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Prof Bron lecture. The A-Z of MGD
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. 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. 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. 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. 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.
22. • Bacterial load is
increased in
anterior
blepharitis
• Likely but less
certain in MGD
Courtesy of N Yokoi 2003
23. 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
24. Evaluation of the Meibomian Glands
Evaporimetry
Interferometry
Meibography
Meibometry
Morphology
Expression
Lipid chemistry
25. 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
26. 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.
27. 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%
28. 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
29. 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
34. 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
35. 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
36. 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
47. 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
50. 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.
51.
52. 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
53. Therapy for the Ocular Surface
To restore and maintain:
•Tissue normality
•Ocular surface environment
•To achieve ocular comfort
55. 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)
57. 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.
58. 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
61. 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
65. Treatment of Dry eye: General Measures
• Personal and Environmental
↑ Relative humidity
↓ Air Conditioning / wind speed
– VDU positioning
– Smoke and chemical fume
exposure
66. 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.
67. 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
68. 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.
69. 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
70. 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
71. 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
76. 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
77. 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
78.
79.
80. 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
86. 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
87. 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
89. 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.
90. 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%
91. 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)
95. 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
96. Development
•
Normal
– Sebaceous primordium
– Control of keratinization
•
Disease
– Congenital aplasia
– Dystichiasis
– Dystichiasis lymphoedema
syndrome
•
Animal Models
– Rhino mouse
98. 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
99. 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
100. 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
101. In the awake subject blinking
spontaneously:
• We assume that:
Secretion = Excretion
• Excretion is most likely
via the lashes and
surface of the skin.
102. 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
105. 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
108. 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.
110. 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.
111. Evaluation of Meibomian Gland Function
Evaporimetry
Interferometry
Meibography
Meibometry
Morphology
Expression
Lipid chemistry
117. Method:(integrated meibometry)
• The full length of the
blot is scanned
• The change in optical
density is integrated
along the length of the
blot
121. 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 )
122.
123.
124. 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
125. 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
129. 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
|
130. 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
131. 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)
134. 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
135. 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
136. 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
137. 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
138. 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
139. 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
140. 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
141. 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
146. 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
147. 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;
149. 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
150. 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
151. 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
152.
153.
154. 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
161. 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
164. 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
165. Meibomian Gland – PATHOLOGY
• Obstructive MGD leads to a progressive
ductal DILATATION and acinar ATROPHY
166. 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.
169. Meibomian Gland – PATHOLOGY
• Obstructive MGD leads to a progressive ductal
DILATATION and acinar ATROPHY
170. 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,
Editor's Notes
Locate ajb and yokoi videos
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 40-45C 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.
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.