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Clinical & Refractive Optometry VOLUME 27, NUMBER 5, 2016
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Rhino-Orbital Mucormycosis AREDS2 Controversies and Facts Diagnosis and Treatment of Ocular Surface Conditions: Focus on Allergy The Science of Dry Eye Hyperosmolarity
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Clinical &Refractive Optometry
Editorial Board • Volume 27, Number 5, 2016 Editor-in-Chief
Associate Editor
Richard Maharaj, OD, FAAO Toronto, Ontario
Leonid Skorin, Jr., OD, DO, MS Albert Lea, Minnesota
Editors Emeriti Brad Almond, OD Calgary, Alberta
Barbara Caffery, OD Toronto, Ontario
John Jantzi, OD Vancouver, British Columbia
Yvon RhĂŠaume, OD Montreal, Quebec
Contributing Editors Scott D. Brisbin, OD Edmonton, Alberta
Gerald Komarnicky, OD Vancouver, British Columbia
Langis Michaud, OD Montreal, Quebec
Barbara Robinson, OD Waterloo, Ontario
Lorance Bumgarner, OD Pinehurst, North Carolina
Bart McRoberts, OD Vancouver, British Columbia
Rodger Pace, OD Waterloo, Ontario
Jacob Sivak, OD, PhD Waterloo, Ontario
Louis Catania, OD Philadelphia, Pennsylvania
Ron Melton, OD Charlotte, North Carolina
Maynard Pohl, OD Bellevue, Washington
Randall Thomas, OD Concord, North Carolina
Publication Staff Publisher Lawrence Goldstein
Managing Editor Mary Di Lemme
Senior Medical Editor Evra Taylor
Layout Editor Colin MacPherson
Graphics & Design Mediconcept Inc.
Mission Statement Clinical & Refractive Optometry is a peer-reviewed professional journal dedicated to the publishing and disseminating of COPE approved CE credit scientific articles. The contents of each issue are composed of a mixture of original: state-of-the-art/technical, therapeutic/clinical, or practice management articles which are of particular interest to and use by practicing optometrists. Participants achieving 70% or more on the questionnaires that accompany each of the articles in the journal, will receive a course credit certificate.
BONUS UPGRADE TO THE PRINT EDITION To upgrade to the Print Edition of CRO which will include 6 consecutive issues, containing a combined total of 24 prepaid COPE CE-Credit course tests, please forward a cheque for $282.50, payable to Mediconcept Communications, to the address shown below. Note: As of 2017, you can take your CE-Credit tests online, for a average cost of $11.77 per test. Subscription Information Title ______ First Name _______________________ Last Name _______________________________________ Number __________ Street _______________________________________________________ Suite __________ City ____________________________ Province _________________________ Postal Code __________________ Office Phone (_____) _______________________ E-mail _____________________________________________
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Clinical& Refractive Optometry
Clinical & Refractive Optometry is published 6 times per year by Mediconcept.
Contents • Volume 27, Number 5, 2016
CE CREDIT ARTICLES
167
Rhino-Orbital Mucormycosis Melissa Ngo, OD; Pauline F. Ilsen, OD ABSTRACT: Although the mortality rate of rhino-orbital mucormycosis is high, this infection can be cured. Early diagnosis through tissue biopsy and culture with immediate and aggressive treatment with an antifungal, surgical debridement, and reversal of pre-disposing conditions if possible is crucial for a more favourable prognosis.
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AREDS2 Controversies and Facts: Delving Deeper into our Knowledge on Eye Health Bernard Hurley, MD INTRODUCTION: Dr. Hurley described the objectives of his presentation: To recognize the impact age-related macular degeneration (AMD) has on Canadians; identify the risk factors associated with AMD; discuss the impact and limitations of the AREDS and AREDS2 studies; recognize the role of ocular vitamin supplementation in the management of patients; understand the status and limitations of pharmacogenetic testing today; and, finally, apply some of these to patients in everyday practice.
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Diagnosis and Treatment of Ocular Surface Conditions: Focus on Allergy Paul M. Karpecki, OD INTRODUCTION: Dr. Karpecki began his presentation by noting that he established his first dry eye clinic in 1997 and in the first ten years of ocular surface disease, there wasn’t a lot to teach about dry eye disease as we were learning as we went along. In addition, there wasn't much practitioners could do for success. In fact, he noted, his success rate was probably less than fifty percent. In a survey conducted before he joined Kentucky Eye Institute, approximately 96% to 98% of patients said they were satisfied or very satisfied with their treatment results. Dr. Karpecki mentioned that in the last six or seven years, great strides have been made in the management of the ocular effects of dry eye disease and allergies.
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The Journal is made available to all optometrists on www.crojournal.com. Advertising insertion orders and copy must be received before the first day of the preceding month for which the advertising is scheduled. While the editorial staff of Clinical & Refractive Optometry exercises great care to ensure accuracy, we suggest that the reader consult the manufacturer’s instructions before using products mentioned in this publication. The views contained in the Journal are those of the respective authors and not of the Publisher. Please direct all correspondence to: Mediconcept Editorial & Sales Office 3484 Sources Blvd., Suite 518 Dollard-des-Ormeaux, Quebec Canada H9B 1Z9 Tel.: (514) 245-9717 E-mail: info@mediconcept.ca Printed in Canada. All rights reserved. Copyright © 2016 Mediconcept. The contents of the publication may not be mechanically or electronically reproduced in whole or in part without the written permission of the publisher. All drug advertisements have been cleared by the Pharmaceutical Advertising Advisory Board.
The Science of Dry Eye Hyperosmolarity Benjamin J. Barrus, OD INTRODUCTION: Dr. Barrus began his presentation by pointing out that dry eye is a common disease in Calgary, where his practice is located, which has a significant negative impact on patients’ quality of life. An important role for optometrists, he said, is to “own” patients’ dry eye problem and provide the best available options for relief. He treats every dry eye patient differently because every individual case is different and requires its own careful workup and differential diagnosis. On average, he sees about four dry eye patients per day.
ISSN: 1705-4850; Date of Issue: October/November 2016
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Cover Image: Vernal shield ulcers are indicative of an eosinophilic reaction. Courtesy of: Dr. Paul M. Karpecki
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Clinical & Refractive Optometry is pleased to present this continuing education (CE) article by Dr. Melissa Ngo and Dr. Pauline F. Ilsen entitled Rino-Orbital Mucormycosis. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 178 for complete instructions.
Rhino-Orbital Mucormycosis
INTRODUCTION
Melissa Ngo, OD; Pauline F. Ilsen, OD, FAAO
Mucormycosis, also referred to as zygomycetes, is an opportunistic invasive fungus that was first described in the literature by German pathologist Paltauf in 1885. It was a case of a systemic infection with gastric and rhinocerebral involvement which he described as “Mycosis Mucorina.”1 The annual incidence rate in 1997 was 0.7 cases per million individuals, then in 2006 it increased to 1.2 cases per million individuals. The annual incidence has almost doubled in a decade. The yearly incidence increased with age from 0.3 per million in children under 9 years old to 3.9 per million in adults 89 years old or older. As risk factors increase, the annual incidence rates increase.2 This is most apparent among patients with diabetic ketoacidosis which has increased by 400% in incidence between 1991 and 2007.3 We present a Case Report on successfully treated rhino-orbital mucormycosis in a patient with diabetic ketoacidosis. We will review common signs and symptoms, etiology, treatment, and management for this condition. Proper diagnosis and management will significantly improve survival rate which is why it is crucial for clinicians to be aware of this deadly condition.
ABSTRACT Background: Mucormycosis is an aggressive fungal infection caused by filamentous fungi of the Zygomycetes class and Mucorales order. It has a high mortality rate classified by the infection site which includes rhino-orbital-cerebral, pulmonary, cutaneous, gastrointestinal, disseminated, and miscellaneous. Clinical hallmarks of this infection is tissue necrosis with black eschar resulting from angioinvasion and subsequent thrombosis. Case Report: A 45-year-old white male presented to the emergency department with diabetic ketoacidosis, orbital swelling and pain with left facial numbness. Computed tomography (CT) revealed left maxillary sinusitis with orbital cellulitis. Surgical drainage and debridement was performed and biopsy and culture of the contents revealed inspissated mucopus. A diagnosis of acute left maxillary sinusitis/orbital cellulitis and likely rhinoorbital mucormycosis with left infraorbital enhancing lesions was made and the patient was aggressively treated with antifungals and survived. Conclusion: Although the mortality rate of rhino-orbital mucormycosis is high, this infection can be cured. Early diagnosis through tissue biopsy and culture with immediate and aggressive treatment with an antifungal, surgical debridement, and reversal of predisposing conditions if possible is crucial for a more favourable prognosis.
M. Ngo — Resident, West Los Angeles Veterans Affairs Healthcare Center, Los Angeles, CA; P.F. Ilsen — Professor, Marshall B. Ketchum University/Southern California College of Optometry, West Los Angeles Veterans Affairs Healthcare Center, Los Angeles, CA Correspondence to: Dr. Pauline F. Ilsen, Marshall B. Ketchum University, West Los Angeles Veterans Affairs Healthcare Center, Optometry Clinic (123) Bldg. 304, Room 2-123, 11301 Wilshire Blvd., Los Angeles, CA USA 90073; E-mail: Pauline.Ilsen@va.gov This article has been peer-reviewed.
CASE REPORT A 45-year-old white male was referred from the hospital emergency room for an urgent eye exam. He presented to our clinic with 8/10 periorbital pain in the left eye, numbness of the left cheek, acute horizontal diplopia, left lid swelling, and a decrease in visual acuity in the left eye. Ocular history was negative for injury, surgery, and ocular disease. His last eye exam was eight months ago which was unremarkable except for incipient cataracts, low refractive error, and low risk glaucoma suspect OU. Medical systemic history includes poorly controlled type 2 diabetes (for six years), hypertension, depression, alcoholism, obesity (body mass index of 34), and posttraumatic stress disorder. He was found by a friend to be unresponsive and lethargic, with an altered mental status prior to being sent to the emergency room. About four to six months prior to being admitted he reported heavily drinking (up to twelve packs of beer per day) due to the recent death of his mother. In the emergency department, they found his blood glucose to be 753 mg/dL which resulted in his diabetic
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A
B
D
E
C
Fig. 1 (A) Axial cranial CT scan at the initial presentation reveals near complete opacification of the left maxillary sinus. (B) Abnormal soft tissue tracks posteriorly along the left orbital floor and infraorbital nerve which resulted in proptosis of the left globe. (C) Coronal and sagittal views (D,E) once again demonstrate the opacification of the left maxillary sinus. There is abnormal thickening of the subcutaneous soft tissues of the left face overlying the maxillary sinus.
coma. He was then placed on an insulin regimen. With good control of his glucose, his diabetic ketoacidosis resolved. However, he developed severe left eye swelling, pain, edema, and redness with subjective blurriness and occasional diplopia upon two days of admission. He was diagnosed with orbital cellulitis during this time with associated left facial numbness, blurred vision, and left maxillary sinusitis. A CT scan revealed left inferior orbital cellulitis, maxillary sinusitis, and preseptal cellulitis (Fig. 1 A-E). He was started on vancomycin and ZosynÂŽ (piperacillin-tazobactam, New York, NY). When his condition was stable, he was transferred into our hospital for management about one week after the initial presentation. Upon being admitted he reported that the diplopia had resolved. However, he still was symptomatic for subjective left face numbness without paresis, left eye pain, swelling, overall weakness, fatigue, and ongoing headaches. The new concern was for fungal sinusitis with orbital involvement. Head and neck department doctors confirmed that there was no necrosis or black eschar upon examination. Upon consulting with the infectious disease department, the patient was put on liposomal amphotericin B and surgical drainage and debridement of the left maxillary sinus was scheduled for the next day. He then had a same day referral to the eye clinic.
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EXAMINATION FINDINGS Ocular examination revealed best corrected visual acuities of 6/6 (20/20) OD and 6/7.5 (20/25) OS with plano — 0.50x100 and +0.50-1.00x100, respectively. Pupils were round and equally reactive to light with no afferent pupillary defect noted OU. Extraocular muscle testing was full. Gross visual fields were full. Primary gaze revealed a flick of exotropia. Exophthalmometry (Hertel) was measured at 19 mm OD and 22 mm OS with a base of 95 mm. Color vision with Ishihara was 9/10 OD and OS. He had decreased sensation along his left maxillary nerve. Intraocular pressure measured 14 mmHg OD and 15 mmHg OS by Goldmann applanation tonometry. Slit lamp biomicroscopy demonstrated no ptosis, mild skin changes with erythema and mild edema. The conjunctiva was white and quiet. The cornea was clear and there was a deep and quiet anterior chamber. The iris was round and reactive with no signs of iris neovascularization. He had trace nuclear sclerosis with a clear vitreous OU. Dilated fundus examination with binocular indirect ophthalmoscopy was unremarkable except for inferior extramacular drusen OU. The cup-to-disc ratios were 0.50 round OD, 0.40 round OS with full rims (Fig. 2 A,B). The macula was flat and even, vessels were within normal
A
B
Fig. 2 (A) Fundus photo of the right eye demonstrating a clear view in with a pink and healthy optic nerve with no signs of edema, pallor, or hemorrhages. Cup-to-disc ratios were 0.50 round deep to lamina with unremarkable vasculature. (B) Fundus photo of the left eye demonstrating a clear view in with a pink and healthy optic nerve with no signs of edema, pallor, or hemorrhages. Cup-to-disc ratios were 0.40 round deep to lamina with unremarkable vasculature.
limits, and the periphery was intact OU. There was no evidence of intraocular involvement and no signs of orbital compression. The patient was instructed to continue amphotericin B, vancomycin, metronidazole, and Zosyn as prescribed by infectious disease, to proceed with surgical debridement the next day, and to return to ophthalmology post-operatively. The patient underwent left endoscopic sinus surgery with maxillary antrostomy and anterior ethmoidectomy. Microscopic anatomic pathology revealed non-specific acute and chronic inflammation. Culture of sinus contents revealed positive Gomori methenamine silver (GMS) stain for non-septate broad base hyphae consistent with mucor and maxillary sinus showed inspissated mucopus on the postoperative pathology report. A diagnosis of left maxillary sinusitis/orbital cellulitis, likely rhino-orbital mucormycosis with left infraorbital enhancing lesions was made. His treatment regimen changed to ceftriaxone 2 g IV q.d., metronidzole 500 mg p.o. t.i.d., and liposomal amphotericin 5 mg/kg IV q.d. by infectious disease. He was discharged home once he became stable and was followed-up 3 times per week in the infectious disease outpatient clinic. He was treated with liposomal amphotericin B with taper for two months and treatment was continued until no residual active disease on imaging before discontinuing amphotericin and “mopping up� the condition with posaconzole 200 mg p.o. q.i.d. During the 4-month follow-up he was improving and was clinically
stable. Repeat MRI was stable showing thickening with enhancement along the inferior aspect of the orbit with no gross changes. He continued posaconazole for the next few months before discontinuing it. About two-and-a-half years later, the patient presented for an eye exam and reported four months of sobriety. However, he still had poorly controlled diabetes, as his last glucose finger stick value was 213 mg/dL. There was no diabetic retinopathy OU and no ocular signs of recurrent rhino-orbital mucormycosis was found OU. The patient was encouraged to maintain sobriety and blood sugar control.
DISCUSSION Epidemiology Due to the relative rarity of the disease, there are varying estimations of the actual incidence and the incidence varies depending on whether the study was in a developed verse developing country. The literature contains a limited number of population studies. In a population-based surveillance study in San Francisco, California from 1992 to 1993 they found that the annual incidence of mucormycosis was 1.7 cases per 1 million individuals which was about 500 cases per year.4 A more recent population-based multicenter study in Spain performed throughout 2005, found the incidence was 0.43 cases per 1 million individuals and 0.62 cases per 100,000 hospital admissions.5
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Table I Clinical presentation of mucormycosis and percentage of diabetics in each study Clinical Presentation
Rhinocerebral/ Rhiono-orbito-cerebral Pulmonary Disseminated Cutaneous Gastrointestinal Diabetic
McCrory (n=40) 2014
Hyo-Lim (n=64) 2013
Spellberg (n=20) 2012
Skiada (n=230) 2011
Chakrabarti (n=178) 2006
Roden (n=929) 2005
Yohai (n=145) 1994
Blitzer (n=179) 1980
60% 18% 10% 8% 5% 58%*
56% 31% 4.6% 5% 9% 67%*
55% 40% 10%
27% 30% 15%
**
9%
48% 24% 3% 19% 7% 36%*
**
65%*
54.5% 7% 9% 15% 8% 81%*
60%*
70.4%
*Highest risk factor in study **This study was specific to rhino-orbital-cerebral mucormycosis which they indicated was the most common
Another multicenter study from 2005 to 2007, included 15 international European countries and found 230 cases of proven or probable mucormycosis. They noted that there was an increase in frequency of the disease due to the rising prevalence of diabetes, increased use of immunosuppressive treatments, and newer antifungals, in particular voriconazole.6 During the same time frame there was another study in India from 2006 to 2007 which found 178 diagnosed cases of mucormycosis (mean average of 35.6 cases/year).7 Lastly, in the largest review of mucormycosis by Roden et al, which compiled a total of 929 cases from 1940 to 2003, they demonstrated an increased incidence over the decades with a decrease in mortality due to the introduction of amphotericin B.8 Given the acute nature of the condition, there is limited literature reporting the prevalence of the disease. However, in an autopsy series the prevalence of mucormycosis has been 1 to 5 cases per 10,000 autopsies.9 Mucormycosis is categorized based on clinical presentation and the primary site of infection at the time of initial diagnosis. The main categories found in literature are: rhinocerebral, rhino-orbital, pulmonary, cutaneous, gastrointestinal, disseminated, and miscellaneous (Table I). Of these, the most common form is rhino-orbital with diabetes as the most common underlying condition.8-11 Roden et al categorizes infections that are limited to the sinus as its own category rather than labeling it “rhinocerebral” to distinguish patients with localized sinus infections from those with “true” cerebral involvement. In his review of 929 cases, he found that sinus infections, which included rhinocerebral, rhino-orbital, sinusitis, and sinopulmonary, as the most common presentation (39%), followed by pulmonary (25%), cutaneous (19%), cerebral (9%), gastrointestinal (7%), general disseminated (3%), and other (6%) being the least common. He found that diabetes is the most common underlying condition (36% of cases) and that sinus involvement consisting of rhinocerebral, sinus, and rhino-orbital
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infections are the most common in patients with diabetes (66% of cases).8 These findings are similar to Chakrabarti’s study that found that rhino-orbital-cerebral mucormycosis is the most common presentation at 54.5% and that uncontrolled diabetes (in 73.6% of cases) is a significant risk factor in all types except in renal involvement.7 Clinical Presentation The clinical hallmark of mucormycosis is tissue necrosis resulting from angioinvasion and subsequent thrombosis.3,10,12,13 The angioinvasion is characterized by a limited inflammatory immune response and is associated with the organism’s ability to hematogenously disseminate from the primary site of infection to other surrounding areas. The infection progresses rapidly and unless there is prompt and aggressive treatment, the prognosis will be poor.3,9 Black necrotic eschar of the nasal mucosa is a characteristic sign of this condition, but its absence does not indicate that mucormycosis is not present.12,14,15 During the initial presentation, black eschar is noted in 19% to 38%, but as the disease progresses 68% to 80% of patients develop it.16,17 It presents unilaterally or bilaterally and is thought to be due to thrombosis of the sphenopalatine vessels in the orbit. It should be considered indicative of terminal vessel necrosis rather than the inoculation site of the infection.14,15,18,19 Non-ophthalmic signs and symptoms The common non-ophthalmic clinical presentations of rhino-orbital mucormycosis include: black nasal eschar 68% to 80%, paranasal sinusitis 78%, granular or purulent nasal discharge 74%, fever 26% to 71.4%, rhinorrhea/cold 57%, palatal involvement 29% to 48%, facial edema/pain 20% to 46%, decreased mental function 34%, toothache 24%, facial palsy/numbness 20% to 22%, leukocytosis 23%, headaches 17% to 20%, hemiplegia or stroke 20%, brain abscess 20%, epistaxis 10% to 20%, hemiparesis 17%, facial necrosis 11% to 15%, meningeal signs 11%, and malaise 11% (Table II).17,19-22
Table II Summary of non-ophthalmic signs and symptoms. Signs and Symptoms
Camara-Lemarroy (n=14) 2014
Bhansali (n=35) 2004
Talmi (n=19) 2002
Rhinorrhea/sinusitis Fever Facial edema Black nasal eschar Nasal discharge/ ulceration VII nerve palsy/paresis Palatal involvement (necrosis, ulcer, etc.) Facial numbness Mental status change/stupor/coma Headache Malaise Facial pain Epistaxis Brain abscess Toothache Hemiparesis/hemiplegia/stroke Facial necrosis Seizures
57% 71.4% 14%
100% 26% 46%
42%
74% 46% 29%
50%
34% 29% 20% 20% 20% 20% 24% 17% 11%
Ophthalmic signs and symptoms The common orbital signs and symptoms of rhino-orbital mucormycosis are: ophthalmoplegia, unilateral proptosis, vision loss or decrease, chemosis, periorbital edema, periorbital or ocular pain, afferent pupillary defect, trigeminal anesthesia of the ophthalmic division, central retinal artery occlusion, cellulitis, corneal anesthesia, and cavernous sinus thrombosis (Table III).17,19-22 Presenting signs and symptoms are orbital and sinus findings consistent with sinusitis or periorbital cellulitis.19 These are followed by rhinorrhea, fever, nasal mucosal ulceration/necrosis, periorbital and facial swelling, decreased vision, ophthalmoplegia, headache, facial pain, and change in mental status within the first 72 hours.17 Many case reports have also indicated elevated white blood cell count.11,21-26 As the infection usually spreads from the ethmoid sinus to the orbit, it affects the extra-ocular muscle function and can cause proptosis as it invades the orbit. Marked chemosis can be seen. Chemosis, proptosis, and loss of extraocular muscle function occur as a result of vascular compromise and indicates the infection has traveled into the orbit. The infection can then spread into neighboring tissues. Onset of ophthalmoplegia and diplopia suggest a cavernous sinus thrombosis, which is an ominous sign. Since the cavernous sinus holds not only the cranial nerves, but also the internal carotid vasculature, the infection can quickly spread systemically and into the central nervous system, causing an extensive infection and indicates a grave prognosis.9,21
94.7% 74% 47% 26%
31.6% 37% 84%
15.8% 10.5%
Yohai (n=88) 1994
Blitzer (n=179) 1980
79% 36% 30% 48% 13% 22% 32%
26% 1% 1% 13% 26%
20% 34% 17% 11% 23% 10% 8% 7% 20% 15% 2%
25% 14.5%
>1% 1% >1%
Etiology, Pathogenesis Rhizopus oryzae is the most common organism isolated causing mucormycosis. It accounts for 47% to 90% of the cases of mucormycosis, followed by Mucor spp., and Lichtheimia corymifera.6-8,22,23,27,28 They are saprophytic ubiquitous fungi occurring in soil, air, bread molds, decaying or rotten fruits and vegetables, and dung.12,23,26 R. Oryzae have an active ketone reductase system and thrive in high glucose and acidotic conditions. These conditions decrease phagocytic activity of the host because of the resulting impaired gluthione pathway.20 They are primarily opportunists and require some breakdown in immune system defenses to cause infections in humans. Once an infection is established, it spreads readily due to their angioinvasive nature and their ability to grow at or above core body temperature.29 Most infections occur secondary to the inhalation of spores into the sinuses and lungs. Infections caused by R. Oryzae typically involve the rhinocerebral and pulmonary sites.29 Other, less common ways of transportation are by ingestion, direct contact via injured skin (burns), trauma with infected soil, and intravenous (IV) drug users.8,20,30 After the spore gets inhaled into the nasal cavity it travels into the paranasal sinuses, spreads inferiorly to the palate, posteriorly to the sphenoid, and laterally to the cavernous sinus which can invade the orbits and cranial cavity.12,14,31
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Table III Summary of ophthalmic signs and symptoms. Clinical Ophthalmic Signs and Symptoms Ophthalmoplegia Proptosis Vision loss/decrease Chemosis Periorbital edema Ocular/Periorbital pain Afferent pupillary defect Trigeminal anesthesia (V1) CRAO Orbital cellulitis Eyelid necrosis Corneal anesthesia Cavernous sinus thrombus Periorbital necrosis Corneal edema/clouding Orbital abscess Endophthalmitis Diplopia
Camara-Lemarroy (n=14) 2014 7% 21.4% 21.4% 28.6%
Bhansali (n=35) 2004
Talmi (n=19) 2002
Yohai (n=80) 1994
Blitzer (n=179) 1980
89% 83% 80% 74% 66% 43%
74% 68% 68% 79% 74%
40%-67% 64% 65% 24% 43% 19% 38% 26% 16% 20%
30% 26% 20%
20% 14%
6%
Mucormycosis have an affinity for blood vessel walls and spread along vascular and neuronal structures. In doing so it infiltrates the walls of blood vessels and may cause cavernous sinus and internal carotid artery thrombosis which can result in soft-tissue infarction. It can also erode the bony walls of the ethmoid sinus which results in the infection progressing into the orbit and brain.31,32 As the infection progresses into the cavernous sinus it clinically manifests as ophthalmoplegia, a loss of consciousness, and neurological signs. Spread from the cavernous sinus or internal carotid may lead to distant cerebral infarction and/or abscess, usually ipsilateral to the initial disease. Bony destruction is relatively uncommon, but can occur.13,18,26,33 Role of iron Iron is an essential growth factor for Mucormycosis which obtains iron from the host by secreting siderophores. Siderophores are low-molecular weight iron chelators that bind iron to be used by the fungi for cell growth and development. Transferrin is a plasma protein which binds serum iron, thus not allowing the fungi to invade and proliferate its host.3,26,34 The impact of iron metabolism on the growth and pathogenicity of R. Oryzae is linked to diabetes mellitus, particularly with ketoacidosis due to the acidosis state preventing the normal fungistatic action of serum toward R. Oryzae.35 In an acidic pH, like in ketoacidosis, transferrin has a decreased affinity to bind iron which allows more iron to be available and utilized by the fungus3,7,30
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14% 13% 11% 6% 6% 1% 4%
>1%
Deferoxamine Deferoxamine is a naturally occurring siderophore and is used by R. Oryzae to facilitate fungal growth.3,26,30 Deferoxamine strips ferric iron from transferrin and attaches itself on the mold through an inducible receptor. There have been many studies that have demonstrated deferoxamine’s role as a siderophore to R. Oryzae.35-38 De Locht et al found that R. Oryzae efficiently used deferoxamine as an iron source in iron overloaded and dialysis patients which increases the risk of mucormycosis in deferoxamine treated patients.36 Boelaert et al demonstrated that human serum inhibits growth of R. Oryzae. This is reversed in an acidosis state. Deferoxamine acts as a siderophore allowing significant iron uptake by R. Oryzae. In vitro studies of radiolabeled iron uptake from deferoxamine in serum showed that R. Oryzae is able to incorporate 8-fold and 40-fold more iron than can Aspergillus fumigatus and C. albicans (respectively).35,37 Modern iron chelators like deferiprone and deferasirox do not have the same siderophore activity for R. Oryzae.3 Angioinvasion Angioinvasion with thrombosis and tissue necrosis is a characteristic pathophysiological feature of mucormycosis.21,29 It is thought to account for their ability to rapidly spread and invade tissues.30 Mucormycosis hyphae invade blood vessels and form endovascular thrombi causing tissue necrosis. Necrotic tissue provides fertile
Table IV Differential diagnosis of rhino-orbital mucormycosis.13,17,27,31,70,71 Condition
Diagnostic Test
Wegener’s granulomatosis
Chest X-ray, PFTs, tissue biopsy for granulomatous lesions, lab work (ANCA serology, CBC, urinalysis, ESR, RF, C-reactive protein) Mainly clinical diagnosis, CT scan of sinus and tissue culture of sinus contents PRN Thyroid function tests (T3, T4, TSH), MRI of orbit (ideally T2-weighted images) Lab work (CMC with differential, blood cultures), CT or MRI of brain and orbit Mainly clinical diagnosis, (+)headaches, ophthalmoplegia, diplopia, fever, tachycardia, MRI/CT (if no MRI available), CBC, cerebral angiography PRN Mainly clinical diagnosis, positive culture from aqueous or vitreous, blood culture PRN Mainly clinical diagnosis and case history
Bacterial sinusitis Grave’s ophthalmopathy Bacterial orbital cellulitis Cavernous sinus thrombosis Bacterial endophthalmitis Preseptal cellulitis
media for fungal growth.21 It can also prevent delivery of leukocytes and antifungal agents to the site of infection. Angioinvasion likely contributes to the capacity of the organism to hematogenously disseminate to other neighbouring areas.28 Host defenses Macrophages and neutrophils are the main host defenses against the invasion of mucormycosis.7,39 Prolonged corticosteroid therapy and diabetes affect circulating neutrophils by impairing their ability to mobilize and migrate to the site of inflammation and their phagocyte function which increases susceptibility to infections. Normally, the metabolic activity of R. Oryzae hyphae is suppressed by the host defenses, but this effect is negated by severe ketoacidosis. An acidic and hyperglycemic environment mediate the invasion and damage to the host and provide a good environment for the fungus to grow.3,14,21,23,30,40,41 Diabetic ketoacidosis patients have elevated levels of free iron in their blood stream which supports growth of R. Oryzae at an acidic pH (7.3-6.88), but not at an alkaline pH (7.78-8.38). Artis et al demonstrated that acidosis temporarily disrupts the capacity of transferrin to bind to iron in acidic environments and suggested this alteration abolishes an important host defense mechanism that permits the growth and proliferation of R. Oryzae.42 Risk Factors The major risk factors for mucormycosis are uncontrolled diabetes with or without ketoacidosis, deferoxamine therapy in patients receiving hemodialysis, prolonged and severe neutropenia, malignancy, chronic renal failure, organ or hematopoietic stem cell transplant, prolonged use of corticosteroids, IV drug use, and major trauma patients 3,20,27,28,43,44 Of the risk factors, uncontrolled diabetes is reported to be the top underlying disease in rhinoorbital mucormycosis specifically (60% to 88.2%) and in all types of mucormycosis (36%).8,17,22,45 Independent predictors of sinus mucormycosis are diabetes and injection
drug use.8 The rise in the number of patients with mucormycosis may be correlated with an increasing population of diabetics in developing and tropical countries. Uncontrolled diabetes which can result in ketoacidosis is predisposes people to infection as low serum pH diminishes the phagocytic effect of macrophages and chemotactic and oxidative burst of neutrophils.7 Differential Diagnoses There are a number of different conditions that present with similar clinical signs and symptoms of rhino-orbital mucormycosis. They can be differentiated by imaging, lab work, and associated findings both ocular and systemic. A summary of differential diagnosis is found in Table IV. Management Successful treatment and management of mucormycosis require four steps: first, early diagnosis; second, reversal of any underlying predisposing risk factors; third, aggressive surgical debridement when possible; and fourth, prompt antifungal therapy.9,15,30,32,43 Early diagnosis In a review by Yohai et al, survival rates declined if treatment was not initiated within six days from the time of initial presentation. In non-diabetics, there were no survivors after 12 days of the disease without treatment.17 These findings are supported by a more recent retrospective study which found that delaying amphotericin B-based therapy among patients with mucormycosis for 6 days or more after the onset of symptoms resulted in a two fold increase in mortality rate and a <20% survival rate at 12 weeks after diagnosis. This effect of delayed treatment was more evident in multivariate analysis and was independent of all other risk factors.46 Thus, early diagnosis is essential to minimize mortality rates. There is currently no specific skin, blood, or serologic polymerase chain reaction (PCR) — based test for the diagnosis of mucormycosis so diagnosis is based on biopsy of infected tissues. Proven mucormycosis is based on the revised definitions of invasive fungal disease found in the
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European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG). A proven case is defined as a histopathologic, cytopathologic, or direct microscopic examination of the specimen obtained by needle aspiration or biopsy revealing broad-based, aseptate, ribbon-like hyphae consistent with Mucorales with evidence of associated tissue damage.9,23,26,44,47-49 Radiographic findings are generally inconclusive and not specific. Magnetic resonance imaging (MRI) is typically more sensitive than computed tomography (CT) scans for detecting orbital and central nervous system involvement. Both of these can be normal or present with subtle findings initially. The most common finding on CT scans of the head or sinuses is subtle sinus mucosal thickening or thickening of the extraocular muscles.12,13,17,21,27 Reversal of any underlying risk factors Chamilos et al found that reversing any underlying predisposing factors (as listed in the risk factor section) and neutrophil recovery was associated with improved survival rates.46 Spellberg et al, reiterates this point by emphasizing that correcting or controlling predisposing host conditions is vital for improving the prognosis. They noted deferoxamine treatments and immunosuppressive medications, particularly corticosteroids, should be minimized or discontinued, if possible. Aggressive management in diabetic ketoacidosis patients to promptly restore euglycemia and normal acid base status is just as vital as treating the mucormycosis.9,50,51 Surgical debridement Angioinvasion resulting in blood vessel thrombosis and tissue necrosis results in poor penetration of antifungal therapies to infected tissues. Even if the causative organism is susceptible to the treating antifungal agent in vitro, the antifungal maybe ineffective in vivo. Therefore, surgical debridement of all necrotic tissues, when possible, will allow systemic medications to penetrate and be more effective.13,21,52 Ideally, the infected tissue should be removed until normal bleeding is encountered.17 There has not been a study that defined the extent and timing of surgical debridement necessary to maximize outcomes of mucormycosis.52 Surgical debridement and resection appears to increase survival (78% survived in debrided patients vs. 57.5% in non-debrided patients). Combined amphotericin B and radical surgery further improved survival especially in diabetics by 89%.53 This is further supported by Roden et al, which showed that 64% of patients treated with an antifungal alone survived, 57% of patients treated with surgery alone survived, while 70% of patients who were treated with both an antifungal and surgery survived.8 It is clear that surgical debridement in combination with appropriate antifungal therapy increases favorable prognosis.
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In rhino-orbital-cerebral mucormycosis, aggressive sinus and palatal disease debridement should be performed wherever possible. This helps reduce the infection load within the sinuses and provides tissues for histopathological diagnosis. Exenteration should only be performed in advanced involvement of the orbit and generally should be considered for an actively infected orbit with a blind, immobile eye. Bhansali et al showed extensive orbital involvement by Mucorales required orbital exenteration in 42% of patients and of those patients 82% survived.22 Surgical debridement earlier in the disease progression has shown higher cure rates (91%).26,45 Chakrabarti et al found that a combination of debridement surgery and amphotericin B therapy yielded significantly better survival rates compared to treatment with amphotericin B alone (79.6% vs. 51.7% survival, respectively).7 This emphasizes once again how important early diagnosis in combination of surgical debridement and treatment is. Antifungal Therapy Polyenes It is well established that the primary antifungal treatment of choice is a polyene, whether its amphotericin B or its lipid formulation. Amphotericin B is a polyene antimicrobial that acts by binding to ergosterol in the fungal cell membrane which results in altering the membrane permeability. It is the only FDA approved antifungal agent for primary therapy of mucormycosis. It is highly protein bound and poorly dialyzable. Therefore, it is important to regularly test creatinine clearance and blood urea nitrogen (BUN) levels to monitor for toxicity. If the serum creatinine exceeds 3.0 mg/100 mL or the BUN levels exceed 40 mg/100 mL, decreasing dosage is recommended. Starting doses of 1 mg/kg/day. Amphotericin B improves the survival rate in diabetics (79% in amphotericin B treatment, versus 37% non-amphotericin B).10,20,52,53 However, it is shown to not be an effective treatment in some cases, particularly in late stage or disseminated disease.29 Liposomal amphotericin B is less nephrotoxic compared to amphotericin B. This allows higher doses to be safely administered in greater concentration and circulation time in infected tissues with increased capillary permeability compared to amphotericin B.10,21,44 The lethal dose of lipid based amphotericin B is approximately 10 to 50 times higher than amphotericin B.54 Lipid formulations may enable better solubility into the central nervous system and are currently the preferred first-line treatment for mucormycosis with a preference for liposomal amphotericin.50 The recommended dosage is 5 mg/kg/day.10,26 It is FDA approved for treatment of invasive fungal infections in patients who are refractory to or intolerant of conventional amphotericin B therapy. Walsh et al investigated the efficacy and safety of lipid based amphotericin B and
found that 71% of patients demonstrated stable and 21% demonstrated improved serum creatinine by end of therapy and 71% of patients with mucormycosis had a complete or partial response. This study demonstrated a significant improvement in renal function following the initiation of therapy with amphotericin B lipid complex, particularly in patients with amphotericin B-induced nephrotoxicity or primary renal dysfunction.55 A more recent study by Spellberg et al found similar results with high treatment and survival rates in patients treated with liposomal amphotericin B.47 Azoles Azoles work by altering the fungal cell membrane by inhibiting ergosterol synthesis which results in either fungal cell death or inhibition of cell growth. The currently available triazoles are fluconazole, intraconazole, voriconazole, and posaconazole.50,56,57 In a study examining the in vitro activities of four triazoles and amphotericin B against 37 clinical isolates of mucormycosis (including Mucor spp. and Rhizopus), they found that overall, the isolates were generally susceptible to posaconazole, itraconazole, and amphotericin B. Of the azoles, posaconazole was the most potent and was shown to have good in vitro activity against mucormycosis. Its minimal inhibitory contribution was about 1.6-fold lower than itraconazole, 33-fold lower than voriconazole, and 47-fold lower than fluconazole. Though it was not as effective as amphotericin B, it has potential to be used to treat mucormycosis.58 Itâ&#x20AC;&#x2122;s standard dose is typically 400 mg given twice daily orally and is highly lipophilic, orally absorbed, and extensively distributed in tissues.10,51 Previous studies have examined the efficacy of posaconazole in patients who were refractory or intolerant to the standard treatment of amphotericin B and showed that it had 60% to 82.2% survival following treatment with posaconazole.57,59 Overall, posaconazole should be considered as salvage therapy. Echinocandins Caspofungin, a member of the echinocandin antifungal class, has no activity against mucormycosis in standard in vitro susceptibility tests.50,60 However, Reed et al. demonstrated that in combination therapy (polyene with caspofungin), the overall success rate in patients with rhino-orbital mucormycosis with CNS disease at 30 days hospital discharge was 100% vs 45% among polyene monotherapy.60 The typical standard intravenous dose is 100 mg daily.10 Iron chelation therapy Deferasirox is FDA approved for the treatment of chronic iron overload.61 Considering that there is a link between iron availability and mucormycosis, Ibrahim et al explored the potential for deferasirox as a possible treatment option. They found that deferasirox was
fungicidal by 24 hours for clinical isolates of mucorales in vitro and that deferasiroxâ&#x20AC;&#x2122;s cidality was time dependent rather than concentration dependent. In diabetic ketoacidosis mice with disseminated mucormycosis, deferasirox was as effective as liposomal amphotericin B (LAmB) therapy. Additionally, combination deferasirox/LAmB therapy synergistically improved survival (80% survival for combination vs 40% monotherapy vs 0% placebo).62 This study is contrasted by Spellberg et al which demonstrated that when deferasirox was added to LAmB in a small (n=20) double blind, prospective, placebo-controlled study, the combination treatment group (deferasirox with LAmB) had a higher mortality rate than the LAmB only group (82% vs 22%) at 90 days. There were more active malignancies, neutropenia, and corticosteroid therapy patients in the combination group, along with less diabetics which could account for the higher mortality.47 Adjunctive therapies including hyperbaric oxygen Several case reports and studies have shown that adjunctive hyperbaric oxygen improved the overall survival rate, ranging from 83% to 100%.17,25,27,63,64 Hyperbaric oxygen treats the lactic acidosis which promotes oxidative action of amphotericin B. It contributes to tissue healing by several mechanisms. It enhances leukocyte-mediated phagocytosis, it significantly elevates tissue oxygen levels which increases the rate of tissue healing, and it significantly elevates the levels of growth factors, which promotes angiogenesis and healing.64,65 The hyperbaric oxygen exerts a fungistatic effect.26 This is demonstrated in experimental studies using 100% hyperbaric oxygen at 1-3 atmospheres.66 There is no clear guideline in terms of how long the duration of therapy should be as the optimal duration of treatment has not been studied prospectively and is generally unknown. However, it is recommended that treatment should be continued until the clinical signs and symptoms are resolved, there is resolution or stabilization of residual radiographic signs of disease on serial imaging, and underlying immunosuppression is reversed. This is determined on a case by case basis.52,63,67,68 Whether hyperbaric oxygen itself has a significant effect on prognosis has not been established by clinical trials due to the rarity of this condition. Prognosis The mortality rate depends on the underlying disease, the infection site, and how advanced the condition is.43 If the fungus penetrates the CNS or enters the major intracranial vasculature, mortality is substantially increased.9 The lowest survival rates were associated with periorbital necrosis (33%) and cavernous sinus thrombosis (40%). There is no significant decrease in survival with increased number of sinuses involved.17 Prognosis is significantly improved with amphotericin B treatment (either as monotherapy or in combination with posaconazole) or
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with posaconazole and other antifungals (in combination or sequentially). Surgical treatment decreased the risk of death by 79%.6,8 Roden et al found that overall mortality was 54%, mortality from rhino-orbital mucormycosis was 25%, and once there was cerebral involvement, mortality from rhinocerebral was 62%. They noted that mortality had improved from 84% in the 1950s to 47% in the 1990s and mortality had been overall stable since the introduction of amphotericin B in the 1960s.8 Complications This infection is rapidly progressive and results in death unless underlying risk factors are reversed (if possible) and aggressive treatment with antifungal agents and surgical excision is promptly initiated.12 Adverse reactions to treatments is something that must be monitored. There are several adverse reactions to amphotericin B, but the most significant is nephrotoxicity (serum creatinine level of greater than or equal to 2.5 mg/dL in adults). Nephrotoxicity may occur in up to 80% of patients and prevents administration of maximally effective therapy. Renal function must be closely monitored by measurement of serum creatinine, blood urea nitrogen, serum magnesium, serum sodium, and serum potassium levels.20,55,69 Posaconazole also has adverse effects which include fever, nausea, vomiting, diarrhea, abdominal pain, dry mouth, headache and fatigue.56 Rare adverse effects of hyperbaric oxygen are spontaneous pneumothorax, seizures from oxygen toxicity, and difficulty equalizing middle ear pressure.66
CONCLUSION In conclusion, mucormycosis remains a severe infectious disease with poor prognosis if diagnosis and treatment is delayed. With the increasing incidence of diabetics and their risk for rhino-orbital mucormycosis, especially if uncontrolled, it is vital that eye care providers are aware of this condition as diagnosis can often be difficult. Prompt and appropriate referrals are of the essence as early diagnosis, reversal of any underlying predisposing risk factors, aggressive surgical debridement when possible and prompt antifungal therapy will increase the prognosis for these patients. â??
6.
7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
21. 22. 23. 24. 25.
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31. Haliloglu NU Yesilirmak Z, Erden A, Erden I. Rhino-orbitalcerebral mucormycosis: report of two cases and review of the literature. Dentomaxillofac Radiol 2008; 37; 161-166. 32. Mathebula SD. Rhino-orbital mucormycosis. South African Optometrist 2006; 65(2): 78-81. 33. Orguc S, Yuceturk aV, Demir MA, Goktan C. Rhinocerebral mucormycosis: perineural spread via the trigeminal nerve. J Clinical Neurosci 2005; 12(4): 484-486. 34. Howard DH. Acquisition, transport, and storage of iron by pathogenic fungi. Clin Microbiol Rev 1999; 12: 394-404. 35. Boelaert JR, Fenves AZ, Coburn JW. Deferoxamine Therapy and mucormycosis in dialysis patients: report of an international registry. Am J Kidney Dis 1991: 660-667. 36. De Locht M, Boelaert JR, Schneider YJ. Iron uptake from ferrioxamine and from ferrirhizoferrin by germinating spores of Rhizopus microspores. Biochem Pharmacol 1994; 47: 1843-1850. 37. Boelaert JR, De Locht M, Van Cutsem J, et al. Mucormycosis during deferoxamine therapy is a sideophore-mediated infection: in vitro and in vivo animal studies. J Clin Invest 1993; 91: 1979-1986. 38. Abe F, Inaba H, Katoh T, Hotchi M. Effects of iron and desferrioxamine on Rhizopus infection. Mycopathologia 1990: 87-91. 39. Diamond RD, Haudenschild CC, Erickson NF III. Monocytemediated damage to Rhizopus oryzae hyphae in vitro. Infection and Immunity 1982; 38: 292-297. 40. Chinn RY, Diamond RD. Generation of chemotatic factos by Rhizopus oryzae in the presence and absence of serum: relationship to hyphal damage mediated by human neutro-phils and effects of hyperglycemia and ketoacidosis. Infect Immun 1982; 38: 1123-1129. 41. Diamond RD, et al. Damage to hyphal forms of fungi by human leukocytes in vitro: a possible host defense mechanism in aspergillosis and mucormycosis. Am J Pathol 1978; 91: 313-328. 42. Artis WM, et al. A mechanism of susceptibility to mucormycosis in diabetic ketoacidosis: transferrin and iron availability. Diabetes 1982; 31: 1109-1114. 43. Hong HL, et al. Risk factors for mortality in patients with invasive mucormycosis. Infect Chemother 2013; 45(3): 292-298. 44. Badiee P, Jafarpour Z, et al. Orbital Mucormycosis in an immunocompetent individual. Iran J Microbiol 2012; 4: 210-214. 45. Nithyanandam S, Jacob MS, Battu RR, Thomas RK, Correa MA, D'Souza O. Rhino-orbito-cerebral mucormycosis. A retrospective analysis of clinical features and treatment outcomes. Indian J Ophthalmol 2003; 51: 231-236. 46. Chamilos G, et al. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis 2008; 47: 503-509. 47. Spellberg B, et al. The deferasirox-AmBisome therapy for mucormycosis (DEFEAT Mucor) study: a randomized, doubleblinded, placebo-controlled trial. J Antimicrob Chemother 2012; 67: 715-722. 48. De Pauw B, et al. Fungal infections cooperative group and the national institute of allergy and infectious disease mycoses study group (EORTC/MSG) consensus group. Clin Infect Dis 2008; 46(12): 1813-1821. 49. Bhansali A, et al. Presentation and outcome of rhino-orbitalcerebral mucormycosis in patients with diabetes. Postgrad Med J 2004; 80: 670-674. 50. Spellberg B, Ibrahim AS. Recent advances in the treatment of mucormycosis. Curr Infect Dis Rep 2010; 12: 423-429.
51. Greenberg RN, et al. Zygomycosis (mucormycosis): emerging clinical importance and new treatments. Curr Opin Infect Dis 2004; 17:517-525. 52. Spellberg B, et al. Recent advantages in the management of mucormycosis: from bench to beside. Clin Infect Dis 2009; 48: 1743-1751. 53. Blitzer A, Lawson M, Meyers BR, Biller HF. Patient Survival factors in paranasal sinus Mucormycosis. Laryngoscope 1980; 90: 635-648. 54. Lister J. Amphotericin B lipid complex (Abelcet) in the treatment of invasive mycosis. The North American Experience. Eur J Hematol 1996; 57: 18-23. 55. Walsh TJ, et al. Amphotericin B Lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases. Clin Infect Dis 1998; 26: 1383-1396. 56. Chang M, et al. Posaconazole (Noxafil), an extended spectrum oral triazole antifungal agent. Drug Forecast 2008; 33(7): 391-426. 57. Greenberg RN, Mullane K, van Burik JA, et al. Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother 2006; 126-133. 58. Sun QN, Fothergill AW, McCarthy DI, et al. In vitro activities of posaconazole, itraconazole, voriconazole, amphotericin B., and fluconazole against 37 clinical isolates of zygomycetes. Antimicrob Agents Chemother 2002; 46: 1581-1582. 59. Van Burik JAH, et al. Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases. Clin Infect Dis 2006; 42: 61-66. 60. Reed C, Bryant R, Ibrahim AS, et al. Combination polyenecaspofungin treatment of rhino-orbital-cerebral mucormycosis. Clin Infect Dis 2008; 47: 364-371. 61. Cappellini MD. Iron-chelating therapy with the new oral agent ICL 670 (Exjade). Best Practice Residency Clinical Haematology 2005; 18: 289-298. 62. Ibrahim AS, Gebermariam T, Fu Y, et al. The iron chelator deferasirox protects mice from mucormycosis through iron starvation. J Clin Invest 2007; 117: 2649-2657. 63. Imbernon A, Aqud JL, Cuetara MS, et al. Successful therapy of progressive rhino-orbital mucormycosis caused by Rhizopus arrhizus with combined and sequential antifungal therapy, surgery and hyperbaric therapy. Med Mycol Case Rep 2014; 51-54. 64. Siddiqui A, Davidson JD, Mustoe TA. Ischemic tissue oxygen capacitance after hyperbaric oxygen therapy: a new physiologic concept. Plast Reconstr Surg 1997; 99: 148-155. 65. John BV, Chamilos G, Kontoyiannis DP. Hyperbaric oxygen as an adjunctive treatment for zygomycosis. Clin Microbiol Infect 2005; 11: 515-517. 66. Ferguson BJ, Mitchell TG, Moon R, et al. Adjunctive hyperbaric oxygen for treatment of rhinocerebral mucormycois. Rev Infect Dis 1998; 10: 551-559. 67. Cornely OA, Arikan-Akdagli S, Dannaoui E, et al. ESCMID and ECMM join clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect 2014; 20(suppl 3): 5-26. 68. Weng DE, Wilson WH, Little R, Walsh TJ. Successful medical management of isolated renal zygomycosis: case report and review. Clin Infect Dis 1998; 26: 601-605. 69. Gallis HA, Drew RH, Pickard WW. Amphotericin B: 30 years of clinical experience. Rev Infect Dis 1990; 12: 308-329. 70. Hu WT, et al. MRI findings of rapidly progressive ophthalmoplegia and blindness in mucormycosis. Teaching Neuroimage 2006; 40. 71. Bhadada S. et al. Bilateral proptosis, ptosis, and vision loss: grave but not graves. Endocrinologist 2006; 16: 7-9.
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QUESTIONNAIRE Rhino-Orbital Mucormycosis Melissa Ngo, OD; Pauline F. Ilsen, OD, FAAO 1. ❑ ❑ ❑ ❑
All of the following statements about the annual incidence of mucormycosis are false, EXCEPT: It has remained relatively stable over the past 10 years It has tripled over the past 15 years It has doubled since 1999 It has almost doubled in a decade
2. ❑ ❑ ❑ ❑
The annual incidence of diabetic ketoacidosis has increased by _______ %. 100 200 300 400
3. ❑ ❑ ❑ ❑
In the Case Report presented, what was the patient’s intraocular pressure? 15 mmHg OD and 14 mmHg OS 14 mmHg OD and 15 mmHg OS 16 mmHg OD and 18 mmHg OS 21 mmHgOD and 23 mmHgOS
Clinical and Refractive Optometry 27:5, 2016
COPE-APPROVED CE CREDIT APPLICATION FORM
As found in an autopsy series, what was the prevalence of mucormycosis? 1 in 5 cases per 10,000 autopsies 2 in 7 cases per 10,000 autopsies 3 in 8 cases per 10,000 autopsies 4 in 10 cases per 10,000 autopsies
5. ❑ ❑ ❑ ❑
According to Roden et al, which of the following is the most common presentation of mucormycosis? Gastrointestinal Cerebral Sinus infections Cutaneous
6. ❑ ❑ ❑ ❑
All of the following statements about mucormycosis are true, EXCEPT: The clinical presentation is tissue necrosis The prognosis is good with early diagnosis and treatment The infection progresses rapidly The presence of black eschar is sometimes noted
7. ❑ ❑ ❑ ❑
All of the following are non-ophthalmic signs and symptoms of mucormycosis, EXCEPT: Facial palsy/numbness Fatigue Toothache Headaches
8. ❑ ❑ ❑ ❑
Rhizopus oryzae accounts for what percentage of cases of mucormycosis? 35% to 70% 42% to 75% 47% to 90% 51% to 92%
9. ❑ ❑ ❑ ❑
Hemiplegia or stroke occurs in what percentage of rhino-orbital mucormycosis? 20% 25% 30% 35%
10. ❑ ❑ ❑ ❑
All of the following are risk factors for mucormycosis, EXCEPT: Chronic renal failure Stem cell transplant Alcohol abuse IV drug use
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4. ❑ ❑ ❑ ❑
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Clinical & Refractive Optometry is pleased to present this continuing education (CE) article in the form of a Meeting Report based on a presentation given by Dr. Bernard Hurley entitled AREDS2 Controversies and Facts: Delving Deeper into our Knowledge on Eye Health in Toronto, ON on May 15, 2016. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 188 for complete instructions.
AREDS2 Controversies and Facts: Delving Deeper into our Knowledge on Eye Health Bernard Hurley, MD
INTRODUCTION Dr. Hurley described the objectives of his presentation: To recognize the impact age-related macular degeneration (AMD) has on Canadians; identify the risk factors associated with AMD; discuss the impact and limitations of the AREDS and AREDS2 studies; recognize the role of ocular vitamin supplementation in the management of patients; understand the status and limitations of pharmacogenetic testing today; and, finally, apply some of these to patients in everyday practice.
IMPACT OF AREDS2 ON AGE-RELATED MACULAR DEGENERATION He began by discussing the scope and effects of macular degeneration, a neurodegenerative condition at the center of the retina. It takes away patients ability to read, to recognize and see their family, to drive, and to live an independent lifestyle; and it's a disease that has a huge impact on society. Ophthalmologists are seeing an overwhelming number of older patients; because of the genetic makeup of the patient population, AMD is a very common condition in Canada that is having huge impacts. Thankfully now, there are treatments available. Beyond the impact on the patient themselves, however, this condition has a huge impact on the families as well. Dr. Hurley mentioned that he sees this frequently in his clinic. Patients coming in month after month to get their treatments for wet macular degeneration, which involves family having to take time off work and find time to drive mom or dad there. People are losing their independence. I have many patients who come in, they've been the driver for their spouse for many years and now they're not able to B. Hurley — Assistant Professor, Department of Ophthalmology and Residency Program Director, University of Ottawa Eye Institute, Ottawa, ON Correspondence to: Dr. Bernard Hurley, University of Ottawa Eye Institute The Ottawa Hospital, General Campus, 501 Smyth Road, Box 307 Ottawa, Ontario K1H 8L6; E-mail: bhurley@toh.ca This article has been peer-reviewed.
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drive; their spouse is so dependent on them to get them from place to place and now they're both dependent on other family members. So it greatly affects family dynamics. It has a huge impact on other conditions, as well. Depression is becoming much more common, in addition to falls and hip fractures; and people who lose their vision don’t live as long as those who see well. There are several studies on this. Dr. Hurley mentioned his colleague in Ottawa, Ralph Buhrmann, who had studied the impact of visual acuity on life expectancy. There are over a million people in Canada with macular degeneration today. More Canadians now live with AMD than breast cancer, prostate cancer, Parkinson's disease, and Alzheimer's disease combined.
RISK FACTORS Naturally, the most significant risk factor for AMD is age and that can’t be changed. Nor can other risk factors such as family history and ethnicity. There are however, a few things that can be controlled. Smoking and risk factors for cardiovascular disease are, in fact, more important than any vitamins or pills, or extra things patients can do. Getting a patient to stop smoking, can have more of an effect on their risk of macular degeneration than anything else. Dr. Hurley stated that advising patients to stop smoking should be part of ophthalmologists’ clinical interactions (not just to help their AMD but to improve overall health as well). Other risk factors are blood pressure control, healthy diet and staying physically active. All of these have been shown to be very helpful for macular degenerations and, of course, the patient's overall health. Often patients want a pill or medication to help them with their disease, but the basic principle is that keeping the patient healthy keeps their eyes healthy.
STAGES OF MACULAR DEGENERATION The stages of macular degeneration are important. The AREDS studies set up categories 1 through 4 (Fig. 1). In category 1, there are just a few small drusen. In category 2, there are what they call some intermediate size drusens, between 63 and 124 microns. People always ask how they arrived at the number of 124 microns to define the size of a large versus an intermediate drusen, and it actually
Stages of AMD: AREDS Categories • AREDS Category 1 (No DMLA) Fewer than 5 small (<63 µm) drusen • AREDS Category 2 (Early DMLA) Multiple small drusen or some intermediate size (63-124 µm) drusen in 1 or both eyes
Category 1
• AREDS Category 3 (Intermediate DMLA) Extensive intermediate sized drusen in both eyes, more than one large (>125 µm) druse, or geographic atrophy that did not involve the center of the macula
at baseline. Dr. Hurley noted that this is important and is often lost on people because they think that studies have shown that supplements will help everybody with AMD; however, they do not. The studies have only shown vitamin supplementation help people who progress at a more rapid rate, in category 3 or 4 on the AREDS rating scale. If a patient had either the large soft drusen or had already lost vision in one eye, the chances of progressing to further vision loss were much greater. Those are the people that had a sufficient rate of progression that a treatment effect was shown in the AREDS studies. This is a very important point.
Category 2
FINANCIAL BURDEN OF AMD
Category 3
• AREDS Category 4 (Advanced DMLA) Central geograpgic atrophy or neovascularization causing vision loss in one eye Category 4
Fig. 1 AREDS staging of AMD.
makes sense. The width of the retinal vessels as they cross the optic nerve shows what 125 microns look at in the eye. To understand how big a drusen is, compare it to the size of the blood vessels and that helps differentiate the large versus the intermediate drusen. Category 3 signifies intermediate AMD and category 4, advanced AMD; category 3 has the larger drusen and in category 4, the patient has already suffered vision loss in one of their eyes. They will have either central geographic atrophy or a choroidal neovascular membrane that's already reduced the vision in one of their two eyes. Dr. Hurley explained that these categories are important because they serve to define the rate at which patient’s AMD will progress. In category 1 or category 2, with very minor changes in the back of the eye, the chances that the patient will progress over 5, 7 or 10 years is extremely low. Those patients are very safe; practitioners can encourage them, explain that they have perhaps a couple of drusen, a couple of gray spots in the back of their eyes, but their probability of losing vision to macular degeneration is extremely low. It’s so low, in fact, that studies couldn't show any treatment effect for patients in these categories who have low likelihood of progression
Vision loss secondary to AMD represents a huge cost in Canada. There's the cost of optometrist and ophthalmology visits, the direct health care costs, all of the related injections, the cost of the medications, the emergency visits all of which amount to an enormous expense. However, there are indirect costs beyond this. These include the loss in productivity, the fact family and friends have to be taken out of their jobs to accompany patients, the transportation to get people to their appointments once they suffer vision loss. Dr. Hurley expressed his enthusiasm that there are, in fact, ways to save money, as described in the optometry white paper that was published in Ontario. It’s a pivotal document providing evidence that there are significant savings – up to $13 million – that can be realized if people are started on ocular vitamins. The paper also proposed a lot of other ways to save money in eye care and Dr. Hurley highlighted that he is a big proponent of reducing cost. The document stipulates that when people have eye problems they should see their optometrist instead of going to the emergency room, along with many other ways of achieving savings that can be realized in macular degeneration.
AREDS TRIALS Regarding the AREDS1 and AREDS2 trials, the first AREDS trial was being done just as Dr. Hurley entered his professional training in ophthalmology. It was of course a landmark study, a huge effort put forth by major funding organizations in the U.S. With the original AREDS trial, at the time, people thought that practitioners could supplement patients with vitamins, specifically, antioxidants and other components that would help break down oxygen free radicals within the eye. That was being proposed, but there were a lot of people with strong resistance against it. Several of the authors of the original AREDS study really felt that there was no proof these supplements were doing anything and that practitioners could be wasting patients’ money. Some who participated thought that the hypothesis of the benefits of vitamins
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Original AREDS AMD Randomization Placebo N=903
Participants received:
Antioxidant N=945
Randomized AMD Participants (Category 2, 3, 4 AMD) N=3640
Vitamin C (500 mg) Vitamin E (400 IU) Beta carotene (15 mg)
Participants received:
Zinc N=904
Zinc oxide (80 mg) Cupric oxide (2 mg)
Antioxidant + Zinc N=888
Mean follow-up = 6.3 years Fig. 2 Neither lutein nor zeaxanthin were readily available for manufacturing in a research (oral) formulation. The original AREDS study included a true placebo group.
would be disproved and that the study would show that taking certain supplements wasnâ&#x20AC;&#x2122;t helpful at all. As is common knowledge, it became quite the opposite. The objective of the trial was to examine if high-dose vitamin C, vitamin E, beta carotene and zinc slow the progression of AMD and AMD-associated vision loss. They knew at that time that the macular keratinoids such as beta carotene and others were important, but at the time of AREDS1, beta carotene was the only one that was really available as a supplement. Lutein and zeaxanthin weren't yet available in the commercial form that could be easily given to patients. So they looked at the antioxidants, vitamins, beta carotene and zinc, and they asked the question: The data suggest that these are beneficial, however, do they actually delay the progression of AMD and vision loss? They randomized nearly 4,000 people into four groups; the placebo group received the water pill, antioxidants, vitamin C, vitamin E and beta carotene; the zinc group â&#x20AC;&#x201C; of course one can't give zinc alone or the person
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will become anemic so copper has to be added to it. Finally, there was the group that received both the antioxidants and the zinc (Fig. 2). The mean follow-up at the time was 6.3 years but, of course, there has been longer data since the initial publications. The take home message from the AREDS trial, for patients who were lucky enough to be randomized to the group that received the zinc and the antioxidants, was that their risk of progression of vision loss was reduced provided they had AREDS category 3 or 4 in macular degeneration. The greatest driving factor was the zinc, so those with the antioxidants did slightly better; those with the zinc did a lot better; the patients with the zinc and the antioxidants were better off still. The number that is always quoted is 25% relative risk reduction in the group that received both the antioxidants and the zinc. That was the key table message; 19% reduced risk for vision loss in those patients, however, the primary take home message is the delayed development by about 25% of advanced AMD.
AREDS2 Study Design Primary Randomization:
Randomized participants
AREDS with Lutein and Zeaxanthin, DHA + EPA, or Both
N=4203; Mean age = 73 years
Lutein and Zeaxanthin 1044
Control 1012
Secondary Randomization
Variations of the AREDS Formula 3036
AREDS with no ß-Carotene with low-dose Zinc, or Both
AREDS 659
DHA and EPA 1068
Lutein/ Zeaxanthin + DHA/EPA 1079
AREDS minus ß-Carotene 863
AREDS + Low Zinc 689
AREDS minus ß-Carotene + Low Zinc 825
Fig. 3 AREDS2 study design comprised 16 groups of subjects.
ROLE OF OMEGA-3 FATTY ACIDS Within that study, said Dr. Hurley, and at the time there was some suggestion that even more than this could be accomplished. The omega-3 fatty acids were really being touted at that time to be beneficial for the eye in terms of dry eye, ocular inflammation, cataract and AMD, as well. So people began to look at it as a nested cohort study within the original AREDS data and there was certainly some strong evidence there that if omega-3 fatty acids were added these patients could be helped. If they were taking in their diet more of the omega-3 fatty acids, their risk of going on to develop choroidal neovascularization or central geographic atrophy was less. The question was: Could the results be even greater if these patients were given the omega-3 fatty acids? This was a cohort study meaning that it wasn't set up to prove a hypothesis; the researchers didn't randomize and
didn't try to control other variables; it was simply looking at the data afterwards. There certainly was a suggestion that it would be beneficial and most people jumped on the bandwagon, including Dr. Hurley. I thought it would be great to give people something else that would help even more. One has to understand the limitations of cohort studies like this. Was it the omega-3 fatty acids that were driving the initial benefit or was it something else? People who ate a lot of fish and took in their omega-3 fatty acids, were they just healthier in general? Were they exercising more? Were they less likely to be doing something that was harmful? Was it not the omega-3 but something else associated that was actually causing the benefit? The researchers went on to set up the AREDS2 trial to look at the effect of the omega-3 fatty acids, but to also look
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at lutein and zeaxanthin because both of them were now commercially available and were proposed to provide more benefit for the eye as well. In addition, there was the issue of beta carotene which is associated with higher risks of lung cancer in smokers. It was considered medically unsound to supplement somebody who was a smoker or a recent ex-smoker with beta carotene because it could increase their risk of lung cancer at the expense of trying to protect their eyes. As a result, they were looking at whether or not they could eliminate that risky component of the original AREDS formula. Zinc was also an issue; in Canada, it was very controversial because of reports that it was causing GI upset, that it was having an effect on the genitourinary tract. The question was whether or not there was too much zinc, and was it making the AREDS supplements less tolerable to patients? Could the amount of zinc therefore be reduced? The researchers wanted to look at all the elements: lutein, zeaxanthin, the omega-3 fatty acids, the effect of eliminating the beta carotene to make the formulation safer, and also, reducing the zinc dose. They hypothesized that if lutein, zeaxanthin and the omega-3 fatty acids could be added, patients would get more bang for their buck and one could further reduce the rate of progression in macular degeneration.
AREDS2 TRIAL Similar to the first AREDS trial, in AREDS2, approximately 4,000 people participated. It was a very well-run study with close follow-up over many years. It was a complicated double randomized design (Fig. 3). The first randomization decided whether or not they would get the lutein and zeaxanthin or the omega-3 fatty acids. Then there was the group that received both, as well as the control group. Dr. Hurley pointed out that at this time, it had already been proven that AREDS1 was overwhelmingly beneficial to the patients so one couldn't withhold the standard of care. Therefore, they all had to get AREDS1 supplements to participate in the study. So everybody got the AREDS1 formulation, therefore, the control group was actually AREDS1 supplements. The second randomization was, which variant of the AREDS1 supplement did a subject receive? All of the groups were secondary randomized. One either got the standard AREDS formulation or the AREDS without the beta carotene; or one got the AREDS with the low zinc; or the AREDS without the beta carotene and the low zinc. This amounted to sixteen different groups of patients within the study. So there was a lot of analysis to be done and the analysis surprised some of the researchers, including Dr. Hurley, because they were really looking for additional benefit being conferred from the omega-3 fatty acids. However, the raw data indicates that the people who were
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given just the omega-3 fatty acids did half a percent worse than those who were getting the original AREDS formulation. So if one added omega-3 fatty acids, lutein and zeaxanthin, there wasn’t as much benefit as with only the lutein and zeaxanthin. It looked like the additional conferred benefit in the second AREDS trial was from the lutein and zeaxanthin. For the group that was lucky enough to be randomized into the group that received the lutein and zeaxanthin, that further reduced their risk by an additional 10%, on top of the benefits from the first AREDS study. The risk reduction was better for those with lower dietary intake of lutein and zeaxanthin. With the lutein and zeaxanthin, without the beta carotene, again, patients did better than if they had all three macular keratinoids. So lutein and zeaxanthin as a replacement for the beta carotene conferred additional benefit, and it was better if patients didn't get the beta carotene at all. There have been some suggestions that one of the limitations of this study is that they took a group of well-nourished, highly motivated, educated people that were interested in staying in a clinical trial for the next ten years and were very concerned about their health. There is debate surrounding the notion that they don't truly represent the general population seen in practitioners’ clinics. They may not be as well-nourished, they may be eating at McDonald's more often than is desirable, they may not be as physically active, and may not be as compliant. As a result, there are suggestions that if a person’s diet is poor, this is even more beneficial. But again, those are just suggestions that have been raised and one can't read into it too much based on the hard fact that the only number that can be quoted is that an additional 10% benefit is conferred if the lutein and zeaxanthin are added. Dr. Hurley related that the researchers were surprised that the omega-3 fatty acids didn't provide the benefit they had been expecting, but he doesn’t tell any of his patients who are taking omega-3 fatty acids to stop them. There was no harm in taking them but they just couldn't say, “You've got to take them now for your wet macular degeneration or for your macular degeneration.” They now could only say, “This doesn't seem to help your macular degeneration but there are other studies that suggest that they're helpful from a neurological standpoint, a cardiovascular standpoint, and with other eye conditions such as inflammation and dry eye.” Practitioners just can't suggest that people take them to specifically address their concern of vision loss due to AMD.
SAFETY PROFILE Dr. Hurley stated that there were no safety concerns raised by either of the AREDS studies. He mentioned that he always highlights the take home message that in the AREDS studies, if a person was lucky enough to be randomized to the group that was actually getting treatment as opposed to the placebo group, their overall mortality was better. People on the AREDS supplements lived longer than their cohorts according to the first and second studies.
VITAMIN AND MINERAL SUPPLEMENTS Regarding beta carotene, Dr. Hurley noted that it can be safely removed from the regimen, ending the controversy revolving around putting people at risk for lung cancer by giving it to them. If it’s replaced with lutein and zeaxanthin, it produces a better outcome. In terms of smoking, with Canada’s current aging population, they came from a generation where smoking was much more common. Sadly, it's starting to become more common again among youth. Based on the AREDS studies that became the standard of care in North America, the new formulation can be used safely regardless of the patient's smoking status. The National Institutes of Health (NIH) came out with the strong recommendation to use AREDS2 supplements and the American Academy of Ophthalmology supported it. Their position papers tell practitioners more about how to manage these patients beyond just vitamin supplements, but evidence level 1 states to use AREDS supplements for intermediate category 3 and advanced category 4 AREDS, so it has the highest level of evidence associated with it. The same information was contained in the Canadian guidelines based on an expert consensus from Canadian practitioners about not only dry but wet macular degeneration, as well. However, regarding the dry form, again, the highest level of evidence supports the use of ocular vitamin supplementation for patients in category 3 or category 4. Dr. Hurley addressed the following question: To whom should vitamins be recommended? The current AREDS2 supplements are vitamin E, vitamin C and copper. Not all AREDS-labelled vitamins follow the AREDS recommendations, this is something to be aware of. There are older supplements, other versions of this on the market today, but if one wants to have the latest evidence, one has to check and ensure that they follow AREDS2. The issue with the zinc was that they wanted to reduce it to see if that would help with some of the side effects and perhaps ensure patient compliance, but the studies didn't show any difference in side effects from 80 mg compared to 25 mg, and didn't show any difference in outcome. It wasn't overly powered so the final result was that since there was no difference, practitioners have to rely on the AREDS1 data. It’s important to recall that zinc drove the overwhelming treatment benefit in AREDS1. According to Dr. Hurley, the key question is: If a practitioner is recommending ocular vitamin supplementation, has the patient been diagnosed with macular degeneration? Dr. Hurley frequently has patients who come to his clinic with their grandmother, grandfather, mother or father who have macular degeneration. An ocular vitamin is suggested, so everybody in the room thinks that it’s a good thing to do, that they should take it, as well. Dr. Hurley underscored that the supplements are of proven benefit only if people have
moderate or advanced AMD, supplements have not be shown to modify progression in early AMD nor have they been shown to halt the onset of AMD An important point to consider, said Dr. Hurley, is do the product’s ingredients match the AREDS formulas? There are still older formulations on the market today that don't follow the AREDS supplementation. Also, consider whether or not the patient has comorbidities. Polypharmacy is a major issue in our society today. Our elderly patients are taking a lot of medicine, and it's difficult and confusing for them. Some of them have advanced cancers; some of them are coming from nursing homes and practitioners have to take the patient in front of them into account. Spend time with that patient to consider what’s best for them. If they’re already terminal, if they're undergoing chemotherapy, the last thing they want is more medicine and more pills, so take that into account with the very sick and elderly patients. Their anticipated life expectancy comes into account when dealing with glaucoma and other medications as well. When dealing with sick and frail people, try to simplify the amount of medication they take. They may have medication fatigue and get confused with how many medicines they’re taking. If more medication is being added, do it with some caution with the very elderly on multiple medications. Get them to talk to their primary care physicians; also, their pharmacist can be extremely helpful in terms of preparing blister packs. Make the overall care of the patient the first consideration. There's talk that some patients have tried one vitamin supplement and they don't like it. Remember that there's more than one supplement available on the market today and sometimes if patients haven't tolerated one, it may be easier for them to take a different pill. In addition, the size of the tablet and other considerations may be important to the patient. Some are easier to take and are easier for the patient to maintain compliance with. There's a suggestion that the soft gels are perceived as the ones that are easier to swallow and easier to take from a patient's standpoint.
PHARMACOGENETIC TESTING HIERARCHY OF EVIDENCE
AND THE
Dr. Hurley posed the question: Can practitioners further refine what they’re giving patients to make it even better for them? This is the area of prognostic and pharmacogenetic testing. There was some excellent research done several years ago showing that the genetic makeup of the patient can predict how they might respond to ocular vitamin supplementation. This was specific to two genes, complement factor H and the age-related macular degeneration sensitivity 2 gene - CFH and ARMS2. Based on the patient's genetic makeup with respect to those two genes, can treatment be improved and tailored to make it more specific to the patient? This concept of pharmacogenetic modification is a big issue in medicine today, most notably in cancers such as ocular cancer and melanoma.
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Table I Pharmacogenetic selection of nutritional supplements. Review of 2013 Awh CC et al Study Results • Over an average of 10.1 years, patients with 1 or 2 CFH risk alleles derived maximum benefit from antioxidants alone (without zinc) • Patients with AMD sensitivity 2 (ARMS2) risk alleles derive maximum benefit from zinc-containing formulations, with a deleterious response to antioxidants • Patients homozygous for CFH and ARMS2 risk alleles derived no benefit from any category of AREDS treatment Conclusion Patients with moderate AMD (category 3 in 1 eye and categories 1–4 in the other eye) could benefit from pharmacogenetic selection of nutritional supplements, potentially leading to improved outcomes through genotype-directed therapy. Awh CC, Lane AM, Hawken S, et al. CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology. 2013; 120: 2317–2323.
The genes are tested to predict the patient's response. It’s done in other cancers as well, especially in breast cancer, so there is some significant backing to this in medicine today. Some very good papers were written about this in 2013 and 2015. Sadly, Dr. Hurley stated, like many things in medicine, it has become an area of controversy and there are now papers that refute some of the initial findings by Carl Awh, by Emily Chew and others. It’s now known that macular degeneration is a multifactorial genetic disease; there are many things that contribute to it, similar to most forms of glaucoma and many other eye conditions. Many genes put a person at risk for macular degeneration. There's no current test to test all of the known ones, but there is one available that will test for two of them, complement factor H and the ARMS2 gene. Carl Awh's paper came out showing that treatment response can be optimized based on complement factor H and ARMS2 genes (Table I). The researchers looked at the patients within the first AREDS trial who had peripheral blood samples available. They could subtype them according to their genetic makeup and then see how each of these subgroups did within the treatment categories. They found that if a patient was at the lowest risk − negative for those two genes – the risk for developing macular degeneration was lower, less than one; lowest if the patient took the antioxidants; and not as good if the patient took the zinc. If they were two alleles positive, so homozygous for complement factor H, there was a much higher risk, no matter what they took. The risk was well over 1 in every one of these supplements. However, there was a better result with the antioxidants, again, than if they received the zinc. Also, if they were heterozygous for CFH and for ARMS2, the zinc seemed to be what was
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providing the greatest benefit as opposed to the antioxidants. Furthermore, if there was double positivity for both of them, every one of the treatment groups crossed unity, so one couldn't really say that any of the vitamins were really helping the patients. Based on this, they concluded that patients with category 3 or category 4 AREDS could benefit from a selection of their nutrients based on their genetic makeup, which is a very interesting proposition. While it was like the original cohort study that looked at the omega-3 fatty acids, this was a cohort study as opposed to a randomized control study. There were sample size issues: Looking at people who had no complement factor H markers and were double positive for ARMS2, for example, there were only 10 such patients in the study and then they're broken down into the four treatment groups. This provides only 2 or 3 patients per treatment group which really opens it up to the effect of chance. When there are so few people, if there is one patient who does poorly or really well for other reasons, that's really going to overdrive the results, and people have raised that as an issue. This was a retrospective subgroup analysis and one can break down and cut up data in many different ways. For example, consider presenting the data by the day of the week that the patient was born. One can keep cutting and sub-cutting data, producing some very spurious results that find if you were born on a Thursday or Friday, you did much worse than if you were born on a Monday, Tuesday or Wednesday. Obviously, there's no scientific merit for that. The fact that it was a Caucasian cohort doesn't bother Dr. Hurley because there were many confounders, and it was based on the original AREDS data. There was a response from the people who were very strong proponents of the AREDS data as being the gospel and they added some additional patients that they had access to with genetic markers. In Emily Chew's report, they could not replicate the original findings of Carl Awh. As a result, their final take home message was that complement factor H and ARMS2 loci didn't alter the benefits from the AREDS supplements across the board. The Awh group came back out with their next publication which analyzed the data as well. They predicted the probability of improvement and found that this did support their original findings, so patients with moderate AMD could benefit from pharmacogenetics. This controversy has led to editorials in some of the major publications in ophthalmology, with some people saying that their data doesn't correctly adjust for the multiple statistical testing and it's a post hoc analysis as well; therefore, those editorials couldn't support the use of pharmacogenetic testing. Emily Chew's article, as well, said that genetic testing is currently not recommended for determining the appropriateness of the AREDS formulation and that practitioners should rely on the original AREDS studies.
In terms of whether or not to test, Dr. Hurley noted that physicians have to remember which type of evidence they're looking at in order to make the best, most informed decision for their patients. He looks at some of the guidelines, for example, those of the American Academy of Ophthalmology, which state that routine genetic testing for complex disorders like AMD and glaucoma should not be done until there is solid data that the patient's response to treatment can actually be modified and better data exists that supports its use. The Canadian expert consensus panel’s paper which also states that further data is needed and practitioners should rely on the highest level of evidence available, the double-blind, placebo-controlled AREDS clinical trials.
CASE STUDIES Dr. Hurley presented several cases relating to whether or not patients should receive ocular vitamins. The first case was of a 58-year-old female of African descent with no AMD currently on ocular examination and no family or background history of the condition. She is not a candidate for vitamin supplements. If there is no AMD to start with, there is no treatment benefit and the rate of progression is too low. In addition, this patient enjoys excellent quality of life, including running long distance marathons and weight training. I didn't write this, I wish I had patients like this in my practice but that's phenomenal, right? Concerning the issue of this patient’s genetics, they’re at risk for polypoidal choroidal vasculopathy, not macular degeneration. This case is an example of a different disease than macular degeneration that presents in Canadians of African descent. The second case was of a 54-year-old male, professional looking, with multiple 125 micron drusen in one eye diagnosed earlier. He is a former smoker with no family history of AMD. The drusens are large, so he's
AREDS category 3. He is a patient for whom ocular vitamin supplementation is absolutely recognized and recommended by the clinical trial. He would benefit from it according to the best evidence at hand. In the third case, a 71-year-old Caucasian female with wet AMD in one eye was receiving injections every month. Her other eye is category 2, but that doesn't matter – she is category 4 based on the vision loss in one eye. She has a neovascular membrane in one eye, and these are the patients who would benefit the most from AREDS supplementation. Much more interesting to Dr. Hurley is the patient with bilateral wet AMD who is already receiving injections in both eyes. Should they take ocular vitamin supplementations? His thought is that it's already wet in both eyes, so what would the treatment be trying to prevent? However, the massive benefit of anti-VEGF medication is known, be it Lucentis® (ranibizumab injection, Roche Canada, Mississauga, ON), Avastin® (bevacizumab, Roche Canada) or Eylea® (aflibercept, Bayer). It allows people to keep driving, for instance, but they're still losing vision due to the underlying background dry degeneration that's progressing at the same time. In many patients, their neovascular membranes have regressed, but the central geographic atrophy is still progressing. They’re going blind slowly, so he continues to do everything he can to help them. So even though they're bilaterally wet, he still puts them on the AREDS supplements.
CONCLUSION With AREDS1 and AREDS2, said Dr. Hurley, it looks like AREDS2 helps define how much practitioners can reduce patients' risk of progression. Physicians’ ultimate goal is to prevent somebody who is seeing well but is at high risk of a neovascular scar, for example, from progressing to geographic atrophy. ❏
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QUESTIONNAIRE AREDS2 Controversies and Facts: Delving Deeper into our Knowledge on Eye Health Bernard Hurley, MD 1. ❑ ❑ ❑ ❑
All of the following are risk factors for AMD, EXCEPT: Age Reduced visual acuity Diet Ethnicity
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All of the following statements about AMD are true, EXCEPT: Studies have shown no treatment effect in patients with low likelihood of progression at baseline In patients with category 2 AREDS, the likelihood of progression is low Vitamin supplementation is effective in all cases Patients with large, soft drusen are more likely to progress
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In AREDS1, what was the relative risk reduction in the group that received both the antioxidents and the zinc? 25% 30% 35% 40%
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In AREDS2, what percentage represented the additional benefit when lutein and zeaxanthin were added to the formulation? 5% 10% 20% 25%
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All of the following statements about the AREDS trials are true, EXCEPT: No safety concerns were raised Patients on the AREDS supplements had improved overall mortality In AREDS2, patients taking beta carotene, lutein and zeaxanthin had better results In AREDS2, the risk reduction was better for patients with lower dietary intake of lutein and zeaxanthin
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All of the following statements about vitamin and mineral supplementation are true, EXCEPT: The AREDS2 formulation can be used safely regardless of the patient’s smoking status There was no difference in side effects between the 80 mg and 25 mg doses The overwhelming treatment benefit in AREDS1 was conferred by zinc Patients with AMD who are heavy smokers should not be prescribed the AREDS2 regimen
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All of the following statements are true, EXCEPT: According to the paper by Dr. Awh et al, treatment response can be optimized based on complement factor H and ARMS2 genes Many genes put a person at risk for macular degeneration Only patients with category 4 AREDS can benefit from a selection of their nutrients based on their genetic makeup In category 4 AREDS, the patient has already suffered vision loss in one of their eyes
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All of the following statements are true, EXCEPT: The patient in Case #1 was a candidate for vitamin supplements based on her ethnicity The patient in Case #3 was categorized as category 4 AREDS If a patient has one eye in category 2 AREDS and the other in category 4, they are considered category 4 If AMD is not present, there is no benefit in ocular vitamins
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Which of the following statements is TRUE? Patients with category 2 AREDS and a family history of AMD may benefit from zinc supplementation Patients with category 1 AREDS and a family history of AMD may benefit from zinc supplementation Patients with extensive intermediate sized drusen in both eyes may benefit from the AREDS regimen Patients with multiple small drusen in both eyes may benefit from the AREDS regimen
10. All of the following statements about the study by Dr. Awh et al are true, EXCEPT: ❑ Patients homozygous for CFH and ARMS2 risk alleles had an excellent response to AREDS treatment ❑ Over an average of 10.1 years, patients with 1 or 2 CFH risk alleles derived maximum benefit from antioxidants alone (without zinc) ❑ Patients with AMD sensitivity 2 (ARMS2) risk alleles derive maximum benefit from zinc-containing formulations, with a deleterious response to antioxidants ❑ Patients homozygous for CFH and ARMS2 risk alleles derived no benefit from any category of AREDS treatment
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Clinical & Refractive Optometry is pleased to present this continuing education (CE) article in the form of a Meeting Report based on a presentation given by Dr. Paul Karpecki entitled Diagnosis and Treatment of Ocular Surface Conditions: Focus on Allergy in Toronto, ON on May 15, 2016. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 199 for complete instructions.
Diagnosis and Treatment of Ocular Surface Conditions: Focus on Allergy Paul M. Karpecki, OD, FAAO
INTRODUCTION Dr. Karpecki began his presentation by noting that he established his first dry eye clinic in 1997 and in the first ten years of ocular surface disease, there wasn’t a lot to teach about dry eye disease as we were learning as we went along. In addition, there wasn't much practitioners could do for success. In fact, he noted, his success rate was probably less than fifty percent. In a survey conducted before he joined Kentucky Eye Institute, approximately 96% to 98% of patients said they were satisfied or very satisfied with their treatment results. Dr. Karpecki mentioned that in the last six or seven years, great strides have been made in the management of the ocular effects of dry eye disease and allergies.
THE CURRENT OCULAR ALLERGY LANDSCAPE When an allergy is seasonal, it's an acute condition; however, in patients with perennial allergies, dry eye and blepharitis, it’s typically chronic. As a result, said Dr. Karpecki, practitioners have to be able to teach them that this is progressive and will typically last for the rest of their life. In addition to chronic, acute, perennial and GPC forms of allergy, the sight-threatening forms, vernal and atopic keratoconjunctivitis, which are not very common, occur at a rate of about 3-5 cases per year in his clinic. Seasonal allergies are by far responsible for the largest proportion of allergies. Fluctuations in weather are particularly hard on allergy sufferers. In fact, what makes it tougher is that patients get a bolus of pollen in the spring depending on the allergen, then relatively little for a few months and then they often get another bolus of allergens in the fall. This pattern makes it difficult on allergy suffers to perform P.M. Karpecki — Director of Corneal Services and the Advanced OSD Clinic, Kentucky Eye Institute, Lexington, KY Correspondence to: Dr. Paul M. Karpecki, Kentucky Eye Institute, 601 Perimeter Drive, Suite 100, Lexington, KY 40517; E-mail: paul@karpecki.com This article has been peer-reviewed
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at their optimum at all times and can affect everything from sleeping to reading and concentration. Environmental allergens, such as grass pollen in summer and ragweed in the fall, are common causes, as well as animal dander and dust mites which are more perennial. Cat dander holds on to the conjunctiva or skin; ragweed resembles burrs and can stick to clothing and even ocular structures; and grass pollen is so small that it can stay in the cul de sac before it’s washed away. This also raises a key clinical pearl when managing allergies: Don't forget to tell patients to wash the allergen away using preservative-free artificial tears. Practitioners often think of artificial tears for dry eye, but they play a key role in allergy because it’s important to dilute all of these elements that are adhering to the conjunctival surface. Perennial Allergy Animal dander is one of the most common forms of perennial allergy, but the biggest cause is dust mites. They’re impossible to get rid of so, unfortunately, if a person is allergic to dust mites, they can’t truly clean a home any more than we do today because these mites are only 10 to 24 microns in size. Furthermore, said Dr. Karpecki, it's not the dust mites themselves that people react to; it's actually their droppings, their waste pellets: they eliminate approximately 10 to 20 a day. One gram of dust equates to about 240,000 dust mite droppings. It has been said that after five years, without a pillow cover, 50% of the weight of one’s pillow is actually dust mite droppings. In terms of the clinical presentation, it’s typically a bilateral condition resulting in a glossy or thematic appearance with mild injection. A unilateral form of type 1 hypersensitivity is contact dermatitis, for instance, a reaction to nail polish. This involves the eyelids more than the eye, and typically it's unilateral as contact dermatitis can affect the conjunctiva, skin and neck. Contact dermatitis is best treated with topical corticosteroids. Dr. Karpecki highlighted that in North America optometry treats allergic conjunctivitis more than any other medical specialty. Symptoms of burning, tearing, redness, itching, photophobia, and grittiness all imitate dry eye disease, making the differential between allergic conjunctivitis and dry eye disease difficult at times. One key differential is that allergic conjunctivitis is associated with rhinitis and dry eye disease is not.
Looking forward, there are some interesting technologies emerging, including those by TearLab (San Diego, CA), which is working on their next innovation. They measure osmolarity right now, but they're working on IgE and inflammatory markers, among other things that may create a multi-chip format allowing us to differentiate the presence of various ocular diseases before we even see the patient. Within a year one would actually sample the tears and know how much allergy is present, compared to dry eye inflammation and even specific inflammatory markers that may dictate the optimal treatment. This currently exists in cardiology with panels of tests, as they’re referred to. These tests aren’t currently available in eye care, therefore, practitioners have to be the ones who differentiate it. Itching, the hallmark symptom of allergies, could be caused by dry eye disease or blepharitis such as demodex blepharitis. When a patient presents at the office and says, “My eyes itch,” a good differentiating question is, “Do you feel better after you rub them?” If so, typically it’s more of a histamine involvement. An additional question relates to the location of the allergy. Allergic conjunctivitis is located on the conjunctiva or in the canthal region. If it’s in the eyelids or eyelid margins, demodex or staphylococcal blepharitis plays a role. A patient recently stated to Dr. Karpecki that her eyes were itchy, but on further questioning was identified as particularly around her lashes. The diagnosis was demodex blepharitis, so he proceeded with Cliradex® (4-Terpineol, Bright Optical, Toronto, ON) treatment on her eyelids. The condition cleared up completely and her itching was resolved. In this case, it wasn't allergies, even though allergy is the first thought when one hears the term itching.
ALLERGY SYMPTOMS AND DIFFERENTIATORS Dr. Karpecki noted that an optometrist can quickly recognize a person with allergies due to a glossy-looking eye. It's not beet red as with most bacterial conjunctivitis and there's no discharge. In allergic conjunctivitis, a tearing or mucin discharge is present. One can sometimes see papillae, especially in the lower fornix area, and possible eyelid swelling; however, the key is the chemotic look of the conjunctiva. These types of differentiating signs and symptoms are crucial to treatment. The other differential is viral forms which not only need to be differentiated from allergic conjunctivitis but also bacterial conjunctivitis. Dr. Karpecki pointed out that when looking for discharge, it’s vital to look at the tear lake or lower tear meniscus. Debris in the tear film is also discharge and can help differentiate a bacterial conjunctivitis. Patients will report that when they woke up their eyes were matted shut and a yellow substance on their lashes was visible; this is more typical in bacterial conjunctivitis.
In viral conditions a watery discharge is more common. These patients tend to have an eye that may not be as red although in some forms such as epidemic keratoconjunctivitis (EKC) it can be. One differentiating factor is preauricular lymphadenopathy, which is why it's always important to check by actually rubbing the preauricular area to try and find a pea-sized nodule. What’s more, in viral forms, it starts in one eye and then spreads to the other, whereas with allergies it is a bilateral presentation immediately. Naturally, mentioned Dr. Karpecki, if patients have had it for more than a week and it’s something like EKC, there may be subepithelial infiltrates which are a help in finding the differential, but the goal is to try and pick up on that sooner than later. If the viral form is detected early, it can often be managed early.
DIAGNOSTIC TOOLS There are a number of diagnostic steps to take, and point of care diagnostics are now available. Rapid Pathogen Screening in Florida makes the AdenoPlus® test. A former colleague and coworker of Dr. Karpecki’s asked for a consult with a case he suspected might be preseptal cellulitis. This patient had one of the most severe cases of conjunctivitis Dr. Karpecki had seen. The patient was extremely chemotic and red, and he determined that it was a case of EKC. He had an AdenoPlus which indicated positive for adenovirus. Some of the worst-looking conjunctivitis cases are EKC, so that's a good way to differentiate it from allergy as well.
TREATMENT OPTIONS FOR EKC The other advantage with EKC in Canada is that there are good treatment options we don’t have in the United States. In the U.S., Zirgan® (ganciclovir ophthalmic gel, Bausch + Lomb, Rochester, NY) has been shown to decrease the course of EKC from about 18 days to roughly 5 days. Another option is Betadine® (povidone iodine, Purdue Pharma, Stamford, CT) and although it’s available in the States in bottle form, Canada has the preservative-free Minims® (povidone iodine 5%, Bausch + Lomb, Vaughan, ON). The dosage is three drops after having put Alcaine® (proparacaine hydrochloride ophthalmic solution 0.5%, Alcon, Mississauga, ON) or Minims Tetracaine (tetracaine hydrochloride 0.5%, Bausch + Lomb, Vaughan, ON) in the eyes, followed by an NSAID drop. Have the patient close their eyes, roll them around for about a full minute, and then use balanced saline to rinse it out completely. Dr. Karpecki stated that it will eradicate the virus immediately. Patients won't typically get subepithelial infiltrates; they'll achieve great results and they'll be grateful, although not immediately as the eye is very uncomfortable for about 24 hours. For this reason, steroid drops q.i.d. for 4 days should also be recommended.
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Fig. 1 Various phases of the allergic conjunctivitis cascade.
Seasonal Allergies With seasonal allergies, it's important to truly understand the mechanisms. What occurs is a cascade of allergic conjunctivitis (Fig. 1). The early stage is characterized by antigens in the tears, a major histocompatibility complex that involves T-cells, plasma cells and an antigen presenting cell in the conjunctiva. The first time an allergen presents, IgE forms on the mast cell. On the second presentation a cross binding occurs between the two IgE on the cell. When this happens, the entire mast cell becomes destabilized and all of the content including histamine is released. In the early stages there is an immediate response which is primarily made up of histamine, heparin, chymase and tryptase (Fig. 2). The person presenting at this stage will complain of itching, sometimes severe. There are two treatment choices, a steroid or an antihistamine combination – and despite what most of my residents answer (steroids for severe itching), the correct answer is an antihistamine combination drop. In the early stages of the allergic conjunctivitis, the main element causing itching
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is histamine and nothing stops itching as effectively as an antihistamine. Pataday® (olopatadine hydrochloride ophthalmic solution, Alcon, Mississauga, ON), Patanol® (olopatadine hydrochloride ophthalmic solution, Alcon, Mississauga, ON) or Bepreve® (bepotastine besilate ophthalmic solution, Bausch + Lomb, Vaughan, ON) in Canada are possible options, in addition to Zaditor® (ketotifen fumarate, Alcon, Mississauga, ON). In the early stages, they’re more effective than a steroid for itching symptoms, even if the condition is severe. If the condition is allowed to progress, the allergic cycle gets to a level called synthesis, which typically doesn't take a long time. This may occur at 48, 72 or even 12 hours in some cases, depending on the severity. At that point, leukotrienes, prostaglandins, cytokines and platelet activating factor (PAF), which are inflammatory components, are present and the most effective treatment at this stage is a topical corticosteroid. Patients will manifest more injection or redness, chemosis and overall inflammatory signs. Dr. Karpecki
Fig. 2 The early phase response occurs in allergic conjunctivitis.
stated that differentiating treatment based on the pathophysiology makes sense given the two treatment options (steroids and antihistamines). The patient’s signs are a key element, most notably the redness and chemosis which may also be considered symptoms. Patients often mention this because they feel self-conscious about how they look. A steroid would be a better choice when the signs are comparable to the symptoms. In fact, with Pataday, and Bepreve, neither of these have a US FDA indication for clinical signs of redness. However, Alrex® (loteprednol etabonate ophthalmic suspension 0.2%, Bausch + Lomb, Vaughan, ON) has an indication for signs and symptoms. The general rule would be: when there are more symptoms of itching than signs, use an antihistamine; when the signs (redness, chemosis, etc.) have caught up, the appropriate choice is a steroid. Sometimes both are appropriate to achieve good control of both elements. In the late phase, the condition is virtually completely inflammatory, however, and therefore corticosteroids may well be the better treatment option (Fig. 3).
There are studies showing that antihistamines are faster-acting against itch than steroids but there are others indicating that steroids have greater efficacy against clinical signs than any antihistamine by far. Antihistamines won't control the chemosis or redness to the level that a steroid will. It is quite a significant disease though, said Dr. Karpecki, and optometrists have become somewhat complacent about it because in North America optometry prescribes more allergy medications than any other discipline. We have to be reminded of the significant morbidity associated with allergic disease. Of the patients who have seasonal allergies, 70% said their reading is greatly affected to the point that it affects work. Driving is affected, which obviously is quite significant. Concentration has been shown to be diminished. Even difficulty sleeping is among the many functions affected by this disease. Therefore, it’s essential to counsel patients, explaining the need for treatment and setting the right expectations about it being a chronic disease in the case of perennial allergies. If their problem is seasonal, it
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Fig. 3 Late-phase reactions occur only in more severe allergic states and represent a cellular response to prolonged allergic challenge in conditions such as vernal keratoconjunctivitis.
will most likely return. In fact, Dr. Karpecki schedules his patients for their follow-up according to their seasonality. If he knows they have spring allergies, he typically sees them in March or April in order to try to alleviate their symptoms. These patients should be educated about how to minimize problems in their environment. The website www.pollen.com indicates the level of pollen in a given city. During “red” days, these patients should be more cautious. For example, if they are avid runners, they ought to run on the treadmill that day. They should keep their car windows up and avoid the outdoors for a short period of time. They should also be advised to wash their linens more frequently than they normally would and to keep the speed of the ceiling fan to a lower level or turn it off. From a palliative perspective, at level 1, a cold compress can have a tremendous impact on chemosis, whether it's a cloth, an icepack or a commercial cool compress over the closed eyes.
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Giant Papillary Conjunctivitis Dr. Karpecki discussed giant papillary conjunctivitis (GPC) which has seen a surge related to silicone hydrogel lenses. It’s much more difficult to treat than it was 20 years ago. It’s still GPC; it just appears to take longer to manifest and is a little more resilient to treatment. GPC is one of the four allergic eye diseases and is defined as large papillae on the upper tarsal plate and is easy to identify not because of itching, but rather, decreased contact lens wearing time and the presence of mucin discharge. Switching patients from silicone hydrogel contact lenses to a non-silicone hydrogel lens is recommended. However, even after six months of treatment, the papillae may still be visible, but the patient may not be symptomatic. What the practitioner should actually be treating is the hyperemic papillae. If the papillae are red, there is too much inflammation. After treatment, if there is a normal pink tarsal plate, even if a few papillae remain, that's acceptable, as long as they're not hyperemic. Dr. Karpecki explained that it’s a matter of active versus
Fig. 4 Vernal shield ulcers are indicative of an eosinophilic reaction.
non-active states. If it's active, hyperemia, and usually a fairly large level of papillae, will be present. It’s important to flip eyelids on patients fairly regularly in order to gauge its presence, especially in people who have worn silicone hydrogel lenses for more than three years. Sometimes the symptoms are related to makeup, however, most of the time it's a contact lens issue. Refractive surgery may be a treatment option, stated Dr. Karpecki. While patients don't want to be out of their contact lenses, if the practitioner can get them to stop their wear for at least a week during treatment, that's more effective. During that week, they should be put on Lotemax® (loteprednol etabonate ophthalmic suspension, Bausch + Lomb, Vaughan, ON) q.i.d. then tapered to b.i.d. before and after contact lens insertion and removal. Even though studies have shown that there has never been an infection complication related to loteprednol and contact lens wear during GPC treatment, there is one study by Dr. Jimmy Bartlett on GPC using Lotemax and it showed incredible effectiveness, more than any other previous steroid has shown, perhaps because it's much more lipophilic. Dr. Bartlett’s study showed that the incidence of significant IOP rise, i.e., 10 mmHg or more increase from baseline, was 8%, rather than the traditional 1% or 2% reported in all the other studies. When it’s put on a lens it becomes a depot and the same complication rate of IOP results as with the older ketone steroids is evident. As a result, he prefers not to put any topical corticosteroid on a contact lens, if possible. Once the patient is back in a lens, reduce the treatment to twice a day, before and after lens wear, continuing for approximately four to six weeks if pressures are normal. Regarding Lotemax gel form, it's still 0.5% concentration, with less preservative; it doesn’t have to be shaken, and there is the advantage of moisturizing agents.
It’s expected to show the same effect, but there has not yet been a study confirming this. An important component of treatment success is hygiene and patient compliance. There is a need for patients to learn to replace their lenses on a regular basis. In most of the patients experiencing problems, they extended the use time, they topped up their solution, or there was some other form of non-compliance. Vernal Keratoconjunctivitis Vernal keratoconjunctivitis (VKC) is a warm weather condition and Dr. Karpecki sees roughly eight to ten cases in the course of a summer. It typically occurs in male children between the ages of roughly 4 and 16 and manifests with very large cobblestone papillae on the upper tarsal plate. The key to diagnosis, because 17% of cases have this, is to note an area of elevation at the limbus. If a child presents with allergic conjunctivitis, the practitioner should look very carefully at the limbus 360 degrees. If there is any elevation, even if it's just one clock hour, that's a diagnosis of VKC. The elevation signifies Horner-Tranta’s dots which are eosinophilic accumulations at the limbus. Dr. Karpecki highlighted that VKC is sight-threatening and can lead to what's called a shield ulcer (Fig. 4). The former thinking was that the papillae rubbing on the surface caused these ulcers. Actually, it's something called basic major protein that is released in the inflammatory cascade or immunology. The limbal accumulations are eosinophils so they release the major basic protein and will cause the epithelium to slough, leading to a shield ulcer; these can scar if they're not treated. Management of the condition includes an antibiotic, antihistamines and low grade anti-inflammatories which might get it controlled over time. One of the best treatments for vernal shield ulcers is a cyclosporine (Restasis®, Allergan, Unionville, ON) twice a day, or even four times a day. Following this, lubricate the eye and use an antihistamine combination, all of which work even better than steroids in cases of VKC.
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Dr. Karpecki addressed the issue of why Restasis works immediately in VKC when in dry eye it takes so long to take effect. The precise answer isn’t known, but it relates to the physiology – the type of cells that are present, and a different mechanism of action. It’s thought that for some reason cyclosporine inhibits major basic protein more than other therapeutics or some key receptor in the inflammatory cascade. The reason why it doesn't work as quickly in dry eye patients is that it primarily affects migrating T-cells, which can take some time to be fully affected. In dry eye, one has to wait for those cells to die off; it takes roughly 90 days for a T-cell to run its normal apoptotic cycle. However, in the case of shield ulcers, major basic protein can be suppressed right away with cyclosporine and other non-approved options such as tacrolimus. Dr. Karpecki emphasized that VKC requires very aggressive treatment. Steroids are essential until the point of a shield ulcer, dosed at every two hours for about the first week, plus the antihistamine, olopatadine, bepotastine, or ketotifen. Systemic antihistamines are an option, even though they dry the eyes. Children don't have as much dry eye, so oral antihistamines should not be a problem. Aspirin has been shown to help children, but the studies on this have been inconclusive. Children should be instructed to avoid eye rubbing as this exacerbates the problem. Another sight-threatening allergic eye disease seen occasionally is atopic keratoconjunctivitis (AKC). It more commonly affects men ages 30 to 50, and the hallmark of atopic keratoconjunctivitis, which is the fourth form of the type I hypersensitivity conditions. Contact dermatitis is a type IV hypersensitivity, the delayed response type of allergies. The key signs of AKC are eczema and neovascularization or pannus on the cornea; classic presentations not seen in any other allergy form. Roughly nine out of ten of these patients have asthma, but 95% have eczema somewhere, often around the eyes, with conjunctivalization in the severe form. Often it's just slight neovascularizational encroachment, especially in a non-contact lens wearer. Typically, these patients can't wear their lenses and they have typical symptoms of burning and itching, therefore, it sounds like allergies; it goes into remission, then there are exacerbation episodes. To treat the eczema, Dr. Karpecki suggests a triamcinolone cream, 0.1% which is a kenalog steroid, or Lotemax ointment if there is concern of the patient getting the cream in their eyes. As these patients have dry eyes, neovascularization is a concern. If that's present, prescribe heavy corticosteroids, every two hours until it can be reversed. Lotemax gel every two hours would be ideal because of its safety profile, however, if it's very severe, Pred Forte® (prednisolone acetate, Allergan, Unionville, ON) works well. A Japanese study showed that Lotemax gel was equivalent to branded Pred Forte. In severe cases such as uveitis and AKC, one can start with Pred Forte and then use Lotemax longer term, but they
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are very comparable now that the gel formulation has come out. Therapy needs to be adjusted on a two-week basis; typically, dosing is every couple of hours for a week or two, then q.i.d. for a week or two. Dr. Karpecki prefers loteprednol because this regimen involves long-term use of steroids. He would rather use the safest agent, but if it's not producing a response, Pred Forte is required. Again, eye rubbing is a concern in this group; and this could be why there's a high incidence of keratoconus in these patients. Regarding comorbidities, for example, in patients with dry eye and rhinitis, Dr. Karpecki recommends avoiding oral antihistamine treatments, which is contrary to current teaching: These patients’ primary complaint revolves around their eyes and their systemic condition can be treated at a later point.
PHARMACOLOGIC AND NON-PHARMACOLOGIC TREATMENT OPTIONS The Role of Oral Antihistamines Regarding oral antihistamines, Dr. Karpecki cited a study by Dr. Osler that came out of Harvard University, showing the effect if a person used Claritin® (loratadine, Bayer, Mississauga, ON) which is actually not one of the most drying antihistamines, taken once a day for four days. It resulted in a drop in tear volume of 34% which is significant – and most of our patients don’t use oral antihistamines for just four days – most use it for a month or the entire allergy season. Imagine the effects on the tear film of Benadryl® (diphenhydramine hydrochloride, Johnson & Johnson, Markham, ON) which has potent antimuscarinic receptor activity. He tells his residents to take their patients off oral antihistamines if they're willing to do so because an antihistamine drop is not going to dry their eyes and is also going to get through their sinuses, throat and non-ocular tissues. This was shown in research involving a drug available in the U.S. called bepotastine which showed statistically significant improvement in the secondary markers, namely, nasal congestion, rhinitis, itchy palate, and itchy throat. The only exception to prescribing an oral antihistamine at the onset of treatment would be allergic sinusitis where a patient presents with pain around their eyes involving the sinus cavities and no signs of infectious sinusitis. If allergic sinusitis is diagnosed, Claritin-D®, Allegra-D® (fexofenadine hydrochloride; pseudoephedrine hydrochloride, Sanofi Canada, Laval, QC) and Zyrtec-D® (cetirizine HCl 5 mg/ pseudoephedrine HCl 120 mg, Johnson & Johnson, Markham, ON) all make sense because a decongestant is needed. But if it's just for allergies and it's the non-decongestant form, Dr. Karpecki would try to avoid it at the early stages of allergic conjunctivitis. Patients think that it’s helping their eyes, however, it's actually drying them by at least 34% after just four days, at once-daily dosing.
Decongestants For the treatment of allergies, decongestants such as Visine-A® (naphazoline, Johnson & Johnson, Markham, ON) or Naphcon-A® (naphazoline, Alcon, Mississauga, ON) are not recommended for three reasons. First, they contain significant amounts of BAK, usually about double what is found in good artificial tears. They represent a significant amount of toxicity potential based on just the preservative. Second, they cause constriction of blood vessels. The reason they're dilated to begin with is they're trying to heal something, so by constricting them, their disease isn’t being helped. A much better choice is a steroid where vascular permeability is maintained. Third, and this is commonly known, decongestants and vasoconstrictors cause rebound hyperemia. Once a patient is on it, they’re “addicted” because the moment they’re off the medication there is a rebound effect that may be even worse than when they started these medications. In fact, if someone comes into the office, a diagnosis of allergic conjunctivitis is made and they say, “I've been using Visine for the last six months,” I wouldn’t recommend immediate discontinuation because their eyes are going to become more injected and they will question the practitioner’s abilities. The best way to get them off of the decongestant/vasoconstrictor is to taper them. Start them on a steroid such as loteprednol q.i.d. for two weeks, then b.i.d. Allow them to use the Visine no more than the steroid such as four times a day for a week, then taper down each week because by then the steroids will have the ocular surface under control. Therefore, said Dr. Karpecki, it’s best just to avoid them in the first place but, unfortunately, if they've already chosen an overthe-counter (OTC) vasoconstrictor, it’s best to switch medication to a corticosteroid and taper them off the vasoconstrictor agent. If a patient has to use an OTC medication, Dr. Karpecki prefers combination agents over vasoconstrictors as his key treatment, including ketotifen, Alaway® (Bausch + Lomb, Rochester, NY) and Zaditor® (Alcon, Fort Worth, TX). There is alcaftadine in the U.S., and in Canada and the U.S., olopatadine and bepotastine are available. Bepotastine is probably the best treatment for severe itch that he has ever seen, but it’s advisable to disguise its taste. Although bepotastine is a very good product, it’s perhaps better reserved for moderate to severe itching. However, it works about as well as olopatadine for mild and moderate allergic conjunctivitis. Ester Steroids and Other Treatments Dr. Karpecki shared that he favors ester steroids, a safer version and yet still very potent for ocular surface conditions such as allergic conjunctivitis. Because there are enzymes known as esterase in the body, it can break down ester steroids. In the case of ketone steroids, there is no enzyme to break down the metabolites that can now attach to the IOP receptors or create a Schiff base on the
crystalline lens, which can lead to cataract development. In fact, there has never been a reported cataract on loteprednol, even after over approximately 40 million scripts. There is still a risk of IOP rise: About 2% of patients on loteprednol have a 10 mm or more increase in pressure so it doesn't mean that it can be prescribed without monitoring IOP. As he noted, he still doesn’t write any refills the first time he writes a prescription for steroids. Dr. Karpecki uses either the on-label option of 0.2% loteprednol (Alrex) in most cases of allergic conjunctivitis or in severe cases, 0.5% (Lotemax). The Lotemax gel has some unique properties; it's still 0.5% concentration but the gel provides more advantages such as significantly less BAK, along with better moisturizers and a longerlasting effect due to the vehicle. Additionally, it doesn’t need to be shaken, which is extremely important as most patients don't shake suspension steroids the required 30 times for true re-suspension. For this reason, drops that don’t need to be shaken are a huge advantage for patients. It can be administered every couple of hours for the first few days in severe forms involving significant chemosis or injection. Patients can’t take it forever; their pressure will still need to be monitored, but it’s extremely effective against the signs that are present in allergic conjunctivitis. Alrex is a 0.2% concentration indicated for temporary short-term relief of signs and symptoms. Dr. Karpecki typically tells patients that a couple of months is good as maximum therapy duration. If they have a lot of itching, he adds the antihistamine component. Dr. Karpecki mentioned that he avoids oral antihistamines, even though the majority of patients think that all antihistamines help relieve their itchy eyes. The frequently used options are oral Claritin, Allegra and Zyrtec. If the eyes are dry and the patient has allergies, the allergen remains. He would therefore avoid these, except in cases of sinus congestion where the decongestant is the key. Regarding pseudoephedrine, which is the common decongestant in most of these oral antihistamine/ decongestant medications, physicians must be cautious in patients with known hypertension as it has been shown to cause a hypotensive state. Dr. Karpecki also pointed out that the newer forms may not be as sedating as the older oral allergy medications, however, they're still very drying to the ocular surface. If a medication like Claritin-D is needed because a patient has sinusitis, simply increase the use of artificial tears. There was an article or research paper published a while ago that discussed anticholinergics and over-thecounter drugs in relation to dementia, and Benadryl is one of those. A recent study reported that anticholinergics like Benadryl are contraindicated because they cause effects in patients with dementia. In terms of mild conditions where patients self-treat, a study showed that over 80% of people will try something over-the-counter before they come into an optometrist's office. Practitioners then have to educate patients about
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vasoconstrictors and how to get off of them, as well as the risks of using them long term because typically that’s a common OTC selection. Dr. Karpecki noted that if there is significant systemic involvement, with rhinitis, itchy throat, cough, or sinus congestion, he would use a topical medication. The use of loteprednol is substantiated in clinical studies. However, if oral administration is the chosen route, Benadryl is an effective choice provided the patient has no risk of dementia, administered before the patient goes to bed. Inhalers such as Dristan® (oxymetazoline, Pfizer, Montreal, QC) or Otrivin® (xylometazoline, Novartis, Dorval, QC) are available in Canada and provide the desired effect where it’s wanted, without going through the drying effects of taking a pill. Regarding long-term corticosteroids, one must bear in mind that cataracts can result, in addition to the low risk of IOP rise, not at the level of drops, but still a risk to consider. Non-Pharmacologic Treatments Dr. Karpecki stated that he favors non-preserved artificial tears because patients with allergies are already atopic; therefore, the less preservatives, the less chance of a reaction. In the early phase or if itching is their chief or only complaint, he prescribes an antihistamine/mast cell stabilizer. If they're saying, “It’s just the itching, it's unbearable, it's incapacitating,” that requires an antihistamine combination agent if it is severe. In terms of non-pharmacologic therapies, mucolytic agents are suitable for severe cases; likewise in severe allergic signs, select Lotemax instead of Alrex. There are many options for preservative-free artificial tears that will work. Dr. Karpecki opined that Canada has some of the best products available, such as HYLO™ (CandorVision, Montreal, QC) and especially for allergic conjunctivitis, HYLO Dual, (CandorVision, Montreal, QC)). In advanced cases, his patients are very appreciative of its effects. Refresh Optic Fusion™ (Allergan, Unionville, ON) is another good product containing hyaluronic acid. On the lipid side, there are Liposic® (Bausch + Lomb, Vaughan, ON), Refresh Optive® Advanced (Allergan, Unionville, ON), Refresh® Ultra (Allergan, Unionville, ON), and Systane® Balance (Alcon, Mississauga, ON). Mast cell stabilizers can be used alone, however, they won’t affect the histamine or relieve the itch, so one might as well use a combination. Equally, Dr. Karpecki doesn’t like to use NSAIDs alone. Looking at the arachidonic acid pathway of inflammation, there are two pathways, the cyclo-oxygenase pathway and the lipoxygenase pathway. NSAIDs only block prostaglandin formation of the cyclooxygenase pathway, not the entire leukotriene pathway, whereas steroids block both pathways. The same occurs with a mast cell stabilizer alone, as it would be preferable to have antihistamine and mast cell stabilization.
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CONCLUSION Dr. Karpecki concluded his presentation by reviewing several clinical pearls. The first of these is to educate patients about the importance of avoiding eye rubbing. If a patient rubs their eyes and feels better for a moment, that's usually a sign of allergies. He advises them to avoid this tendency because they’re going to mechanically degranulate the mast cells and make the condition worse over the long term. Second, refrigerate eye drops. Sometimes, the first time a person will ever put drops in their eyes is when they have allergies and so they're missing their eye, and they can't tell if it went in or not. By refrigerating them, they can tell if it's in the eye, plus it provides a soothing, cool compress effect. Next, tell patients to keep ceiling fan speeds lower; change their lenses more often, place protective covers on pillows, shower before sleeping; avoid being outdoors during the peak season; and keep house and car windows closed, if possible. In terms of medications, be aware of the side effects of some of the oral antihistamines. Most of these patients are going to present on an oral antihistamine, but may not even list it on their medication intake form because it is OTC; educate them about the potential side effects of these agents. Furthermore, when treating with topical corticosteroids, be sure to check their intraocular pressures in three to four weeks. Write zero refills the first time, just to be on the safe side. That way, they have to come back in three or four weeks to get another prescription. Dose these b.i.d. with a contact lens wearer, as previously discussed, with GPC. Get them out of their lens when they’re on Lotemax q.i.d., but then put them in a new lens and use the drops before and after lens wear. With regard to prescribing Patanol versus Pataday, Dr. Karpecki typically starts with Pataday as he feels it offers better efficacy, with slightly higher concentration. However, if the patient says, “I'm having to use this much more than once a day” when they return, and there are many who do, this often means that they either need a steroid or are better served with a b.i.d. antihistamine/mast cell stabilizer agent. If they're on a steroid and they're still saying that, he’ll prescribe Patanol where they can justifiably use it a couple of times a day and achieve slightly better results. A preferred solution is adding in a steroid if there is more clinical sign involvement. Dr. Karpecki’s rationale is that many times, patients will say, “The itching is fine, but I'm using it more often because I can't get this redness controlled.” That would be an indication for adding a topical corticosteroid. Concerning the issue of when to remove contact lenses in patients with seasonal allergies, the answer may be in the upper eyelids. Evert the upper eyelid and if it's hyperemic, the contact lens is contributing to their symptoms and it does need to be taken out for a while. If the eyelid looks normal, simply advise the patient to use drops before and after contact lens wear, along with preservative-free hydrogen peroxide solutions. In addition, instruct patients to hydrate their lenses regularly throughout their wear. ❏
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This course is valid for 1 hour of COPE-approved CE credit provided that it is submitted for receipt by CRO no later than November 1, 2019. Please do not submit after this date. The cost of this CE-credit article test is $25.00, payable by cheque to Mediconcept Communications at the address shown below. In order to obtain CE credit for this article, please complete the identification section and answer all 10 multiple choice questions in the test questionnaire below. If you score 70% or more, a COPE-approved CE Credit Certificate will be forwarded to you by your preference of either (please indicate) e-mail____ or regular mail_____ Please mail this CE credit application form and your cheque to: Mediconcept, 3484 Sources Blvd, Suite 518, Dollard-des-Ormeaux, QC, H9B 1Z9
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QUESTIONNAIRE Diagnosis and Treatment of Ocular Surface Conditions: Focus on Allergy Paul M. Karpecki, OD, FAAO 1. ❑ ❑ ❑ ❑
Which of the following types of allergy is most common? Perennial Chronic Giant papillary conjunctivitis Seasonal
2. ❑ ❑ ❑ ❑
All of the following statements about perennial allergy are true, EXCEPT: Contact dermatitis involves the eyelids more than the eye Typically it’s unilateral In North America, optometry treats allergic conjunctivitis more than any other medical specialty Contact dermatitis is best treated with topical corticosteroids
3. ❑ ❑ ❑ ❑
All of the following are possible signs of allergic conjunctivitis, EXCEPT: Glossy-looking eye Papillae Deep red coloration Eyelid swelling
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COPE-APPROVED CE CREDIT APPLICATION FORM
Which of the following is NOT characteristic of viral forms of allergy? Watery discharge Preauricular lymphadenopathy It begins unilaterally, then spreads to the other eye It begins bilaterally
5. ❑ ❑ ❑ ❑
All of the following statements about seasonal allergies are true, EXCEPT: Steroids have been shown to be faster-acting than antihistamines against itch When the signs are comparable to the symptoms, corticosteroids are the preferred treatment Overall inflammatory signs are typical Chemosis may be present
6. ❑ ❑ ❑ ❑
What percentage of patients with seasonal allergies reported that their reading was greatly affected? 50% 70% 80% 85%
7. ❑ ❑ ❑ ❑
In Dr. Osler’s Harvard University study concerning seasonal allergies, Claritin® resulted in what percentage of decrease in tear volume? 22% 34% 44% 56%
8. ❑ ❑ ❑ ❑
Giant papillary conjunctivitis (GPC) is characterized by all of the following, EXCEPT: Large papillae on the upper tarsal plate Mucin discharge Ocular swelling Decreased contact lens wearing time
9. ❑ ❑ ❑ ❑
In Dr. Bartlett’s study on GPC, Lotemax resulted in what percentage of IOP increase from baseline? 5% 6% 7% 8%
10. ❑ ❑ ❑ ❑
Which of the following describes the profile of a patient with vernal keratoconjunctivitis (VKC) Male children between the ages of roughly 4 and 16 Female children between the ages of roughly 4 and 16 Male children between the ages of roughly 5 and 17 Female children between the ages of roughly 5 and 10
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4. ❑ ❑ ❑ ❑
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Clinical & Refractive Optometry is pleased to present this continuing education (CE) article in the form of a Meeting Report based on a presentation given by Dr. Benjamin J. Barrus entitled The Science of Dry Eye Hyperosmolarity at the CRO 2016 Meeting in Vancouver, BC on May 16, 2016. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 207 for complete instructions.
The Science of Dry Eye Hyperosmolarity Benjamin J. Barrus, BSc, BOptom (Hons), OD
INTRODUCTION Dr. Barrus began his presentation by pointing out that dry eye is a common disease in Calgary, where his practice is located, which has a significant negative impact on patients’ quality of life. An important role for optometrists, he said, is to “own” patients’ dry eye problem and provide the best available options for relief. He treats every dry eye patient differently because every individual case is different and requires its own careful workup and differential diagnosis. On average, he sees about four dry eye patients per day. Dr. Barrus recommended that dry eye symptoms be assessed in a follow-up appointment rather than as a component of a standard eye exam. This ensures there will be enough time to conduct a proper assessment and educate the patient about the pathology of the condition. He often uses images to help patients understand the condition, including images he takes himself while expressing their meibomian glands, so patients can better understand gross meibomian gland dysfunction (MGD). He also takes images of keratitis he identifies in contact lens wearers to show to patients. He finds that allowing patients to visualize what is happening in their eyes improves both understanding and compliance.
SELECTING TESTS AND EQUIPMENT Many clinical definitions of dry eye and “cookbooks” on its diagnosis and treatment are available, said Dr. Barrus, but to really learn how to manage the condition, optometrists require direct clinical experience. He recommended that optometrists new to the management of dry eye disease wait before investing in expensive diagnostic equipment. Rather, they should take a few months to decide if they want to focus on dry eye and consider what tests, tools, and equipment they have available already before making a large investment. Consider carefully what each test is measuring and diagnosing, he said. B.J. Barrus — IRIS The Visual Group, Calgary, AB Correspondence to: Dr. Benjamin J. Barrus, Chinook Centre, 148A - 6455 Macleod Trail South, Calgary, AB T2H 0K9; E-mail: drbenbarrus@gmail.com Dr. Barrus has no financial interests in any businesses or products mentioned in this meeting report. This article has been peer reviewed.
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A battery of tests is needed to thoroughly benchmark the different components of tear film, said Dr. Barrus. “Paint yourself a good picture,” he recommended. Tear film breakup time (TFBUT) testing identifies the presence of a problem but does not pinpoint precisely what the problem is or even its severity. Let patient presentation guide test selection, he advised. Overall, he performs about five to seven tests on each new dry eye patient to create a diagnostic differential list and determine with which clinical component to move forward. Testing mucin layer can be particularly challenging because good, definitive tests are lacking in this area now that rose bengal staining is no longer available, said Dr. Barrus. He pointed out that rose bengal staining devitalizes cells in the absence of a functional mucin layer rather than simply identifying dry eye damaged cells, as many have been taught. In fact, both sodium fluorescein and rose bengal devitalize epithelial cells. He recommended using lissamine green instead, since it does not kill epithelial cells. He explained that it can be obtained from compounding pharmacies but it is expensive, costing upward of $90 for a 15 mL bottle. Fortunately, only onehalf drop is required for testing. When developing a consistent practice, said Dr. Barrus, try to choose tests that themselves offer consistency, including both intra- and inter-operator repeatability. Lack of both intra- and inter-operability, for example, are why Dr. Barrus avoids the Maddox rod test — two different operators performing the test or even the same operator performing the test twice on the same patient at two different time points often obtain two different results. Dr. Barrus uses the lid expression test, but he acknowledged it also has poor repeatability because there is no standard for grading it. Fluorescein staining has the same limitation if grading systems are not incorporated in practice. This is one reason why new dry eye practitioners should wait before investing in expensive equipment. It is better to take a few months to learn about available tests and what their strong and weak points are before investing in them. Valuable tests, according to Dr. Barrus, include meibography, meibum expression, tear interferometry, and Schirmer’s test. Dr. Barrus gives every patient undergoing an initial assessment for dry eyes a Schirmer II
Tear Osmolarity “The most accurate way to test for DED” • salt (by far biggest driver) = ~ 95% • proteins < 2% • sugars < 2%
• lipids < 2% • mucins < 2%
Main concentration of electrolytes in the tear film Concentration in mmol/kg Na+
K+
120-170
6-42
Ca2+
µmol/kg Mg2+
Zn2+
0.3-2.0 0.3-1.1 50-100
Mn2+
mmol/kg CI–
0.2-0.9 106-135
HCO3–
PO43–
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Fig. 1 Compounds that contribute to tear osmolarity. (Tomlinson A et al. Tear film osmolarity: determination of a referent for dry eye diagnosis. Invest Ophthalmol Vis Sci 2006; 47(10): 4309-4315. Lemp MA et al. Tear osmolarity in the diagnosis and management of dry eye disease. Am J Ophthalmol 2011; 151(5): 792-798. Stahl U et al. Osmolality and tear film dynamics. Clin Exp Optom 2012; 95(1): 3-11.)
(not Schirmer I) test, with anesthetic, to identify potential autoimmune dysfunction aqueous deficiency. This effectively narrows down the potential pathology and provides a framework for moving forward. He said that he recommends Schirmer’s tests to optometrists across the country because of its high validity in diagnosing aqueous deficient variants of dry eye. For meibography, Dr. Barrus said he usually refers patients to an ophthalmologist because the equipment is so expensive for most clinics. “Pick your easy options, and upgrade your clinic as you go along,” he recommended. Focus on simple, clinical tests over spending money.
DEVELOPING CONSISTENT PROCESSES FOR DRY EYE MANAGEMENT Optometrists should develop their own processes or “cookbooks” for managing dry eyes, recommended Dr. Barrus. He emphasized the creation of repeatable habits and processes based on evidence. “When you start doing the same thing over and over and over, you get an intuitive sense of normal vs. abnormal,” he explained. This involves developing automatic systems while also actively considering differential diagnoses rather than just functioning in “robot mode.” It is important to complete every step, every time, without skipping anything to develop an instinct, he said. It is also important to understand the underlying rationale for each step.
PATHOLOGIES OF DRY EYE Some dry eye pathologies, said Dr. Barrus, will repair themselves when other pathologies are addressed. For instance, a patient with a poor TFBUT, elevated high tear osmolarity (e.g., 310 to 315 mOsm/L), and MGD should first be treated with the easiest to manage aspect of the pathology, which in this case is MGD. Getting the gland to express cleanly and giving patients omega-3’s will frequently also improve tear osmolarity because the pathologies overlap. Thus, it is possible to synergistically treat patients by understanding their underlying pathologies.
Dr. Barrus pointed out that there are multiple interlinked components to dry eyes, and both patients and optometrists must understand the components as a whole in order to create a “pattern of understanding” of the pathology. This understanding helps patients recognize, for instance, the importance of yearly follow-up visits. He used the analogy of good dental care to explain that treating dry eyes involves both good maintenance (i.e., teeth brushing) and repairing pathologies as they arise (i.e., filling cavities). While there is no cure for dry eyes, the condition can be managed effectively with this approach.
PATIENT EDUCATION The ongoing inflammatory cycle creates a negative feedback loop that can worsen and result in severe pathology, warned Dr. Barrus. Patients may have extremely short TFBUT but insist they do not have dry eyes because they have no symptoms. In such cases, optometrists must explain to them that the pathology is present in a severe form and must be treated. Patient education is paramount. He emphasized that patients must be educated about early symptoms of dry eyes, such as blurry vision, the need to blink more often, red eyes at the end of the day, and eye strain so they can return for an appointment when needed.
TEAR OSMOLARITY Dr. Barrus explained that osmolality is defined as the number of osmoles in a solute by mass of solvent, while osmolarity is the number of osmoles in a solute by volume of solvent. They both reflect the same concept, but one is expressed by mass and the other by volume. For practical purposes, he said, the difference is not important. Tear osmolarity refers essentially to the salt content of tears, he said. An eductational analogy he often uses in clinic is the saltiness of sea water. Increasing salt (i.e., Atlantic/ Mediteranean/Red Sea/Dead Sea) changes the properties of the water, causing it to increase buoyancy as well as burn the eyes. Similarily, as tear salt concentration increases, so do burning symptoms and damage to cellular structures in the eye. Salts present in tears include sodium chloride (NaCl), potassium chloride, and bicarbonate. Other compounds, including proteins, sugars, lipids, and mucins, are also present but in such low concentrations as to be clinically irrelevant because they do not contribute to osmotic pressure difference (Fig. 1). When a salt comes into contact with water, it breaks into its component electrolytes (e.g., NaCl breaks up into Na+ and Cl–). This means a single molecule of a salt actually creates the pressure of two within the eye. It is important to explain this concept to patients, using layman’s terms, said Dr. Barrus.
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Osmolarity All Studies 1978-2005
Probability
Normal eyes Mean = 302.2 SD = 9.7
Dry eyes Mean = 326.9 SD = 22.1
260
280
300
320
340
360
380
400
Osmolarity (mOsm/L) Fig. 2 Normal distribution of tear osmolarity across studies conducted from 1978-2006 – normal eyes vs. dry eyes. (Baudouin C, et al. Role of hyperosmolarity in the pathogenesis and management of dry eye disease. Ocul Surf 2013; 11: 246-258.)
MEASURING TEAR OSMOLARITY Historically, said Dr. Barrus, tear osmolarity has been tested using freezing point depression and vapor pressure depression, but this requires massive machinery. In the past five years, newer technologies using electrical conductivity to determine differential and osmotic balance have become available. Osmolarity can be measured using osmometers that use electroconductivity to charge particles in tears and determine their concentration based on the degree of resistance to an electric charge. The TearLabTM Osmolarity System (San Diego, CA) works in this manner. For this device, tears must be placed into the device. Another osmometer is the i-Pen® (I-MED Pharma, Montreal, QC), which tests tears in situ. The National Dry Eye Disease Guidelines for Canadian Optometrists, published in the Canadian Journal of Optometry is a definitive, easy-to-follow guide to the management of dry eye disease, said Dr. Barrus. It states that tear film osmolarity is the most accurate single test for dry eye disease. As a result, a tear osmolarity machine is an important investment for every dry eye clinic, he added.
TEAR OSMOLARITY LEVELS Christophe Baudouin has conducted several studies on tear osmolarity testing, reported Dr. Barrus. His work has demonstrated that optimum osmolarity varies from study to study, depending on how it was tested (Fig. 2). Conductivity osmometers, for instance, generally produce lower readings than freezing point or vapor pressure osmometers because there is a lower limit to what they can read. Normal osmolarity is estimated to be approximately 300 mOsm/L. For dry eye patients, osmolarity is an average of about 326 mOsm, with a standard deviation of 22.
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The osmolarity of blood is approximately 290 to 295 mOsm, so that is the ideal osmolarity of tears. The fact that the average tear osmolarity is closer to 300 mOsm/L reflects the fact that tears are an open system and that everyone experiences at least some evaporative dry eye, said Dr. Barrus. This varies from region to region depending on ambient humidity levels. An individual’s tear osmolarity will also fluctuate during the day depending on their environment. Dry office air, for instance, can increase osmolarity. This means tear osmolarity values will vary depending on the time of day patients are tested and what they were doing beforehand. It is possible to obtain normal tear osmolarity results first thing in the morning for a patient who experiences dry eye symptoms toward the end of the workday. In such cases, it is important to educate the patient and book appointments for the time of day when symptoms are in evidence. Dr. Barrus said he finds it particularly important to see nurses and doctors at the end of their shifts because the nature of their work and the dry hospital air is particularly conducive to severe dry eye symptoms. It is important to “think outside the box” when treating dry eye patients, said Dr. Barrus. For instance, he said he finds he is only able to manage nurses’ dry eye symptoms using bandage contact lenses or scleral lenses. He tells dry eye patients not to sleep with a fan at night, as this can contribute to dry eye symptoms. Using a cool (not hot) mist humidifier instead can be helpful.
TEARLAB VS. i-PEN Dr. Barrus uses both the TearLab and the i-Pen devices in his practice. The TearLab has been available since about 2002 and thus has a long history of published evidence supporting its use, but the in situ testing is an advantage of the i-Pen because it tests hydrated porous tissue, not just an aliquot of tears. Both instruments have been approved by Health Canada. For both devices, proper technique is essential to obtaining proper results. To use the i-Pen, explained Dr. Barrus, the operator must tip the eyelid down and test against the tarsal conjunctiva on the inferior lid. Conversely, the TearLab draws straight out of the tear prism on the temporal aspect. It is important to train staff to use the devices properly and provide ample opportunity for practice. Expect that the first batch of tears collected by a novice operator will not provide valid results, he said. Accidentally rubbing against the edge of the eyelid margin with the TearLab will liberate dried salt resting there, producing falsely high results. Similarily, placing the i-Pen without the metal contacts having equal pressure on the palpebral conjunctiva will produce an error message. Since the two devices use different testing mechanisms, one cannot assume they will provide identical results. Dr. Barrus described his ongoing aftermarket clinical
Fig. 3 The appearance of a dry eye right after fluorescein instillation. (Abelson M.B. The pros and cons of dry-eye tests; August 2011; http://www.reviewofophthalmology.com/article/the-pros-and-cons-of-dry-eye-tests-29630)
correlation study of the TearLab vs. the i-Pen. So far, he has recruited about 80 patients. They are being tested using the TearLab first, followed by the i-Pen, because touching the inside of the eyelid with the i-Pen would disrupt the tear index, skewing the readings from a subsequent TearLab test. So far, results of the trial indicate that the two devices produce very similar results, with the i-Pen giving values marginally lower than those of TearLab.
IMPACT OF TEAR OSMOLARITY Tear osmolarity said Dr. Barrus, provides an indicator of where water is being stored within the eye. Only water and oxygen move freely through the tissues and membranes of the eye. Water is always drawn through membranes from areas of lower to higher salt concentration, he explained. Thus, an osmotic shift results in water loss within the cell, altering cell structures and reducing the ability of the cell to function properly. Unlike water, salts require an active pump for movement through cell membranes. Cells pump molecules through membranes to protect their cellular metabolites, enzymes, proteins, and DNA. Cell vacuoles draw nutrients from the bloodstream into the cells. Ideally, the osmolarity of interstitial fluid within the cells of the eye match that of the blood, at about 290 mOsm/L. When pathologies such as diabetes or kidney disease affect tear osmolarity, the cells of the eye are no longer able to draw the nutrients they need from the blood. The lacrimal gland stimulates tear production by secreting salt and other molecules into the central lumen. This in turn draws out fluid, producing a tear with an osmolarity of about 290 mOsm/L. Accessory glands in the conjunctiva stimulate that same tear production. Tears are
continuously produced to replace fluid lost to evaporation, creating an ongoing cascade. Mucin layer helps control local evaporation rate across the cornea by stabilizing aqueous adhesion to the ocular surface. Lipid layer further reduces general evaporation and improves consistency of the aqueous layer. A malfunction in any of these processes can disrupt tear osmolarity, explained Dr. Barrus. For instance, a poor mucin layer, small corneal defect, missing epithelial cell, or advanced MGD will all disrupt TFBUT. With evaporative dry eye, tears at the cornea can reach osmolarity levels of almost 600 mOsm/L during an inter-blink phase. This sectoral drying results in portions of the eye that are profoundly more irritated and damaged than other areas. Once the eye begins to lose epithelial cells from that irritation, it produces a vicious cycle of continued TFBUT disruption and further increased osmolarity and irritation. As a result, said Dr. Barrus, small areas of punctate staining in the nasal canthus on the conjunctiva can be a sign of the beginning of a degenerative process that will cascade across the cornea without intervention. Dr. Barrus said that research on tear osmolarity reveals that an imbalance in intracellular and extracellular osmolarity caused by tear osmolarity â&#x2030;Ľ 320 mOsm/L produces an inflammatory cascade, causing massive damage that impairs the ability of the epithelial cells to migrate across the cornea and re-epithelialize. It upregulates immune modulators (MMP-9s) and cytokines, damaging the structural framework of cells so that microtubules that provide cell structure stop functioning properly and may even disrupt DNA function. Without intervention, this process eventually leads to cell apoptosis, identified by diffuse punctate staining. Cells have the intrinsic ability to regulate their osmolarity, so why does this damage occur? asked Dr. Barrus. Studies show that massive epithelial loss occurs only with osmolarity < 270 msOm/L. Placing high osmolarity saline solution on the eye does not produce cell apoptosis. Thus, there remains much to be learned about the pathology of dry eyes, concluded Dr. Barrus. The condition requires further study.
EVALUATING DRY EYES Typically, patients in the early stages of dry eye have more pain than those in the later stages, and younger patients have more severe symptoms than older patients, said Dr. Barrus. When studying tears, it is important to take the necessary time to prepare the eye properly and look closely, he advised. The best staining analysis can be performed only after fluorescein dye has been in the eye for three to five minutes (Fig. 3). Avoid using too much fluorescein. Proper staining allows for the visualization of epithelial edema.
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Most dry eye clinics have patients who complain of dry eye symptoms, but testing does not reveal any abnormalities. It is important to take a second look at those patients because their symptoms indicate there is pathology present, recommended Dr. Barrus. Do not dismiss their symptoms or recommend use of drops with preservatives for relief, he warned. Ongoing exposure of the eye to preservatives causes almost as much stress to the cells as poor osmolarity. It is important not only to diagnose dry eyes but also to eliminate other pathologies, said Dr. Barrus. Symptomatic patients should have their tear osmolarity measured. He also tests how patients respond to Restasis® (cyclosporine ophthalmic emulsion 0.05%, Allergan Inc.) plus twice daily Lotemax® (loteprednol etabonate ophthalmic suspension 0.5%, Bausch + Lomb, Vaughan, ON) for one month, followed by Restasis® alone. After completing a 9 or 12 month Restasis protocol, patients may return complaining of eye pain as soon as they discontinue treatment, which provides insight into their underlying pathology.
NEURORECEPTORS Neuroreceptors are often overlooked in dry eye, said Dr. Barrus, but the cornea contains a high concentration of sensory nerve fibers. Mechano-nociceptors are preferentially activated by mechanical forces. Polymodal nociceptors respond to heat, exogenous irritant chemicals, and endogenous inflammatory mediators, and thermoreceptors are primarily activated by small reductions of the ocular surface temperature. All of these nerve fibers are disrupted by increased tear osmolarity, creating ongoing neuropathies that can persist even after the tear osmolarity is regulated. Damaged nerve fibers require time to heal. It takes about one year for nerve regeneration following ablation of corneal nerve fibers from laser treatment, for instance.
DRY EYE-LIKE PAIN Dry eye-like pain (DELP) is a new concept developed on by ophthalmologists in the United States, said Dr. Barrus. For patients with DELP, osmoprotectants help manage osmolarity, creating an iso-osmolarity environment, with 290 mOsm/L as the benchmark. Dr. Barrus warned against using eye drops which have an osmolarity < 290
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mOsm/L because these will force water into cells and stimulate cell apoptosis. Currently available osmoprotectants include sodium hyaluronate, which has been shown in studies to reduce immune responses. HYLO™DUAL (0.5 mg/ml sodium hyaluronate, 20 mg/ml ectoine, CandorVision, Montreal, QC) contains both hyaluronic and another osmoprotectants, ectoine. Other options are i-drop® Pur Gel (0.3% sodium hyaluronate and glycerin, I-MED Pharma, Montreal, QC) and Thealoz® (trehalose 3%, Labtician Ophthalmics, Inc., Oakville, ON). Can-C™ (glycerine 1%, carboxymethylcellulose sodium 0.3%, N-acetylcarnosine 1%, Profound Products) will soon be available on the market, said Dr. Barrus. N-acetylcarnosine is an antioxidant that has been studied in mice. The mice were placed in an environment with 12% ambient humidity and a temperature of 22ºC, which produced an upregulation of immune modulators in the eyes, including tumor necrosis factor (TNF)-a. Drops containing N-acetylcarnosine prevented this immune cascade. There have also been claims the product can cure cataracts, but Dr. Barrus recommended against using it for this indication until its efficacy has been proven. When sales representatives visit with products, he said, it is important to pay attention to the science behind the product and to vet the research presented. Ask to see the studies that they cite as their evidence so that you can review the literature yourself, he recommended Dr. Barrus added that dry eyes can also be treated with several alternative methods. These include heat packs and omega-3s, which reduce inflammation and promote nerve healing. Lubricants and autologous serums are also helpful. Dr. Barrus said he finds autologous serums to be very effective even for severe cases, but it is important to have them compounded by a pharmacist who knows how to do it correctly. It should be a 20% to 30% autologous serum that is pH matched with an osmolarity of 290 mOsm/L. Serum drops can promote increased healing of the underlying dry eye pathology.
CONCLUSION Dr. Barrus concluded by re-stating the importance of considering and investigating the underlying pathology of dry eyes and aiming to treat it, rather than just masking the disease with moisture drops. ❏
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QUESTIONNAIRE The Science of Dry Eye Hyperosmolarity Benjamin J. Barrus, BSc, BOptom (Hons), OD 1. ❑ ❑ ❑ ❑
Dry eye symptoms are BEST evaluated: When patients first complain of symptoms that suggest dry eye disease During a follow-up appointment dedicated to evaluating dry eye disease As one component of an overall eye exam First thing in the morning
2.
Based on the clinical experience of Dr. Barrus, approximately how many tests are typically required to accurately diagnose dry eye disease? 1-3 3-5 5-7 7-9
❑ ❑ ❑ ❑ 3. ❑ ❑ ❑ ❑
Which of the following tests are recommended for evaluating dry eye disease without risk of devitalizing epithelial cells? Rose bengal Maddox rod test Lissamine green Sodium fluorescein
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Which of the following is a limitation of the lid expression test? Poor repeatability Poor validity Lack of relevance for dry eye disease Widespread poor technique
5.
A patient who presents with poor tear film breakup time, elevated high tear osmolarity, and meibomian gland dysfunction should FIRST be treated: With an approach that addresses all these concerns at once For tear film breakup time For elevated tear osmolarity For meibomian gland dysfunction
❑ ❑ ❑ ❑ 6. ❑ ❑ ❑ ❑
According to The National Dry Eye Disease Guidelines for Canadian Optometrists, which of the following is the most accurate single test for dry eye disease? Tear film osmolarity Tear film breakup time Lissamine green Schirmer’s test
7. ❑ ❑ ❑ ❑
Based on research by Dr. Baudouin, normal tear osmolarity is estimated to be approximately: 280 milliosmoles per liter 290 milliosmoles per liter 300 milliosmoles per liter 310 milliosmoles per liter
8. ❑ ❑ ❑ ❑
Ideally, osmolarity of the interstitial fluid within the cells of the eye matches that of the blood, at: 280 milliosmoles per liter 290 milliosmoles per liter 300 milliosmoles per liter 310 milliosmoles per liter
9. ❑ ❑ ❑ ❑
Patients with dry eye disease typically have more severe symptoms: If they are older If they are male When they first wake in the morning When they are in the earlier stages of the disease
10. ❑ ❑ ❑ ❑
All of the following are recommended alternative methods of treating dry eye disease EXCEPT: Heat packs Artificial tears with preservatives Omega 3-s Lubricants
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4. ❑ ❑ ❑ ❑
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