MGDholocrine secretion Workshop Knop et al. 2007 MGD Workshop Knop et al. 2011
    145. 145. Meibomian Gland – PATHOLOGY • Obstructive MGD leads to a progressive ductal DILATATION and acinar ATROPHY
    146. 146. Definition of MGD • Progressive , focal or diffuse disease of meibomian glands, with • Terminal duct obstruction • Qualitative and quantitative changes in their secretion • Can result in – – – – – Lid irritation alterred tear film, eye irritation, ocular surface inflammation Evaporative dry eye.
    147. 147. Dynamic interferometry in 6 normal adult subjects
    148. 148. Piera Versura
    149. 149. Meibomian Gland – PATHOLOGY • Obstructive MGD leads to a progressive ductal DILATATION and acinar ATROPHY
    150. 150. Definition of Blepharitis • Blepharitis:inflammation of lid as a whole, • Marginal blepharitis: - of the lid margin. • Anterior blepharitis: lid margin inflammation anterior to the gray linea especially around lashes.1 • Posterior blepharitis: any inflammation of the posterior lid margin – includes MGD,

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