sign in sign up
<<
Home , Dry eye syndrome, Exophthalmos

5/21/2014

29 yo white female CC: Decreased VA OD X few days Women of Vision Present Are We PMHx: 5 months pregnant at Risk for Vision Morbidity MODERATOR BVA: 20/30 OD 20/20 OS : (-) APD Louise Sclafani O.D. Louise A. Sclafani, OD, FAAO CF: FTFC OD/OS Co-instructors: Jill Autry, OD, Melissa Associate Professor Barnett, OD, Susan Cotter, OD, Diana University of Chicago Hospital Shechtman, OD

GOALS It’s a BOY… • Our panel will take on this challenge and discuss this population as it relates to the following conditions optic neuritisOCT Women at Risk: Retinal Issues Fetus ??? evaluation, AMDnutritional controversy, psychosocial issuesmanagement options with , ocular concerns for common Diana Shechtman, OD systemic pharmaceuticals, safety issues with [[email protected]] ophthalmic drugs, and the hormonal influence Associate Professor of at on ocular surface disease NOVA Southeastern University College of Optometry Courtesy of Dr. M Rafieetary

CASE PRESENTATION SUMMARY So why would’t ICSC (idiopathic central serous chorioretinopathy) WE (female gender) be stressed out? Serous macular detachment due to RBR breakdown • As ODs we need to place a higher priority on those individuals at increased risk for vision- threatening ocular disease. It has been estimated that the female gender represents 23 of all visually compromised individuals due to inherent risk factors and lack of access to healthcare.

Diana Shechtman OD FAAO

1 5/21/2014

Hyperpermeability at RPE site is associated with choroidal Which of the following drugs in Not associated CSR in women circulation disruption/vascular congenstion with ICSC? Quillen et al. Ophthlamology jan 103: 72-9

• Viagra (PDE-5 inhibitor) • 51 women w active CSR divided into 3grps: • (any form) – Idiopathic, use, related • Anti-VEGF therapy • Results • Pseudoephedrine (nasal decongestant) – idiopathic: • Cancer (i.e. sorafenib) • Clinical findings were similar to those classic MALE • These women tended to be OLDER – Steroid related (exogenous) presentation • tended to be BILATERAL with SUBRETINAL FIBRIN – Pregnancy related FOCAL LEAKAGE but definitive cause is unknown • tended to resolve 1-2M s/p delivery

Dxed with possible previous ICSC Clinical characteristic of CSC in females maculopathy 2 yrs ago idiopathic central serous chorioretinopathy • Retrospective study on 78 women w ICSC • Acute No direct cause Affects macular area • Results • Unilateral – 62% had spontaneous COMPLETE recovery within 5M. • Young (20-45) – ~30yo Longer resolution was associated with • Type A personality – Increase age & PED formation – Final VA in 88% >20/40 & more likely associated: A Males DISEASE??? Associated with a • lack subretinal precipitates & a single presentation F:M 2:10 choroidal circulatory dysfunction that – (+)factors associated with COMPLETE recovery included manifests in the neurosensory • No HRT, no recurrence, duration <5M, no subretinal Fluid filled detachment precipitates

DFE was only performed 2 weeks after given birth (2 yrs ago) Perkins etl al. Ophthal 2002

Which of the following conditions in Not Systemic conditions or medications associated with ICSC? can increase presentation in female The women with ICSC • Tends to me OLDER • Vogt–Koyanagi–Harada syndrome (VKH) – Late 40s-early 50s • Cushing’s syndrome rd More common in 3 trimester • Subretinal precipitates are noted in 30-50% of • Tends to spontaneously resolve 1-2M sp delivery cases • Organ transplant or conditions requirement use of ling term steroids • Like in MALES, spontaneous resolution & visual recovery >20/40 is common (78-88% of women) • Hypercholesterolemia – Yet, Spaide reported that men and women older than • Sleep apnea 50 with CSC were more likely to have lower vision and • H. Pylori (helicobacter pylori of the stomach) diffuse RPE decompensating at presentation.

2 5/21/2014

BE CAREFUL Take a SLAB 65 HF Decreased vision X 1wk Value of OCT in OD 20/20 OS 20/30 F The classic 2011 A Dx modality Pooling dye superficial deeper

Classic “smoke stack”

OCT or FA may be required to identify absence of possible CNV

As it resolve…OCT images The Classic FA But how many pts have this? vary

In ANY older patients with CSC, it is important to consider the possibility of age-related or idiopathic CNV.

sneretina.com/retinal-diseases-and-treatments/central-serous-.asp

Use of diagnostic modalities OCT showing smoke stag

The value of OCT in the management of ICSC in 2011 • FA • FAF

20/40 3 wks 1M 2M • OCT 20/40 20/25+ 20/20

3 5/21/2014

Pt with hx of recurrence

20-50% will have at least one recurrence Another dx modality: FAF Within the yr Associated with “sick” RPE 54 WF

Decreased vision longstanding Courtesy of Dr. M Dunbar

OCT on chronic (>3-6M) or recurrent case may show this appearance

EDI…may explain recurrence

Choroidal thickness at SITE of ICSC, which correspond to FA leakage Increase vessel permeability due to increase hydrostatic pressure

4 5/21/2014

The image part with relationship ID rId5 was not found in the file. So when to refer? Chronic case have more widespread decompensating RPE (Diffuse Retinal Pigment Epitheliopathy: Variant of ICSC) 1. 68 WF 20/50 (visual disturbances) May be associated with worse prognosis than TYPICAL presentation. Cases may benefit from PDT…may be seen in FEMALES  Over 39k women health professionals 2 w/o AMD were evaluated  The treated grp was given 600 IU Vit E every other day (Higher than AREDS)  No difference in the development of AMD observed after 10 yrs b/t groups CONTROVERSIES

Christen WG, et al. Vitamins E and C and Medical Record-Confirmed Age-Related Macular Degeneration in a Randomized Trial of Male 3. CHRONIC (persistent for 3-6M) or recurrent Physicians. . 2012 & Christen et al. Ophthalmology. 2010 Jun;117(6):1163-8

The image part with relationship ID rId5 was not found in the file.

1. Increase Calcium requires… ` 2. High dose Vit A is associated with hip fractures in the elderly because… 3.Shouldn’t supplement lutein & beta- carotene together because… 4. Affects on liver/kidney have to be 1M f/u considered Initial 1M F/u s/p laser 20/25 20/50 20/30 20/50

TX INITIATED “Downright dangerous!” A. Observation (>60% recover w/i 4-8 wks with good outcomes) B. Laser photocoagulation RESOLVED ON ITS OWN C. PDT D. Anti-VEGF therapy E. ASA Can anything we take OTC be a problem? Referral: Doesn’t follow typical natural hx, visual needs, recurrent

Laser still commonly implemented More controversies WOMEN & AMD when tx is required 2011

• Who is MORE at risk for N=>30K women AMD: Female or males?

• Is there a correlation MV , Vit B6, folic acid, Mg, zinc , iron & copper may be associated with increase mortality rate b/t MPOD & gender?

• PDT works on chronic cases • Note that 5% of pts can experience LONG term severe permanent VL; due to long term affect on photoreceptors

5 5/21/2014

Vitamin D Hormones Women loose Vit D as they AGE • Increased Vit D consumption leads to less (severe) • Hormone change during menopause could worsen DES AMD • Thought sex hormone replacement therapy (SHRT) may relieve DES – Monozygotic twin study w asym. AMD: those w • Epidemiologic studies indicate DES incidence in women on SHRT is Hormone Influence on greater than women not on SHRT less severe AMD had more Vit D intake: 200 vs • Specifically, higher incidence of DES of older women on SHRT, 170 IU Ocular Surface Disease especially using estrogen alone. With longer SHRT use, DES frequency and symptomology increased • Seddon et al. Ophthalmology . 2011;118:1386–1394 • • Findings disagree with other studies • Higher 25OH-VitD leads to less AMD – Menopause found to be a risk factor for DES, but SHRT was instead some benefit Melissa Barnett, OD, FAAO – highest vs lowest quintile in <75yo WOMEN • Other studies show estrogen therapy in women triggered or Department of Ophthalmology & Vision Science worsened DES and of Sjogren’s syndrome • Millen et al. . Arch Ophthalmol . 2011;129:481–489 University of California, Davis

Vitamin B complex and Prevalence of Dry Disease SHRT relationship to AMD 7.3yrs f/u w 5205 women • An estimated 25 million Americans report suffering from dry • Theory for conflicting conclusions eye. • Outcome of SHRT depends on Treatment group: • 12.76 million postmenopausal women 1. Estrogen dosage • 3 million men age 65 and older 2. Age of the individuals when therapy is first initiated folic acid (2.5 mg/d) • Estrogen may only benefit younger women vitamin B6 (50 mg/d) • Estrogen detrimental and / or pro-inflammatory in postmenopausal women vitamin B12 (1 mg/d) 3. Type and combination of SHRT applied • Estrogen at physiological doses supportive of function and preservation of anterior ocular surface health at early Rx grp had a lower AMD ages association • At higher doses and / or in combination with other hormonal supplements would be harmful and / or induce inflammation. B-Complex and incident AMD in women. • Elderly women would be more susceptible WAxFACS: Arch Intern Med. 2009 Feb

Dry Eye Syndrome Hormones and Dry Eye

• Ocular surface homeostasis is altered by hormone changes • • Contribute to dry eye The great deBate: • Androgens impact structure and function of meibomian and lacrimal • Prevalence is much higher among women glands do you recommend O3 for AMD • Androgen deficiency is associated with the etiology of dry eye • Aging is a risk factor • In contrast, reports of the effects of estrogen and progesterone for the ocular surface are contradictory Particular women prone to DES • Sex hormones are key factors • Mechanisms of action of these female-specific sex hormones in the eye are not well understood. Best to be selective in choosing the • Changing hormone levels / decreased • Conflicting reports of relationship between hormone replacement therapy RIGHT pt androgens are contributory and of dry eye • New research – Average results may not apply to • Sex hormone influences the , suggesting that estrogen the individual pt may modulate a cascade of inflammatory events, which underlie dry eye.

6 5/21/2014

Systemic Medications May Induce Dry Eye Thyroid Disease Thyroid Testing

• Lacrimal glands • Clinical exam - Thyroid palpation • Multinodular Goiter • Systemic drugs may cause dry eye secondary to – Iodine deficiency – Decreased tear production • Larger than controls in patients with DES and thyroid • Thyroid Enlargement : • Soft disease • Diffuse Enlargement – Graves Disease , may have bruit – Alteration of nerve input including reflex secretion – Isthmus and lateral lobes, no • Firm and decreased corneal sensation or a direct • Biopsies of salivary glands nodules. Grave’s disease, – Hashimoto’s thyroiditis, malignancy, + + Hashimoto’s thyroiditis, endemic benign and malignant nodules inflammatory effect on secretory glands. • Infiltrating lymphocytes (mainly CD3 T) with a CD4 T / goiter • Tender + – May cause increased evaporation by changes in tear CD8 T (ration 2:1) • Single node – Thyroiditis – Cyst, benign tumor, false positive • Systolic or continuous bruit film composition, ocular surface abnormalities, • Activation markers (only one nodule of multinodular – May be heard over lateral lobes in number and quality of blinking, changes in mucus goiter detected). • Human leukocyte antigen (HLA) class II molecules – Elevates index of suspicion for producing cells, and inflammatory changes in various malignancy. • Interleukin (IL)-2 receptor (CD25) ocular tissues. – Assess for risk factors: radiation exposure, hardness, rapid growth, fixation to surrounding tissue, cervical LAD, male, others.

Thyroid Testing Thyroid Disease Thyroid Disease • Thyroxine (T4 – contains four iodine atoms) • Major thyroid hormone secreted by thyroid gland • DES a of an autoimmune condition • Recent studies • Amount of T4 produced by thyroid gland controlled by TSH related to Hashimoto's thyroiditis and /or Graves' Coexistence between thyroid diseases and Sjögren's ophthalmopathy • syndrome • Graves' ophthalmopathy • Thyroid stimulating hormone (TSH) • Ocular surface inflammatory responses in both conditions – DES due due to enhanced environmental exposure and lid • High TSH indicates thyroid gland failing due to problem directly affecting the mechanical impairment • Likely that dry eye in thyroid disease is an autoimmune- thyroid (primary hypothyroidism) • Inappropriate lid closure caused by induced response. • Low TSH indicates that person with an overactive thyroid is producing too – Superior retraction, eye proptosis, and much thyroid hormone (hyperthyroidism) impaired blinking. • All these factors contribute to inadequate tear film lubrication on the ocular surface and higher evaporation.

Thyroid Disease Thyroid Disease Thyroid Treatment

• Thyroid gland – butterfly-shaped endocrine gland • Autoantibodies against thyroid stimulating hormone • Thyroid hormone replacement • Located in the lower front of the neck (TSH) receptor in patients with thyroid-associated • Iodine suppression • The thyroid makes thyroid hormones ophthalmopathy (Hashimoto’s thyroiditis and Grave’s • Immunomodulators • Secreted into blood and carried to every tissue in the body disease) • Local radiotherapy • Thyroid hormone helps the body use energy, stay warm and • TSH receptors present in the lacrimal gland • Orbital decompression keep the brain, heart, muscles, and other organs working as • Autoantibodies present in Sjögren’s syndrome • Oral they should. • Suggest mechanism where disrupts interaction of hormone and tissue due to antibody binding to hormones and / or receptors, leading to lacrimal gland dysfunction

7 5/21/2014

Thyroid Treatment Sjögren's Syndrome Sjö testing

• Difficult to determine in literature if treatments contribute to dry • Traditional testing • Finger prick eye development and / or progression • Autoantibodies as diagnostic markers • Obtain a blood sample • No clinical trials • Anti-Ro / SSA • Study – 70% positive in Sjögren’s patients • Apply sample to the collection card • 9 years follow up • Anti – La / SSB – 40% positive in Sjögren’s patients • Send card to be analyzed • Patients received treatment for Graves’ ophthalmopathy • Anti-nuclear antibodies (ANA) • 25% DED – 70% positive in Sjögren’s patients • Rheumatoid Factor (RH) – Positive in many rheumatic diseases – Performed for the diagnosis of (RA) – Positive 60-70% of patients with Sjögren’s

New Treatment Option Sjögren's Syndrome Oral testing for Sjögren’s

• Methotrexate for the treatment of thyroid (TED) • New studies additional autoantibodies in Sjögren's Syndrome to • Salivary Flow – Salivary gland protein 1 (SP-1) • 36 consecutive patients with active TED – Measures amount of produced over a certain – Carbonic anhydrase 6 (CA6) period of time • Previously treated with corticosteroids but stopped due to side effects – Parotid secretory protein (PSP) • Autoantibodies present in two animal models for Sjögren's Syndrome • Salivary Scintigraphy • Two different weekly doses depending patient weight (7.5 mg or 10 mg) • Occurred earlier in the course of the disease • Evaluated retrospectively at 3, 6, and 12 months, compared with baseline – Nuclear medicine test that measures salivary gland data. • Patients with Sjögren's Syndrome also produced antibodies to SP-1, CA6 and PSP function • Antibodies found in 45% of patients meeting the criteria for Sjögren's Syndrome • Clinical activity score (7-CAS) – Statistically significant improvement * Salivary gland biopsy • Visual acuity (VA) – no significant change who lacked antibodies to Ro or La. • • Ocular motility – improvement * • SP-1, CA6 and PSP – Typically performed in the lower lip • – no significant change – Useful markers to identify patients with Sjögren's Syndrome at early stages of – Confirms inflammatory cell (lymphocytic) infiltration • Eyelid position - no significant change the disease • May be considered an alternative treatment with TED who cannot tolerate – Useful markers to identify those that lack antibodies to either Ro or La of the minor salivary glands. steroids.

Sjögren's Syndrome The Sjö™ In-Office Testing Kit Sjögren's Syndrome

• European-American consensus group • Two forms of Sjögren's syndrome • Ocular surface disease due to disease of the lacrimal functional unit. • Primary Sjögren’s syndrome • Numerous mechanisms for lacrimal gland dysfunction. • Aqueous-deficient dry eye • Dry mouth with the presence of autoantibodies • Cholinergic blockade from autoantibodies to muscarinic • Reduced salivary secretion acetylcholine receptor 3 • Positive focus score on minor salivary gland biopsy • Inhibition of acinar secretion by inflammatory cytokines such as IL-1 • Secondary Sjögren’s syndrome • All characteristics of Primary Sjögren's syndrome • Cytokine-mediated epithelial cell death • With autoimmune connective tissues disease • Replacement of acini by lymphocytes • Most commonly rheumatoid arthritis

• Nine out of ten patients with Sjögren’s are women.

8 5/21/2014

Sjögren’s Inflammadry

• New research • If positive, over 40 ng/ml of MMP-9 Future Treatments • Clinically significant ocular surface disease • MMP-9 is a proteolytic enzyme from stressed epithelial cells on the • May be present with normal tear production and tear ocular surface. Anti-inflammatory Drugs and volume. • These are cells that have been subjected to dry eye. • MMP-9 is a non-specific marker of inflammation. Immunomodulators • Inflammatory mediators that cause ocular surface • Does correlate with dry eye, ocular surface disease and some epithelial disease clinical findings. • Matrix metalloproteinases (MMPs) – Increased production of MMP-3 and MMP-9 • Inflammatory cytokines and T helper (Th) cell associated cytokines.

Ocular Testing Tear Osmolarity Cyclokat (Nova22007) • Measures osmolarity of proteins in . • The TearLab Osmolarity System (TearLab Corporation • Topical cyclosporine • Sensitive marker for dry eye. • 0.1% vs. 0.05% Restasis • Increased rates of evaporation lead to a more concentrated • Novel delivery system tear film (increased osmolarity). • Cationic emulsion of cyclosprine A • Both aqueous deficient and evaporative dry eye disease. • Positively charged emulsion electrostatically adhers to • Abnormal tear osmolarity – failure of homeostatic osmolarity negatively charged epithelial layer of the eye regulation

Inflammadry Tear Osmolarity Cyclokat (Nova22007)

Inflammadry (Rapid Pathogen Screening, Sarasota, Fla.) • Determines tear osmolarity using 50 nanoliter (nL) volumes of tear Phase III trial • fluid. • • Test similar to an at-home pregnancy test. • Collected directly from the eyelid margin. • 6 month, multicenter, randomized, controlled, double- • Takes a sample of a patient’s tears and gives a positive (ocular • Utilizes a temperature-corrected impedance measurement. masked trial surface disease) or negative (no ocular surface disease) result. • Indirect assessment of osmolarity. • 492 patients moderate to severe dry eye • Test takes ten minutes. A red line indicated elevated MMP-9. • After applying a lot-specific calibration curve, osmolarity is calculated • Cyclokat daily vs. vehicle and displayed as a quantitative numerical value. • Test is based on a quantifiable value of the amount of matrix • Because dry eye disease is bilateral, but sometimes asymmetrical, the • Statistically significant improvement in staining metalloproteinase-9 in the tears. higher of the two should be used for diagnosis. • Better outcomes in patients with more severe • Osmolarity values above 308 mOsms/L are generally indicative of dry eye disease. • Currently undergoing additional phase III clinical trial in US

9 5/21/2014

CyclASol™ Rebamipide Ophthalmic Suspension • OPUS – 2 study • Clear cyclosporine 0.05% solution • Phase 3 • Rebamipide ophthalmic suspension (OPC-12759 , Otsuka Pharmaceuticals) • Novaliq GmbH • 718 patients with moderately symptomatic dry eye • Multicenter double masked placebo-controlled trial • Derivative of quinolone-class • Received US and European patent approval • 12 weeks • Mucin secretagogue • Phase 1 studies • Oral therapeutic • Formulate in preservative free and multi dose bottles for DED • Randomized 1:1 to placebo or lifitegrast ophthalmic solution 5% – Treat gastric ulcers and gastritis in humans by increasing mucin levels • Lifitegrast met primary endpoint for patient-reported symptom of eye dryness • Approved in Japan for protection of gastric mucosa and for treatment • Lifitegrast did not meet sign of inferior corneal staining score with fluorescein of dry eye staining compared with placebo. • Enhances mucin secretion to support tear film adhesion and slow tear • OSDI improvement, including vision related endpoint film break-up time in human and animal studies • Well tolerated • Phase 3 Clinical Trials • No serious adverse events

Resolvins EGP-437 Rebamipide Ophthalmic Suspension

• Resolvin E1 (RvE1) • 40mg/mL dexamethasone phosphate solution • Multicenter (17 sites) • Delivered via ocular iontrophoresis platform, the EyeGate II system • 154 patients with dry eye • New class endogenous immune response mediators • Iontophoresis places drug molecules in small electric field created on ocular surface • 2% Rebamipide • Derived from lipoxygenation of Omega 3 • May increase mobility of dry molecules and lead to higher concentration of drug in the • 1 drop each eye qid x 52 weeks polyunsaturated fatty acids, eicosapentaenoic acid, tissues docoahexaenoic acid • Signs and symptoms dry eye measured at baseline, weeks 2 and 4, and every 4 weeks after • Phase II study • At week two • Prospective, single-center, double-masked randomized controlled trial • Improvement in all objective signs and subjective symptoms • In animal model (mouse) • 103 subjects with dry eye • Objective signs • Statistically significant improvement in signs and symptoms of dry eye over 3 weeks – Fluorescein corneal staining • Improved corneal staining and density • Adverse events – 87% patients – Lissamine green conjunctival staining • Phase II trial • Most adverse events mild and no severe adverse events – Tear break up time • Dose dependent and statistically significant • Lenticular opacities, vitreous , corneal deposits • Subjective • Not seen in placebo group – Ocular symptoms (FB sensation, dryness, , eye pain, ) improvements for dry eye • Further improvements of scores at every visit up to week 52 • Phase III study completed, awaiting results • Treatment well tolerated

Lifitegrast (SAR 1118) Topical Rebamipide for SLK

• Retrospective study • Lifitegrast (SARcode BioScience) Future Treatments • 33 eyes from 20 thyroid eye disease patients • Novel small-molecule lymphocyte function- • 2% Rebamipide Mucin Secretagogues • Measured at baseline and 4 weeks later associated antigen-1 (LFA-1) antagonist – Presence or absence of SLK – staining – Area and classification of fluoresceing staining • Mechanism – Schirmer I – Tear break up time • Prevents protein from binding to the cell – Hertel exophthalmometry – Margin reflex distance 1 and 2 • LFA-1 binds on T cells • 28 eyes – SLK completely resolved • Inhibits T-cell activation and the inflammatory • Other 5 eyes – significant improvement cascade. • No serious adverse effects

10 5/21/2014

Diquafosol Tetrasodium Anti-inflammatory Antibiotics ASED

• Mucin secretagogue • Topical tetracyclines formulations are being studied • Studies • Topical P2Y2 receptor agonist • Tetracyclines effective due to anti-inflammatory and • ASED more effective than artificial tears • Activation of Gq protein-coupled P2Y2 receptor results in nonglandular lipid-regulating properties • Improved TBUT, corneal staining, symptoms secretion of mucin and water • Potential to restore conjunctival goblet cells • Anti-inflammatory by inhibition of activation of MAPK, • From the patients’ point of view, the positive effect of ASED • Stimulate lipid production from meibocytes MMPs, cytokines, lymphocytes and neutrophils decreased with time. • Liposomal-bound topical doxycyline may increase • Phase II and III studies bioavailability of doxycyline • Concern about the risk microbial growth • Topical diquafosol 1% and 3% • Topical azithromycin 1% effective to treat DED • Concern about high protein content in ASED, which increases • Dose-dependent improvements in ocular surface staining associated with and contact wear risk of microbial growth 3% more effective than 1% • • Additional studies needed • Improvements in staining maintained for 52 weeks

Autologous Serum Eye Drops (ASED) Homeopathic Treatment

 Future Treatments Tear components not found in artificial tear products • Tear Stimulation Eyedrops  Epidermal growth factor (EGF) • Stimulate the production of all three tear film Ocular Lubricants  Fibronectin layers  • Two separate formulas  All support the proliferation, maturation, migration and One for women differentiation of corneal and conjunctival epithelia. •  Serum contains IgG, and complement, which have • And one for men bacteriostatic properties. • Relieve symptoms caused from inflammation due to aqueous deficiency.

ASED Cost Sodium Hyaluronate Homeopathic Treatment – Ingredients

• • Cost for blood draw and a three-month supply of ASEDs is • Alumina HPUS 10x : Indicated for dryness of the eyes and other $300. mucous membranes due to lack of aqueous secretion, "Sjogren's • Help DED by increasing ocular surface wettability Syndrome". • Average annual direct cost approximates $1,200 dollars. • Arsenicum album HPUS 12x : Indicated for severe dryness due to • Improve tear film stability inflammation and ulceration. • Phase II / III studies • Nux moschata HPUS 6x : Nux m. is the main remedy indicated for • More effective than carboxymethylcellulose to severe aqueous deficiency such as with Sjogren's Syndrome. • Zincum met HPUS 10x : Indicated for extreme dryness, inflammation improve DED and burning. • Hypotonic 0.18% sodium hyaluronate drop • Euphrasia (Eyebright) HPUS 5x : Eyebright is often referred to as a "tonic for the eyes" and is indicated for inflammation of the • Statistically significant improvement in symptoms , and lids, including meibomian glands. Symptoms and signs of DED include redness, dryness, lachrymation and burning of the lid margin.

11 5/21/2014

Homeopathic Treatment Rituximab EBI-005

• Oral Pellets • Monoclonal antibody directed against CD 20 • Phase 1b/2a clinical trial study • Double-masked, multi-center, randomized, placebo-controlled study • Targets B cells • Evaluate two doses of EBI-005 over 6 weeks in subjects with DED. • Same ingredients as the eye drops. • B cell depleting • 74 subjects • Higher potency. • Multiple centers throughout the United States. • Oral form. • Studied for systemic manifestations Sjogren’s • May be used in conjunction with the drops to increase • Less known about treatment KCS • EBI-005 compared to vehicle control. effectiveness by applying dual administration routes with • OSDI and corneal fluorescein staining. multiple potencies. • Demonstrates short term benefit • Greater improvement in signs and symptoms in EBI-005 treated group compared to vehicle-treated subjects • One to three pellets two times per day. • Suggest B cell targeted therapies potential • Statistically significant improvements in signs and symptoms of DED dry eye treatment for KCS disease in the EBI-005 treated subjects compared to baseline.

Future Treatments for Sjögren’s Gene Therapy EBI-005

• Stimulate tear production with • Promising approach for targeted and long-term • Rapid onset of action management • Clinically relevant improvement as early as 2 weeks after initiating • • Advantage to avoid multiple eyedrops daily dosing. • Significant reduction in the use of rescue tears in EBI-005 treated • Diquafosol • Gene therapy compared to vehicle-treated subjects. • Approved for treatment in Japan • Gene introduced into organ of choice by viral vector • Safe and well-tolerated in clinical and preclinical studies. • In mouse models some success for dry eye • Target lacrimal gland and corneal • Treatment well tolerated • Improvement in inflammation • Improvement in tear production

Cevimeline EBI-005 MIM-D3

• Activates M3 receptors • Eleven Biotherapeutics (EBI-005) • MIM-D3 first in a class of molecules called TrkA agonists. • Used to treat xerostoma (dry mouth) in patients with • First Interleukin-1 Inhibitor • Stimulates mucin production Sjogren’s • Treat DED or severe allergic . • May have additional benefits • Study to evaluate efficacy of cevimeline in KCS • Statistically significant improvements in signs and symptoms of – Potential to improve neural function • Cevimeline improved Shirmer’s, rose Bengal staining, DED compared to baseline. – May improve corneal sensitivity and integrity fluorescein staining, TBUT • EBI-005 was generally safe and well tolerated. • Improved patients symptoms • Side effects • Nausea, abdominal pain, sweating, headache, dizziness, cardiac arrhythemia • Withdrawal rate 14-19%

12 5/21/2014

MIM-D3 SUMMARY Types of Patients

• Phase 2 study • Adult strabismus, whether recent-onset or • Childhood onset • Two-center, randomized, double-masked, placebo-controlled study longstanding, compromises binocular • 150 subjects DED function, can cause and other • Randomized 1 :1 :1 for 1% MIM-D3, 5% MIM-D3 and placebo symptoms, and is associated with wide- • Dosed twice daily for 28 days • Statistically significant improvements signs and symptoms of ranging effects on various aspects of women's’ DED lives, particularly psychosocial functioning. An • Improvements in ocular staining 2 weeks after treatment. overview of psychosocial issues • Safe and well-tolerated • Mild ocular adverse events and management options for women with strabismus will be presented.

MIM-D3 Spectrum of Patient Concerns Types of Patients

• Phase III • Function • Adult onset 400 patients • – Diplopia – CNP 3, 4, 6 • Patients will be randomized to receive 1% MIM-D3 ophthalmic solution or placebo – Visual confusion – Divergence Insufficiency ET • Twice daily for 8 weeks – Poor stereopsis – XT new or consecutive • Primary endpoints – Graves Disease, myasthenia gravis, MS, trauma, CNS issues • Corneal fluorescein staining score • Anomalous head posture • Ocular dryness • Safety and comfort of MIM-D3 compared to placebo

Spectrum of Patient Concerns Clinical Evaluation

• Psychosocial concerns – Quality of Life • Eye Alignment: Cover testing at distance and Adult Strabismus – • Social anxiety near and different positions of gaze Scope of the Problem • Social Avoidance • Sensory Fusion • Employment/ promotion – Correspondence – Second-degree fusion Susan A. Cotter, O.D. , M.S., F.A.A.O • Headhunters – Stereopsis Professor of Optometry • Military • Motor Fusion Southern California College of • Dating – finding a partner Optometry

13 5/21/2014

Which Meds Cause Dry Eye? Sjögren’s Syndrome and Testing Management

• Goals • Blood pressure pills • Chemotherapeutic • Inflammatory disorder often in association with other autoimmune diseases – Diuretics medications • Treatment options • Classically consists of a triad of conditions: • Lenses – Beta-blockers • Topical preservatives – Rheumatoid arthritis • Birth control pills • Accutane – Dry eye syndrome • Prism – Dry mouth • Hormone replacement • Retin-A • Up to 3 million Americans; Women: Men 8:1 • Vision therapy • • Ulcer medications • Often misdiagnosed or underdiagnosed for an average • Surgery • Decongestants of 5 years • • Untreated cases can lead to worsening symptoms, lung disease, and even lymphoma

Sjögren’s Syndrome TX: CYCLOSPORIN = RESTASIS

• American-European Consensus Sjögren’s • Decrease inflammation in the cornea, MEDICATIONS AND THEIR Syndrome Classification Criteria conjunctiva, and lacrimal gland EFFECT ON WOMEN • New diagnosis/ management guidelines in • Increase tear production 2012 • Increase goblet cell density Jill C. Autry, O.D., R.Ph • Sjogren’s Syndrome Foundation • Decrease SPK Eye Center of Texas • www.sjogrens.org • Decrease dependence on artificial tears • Excellent safety profile – Cyclosporine undetectable in blood

Restasis ® Recommendations Medications and the EYE Sjögren’s Syndrome Classification

• More women than men have dry eye • I. Ocular Symptoms (at least one) • IV. Histopathology • BID dosing in most cases-not PRN • Dry eyes >3 months? • Lip biopsy showing focal lymphocytic • Hormone factors contribute to dry eye • Foreign body sensation in the eyes? sialoadenitis (focus score ≥1 per 4 2 • Severe cases use QID with a steroid initially – Estrogens vs Androgens • Use of artificial tears >3x per day? mm ) • II. Oral Symptoms (at least one) • V. Oral Signs (at least one) • Continue artificial tear use initially • More women have auto-immune diseases putting them • Dry mouth >3 months? • Unstimulated whole salivary flow at increased risk for dry eye (≤1.5 mL in 15 minutes) • Burning initially or later as ocular surface heals • Recurrent or persistently swollen • Abnormal parotid sialography – Rheumatoid arthritis salivary glands? • Use before and after contact lenses (15 minutes) • Need liquids to swallow dry foods? • Abnormal salivary scintigraphy – Lupus • III. Ocular Signs (at least one) • VI. Autoantibodies (at least one) • Persistence with therapy – Sarcoid • Schirmer's test, (without ) • Anti-SSA (Ro) or Anti-SSB (La) ≤5 mm/5 minutes – Results are 2-3 months away – Sjogren’s • Positive vital dye staining (van • Discuss long-term therapy Bijsterveld ≥4) • More women use medications associated with causing – May attempt once daily dosing when controlled dry eye • Mail order (90 day supply);2 boxes=1 month supply

14 5/21/2014

® Topamax™ Ocular side effects Chloroquine/Hydroxychloroquine (Plaquenil) Tamoxifen OCULAR FINDINGS

• Estrogen antagonist – Acute and 2 ° angle closure • RETINAL CHANGES • Increased risk of • Indications for treatment of the following cancers: • Usually within first month of initiation of topamax – Early changes retinopathy: – Breast, Ovarian, Pancreatic, Malignant melanoma • Associated with supraciliary effusion resulting in • Retinal parafoveal – > 5 years use granularity of RPE • Ocular side effects reported include the following: anterior displacement of the lens and – Cumulative dose > 1000 g – Late changes – Corneal opacities • Choroidal effusion and edema – Daily dose > 400 mg/day • White-yellow subepithelial opacities • Bull’s eye appearance of • Iniatially see up to 6-8 diopters of myopic shift – Elderly – Retinal opacities with and without CME the macula • Then a secondary angle closure without pupillary block • Choroidal filling defects • Most severe ocular association with tamoxifen – Kidney or liver disease begins to form on FA – Anterior subcapsular – Concurrent • Then IOP starts to increase – -rare • Distorted color vision retinal/macular disease – Macular hole-association not fully determined

Tamoxifen ® Retinopathy Revised recommendations on screening for TOPAMAX INDUCED ANGLE CLOSURE chloroquine/hydroxychloroquine retinopathy

Bilateral yellow-white crystals in ring-like TREATMENT • Screening: • Baseline examination • – mfERG or SD-OCT or FAF – Within 1 st year of therapy pattern – Need to DC med as quick as possible – 10-2 VF (white-on-white) – Counsel patient about risk • Repeat promptly if changes – May need taper; consult with prescribing physician • Annual screening – 13-35 microns – Fundus examination – MINIMAL guidelines – Fundus photography – Begin immediately if high risk – Location is debatable: NFL, RPE, IPL, OPL • Topical cycloplegic • Not for screening; may be useful for documentation – Begin after 5 years of use – Superficial to vasculature • topical antiglaucoma agents – No longer: Amsler grid, color • All patients vision, FA, etc. If toxicity – Hyperosmotic therapy • • ± – Consider discontinuing • May need IV mannitol if IOP cannot be controlled • Crystals usually do not resolve with – Slow clearing • PI will not restore anatomy discontinuation of therapy • Visual function may – Not related to pupillary block continue to deteriorate

Ophthalmology. 2011 Feb;118(2):415-22

Topamax™ Plaquenil ™ Hydroxychloroquine PSEUDOTUMOR CEREBRI

• Indications: • Indications • – Epilepsy – Malaria • Negative MRI of Brain • Monotherapy, adjunctive therapy – • Negative MRV of Brain Rheumatoid arthritis – Migraines – • Increased opening pressure on lumbar puncture • Prophylaxis • Precise mechanism of action: not known • Normal CSF composition – Off-label – Acute effects on metabolism of retinal cells • Obese females (Diamox and weight loss) • Bipolar disorder, weight reduction, depression, • Ocular Side Effects neuropathic pain • Pregnancy (Diamox after 20 weeks gestation) – Bilateral ring of RPE depigmentation sparing the fovea – With vision threatening loss of macular function • Medication induced (remove offending agent)

15 5/21/2014

MEDICATION INDUCED PSEUDOTUMOR STEROID SIDE EFFECTS PREGNANCY

• Accutane • Amiodarone • Increased intraocular pressure • Medication Dosing • Steroids • Isoniazid – Topical will increase in 2-4 weeks – Shortest course of treatment necessary to • Vitamin A • HRT/BC pills – Oral/IV can increase within 3-4 days eliminate pathology if possible • • Tetracycline • Lithium – Topical treatment preferred over oral – Usually posterior subcapsular • Doxycycline • Nitroglycerin – Punctal occlude • Steroid induced /decrease control • Minocycline • Chemo meds – FDA Pregnancy Categories for Drugs • Adrenal suppression • Amiodarone • Reduced immunity/infections • Mood swings/erratic behavior

Ethambutol (Myambutol) AMIODARONE OPTIC NEUROPATHY BREASTFEEDING

• Tuberculosis treatment • Optic neuropathy secondary to decreased • Medication Selection • toxicity axoplasmic flow – Choose medications with the shortest half-life possible. • Dose related • Resulting optic nerve edema – Choose medications with the highest protein- – 50% at a dose of 60-100mg/kg/day • Seen within weeks of initiation of drug binding ability. – 5-6% at a dose of 25 mg/kg/day • Discontinue use – Choose medications with the lowest lipid – 1% at or below 15mg/kg/day • Can mimic NAION solubility. • May continue to lose vision despite – Visual acuity less affected than NAION – Choose medications with the lowest oral discontinuation of meds – Edema takes longer to resolve than NAION absorption.

ETHAMBUTOL TOXICITY PREGNANCY BREASTFEEDING

• Optic nerve starts 2-5 months after starting ethambutol – Optic atrophy with decreasing visual acuity • Medication Selection • Medication Dosing – Loss of color vision – Visual field defects – Choose medications from Category A or B if – Administer single daily-dose medications just – Bilateral – Sometimes asymmetric possible before the longest sleep interval for the infant, • Management • Baseline exam – Category C if benefit outweighs risk usually after the bed-time feeding. – Visual acuity – 10-2 Visual field – Category D and X should be avoided completely – Breast-feed infant immediately before medication – Color vision dose when multiple daily doses are needed. – OCT NFL – OK to dilate patients for routine examination – Optic nerve photos • Monthly eamination if doses>15mg/kg/day during pregnancy • If visual signs/symptoms occur – DISCONTINUE drug immediately

16 5/21/2014

PAIN MANAGEMENT AND PG EYE INFECTION AND PG ANTI-VIRALS

• Tylenol #3 (acetaminophen and codeine) • Bacterial conjunctivitis/Anterior or Posterior ANTIVIRALS ORAL ANTIVIRAL DOSING Blepharitis • Trifluridine—Category C • – OK in pregnancy • Zirgan-Category C • In place of topical – Erythromycin ointment – NO in breastfeeding • Oral Acyclovir-Category B treatment – Azasite – Acyclovir 400mg 5x day x • Oral Famciclovir-Category 10 days • Vicodin (acetaminophen and hydrocodone) B • Corneal ulceration or prophylaxis – Famvir ® 250mg tid x 7 days – OK in pregnancy and breastfeeding • Oral Valcyclovir-Category – Valtrex ® 500mg tid x 7 days – Tobramycin B • For prevention of – Compound cephalosporins recurrences • Cefazolin (1 st gen) – Acyclovir 400mg qd-bid • Ceftazidime (3 rd gen) – Famvir ® 250mg qd – Valtrex ® 500 qd

DRY EYE TREATMENT AND PG TOPICAL OPHTHALMIC STEROIDS AND PG

• Restasis in contraindicated in pregnancy • Pregnancy • Consider: – Category C Medications – No treatment? • Category C – Risk vs. Benefit ratio should be considered • Consider decreasing CL wear – Use lowest dosage possible for shortest length of time • IOP often decreases during pregnancy possible • Consider SLT • Non-preserved artificial tears/gels/ointments – Highest risk would be between 8-11 th weeks of • 90 day plugs; repeat prn pregnancy – Punctal occlusion • Stop oral if possible • Breastfeeding – Prednisone and both penetrate poorly into breast milk and are safe for short term use

SOFT TISSUE DISEASE AND PG GLAUCOMA AND PG

• Penicillins • Dual Acting • Brimonidine – Augmentin • 875mg bid Anti-Allergy Medications – Alpha-agonist – Amoxicillin • 875 mg bid – Category B • Cephalosporins – Discontinue if breast feeding – Cephalexin • 500mg bid • Effects in infants due to penetration of BBB • Azithromycin • Reported with infants less than 2 months of age – Zpack • Dipivefrin • Erythromycin – 500mg bid – Category B • Category B Topical Antibiotics

17 5/21/2014

GLAUCOMA AND PG

• Prostaglandins – Contraindicated at all stages of pregnancy – Consider using post-partum – PG important during labor – Potentially • Induce miscarriage • Premature labor • Carbonic Anhydrase Inhibitors – Oral is contraindicated in pregnancy – Topical preferred if warranted – Acetazolamide OK in breastfeeding according to the American Academy of Pediatrics

GLAUCOMA AND PG

Category C Medications • Beta-blockers – OK after first trimester up to one week before delivery – OK during lactation according to American Academy of Pediatrics if use lowest dosage possible • Pilocarpine – Considered safe in pregnancy with literature review – Breastfeeding unknown

Thank you

[email protected]

18