CRO - Volume 26, Number 2, 2015 by MediConcept

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Clinical & Refractive Optometry Online VOLUME 26, NUMBER 2, 2015

CLICK HERE TO DOWNLOAD AND PRINT THIS ISSUE The Role of Ointments in Clinical Practice A Case Report: Malignant Hypertension and Bilateral Serous Macular Detachment Posterior Reversible Encephalopathy Syndrome Differential Diagnosis and Management of Orbital Apex Syndrome

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Clinical&Refractive Optometry: Online Edition Editorial Board • Volume 26, Number 2, 2015

Editor-in-Chief

Associate Editor

Yvon Rhéaume, OD Montreal, Quebec

Richard Maharaj, OD Toronto, Ontario

Leonid Skorin, Jr., OD, DO, MS Albert Lea, Minnesota

Editors Emeriti John Jantzi, OD Vancouver, British Columbia

Brad Almond, OD Calgary, Alberta

Barbara Caffery, OD Toronto, Ontario

Contributing Editors Jean Bélanger, OD Montreal, Quebec

Paul Dame, OD Calgary, Alberta

Gerald Komarnicky, OD Vancouver, British Columbia

Rodger Pace, OD Waterloo, Ontario

Scott D. Brisbin, OD Edmonton, Alberta

Danielle DeGuise, OD Montreal, Quebec

Bart McRoberts, OD Vancouver, British Columbia

Maynard Pohl, OD Bellevue, Washington

Lorance Bumgarner, OD Pinehurst, North Carolina

Pierre Forcier, OD Montreal, Quebec

Ron Melton, OD Charlotte, North Carolina

Barbara Robinson, OD Waterloo, Ontario

Louis Catania, OD Philadelphia, Pennsylvania

Guy Julien, OD Montreal, Quebec

Langis Michaud, OD Montreal, Quebec

Jacob Sivak, OD, PhD Waterloo, Ontario 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: Online Edition 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.

About This Issue This online issue of CRO (Clinical & Refractive Optometry) is being sent to you at no charge with the compliments of the CSCRO (Canadian Society of Clinical & Refractive Optometry). Each of the scientific articles contained in this issue have been approved by COPE for 1-hour of CE credit and are available at a cost of $25 per course. To take any of the CE credit courses in this issue, please follow the instructions on the test questionnaire pages. Please note that you can upgrade to a print edition subscription to CRO (Clinical & Refractive Optometry) which includes prepaid CE credit courses in every issue. For more details and to subscribe, please see the subscription upgrade offer on the next page.

Clinical&Refractive Optometry: Online Edition Contents • Volume 26, Number 2, 2015

The Role of Ointments in Clinical Practice Paul M. Karpecki, OD INTRODUCTION: Ophthalmic ointments have a long history dating back to ancient times and yet are still evolving with recent approvals involving technologies that allow the medication to be preservative-free. The understanding of the use, positive characteristics and side effects has also evolved to better help us position these products to most assist our patients with ocular diseases.

A Case Report: Malignant Hypertension and Bilateral Serous Macular Detachment Petra Jo, OD; Richard G. Gardner, OD ABSTRACT: Malignant hypertension is a medical emergency affecting 1% of the hypertensive population. We present the case of a 44-year-old African-American male who was referred to the Dorn VA Medical Center emergency room following an eye exam and diagnosis of acutely elevated blood pressure by a civilian optometrist. This case report depicts an uncommon ophthalmic complication of malignant hypertension and reviews the proper management of such patients.

Posterior Reversible Encephalopathy Syndrome Sarah E. Shim, OD; Pauline F. Ilsen, OD ABSTRACT: Posterior reversible encephalopathy syndrome is a state of reversible vasogenic edema predominantly in the posterior circulation territories reflected by its unique pattern in magnetic resonance imaging. It is a neurotoxic state associated with clinical conditions such as malignant hypertension, eclampsia/ pre-eclampsia, autoimmune diseases, immunosuppressive medications, infections, organ transplant, or chemotherapy, and is accompanied by complex of symptoms such as vision loss, other visual disturbances, seizures, headaches, or altered mental status.

Differential Diagnosis and Management of Orbital Apex Syndrome Denise Goodwin, OD; Tracy C. Doll, OD

Clinical & Refractive Optometry: Online Edition is published 4 times per year by Mediconcept. The Journal is made available to all optometrists on www.crojournal.org. 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: Online Edition 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 2113 St. Regis, Suite 250 Dollard-des-Ormeaux, Quebec Canada H9B 2M9 Tel.: (514) 447-1110 E-mail: info@mediconcept.ca Printed in Canada. All rights reserved. Copyright © 2015 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.

ABSTRACT: Orbital apex syndrome is a rare condition that presents with a set of symptoms that include visual loss, ophthalmoplegia, periorbital pain, ptosis, proptosis, and upper eyelid and forehead anesthesia. We report here on a case of a patient who presented with periorbital pain, ophthalmoplegia and acute visual loss in the setting of a latent tuberculosis infection.

News & Notes Dr. George Woo Receives Distinguished Asian Pacific American Alumni Award; Johnson & Johnson Vision Care to be Headline Sponsor of the 1st World Congress of Optometry; Registration Now Open for International Vision Expo West

ISSN: 1705-4850; Date of Issue: June/July 2015

Cover Image Exposure keratopathy in a 52-yearold patient with an incomplete blink secondary to Bell’s palsy. Courtesy of: Dr. Paul M. Karpecki

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Clinical & Refractive Optometry: Online Edition is pleased to present this continuing education (CE) article by Dr. Paul M. Karpecki entitled The Role of Ointments in Clinical Practice. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 42 for complete instructions.

The Role of Ointments in Clinical Practice Paul M. Karpecki, OD, FAAO

INTRODUCTION Ophthalmic ointments have a long history dating back to ancient times and yet are still evolving with recent approvals involving technologies that allow the medication to be preservative-free. The understanding of the use, positive characteristics and side effects has also evolved to better help us position these products to most assist our patients with ocular diseases. New products of the future, may further change how ophthalmic ointments are utilized and help in treating some of the most common as well as most severe ocular pathologies we face.

THE HISTORY OF OPHTHALMIC OINTMENTS In Egypt in 1500 BC, the first notations of something that might resemble an ophthalmic ointment was noted. A thick eye paste consisting of antimony or the soot from incense and oil applied to the brow and lid margins was used to protect the eye from sun glare and infections.1 Castor seeds or ricinus communis, were found in Egyptian tombs dating back to 4000 BC so ointments could have gone back even further, but there is no specific evidence the oils were used for the eye. They were likely also used in India since they are indigenous to that location. Even natural made ointments (from plants for example) were documented in Egypt in ancient times. Collyrium, which means eyewash, is found in Hippocratic books dating back about 2000 years. Romans specifically documented the term collyriums that involved the use of eye salves,

P. M. Karpecki — Cornea Services and Clinical Research Director, Koffler Vision Group, Lexington, Kentucky Correspondence to: Dr. Paul M. Karpecki, Koffler Vision Group, 120 N. Eagle Creek Drive, Suite 431, Lexington, KY 40509; E-mail: paul@karpecki.com Dr. Karpecki is a consultant to Bausch & Lomb, Allergan, Alcon, AMO, OcuSoft, Shire, Akorn, Focus Laboratories. This article has been peer-reviewed.

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pastes and ointments from 31 BC to 312 AD.1 Although they may have used the word collyrium to refer to the vehicles that held the ointments that today may be considered the bottle or droppers. Petroleum jelly, the precursor to most ointments used today, was first patented in 1872 (U.S. Patent 127,568). But it was not until the early 1900’s that tear substitutes like sodium chloride were introduced to make eye ointments and drops more similar to our natural tears.2 And in the 1930’s viscosity agents like gelatin and methylcellulose were introduced.2 Today, ophthalmic ointments are a mainstay and a key vehicle for the management of various ocular conditions.

ADVANTAGES AND DISADVANTAGES OF OINTMENTS Benefits of ointments include an increased contact time and the potential to provide an added barrier or protection to the ocular surface. Increased contact time allows for the drug to reside longer in the vehicle and be available for absorption.3 Studies have shown a higher concentration of fluoromethalone in the anterior chamber when an ointment vehicle is used compared to that of the same drug in a suspension.4 Another advantage is that ointments are easier for patients to apply compared to instilling drops. In one particular study involving post-cataract surgery patients not only was patient satisfaction higher with a ‘bandage ointment’ (meaning a thick ointment coverage of the eye) over drops, but patients described significantly less postoperative pain and discomfort — especially in the first 10 hours after the procedure.5 Studies have also found ophthalmic ointments to be as good or superior to pressure patching when comfort and healing was measured in patients with traumatic corneal abrasions.6 In one particular study comparing relatively similar abrasion sizes, the group receiving ophthalmic ointments had significantly less pain and faster epithelial healing than the pressure patched group at all time points measured.7 Disadvantages of ointments include blurred vision and tear film instability. In a study involving the use of day time artificial tears for dry eye sufferers, patients using artificial tear ointments had a much lower level of

Fig. 1 Exposure keratopathy in a 52-year-old patient with an incomplete blink secondary to Bell’s palsy.

Fig. 2 A patient with significant scarring secondary to longstanding nocturnal lagophthalmos being treated with ointments overnight.

compliance than those using artificial tears in the drop formulation.8 This is likely due to blurring of vision that may occur with more viscous ointments.9 For that reason many clinicians recommend artificial tear ointments at night in less severe ocular surface disease conditions. That provides greater coverage during sleep and may serve a protective role in patients with lagophthalmos.10 Patients may report that ointments can be messy if too much is applied and may get on their pillows or in their hair, so appropriate instructions as to the proper amount of ointment to be applied is imperative. Patients should apply the ointment into the lower fornix not overfill the fornix. Typically about a 1/4 inch strip or one line of ointment from the dispenser is recommended into the lower fornix and sometimes a 1/2 inch strip for more significant ocular diseases. Also the use of ophthalmic ointments will not work well in patients wearing contact lenses such as with a bandage lens as it may coat the lens or dislodge it.11 Ointments, because of the increased contact time, could result in an allergic or toxic reaction, especially for those preserved with benzalkonium chloride when used longterm.12 And long-term use of steroid ointments can lead to thinning of the epidermis of the skin tissue.13 Finally ointments should not be injected into the anterior segment after a surgical procedure for example, as the vehicle may result in toxic anterior segment syndrome.14 As an example, ophthalmic ointments can cover or protect the cornea in cases of exposure keratopathy/ lagophthalmos, trauma, infection, eyelid tumors, incomplete blink or a whole host of other contributing conditions (Fig. 1).15,16 Ointments have been particularly effective for patients suffering from nocturnal lagophthalmos because of their residence time in protecting the inferior cornea during sleep (Fig. 2).15

Ophthalmic ointments are routinely used after various surgical procedures,17 and in neonatal applications.18 The most common surgical procedure that involve ophthalmic ointments are typically those performed by oculoplastic surgeons, such as a blepharoplasty. The ointments, which are more typically antibiotic ointments like erythromycin, but may include OTC ointments like lacrilube, help in lubricating the skin tissues and may decrease the irritation and dryness surrounding the incisions. The antibiotic ointments of course serve a prophylactic role in preventing an infection. Neonatal applications of ophthalmic ointments date back to a need that was discovered in the late 1800s. Although antibiotics were not invented until the mid1900’s, the incidence of ophthalmic neonatorum (ON) was about 10% at that time resulting in corneal damage to 20% of those infected and blindness to 3%.19 The cause of ON was found to be the bacteria, nisseria gonorrhea. At that time silver nitrate 2% was introduced to prevent ON and turned out to be effective against gonorrhea resulting in a significant decrease in the incidence of ON.19,20 Topical tetracycline ointment was also used extensively in other parts of the world with good efficacy.20 However currently Chlamydia is the most common cause of ON and was resistant to silver nitrate. With the invention of antibiotics in the mid 1900’s, erythryomycin ointment became the traditional method of prophylaxis at birth. It had advantages in that it prevented ON from chlamydia and was not as toxic or uncomfortable as silver nitrate.21 It is still used today on almost every birth in Canada and the US. Perhaps one of the most common uses of ophthalmic ointment is for lid diseases such as blepharitis.22 Blepharitis can be divided into anterior and posterior forms. Although ophthalmic ointments may work for both

The Role of Ointments in Clinical Practice — Karpecki

Fig. 3 Anterior Staphylococcal blepharitis.

Fig. 4 Demodex blepharitis.

forms, it can also cause blurring of vision if used in the eye such as for posterior blepharitis or meibomian gland dysfunction (MGD). Thus for anterior blepharitis, it holds numerous advantages including effectiveness, contact time and benefits against multiple forms of the disease. The most common cause of blepharitis is from staphylococcus (Fig. 3) and many ointments including bacitracin, tobramycin and erythromycin are effective against gram positive pathogens. Although clinicians should be cognizant of multi-resistant staphylococcus such as MRSA/MRSE as an occasional culprit and thus culturing non-responsive cases may be prudent.23 In these cases none of the aforementioned antibiotics would likely treat the condition.24 Compounded vancomycin or polytrim or other medications known to be effective against MRSA and MRSE would be required. One particular study in 2007 showed that of 915 ocular disease cases involving Staphylococcus aureus isolates, that 88 were MRSA. Of this group the most common ocular condition was blepharoconjunctivitis with 78% of the group that had MRSA, manifesting this ocular condition involving blepharitis.25 Also combination agents such as tobramycin dexamethasone ointment have been shown to be effective in blepharitis.26 In one study on 148 patients randomized to tobramycin dexamethasone ointment versus placebo, the group actively treated had a statistically significant improvement in both signs and symptoms even though both groups used warm compresses, mechanical washing of the eyelids and artificial tears. However it is important to note that the group treated with tobramycin dexamethasone had a significant elevation in IOP was 3.7% compared to 1.5% in the placebo group.26 Patients known to have significant demodex (Fig. 4) have a very high association with blepharitis.27 Although this condition often requires tea tree oil to achieve an effective cure,

there is some thought that ointment can play a secondary role in suffocation of the nits associated with the disease. Likewise although even more rare, pediculosis caused by pubic lice on the eyelashes requires a bland ointment to assist in suffocating the eggs that are present.28 Other areas of application may include allergic eye diseases including giant papillary conjunctivitis,29 vernal keratoconjunctivitis,30 atopic keratoconjunctivitis,31 and even more severe forms of seasonal allergic conjunctivitis.32 Finally corneal conditions (Fig. 5) are a major area of treatment given the contact time and protection of ointments. Conditions where ointments have been shown to be effective include filamentary keratitis,33 keratoconjunctivitis sicca,34 corneal staining and corneal abrasions.35

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MOST COMMON USES OF OPHTHALMIC OINTMENTS AND POTENTIAL APPLICATIONS One of the most common applications for ophthalmic ointments is that of blepharitis, although new understanding and research in the field of lid margin disease is now changing our treatment paradigms. For acute cases of blepharitis, often presenting as blepharoconjunctivitis, a pure antibiotic ointment is often sufficient to treat most bacterial pathogens. Variance of this include angular blepharitis and once again were effectively treated with an antibiotic ointment. Combination ointments were primarily used in conditions that involved both an infectious process combined with inflammation. This was often prescribed for conditions such as anterior blepharitis. But overuse and greater contact times could lead to bacterial resistance.36 As new understanding has developed in the role of meibomian gland dysfunction or posterior blepharitis and the role of inflammation, a shift to steroid only â&#x20AC;&#x201D; monotherapy ointments is occurring. For example,

Fig. 5 Severe exposure keratopathy resulting in epithelial erosion.

Fig. 6 Peripheral synechia in a patient with anterior uveitis secondary to Crohnâ&#x20AC;&#x2122;s Disease.

patients with morning symptoms and a diagnosis of MGD tend to find their symptoms improve significantly with an overnight steroid ointment. Other novel application include the use of steroid ointments for the treatment of noninfectious anterior uveitis. In the past, steroid drops were primarily used aggressively, with dosing of Q2H or Q1H being typical, but then no treatment was administered overnight. The corollary to anterior uveitis on the infectious side would be a keratitis/corneal ulcer. As clinicians we always consider overnight drops or ointments in the management of a bacterial ulcer. Likewise it makes sense to apply an ointment overnight combined with steroid drops Q1H or Q2H during the day in the management of anterior uveitis. Since incorporating this into my clinic, which has a large uveitis population, I have seen a dramatic improvement in the resolutions of anterior chamber cell and flare as well as breaking of synechiae over the last 3 to 4 years (Fig. 6). Future study is warranted but the improved treatment results of the addition of a steroid ointment are unmistakable.

treated patients than vehicle treated patients had complete resolution of ACI and zero pain at day 8 (p<0.0001 for both). Fewer Lotemax patients had ocular adverse events (p<0.0001) and fewer required rescue medications compared to the placebo group. The most common adverse events included anterior chamber inflammation, photophobia, corneal edema, conjunctival hyperemia, eye pain and iritis. Four patients had an increase in IOP more than 10 mmHg of which three of the patients were in the LE-ointment group and one was in the placebo group. Perhaps the reason for such a low IOP rise in over 400 patients may be due to the fact that loteprednol is an ester based steroid. Ester-based steroids (loteprednol) unlike ketone-based steroids (prednisolone, fluoromethalone, dexamethasone), can have their metabolites broken down by the naturally occurring esterases.37 I think this is established because these metabolites do not remain, they are less likely to reach receptors that could result in increased intraocular pressure or be likely to create a Schiff base that could result in posterior sub capsular cataract development.38 Studies comparing ester based steroids to ketone based steroids showed half the incidence of significant IOL elevation.39 Another study comparing healthy adults showed a 7.48% incidence of IOP rise greater than 10 mmHg for patients on dexamethasone, compared to 1.95% for patients on loteprednol, but yet the efficacy of each drug in controlling inflammation was found to be the same.40 A multicenter, randomized, parallel-group, clinical trial comparing the safety and efficacy of loteprednol etabonate 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the treatment of Chinese patients with blepharokeratoconjunctivitis. LE-ointment has also shown a very favorable safety profile consistent with previous studies on loteprednol suspension. It has

NEW DEVELOPMENTS IN OPHTHALMIC OINTMENTS Just recently LotemaxÂŽ ointment (Bausch + Lomb, Vaughan, ON) was approved in Canada, which is the first new ophthalmic ointment approved in over a decade. Safety and efficacy was conducted comparing loteprednol etabonate ophthalmic ointment 0.5% (LE ointment) to the vehicle for the treatment of inflammation and pain following cataract surgery in 805 patients. Efficacy outcomes included the proportion of patients with complete resolution of anterior chamber inflammation and the proportion of patients with no (grade 0) pain at postoperative day 8. Safety outcomes looked at adverse events, ocular symptoms, intraocular pressure changes and visual acuity (VA). Significantly more LE ointment

The Role of Ointments in Clinical Practice â&#x20AC;&#x201D; Karpecki

Table I Ocular conditions and their recommended treatment agents Acute blepharoconjunctivits: Antibiotic ung applied to eyelid and eyelashes QHS or BID for 10-14 days. Chronic blepharitis: Antibiotic/steroid combination ointment applied to eyelid/eyelash area QHS or BID x 10-14 days, if further treatment is required for inflammation, consider a steroid ung QHS. Nocturnal lagophthalmos: Bland ointment QHS (Ocunox as an effective preservative-free example) with or without eyelid taping indefinitely. Anterior non-infectious uveitis: Prednisolone Forte Q1H or Q2H during the day + cycloplegia + overnight steroid ointment (Lotemax ung preferred) QHS. Taper slowly as improvement in anterior chamber cell and flare or breaking of synechiae occurs. Severe MGD/meibomitis: Commercial warm compress QD x 10 minutes, lid hygiene QD, combination drops BID and steroid ung QHS x 10-14 days then taper steroid options and maintain warm compresses and lid hygiene + artificial tears.

been shown to be effective and well tolerated by patients for the treatment of ocular inflammation following cataract surgery.41

phosphorous-free which can be especially important in post-traumatic cases such as post-surgical dry eye where calcium has been shown sometimes be released. Insoluble crystals can be formed due to the reaction of phosphorous with calcium and may impair your vision. This can also be applied to the eyelid margins if conditions such as seborrheic blepharitis where dry or chaffing skin is present.

CONCLUSION Although it is critically important for eye care practitioners to be aware of the various therapeutic agents available to them, it is also equally important to understand the vehicle that the drug resides in (Table I). It is important to have a protocol for knowing when to use drops versus ointments depending on the condition and how to best educate patients. Being aware of new ointments, understanding their advantages and disadvantages, can assist in making good clinical decisions. â??

REFERENCES 1. 2.

PRESERVATIVE-FREE INNOVATIONS Lotemax ointment is noted as being preservative-free even though it is not in a unit dose vial. This is possible because non-aqueous formulations cannot support microbial growth. A certain level of water, based on a ratio of vapor pressure of water in product to vapor pressure of pure water at the same temperature (known as aw) must be present for microorganisms to grow.25 Lotemax ointment does not reach that ratio. Microorganisms have been categorized with respect to their capacity to grow and produce metabolites in various conditions based on the aw ratio.25 Bausch + Lomb also conducted its own safety study were several lots of lotemax ointment were inoculated with various microorganisms including staphylococcus aureus, pseudomonas aeruginosa, e-coli, fusarium solani, serratia marcescens, stenotrophomonas maltophilia and bipolaris australiensis.42 The units were stared at 20-25 C and samples were tested at 7, 14 and 28 days post-inoculation by plating serial dilutions of sample aliquots on appropriate growth media and counting colony forming units (CFUs) following incubation. Results showed that growth of the microorganisms was not supported in any of the Lotemax ointment lots tested during all three time periods.26 Another innovation in preservative-free ointments is that of OcunoxTM (CandorVision, Montreal, QC). This product is meant for dry eye disease management as an overnight treatment. The formulation contains retinol palmitate or vitamin A, a natural component of tears that allows for better integration with a patients existing tear film. It also comes in a tube, not a vial, and was also created preservative-free. Furthermore, the formulation is

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12. 13.

Hirschberg, J. (1982). The History of Ophthalmology, Vol. 1: Antiquity. Bonn: Verlag J. P. Wayenborgh Caffery B. The history of dry eye diagnosis and management. Contact Lens Spectrum. January 1, 2000. Available at: http://www.clspectrum.com/printarticle.aspx?articleID= 11752. Accessed January 3, 2015 Scruggs J, Wallace T, Hanna C. et al. Route of absorption of drug and ointment after application to the eye. Ann Ophthalmol 1978; 10(3): 267-271. Sieg JW, Robinson JR. Vehicle effects on ocular drug bioavailability i: evaluation of fluorometholone. J Pharm Sci 1975; 64(6): 931-936. Sipos E1, Stifter E, Menapace R. Patient satisfaction and postoperative pain with different postoperative therapy regimens after standardized cataract surgery: a randomized intraindividual comparison. Int Ophthalmol 2011; 31(6): 453-460. Menghini M, Knecht PB, Kaufmann C. Treatment of traumatic corneal abrasions: a three-arm, prospective, randomized study. Ophthalmic Res 2013; 50(1): 13-18. Le Sage N, Verreault R, Rochette L. Efficacy of eye patching for traumatic corneal abrasions: a controlled clinical trial. Ann Emerg Med 2001; 38(2): 129-134. Swanson M. Compliance with and typical usage of artificial tears in dry eye conditions. J Am Optom Assoc 1998; 69(10): 649-655. Hiraoka T, Yamamoto T, Okamoto F et al. Tie course of changes in ocular wavefront aberration after administration of eye ointment. Eye 2012; 26(10): 1310-1317. Pereira MV, Gloria AL. Lagophthalmos. Semin Ophthalmol 2010; 25(3): 72-78. Donnenfeld ED1, Selkin BA, Perry HD et al. Controlled evaluation of a bandage contact lens and a topical nonsteroidal anti-inflammatory drug in treating traumatic corneal abrasions. Ophthalmology 1995; 102(6): 979-984. Tu EY. Balancing antimicrobial efficacy and toxicity of currently available topical ophthalmic preservatives. Saudi J Ophthalmol 2014; 28(3): 182-187. Shlivko IL, Kamensky VA, Donchenko EV, Agrba P. Morphological changes in skin of different phototypes under the action of topical corticosteroid therapy and tacrolimus. Skin Res Technol 2014; 20(2): 136-140.

14. Werner L, Sher JH, Taylor JR et al. Toxic anterior segment syndrome and possible association with ointment in the anterior chamber following cataract surgery. J Cataract Refract Surg 2006; 32(2): 227-235. 15. Katz J, Kaufman HE. Corneal exposure during sleep (nocturnal lagophthalmos). Arch Ophthalmol 1977; 95(3): 449-453. 16. Smith MF, Goode RL. Eye protection in the paralyzed face. Laryngoscope 1979; 89(3): 435-442. 17. Trussler AP, Rohrich RJ. Blepharoplasty. Plast Reconstr Surg. MOC-PSSM CME article: 2008; 121(1 Suppl): 1-10. 18. Faucher MA, Jackson G. Pharmaceutical preparations. A review of drugs commonly used during the neonatal period. J Nurse Midwifery 1992; 37(2 Suppl): 74S-86S. 19. Klauss V, Schwartz EC. Other conditions of the outer eye. In: Johnson GJ, Minassian DC, Weale R, eds. The epidemiology of eye disease. London, Chapman & Hall, 1998. 20. Laga M, Meheus A, Piot P. Epidemiology and control of gonococcal ophthalmia neonatorum. Bull World Health Organ 1989; 67(5): 471-477. 21. Darling EK, McDonald H. A meta-analysis of the efficacy of ocular prophylactic agents used for the prevention of gonococcal and chlamydial ophthalmia neonatorum. J Midwifery Womens Health 2010; 55(4): 319-327. 22. Remitz A, Virtanen HM, Reitamo S, Kari O. Tacrolimus ointment in atopic blepharoconjunctivitis does not seem to elevate intraocular pressure. Acta Ophthalmol 2010. Jan 8 23. Khan JA, Hoover D, Ide CH. Methicillin-resistant Staphylococcus epidermidis blepharitis. Am J Ophthalmol 1984; 98(5): 562-565. 24. Kejela T1, Bacha K. Prevalence and antibiotic susceptibility pattern of methicillin-resistant Staphylococcus aureus (MRSA) among primary school children and prisoners in Jimma Town, Southwest Ethiopia. Ann Clin Microbiol Antimicrob 2013; 12: 11. 25. Freidlin JL, Acharya N, Lietman TM. et al. Spectrum of eye disease caused by methicillin-resistant Staphylococcus aureus. Am J Ophthalmol 2007; 144(2): 313-315. 26. Yan XM1, Sun XG, Xie et al. Effects of tobramycin dexamethasone eye ointment for blepharitis: multi-center clinical trial. Zhonghua Yan Ke Za Zhi. 2013; 49(1): 16-21. 27. Zhao YE1, Wu LP, Hu L. Association of blepharitis with Demodex: a meta-analysis. Ophthalmic Epidemiol 2012; 19(2): 95-102.

28. Couch JM, Green WR, Hirst LW, de la Cruz ZC. Diagnosing and treating Phthirus pubis palpebrarum. Surv Ophthalmol 1982; 26(4): 219-225. 29. Kymionis GD, Goldman D, Ide T et al. Tacrolimus ointment 0.03% in the eye for treatment of giant papillary conjunctivitis. 30. Vichyanond P, tantimongkolsuk C, Dumrongkigchaiporn P. Vernal keratoconjunctivitis: Result of a novel therapy with 0.1% topical ophthalmic FK-506 ointment. J Allergy Clin Immunol 2004; 113(2): 355-358. 31. Nivenius E, van der Ploeg I, Jung K et al. Tacrolimus ointment vs steroid ointment for eyelid dermatitis in patients with atopic keratoconjunctivitis. Eye (Lond) 2007; 21(7): 968-975. Epub 2006 May 5. 32. Kari O, Saari KM. Updates in the treatment of ocular allergies. J Asthma Allergy 2010; 24; 3: 149-158. 33. Diller R, Sant S. A case report and review of filamentary keratitis. Optometry 2005; 76(1): 30-36. 34. Williams DL. A comparative approach to topical cyclosporine therapy. Eye (Lond) 1997; 11(Pt 4): 453-464. 35. Comstock TL, Paterno MR, Singh A. Safety and efficacy of loteprednol etabonate ophthalmic ointment 0.5% for the treatment of inflammation and pain following cataract surgery. Clin Ophthalmol 2011; 5: 177-186. Epub 2011 Feb 10. 36. Noah S. A primer on topical antibiotics for the skin and eyes. J Drugs Dermatol 2008; 7(4): 409-415. 37. Druzgala P, Wu WM, Bodor N. Ocular absorption and distribution of loteprednol etabonate, a soft steroid, in rabbit eyes. Curr Eye Res 1991; 10(10): 933-937. 38. Comstock TL, Decory HH. Advances in corticosteroid therapy for ocular inflammation: loteprednol etabonate. Int J Inflam. 2012; 2012: 789623. Epub 2012 Mar 28 39. Chen M, Gong L, Sun X et al. A multicenter, randomized, parallel-group, clinical trial comparing the safety and efficacy of loteprednol etabonate 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the treatment of Chinese patients with blepharokeratoconjunctivitis. Curr Med Res Opin 2012; 28(3): 385-394. 40. Holland EJ, Bartlett JD, Paterno MR, Effects of loteprednol/ tobramycin versus dexamethasone/tobramycin on intraocular pressure in healthy volunteers. Cornea 2008; 27(1): 50-55. 41. Troller JA. Trends in research related to the influence of “water activity” on microorganisms in food. Adv Exp Med Biol 1991; 302: 305-313. 42. Bausch & Lomb Inc. protocol #7066-R0498-LSG-041911-A

The Role of Ointments in Clinical Practice — Karpecki

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QUESTIONNAIRE The Role of Ointments in Clinical Practice Paul M. Karpecki, OD, FAAO 1. ❑ ❑ ❑ ❑

All of the following are advantages of ointments, EXCEPT: Added barrier of protection to the ocular surface Increased contact time Cost savings to patient Higher concentration of fluoromethalone in the anterior chamber

2. ❑ ❑ ❑ ❑

All of the following are disadvantages of ointment, EXCEPT: Blurred vision Lack of proven efficacy Tear film instability Inconvenience of application

3. ❑ ❑ ❑ ❑

All of the following statements about ointments are true, EXCEPT: They are particularly effective for patients with nocturnal lagophthalmos They are commonly used in blepharoplasty They can protect or cover the cornea in cases of incomplete blink They have shown a high level of efficacy with bandage lenses

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4. ❑ ❑ ❑ ❑

Conditions where ointments have been shown to be effective include all of the following, EXCEPT: Filamentary keratitis Corneal staining Corneal abrasions Cataracts

5. ❑ ❑ ❑ ❑

In clinical studies, ester-based steroids showed what percentage of IP elevation versus ketone-based steroids? 20% 30% 40% 50%

6. ❑ ❑ ❑ ❑

All of the following statements about ophthalmic ointments are true, EXCEPT: They are a treatment of choice as they rarely result in an allergic or toxic reaction Long-term use of steroid ointments can lead to thinning of the epidermis of the skin tissue Many clinicians recommend artificial tear ointments at night in less severe ocular surface disease conditions They may be as good or superior to pressure patching in patients with traumatic corneal abrasions

7. ❑ ❑ ❑ ❑

All of the following statements about the neonatal population and use of ointments are true, EXCEPT: Ointments are rarely used in neonatal settings because of potential toxicity among newborns Chlamydia is the most common cause of ophthalmic neonatorum (ON) Erythromycin ointment is less toxic than silver nitrate Erythromycin ointment is the traditional method of prophylaxis of ophthalmic neonatorum

8. ❑ ❑ ❑ ❑

Ointments may be used in all of the following conditions, EXCEPT: Blepharoconjunctivitis Infectious uveitis Meibomian gland dysfunction Angular blepharitis

9. ❑ ❑ ❑ ❑

For which of the following conditions is this treatment regimen used: Prednisolone Forte Q1H or Q2H during the day plus cycloplegia plus overnight steroid ointment (Lotemax® ung preferred) QHS? Chronic blepharitis Severe MGD/meibomitis Acute blepharoconjunctivitis Anterior non-infectious uveitis

10. ❑ ❑ ❑ ❑

All of the following statements about treatment regimens with ointments is true, EXCEPT: The shift to steroid-only monotherapy is increasing The trend toward combination therapy is increasing Overnight ointments combined with daytime steroid drops is a common regimen In acute cases of blepharitis, a pure antibiotic ointment is often sufficient

The Role of Ointments in Clinical Practice — Karpecki

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Clinical & Refractive Optometry: Online Edition is pleased to present this continuing education (CE) article by Dr. Petra Jo and Dr. Richard G. Gardner entitled A Case Report: Malignant Hypertension and Bilateral Serous Macular Detachment. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 50 for complete instructions.

A Case Report: Malignant Hypertension and Bilateral Serous Macular Detachment Petra Jo, OD; Richard G. Gardner, OD, FAAO

ABSTRACT Malignant hypertension is a medical emergency affecting 1% of the hypertensive population. Associated complications can include brain and cardiac damage, renal failure, pulmonary edema, and retinopathy. We present the case of a 44-year-old African-American male who was referred to the Dorn VA Medical Center emergency room following an eye exam and diagnosis of acutely elevated blood pressure by a civilian optometrist. Following blood pressure management, the patient was referred to our eye clinic for re-evaluation. Dilated fundus examination revealed hypertensive retinopathy with heavy macular and paramacular exudation. Cirrus optical coherence tomography revealed bilateral serous macular detachments. Upon two-month and five-month follow-ups, the exudates remain and the macular detachments were fully resolved with normalization of acuity in both eyes. This case report depicts an uncommon ophthalmic complication of malignant hypertension and reviews the proper management of such patients.

INTRODUCTION Hypertension affects 30% of adults in the United States, or more than 65 million Americans, and is a major risk factor for myocardial infarction, stroke and renal failure.1,2,3 The estimated prevalence of controlled hypertension among those affected is 44%.1 Malignant hypertension is a life-threatening condition that affects 1% of the hypertensive population, occurring more commonly in young African-American adults.4 It affects men two times more frequently than women and can arise de novo, from primary (essential) hypertension or from secondary hypertension.5,6 Clinically, patients P. Jo; R.G. Gardner — William Jennings Bryan Dorn VA Medical Center, 6439 Garners Ferry Road, Columbia, SC Correspondence to: Dr. Richard G. Gardner, William Jennings Bryan Dorn VA Medical Center, 6439 Garners Ferry Rd, Columbia, SC 29209; E-mail: Richard.Gardner@va.gov This article has been peer-reviewed.

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with malignant hypertension present with severely elevated blood pressure and may have a history of previously controlled hypertension.6,7 Patients may present with hypertensive retinopathy grade 3 or 4 as defined by the Keith-Wagener-Barker (KWB) classification system, cardiovascular and neurological complications, renal manifestations, and electrolyte/hematologic abnormalities.5,6 Additional symptoms may include generalized weakness, malaise, fatigue and weight loss.6 Decreased vision may be the presenting symptom in up to 35% to 60% of patients with malignant hypertension.6,7 This report presents a case of a patient with systemic malignant hypertension and hypertensive retinopathy with bilateral serous macular detachments. Blurred vision was the patient’s first presenting symptom prior to the diagnosis of malignant hypertension. Stabilization and control of his blood pressure led to the resolution of macular detachments and thus good visual prognosis. This report further discusses hypertensive crisis, as well as malignant hypertension and its ocular pathophysiology, association with macular detachments, and both systemic and ocular management.

CASE REPORT A 44-year-old African-American male presented to a civilian eye clinic for evaluation of blurred vision in both eyes (OU) and was then referred to the Dorn VA Medical Center emergency room for evaluation and management of acutely elevated blood pressure of 220/140 mmHg. Upon arrival to the emergency room, the patient’s blood pressure was 211/114 mmHg. The patient was diagnosed with uncontrolled hypertension and chronic renal failure, and was admitted to the hospital. Following blood pressure management while in the hospital for five days, the patient’s final diagnosis was malignant hypertension and his blood pressure at discharge was 115/69 mmHg. He was then referred to our eye clinic at the Dorn VA Medical Center for re-evaluation. The patient presented to our eye clinic two weeks after onset and complained of continued blurred vision OU. His blood pressure earlier at home was 127/73 mmHg. There was no personal or family ocular history. His medical history was significant for post-traumatic stress disorder, hydronephrosis, chronic glomerulonephritis, nephrotic syndrome, hyperlipidemia, hypertension, and

Fig. 1 Fundus photographs with corresponding horizontal optical coherence tomography (OCT) scans of our 44-year-old African-American male patient with malignant hypertension. (A) Fundus view of the right eye (OD) at initial exam demonstrates grade 4 hypertensive retinopathy (cotton-wool spots and hemorrhages in arcades, questionable disc edema and exudative macular star with retinal elevation). (B) The corresponding OCT OD shows a serous macular detachment with central macular thickness (CMT) of 435 µm. Note the intraretinal exudates and hyper-reflective subretinal fluid, where the fluid turbidity is suggestive of protein and fibrin leakage. (C) The fundus view OD two months after initial presentation shows similar retinal findings. However, retinal elevation of the macula is not clinically apparent. (D) OCT image confirms near resolution of the serous detachment, with possible trace subretinal fluid still present. Note the intraretinal exudates. The CMT is reduced from initial presentation to 218 µm. (E) Fundus photograph of the left eye (OS) demonstrates findings of grade 4 hypertensive retinopathy. (F) OCT OS confirms a serous macular detachment with CMT of 363 µm. (The OCT image is an artifact.) (G) Retinopathy and macular star OS continue to be present two months after initial visit. (H) Corresponding OCT scan OS reveals nearly resolved serous macular detachment with only trace subretinal fluid present and CMT decreased to 219 µm. Intraretinal exudates are also noted.

Malignant Hypertension and Bilateral Serous Macular Detachment — Jo, Gardner

Fig. 2 Horizontal optic coherence tomography (OCT) scans of maculae at a five-month follow-up from initial presentation in our patient with malignant hypertension and bilateral serous macular detachments. (A) No subretinal fluid is noted on an OCT image of the right eye. The macula appears flat with central macular thickness (CMT) of 219 µm. (B) OCT image of the left eye also demonstrates flat macula with no subretinal fluid. CMT measures 241 µm.

lumbosacral spondylosis. His medications included amlodipine besylate, cholecalciferol, clonidine, hydralazine, mycophenolate, and rosuvastatin. He had a known allergy to fluoxetine, a selective serotonin reuptake inhibitor. Entering uncorrected visual acuities were 6/21(20/70-) in the right eye (OD) and 6/12- (20/40-) in the left eye (OS), with no improvement on pinhole. Bestcorrected visual acuities (BCVA) with +0.50 D spherical refraction OU were 6/21- (20/70-) OD and 6/9+ (20/30+) OS. Pupillary responses, extraocular motilities and confrontation fields were unremarkable. Anterior segment evaluation was unremarkable. Intraocular pressures (IOP) were 14 mmHg OU. Dilated fundus exam (DFE) revealed cup-to-disc ratios of 0.3/0.3 OU, no optic nerve pallor OU, questionable blurring of disc margins OU, exudative macular star OD>OS with retinal elevation extending into inferior-temporal arcades, few flame-shaped hemorrhages and exudates along arcades OU, two cotton-wool spots along superior-temporal arcade OD, and scattered exudates with retinal thickening superior to the nerve OD. Cirrus (Carl Zeiss Meditec, Inc.) optical coherence tomography (OCT) showed serous macular detachments OU (Fig. 1). The patient’s diagnosis was grade 4 hypertensive retinopathy with bilateral serous macular detachments OU. He was to continue care with his primary care provider (PCP) and nephrologist for blood pressure management and associated complications. At two-month follow-up, the patient presented with no changes to his medical history or his medications and noted an improvement in vision since last visit. BCVA was 6/7.5-1 (20/25-1) OD and 6/6 (20/20) OS. Pupils, extraocular motilities, confrontation fields and anterior segment evaluation remained unremarkable. IOP was 16 mmHg OD and 15 mmHg OS. DFE revealed questionable disc edema with no optic nerve pallor OU, partial exudative macular star OD>OS, scattered pinpoint exudates OU, and a hemorrhage and cotton-wool spot

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along superior-temporal arcade OS. Cirrus OCT showed nearly fully resolved serous macular detachments (Fig. 1). The patient was educated to continue care with his primary care provider and nephrologist and was scheduled in three months for a follow-up exam with dilation. At a further three-month follow up — five months from initial exam — the patient presented with no changes to his medical or ocular history and no ocular or visual complaints. There was no change in his medications except an adjustment in the dosage due to recent blood pressure fluctuations. The BCVA was 6/6-1 (20/201) OD, OS. Pupils, extraocular motilities, confrontation fields and anterior segment evaluations were unremarkable. Intraocular pressure measured 15 mmHg in each eye. Blood pressure in office measured 180/105 mmHg. Dilated fundus exam revealed optic nerve heads with distinct margins and no pallor OU. Both maculae showed significantly improved macular exudation. Epiretinal membranes were also present in both maculae. Scattered pinpoint exudates and several blot hemorrhages were noted along the vessel arcades OU. Unfortunately, the patient was unable to stay for fundus photography at this visit. Cirrus OCT showed no subretinal fluid (Fig. 2). The patient was strongly educated to continue with his PCP and nephrologist regarding systemic management and was to return for a three-month follow-up with dilation. Unfortunately, the patient has not shown up for any further optometric follow-up appointments.

DISCUSSION The clinical guidelines by the Seventh report of the Joint National Committee (JNC-7) outline hypertension management as well as classify blood pressure into four categories (Table I). Hypertensive crisis is recognized as blood pressure beyond stage 2 hypertension, typically >180/120 mmHg, and is further categorized into hypertensive urgency and hypertensive emergency based on the presence or absence of target organ damage (TOD).5,6,8,9,10,11

Table I The classification of blood pressure as outlined by the Seventh report of the Joint National Committee (JNC-7).8

Table II The traditional classification of hypertensive retinopathy by Keith-Wagener-Barker.16

Category

Systolic blood pressure (mmHg)

Diastolic blood pressure (mmHg)

Retinopathy grade

Retinal findings

Normal Pre-hypertension Hypertension, Stage 1 Hypertension, Stage 2

<120 120-139 140-159 â&#x2030;Ľ160

<80 80-89 90-99 â&#x2030;Ľ100

Grade 1 Grade 2

Mild vascular changes (arteriolar narrowing) Moderate-severe vascular changes, focal constriction, arterio-venous crossing changes Grade 2 plus cotton-wool spots, hemorrhages, exudates Grade 3 plus optic nerve swelling

Hypertensive urgency presents as a severe elevation in blood pressure without progressive TOD; however, it may present with severe headache, shortness of breath, epistaxis or severe anxiety.8 Hypertensive emergency is characterized by severe elevation in blood pressure as well and is additionally complicated by impending or progressive TOD, most commonly affecting the central nervous, cardiovascular and renal systems.5,6,8 TOD in such cases may include hypertensive encephalopathy, cerebral infarction, intracerebral or subarachnoid hemorrhage, acute myocardial infarction, acute left ventricular failure with pulmonary edema, unstable angina pectoris, dissecting aortic aneurysm, and eclampsia.5,6,8 Although the JNC-7 does not define the term malignant hypertension, malignant hypertension has historically been used to refer to hypertensive emergencies with associated signs or symptoms of TOD and continues to be a term commonly used today.5,12 The term was first described in 1928 due to the high 80% one-year mortality rate at that time.13 In regard to the eye, the JNC-7 report does not specify what level or grade of hypertensive retinopathy constitutes TOD and the term malignant hypertension has traditionally been used to describe hypertensive retinopathy with optic disc edema.4,8,12 Systemic hypertension may manifest in many ocular conditions, including non-arteritic ischemic optic neuropathy, vascular occlusions, cranial nerve palsies, macroaneurysms, ocular ischemic syndrome, subconjunctival hemorrhages, choroidal infarctions, idiopathic polypoidal choroidal vasculopathy, progression of diabetic retinopathy, glaucoma, and hypertensive retinopathy.14 Hypertensive patients have a 50% to 80% chance of developing retinopathy at some point in their life.15 Hypertensive retinopathy has traditionally been graded using the KWB classification, however more prognosisoriented classification approach has recently been suggested by Wong et al (Tables II, III). Patients with malignant hypertension typically present with retinopathy (retinal hemorrhages, cottonwool spots, and hard exudates), choroidopathy, and optic neuropathy.4 Macular star of lipid exudates may also form in association with optic disc edema; however, they may also be seen in chronic hypertension without malignant hypertension.4 It is a classic but non-specific finding in hypertensive retinopathy and other differential diagnoses may need to be ruled-out, including neuroretinitis, diabetes,

Grade 3 Grade 4

coagulopathies, and collagen-vascular diseases.18,19 No further work-up was initiated in our patient since malignant hypertension was a known diagnosis at the time of presentation and no other signs or symptoms were present in his history. The pathophysiology behind the abrupt elevation in blood pressure in hypertensive crisis is not well understood, but is thought to be related to a dysfunction of the autoregulatory system and an increase in systemic vascular resistance, leading to tissue and organ ischemia.9,20 The pathophysiology of ocular changes in hypertensive retinopathy is the result from an ongoing systemic vascular involvement. Arteriosclerotic changes result from reduced lumen size from cholesterol build-up in hypertension.21 The breakdown of the inner bloodretinal barrier leads to retinal hemorrhages.4 Cotton-wool spots are retinal infarcts within the nerve fiber layer and form once the autoregulatory mechanism in the retina is overcome, which typically occurs at a diastolic blood pressure >110 mmHg.21 Exudates denote vascular leakage of pre-capillary arterioles and loss of the blood-retinal barrier, and macular star is due to the accumulation of exudates in the outer plexiform layer.4,21 The mechanism of optic disc edema is not well understood but is believed to be related to a hypertension-related increase in intracranial pressure, typically occurring with blood pressure >250/150 mmHg.4,21 In hypertensive retinopathy, acute elevations in blood pressure are most likely to affect the choroid leading to Elschnig spots, Siegrist streaks and serous retinal detachments.4 Specifically, Elschnig spots result from choroidal ischemia and subsequent necrosis of the retinal pigment epithelium; Siegrist streaks result from ischemia of the choroidal lobules.22 Subretinal fluid seen in malignant hypertension can be a consequence of incompetent retinal vasculature, choroidal ischemia or optic disc edema.4 In the case of malignant hypertension, macular star is thought to be a sign of resolving macular edema as well as serous retinal detachment.18 It is also possible that macular involvement in severe hypertension is predominantly due to serous detachment rather than macular edema, which would account for the fast, spontaneous resolution of macular thickness and good visual prognosis.18,23 Similarly, the OCT scans of our patient suggest primarily a serous detachment, rather than macular

Malignant Hypertension and Bilateral Serous Macular Detachment â&#x20AC;&#x201D; Jo, Gardner

Table III The more recently proposed Mitchell-Wong “simplified” classification of hypertensive retinopathy.12,17 Retinopathy grade

Retinal findings

Systemic associations

Diastolic blood pressure (mmHg)

Mild

Generalized or focal arteriolar narrowing, arterio-venous nicking changes Hemorrhages, microaneurysm, cotton-wool spots, exudates death from cardiovascular disease Moderate grade plus optic disc swelling

Modest association with risk of stroke, heart disease and death

>90 and <110

Strong association with risk of stroke, cognitive decline and

≥110 to 120

Strong association with death

≥120

Moderate

Severe/Malignant

edema. Maculopathy in malignant hypertension is mainly a choroidopathy which leads to the retinal pigment epithelium dysfunction and outer blood-retinal barrier breakdown resulting in a retinal detachment. This differs from retinopathy and macular edema, which is caused by the breakdown of either outer or inner blood-retinal barrier.18,23 Furthermore, the subretinal fluid observed with OCT in serous detachment in malignant hypertension is hyper-reflective, which suggests protein and fibrin leakage and thus underlying choroidopathy.18 This turbidity of the serous fluid was also observed in our patient. Cases of serous retinal detachments in hypertensive retinopathy have been reported.18,24-30 Although most reported cases have been isolated reports, Shukla et al described an observational case series of 14 patients with hypertensive retinopathy and serous retinal detachment and concluded that serous macular detachment predicted systemic malignant hypertension more consistently than papilledema.18 The patients had a mean age of 44, mean blood pressure of 208/117 mmHg, mean VA of 6/12 (20/40), and presented with grade 3 or 4 hypertensive retinopathy. Coincidentally, we found the mean age, blood pressure and VA measurements of our patient to be similar to the report’s mean values. Macular detachments in hypertensive retinopathy may be unilateral, bilateral or bilaterally asymmetrical. They may not always be present in malignant hypertension, however serve as a strong indicator of malignant hypertension with or without papilledema.18 Macular detachment in malignant hypertension have not been frequently reported in the literature possibly due to some detachments being too shallow to be clinically appreciated without OCT or due to interpretation of retinal thickening as intraretinal macular edema.18 Our patient presented with bilaterally asymmetrical serous macular detachments and only questionable optic disc swelling. His macular detachments were nearly resolved at two-month follow-up and completely resolved at five-month follow-up. Regression of hypertensive retinopathy varies depending on the particular ocular finding: arteriosclerotic changes persist despite blood pressure control; cottonwools spots develop within 24 to 48 hours after acute rise in blood pressure and persist for 2 to 10 weeks; macular

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star may take several weeks to develop and persists months to years following blood pressure management; and papilledema develops in days to weeks after rise in blood pressure and resolves in weeks to months.21 Macular detachments in malignant hypertension have been reported to resolve in 10 to 40 days.18 Systemic management of hypertensive crisis will depend on the presence or absence of TOD, and is divided into hypertensive emergency or urgency, respectively.8,9,10,11 Blood pressure elevations in hypertensive urgencies are treated with oral agents with the goal of controlling blood pressure within 24 to 48 hours.9,10,11 On the contrary, blood pressure in hypertensive emergencies should be reduced gradually by 15% to 30% with parenteral agents for the first several hours.9,10 Once stable at a lower level, treatment may be switched to oral agents until acceptable blood pressure is achieved.9,10 With the exception of aortic dissection, blood pressure in a hypertensive emergency must be reduced in this slower, step-wise manner due to an altered autoregulation in such patients. Rapid reduction of blood pressure to normal or baseline levels would otherwise result in cerebral hypoperfusion.9,11 Optometric management of hypertensive retinopathy includes properly identifying hypertensive crisis. Nonurgent cases of hypertensive retinopathy should be followed every 2 to 3 months and then 6 to 12 months.19 Further guidelines on optometric management of hypertensive crisis have recently been suggested using the newer prognosis-oriented classification of hypertensive retinopathy.12 A patient with acutely elevated blood pressure >180/110 mmHg, mild retinopathy, possible headache and no acute TOD is considered to have severe hypertension and should be urgently referred to a PCP for management within 3 to 7 days. Optometric follow-up should be scheduled within 1 to 3 months for such patients. A patient with elevated blood pressure >180/120 mmHg, moderate retinopathy, possible headache, dyspnea or peripheral edema is considered a hypertensive urgency and should be consulted to PCP or possibly the emergency room for management of blood pressure within 24 to 72 hours. The optometric follow-up in such cases should be scheduled for one month. Lastly, a patient with hypertensive emergency will present with blood

pressure >180/120 mmHg, moderate retinopathy with papilledema and symptoms of TOD and thus should be referred to the emergency room for immediate blood pressure reduction. Optometric re-evaluation should be scheduled one month after the patient is discharged from hospital. When comparing the two classification systems of hypertensive retinopathy, Downie et al found that the simplified system by Wong et al was reliable, repeatable, and just as efficacious as the KWB system. They concluded the advantage of the updated classification system was the ability to correlate retinal microvascular signs to cardiovascular risk and prognosis.31 However, it should be noted that systemic malignant hypertension has been reported with or without optic disc edema (i.e., grade 3 or 4 retinopathy using the KWB system) and constitutes an emergency with an immediate referral, while moderate retinopathy without optic disc edema in the newly proposed prognosis-oriented system (essentially KWB grade 3 retinopathy) does not call for emergent management.12,17,18

Malignant hypertension is a condition rarely seen in optometric practice and is a medical emergency that requires immediate management of blood pressure. Since a visual disturbance may be the presenting symptom for many of these patients, it is important for optometrists to be familiar with the presentation and appropriate referral for the management of this life-threatening condition. We presented a case of a patient with malignant hypertension and bilateral serous macular detachments, which resolved with proper blood pressure management. As reported in the literature, hypertensive retinopathy with a serous macular detachment may serve as a strong indicator of systemic malignant hypertension, and needs to be referred immediately for proper evaluation and intervention. Following proper blood pressure control, patients with hypertensive retinopathy and macular detachments have a good visual prognosis. ❏

REFERENCES

2. 3. 4. 5. 6.

9. 10. 11. 12. 13. 14.

15.

16.

17.

CONCLUSION

Keenan NL, Rosendort KA. Prevalence of hypertension and controlled hypertension – United States, 2005-2008. Morbidity and Mortality Weekly Report (MMWR) Jan 14, 2011; 60(1) (suppl): 94-97. Ong KL, Cheung BM, Man YB et al. Prevalence, awareness, treatment, and control of hypertension among United States adults 1999-2001. Hypertension 2007; 49: 69-75. Fields LE, Burt VL, Cutler JA, et al. The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension 2004; 44: 398-404. Hammond S, Wells JR, Marcus DM, Prisant LM. Ophthalmoscopic findings in malignant hypertension. J Clin Hypertens 2006; 8(3): 221-223. Johnson W, Nguyen ML, Patel R. Hypertension crisis in the emergency department. Cardio Clin 2012; 30: 533-543. Kitiyakara C, Guzman NJ. Malignant hypertension and hypertensive emergencies. American Society of Nephrology 1998; 9(1): 133-142.

18.

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20. 21.

22. 23.

24.

25.

26.

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28. 29.

30. 31.

Kincaid-Smith P, McMichael J, Murphy EA. The clinical course and pathology of hypertension with papilledema (malignant hypertension). QJM 1958; 37: 117-153. Chobonian AV, Bakris GL, Black HR, et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003; 42: 1206-1252. Polly DM, Paciullo CA, Hatfield CJ. Management of hypertensive emergency and urgency. Adv Emerg Nurs J 2011; 33(2): 127-136. Feldstein C. Management of hypertensive crises. Am J Ther 2007; 14(2): 135-139. Gegenhuber A, Lenz K. Hypertensive emergency and urgency. Herz 2003; 28(8): 717-724. Meetz RE, Harris TA. The optometrist’s role in the management of hypertensive crises. Optometry. 2011; 82(2): 108-116. Keith NM, Waegner HP, Keronohan JW. The syndrome of malignancy hypertension. Arch Intern Med 1928; 4: 262-278. Shechtman DL, Falco LA. Hypertension: more than meets the eye. Review of Optometry 2007; Sept 15, 144(09). Available: http://www.revoptom.com/content/d/retina/c/15347/dnnprintmode/ true/?skinsrc=%5Bl%5Dskins/ro2009/pageprint&containersrc=%5Bl %5Dcontainers/ro2009/simple. Accessed Dec 15, 2012. Klein R, Klein BE, Moss SE, Wang Q. Hypertension and retinopathy, arteriolar narrowing, and arteriovenous nicking in a population. Arch Ophthalmol 1994; 112(1): 92-98. Keith NM, Wagener HP, Barker NW. Some different types of essential hypertension: their course and prognosis. Am J Med Sci 1974; 268(6): 336-345. Wong T, Mitchell P. Hypertensive retinopathy. N Engl J Med 2004; 351: 2310-2317. Shukla D, Ramchandani B, Vignesh TP, et al. Localized serous retinal detachment of macula as a marker of malignant hypertension. Ophthalmic Surg Lasers Imaging 2010; Mar 9: 1-7. Kunimoto DY, Kanitkar KD, Makar MS, eds. Hypertensive retinopathy. In: The Wills Eye Manual. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2004: 259. Patel HP, Mitsnefes M. Advances in the pathogenesis and management of hypertensive crisis. Curr Opin Pediatri 2005; 17: 210-214. Sowka JW, Gurwood AS, Kabat AG. Hypertensive Retinopathy. Handbook of Ocular Disease Management 2001. Available: http://cms.revoptom.com/ handbook/ SECT41b.HTM. Accessed Dec 15, 2012. Bourke K, Patel MR, Prisant LM, Marcus DM. Hypertensive choroidopathy. J Clin Hypertens (Greenwich) 2004; 6: 471-472. Hayreh SS. Hypertensive fundus changes. In: Guyer DR, Yannuzzi LA, Chang S, Shields JA, eds. Retina-Vitreous-Macula. Philadelphia: WB Saunders, 1999; 345-371. Suzuki M, Minamoto A, Yamane K, et al. Malignant hypertensive retinopathy studied with optical coherence tomography. Retina 2005; 25(3): 383-384. De Venecia G, Jampol LM. The eye in accelerated hypertension. II. Localized serous detachments of the retinal in patients. Arch Ophthalmol 1984; 102(1): 68-73. Isaacs TW, Acheson JF. Reversible visual failure due to exudative retinal detachments in a patient with uncontrolled systemic hypertension. J R Soc Med 1994; 87(9) 557-558. Olson JL, Prall FR, Ciardella AP. Bilateral foveal neurosensory detachment in hypertensive retinopathy demonstrated by optical coherence tomography. Eye (Lond) 2006; 20(12): 1370-1371. Tajunisah I, Patel DK. Images in clinical medicine. Retinal detachments in malignant hypertension. N Engl J Med 2009; 361(9): 899. Khairallah M, Ben Yahi S, Messaoud R, et al. Macular hole and macular detachment in severe hypertensive retinochoroidopathy. Arch Ophthalmol 2003; 121(10): 1504-1505. Schartz H. Diagnostic challenges: retinal detachment in acute systemic hypertension. Retina 1995; 15: 524-526. Downie LE, Hodgson LA, Dsylva C, et al. Hypertensive retinopathy: comparing the Keith-Wagener-Barker to a simplified classification. J Hypertens 2013; 31: 960-965.

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QUESTIONNAIRE A Case Report: Malignant Hypertension and Bilateral Serous Macular Detachment Petra Jo, OD; Richard G. Gardner, OD, FAAO 1. ❏ ❏ ❏ ❏

In which of the following population groups is malignant hypertension most prevalent? Caucasian Asian African-American Native American

2. ❏ ❏ ❏ ❏

What percentage of adults does hypertension affect in the United States? 10% 20% 30% 35%

3. ❏ ❏ ❏ ❏

All of the following are symptoms of malignant hypertension, EXCEPT: Malaise Fatigue Weight loss Anemia

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4. ❏ ❏ ❏ ❏

In the Case Report presented, the patient’s history included all of the following, EXCEPT: Anxiety disorder Nephrotic syndrome Hypertension Hyperlipidemia

5. ❏ ❏ ❏ ❏

Transient Ocular Deviation (TOD) may include all of the following, EXCEPT: Cerebral infarction Hypertensive encephalopathy Acute myocardial infarction Cerebral stroke

6. ❏ ❏ ❏ ❏

Hypertensive patients have what percentage likelihood of developing retinopathy at some point? 20% 30% to 40% 50% 50% to 80%

7. ❏ ❏ ❏ ❏

In the classification of blood pressure by the JNC-7, which of the following is systolic blood pressure in Hypertension, Stage 1? <120 mmHg 120-139 mmHg 140-159 mmHg ≥160 mmHg

8. ❏ ❏ ❏ ❏

Mild retinopathy is characterized by all of the following, EXCEPT: Strong association with risk of cognitive decline Modest association with risk of stroke Modest association with risk of heart disease Modest association with risk of death

9. ❏ ❏ ❏ ❏

In malignant hypertension, what percentage of patients may have decreased vision as the presenting symptom? Up to 20% Up to 40% to 50% 50% Up to 35% to 60%

10. ❏ ❏ ❏ ❏

Systemic hypertension may manifest as all of the following, EXCEPT: Vascular occlusions Retinal detachment Cranial nerve palsies Glaucoma

Malignant Hypertension and Bilateral Serous Macular Detachment — Jo, Gardner

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Clinical & Refractive Optometry: Online Edition is pleased to present this continuing education (CE) article by Dr. Sarah E. Shim, and Dr. Pauline F. Ilsen entitled Posterior Reversible Encephalopathy Syndrome. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 65 for complete instructions.

Posterior Reversible Encephalopathy Syndrome Sarah E. Shim, OD; Pauline F. Ilsen, OD, FAAO

ABSTRACT Background: Posterior reversible encephalopathy syndrome (PRES) is a state of reversible vasogenic edema predominantly in the posterior circulation territories reflected by its unique pattern in magnetic resonance imaging. It is a neurotoxic state associated with clinical conditions such as malignant hypertension, eclampsia/pre-eclampsia, autoimmune diseases, immunosuppressive medications, infections, organ transplant, or chemotherapy, and is accompanied by complex of symptoms such as vision loss, other visual disturbances, seizures, headaches, or altered mental status. First described in 1996 by Hinchey et al, reports of PRES-associated conditions, different clinical presentations, and radiologic variations continue to appear in the literature. The pathophysiology and mechanism leading to posterior reversible encephalopathy is not fully understood. Case Report: A 76-yearold man with a longstanding right homonymous hemianopsia secondary to a history of cerebral infarct presented with acute bilateral vision loss in the absence of ocular pathology. Neuroimaging confirmed the presence of vasogenic edema in the posterior circulation region which was attributed to the patient’s hypertensive state. His hypertension was brought under control, and a return to visual baseline was evident several months subsequently. Conclusion: Posterior reversible encephalopathy syndrome should be considered in the differential diagnosis for patients who exhibit acute vision loss in the context of systemic entities which are known to cause this condition. S.E. Shim — Resident, West Los Angeles VA Healthcare Center, Los Angeles, CA; P.F. Ilsen — Professor, Marshall B. Ketchum University, 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 90073; E-mail: Pauline.Ilsen@va.gov This article has been peer-reviewed.

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Neuroimaging studies are recommended to establish an early diagnosis. Prompt consultation with a primary care physician and appropriate specialists for proper management of the underlying etiology may fully reverse the clinical presentation and prevent cerebral infarction.

INTRODUCTION Although apparent in many different settings of acute illness, it was not until 1996 that posterior reversible encephalopathy syndrome (PRES), initially termed reversible posterior leukoencephalopathy syndrome, was first introduced in the literature by Hinchey et al.1 The clinical presentation and contributing factors vary, but the feature that identifies PRES is a highly characteristic pattern of acute vasogenic edema of the cerebral white matter without infarction.2-5 In the past decade or so, PRES has increasingly been a topic of numerous case reports and a center of controversy. It has been subject to a range of debates, from its pathophysiology to nomenclature. It is no longer an unfamiliar phenomenon in the medical world, as it has been widely reported to be associated with multitude of different conditions including acute hypertensive events, pre-eclampsia/eclampsia, autoimmune diseases such as systemic lupus erythematosus, immunosuppressive agents such as cyclosporine, and renal disease.1,2,6-12 Neuroimaging studies conducted with magnetic resonance imaging (MRI) and computed tomography (CT) have revealed unique patterns of vasogenic edema that are frequently reversible with prompt treatment.3,12-18 Neuroimaging will often demonstrate predominantly posterior cerebral involvement, which is typical of this syndrome, and as appropriately described in its current name.3,5,7,11,20,21 The clinical findings are nonspecific, so neuroimaging must also be performed for a definitive diagnosis to be established.2,4,5,8 Posterior reversible encephalopathy syndrome has aptly been referred to as a “clinicoradiographic” or “clinicoradiologic” syndrome.4,7 This syndrome is accompanied primarily by the clinical signs and symptoms of headache, seizures, visual disturbance/loss, and altered mentation.1,3,5,8,9,16,17,22-42 A case report of a patient with an episode of acute visual disturbance due to PRES will be presented, followed by a review of posterior reversible encephalopathy syndrome.

Fig. 1A, 1B: Humphreys 81 point screening field demonstrates right homonymous hemianpsia

CASE REPORT A 76-year-old male first presented with a chief complaint of decreased near vision and a request for reading glasses. The patient’s medical history was significant for hypertension, cigarette smoking, and trauma to the right side of the head approximately ten years ago. He also had a vague recollection of having had a stroke. He was only taking hydrochlorothiazide for the elevated blood pressure. His last eye examination was ten years ago. Ocular history was negative for injury, surgery, or disease. There was no known family history of ocular pathology. The best corrected visual acuity was 6/9 (20/30) OD and 6/7.5- (20/25-) OS. Cover testing revealed minimal phoria at near and orthophoria at distance. The extraocular muscles had a full range of motion. The pupils were equal, round, and fully reactive to light, with no afferent pupillary defect. His blood pressure was 150/90 mmHg (right arm sitting). He was observed to have normal gait and speech. Upon slit lamp evaluation, he was found to have dermatochalasis, grade 1+ corneal arcus, and mild (grade 1+) nuclear sclerotic, anterior and posterior cortical cataracts (grade ½ to 1+). The patient’s intraocular pressures were 15 mmHg OU by Goldmann applanation tonometry prior to dilation, and 16 mmHg OD, 17 mmHg OS post-dilated. The reliability on a Humphrey’s Full-Field

81 point screening was poor; however, a right homonymous hemianopic defect was apparent (Fig. 1). Dilated evaluation of the posterior segment revealed clear media and distinct margins OU, cup-to-disc ratios of 0.50 OU and pink optic nerve rims. Moderate arterio venous crossing changes were apparent. There was mild pigment mottling at both maculas. The retinal periphery was intact. New eyeglasses were prescribed. Additionally, he was diagnosed with a right homonymous hemianopsia suspected to be due to stroke. The primary care provider was informed of the examination findings and an MRI of the brain was ordered. The patient was asked to return within 1 to 2 months for a Humphrey’s central 30-2 visual field test. Two months later, MRI with T1 weighted sagittal and axial, T2, gradient reverse echo (GRE) and fluid attenuation inversion recovery (FLAIR) sequences were obtained. The results were reported as follows: First, there was evidence of an old infarct within the left posterior cerebral artery (PCA) territory involving the gray white matter and the left cacarine cortex. Second, there was an old infarct in the right lateral temporal lobe with laminar necrosis. Third, a small focus of GRE blooming was present within the left thalamus consistent with a small old hemorrhagic infarct. Fourth, moderate to severe white matter ischemic changes were present.

Posterior Reversible Encephalopathy Syndrome — Shim, Ilsen

Fig. 2A, 2B: Humphreys central 30-2 threshold field confirms right homonymous hemianopsia

The patient did not return for field testing until six months after the initial examination. Humphrey’s central 30-2 visual field results proved consistent with the MRI findings in its diagnosis of incomplete right homonymous hemianopsia (Fig. 2). At this visit, patient’s medications included aspirin 81 mg, hydrochlorothiazide, hydrocodone, ibuprofen, lisinopril, and simvastatin. The patient’s most recent blood pressure measurement was recorded as 170/81 mmHg. The ocular findings were unchanged from the previous visit. Orientation and mobility services were recom-mended and the patient was instructed to return for further evaluation with the low vision clinic; he was also advised to discontinue driving. He did not return until three years later. At that time, the patient presented to the emergency department with a complaint that he “woke up this morning blind.” He reported to the emergency department physician that the vision loss began the night before and he awoke with worse vision. He indicated that he was able to make out shapes but was unable to see faces, read, or distinguish between one or two fingers held about a foot away from his face. He could distinguish between light and dark. He denied any eye pain or floaters. He denied any extremity weakness or numbness. He did have a headache above his left temple that had been worsening over the past 2 to 3 weeks, since hitting his head during a fall. He was homeless, admitted to a problem with alcohol abuse, and had not been taking any medications for an indeterminate period of time — he could not even recall whether or not he was supposed to be taking blood pressure medication. The patient’s blood pressure at presentation to the emergency department was 221/97 mmHg. Other than the reduced vision, neurological screening was significant for reduced attention and memory, although these had been noted three years earlier. Several laboratory tests were ordered; significant results were as follows: There was proteinuria (100 to 200

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mg/dL), trace ketonuria and bilirubinuria. The prothrombin time was 12.8 seconds (normal range 11.8 to 13.5), International Normalized Ratio (INR) was 1.0 ratio (normal), and activated partial thromboplastin time was 25.9 seconds (normal 23.0 to 33.0). Complete blood count demonstrated low red blood cells (3.93 M/uL, normal 4.4 to 5.9), but was otherwise normal. The creatinine was elevated (1.57 mg/dL idms, normal 0.66 to 1.28) and estimated glomerular filtration rate was low at 52 mL/min/m2. Serum glucose was 101 mg/dL (normal 70 to 110). Sodium, potassium, chloride, magnesium, phosphorus, and calcium levels were all normal. Carbon dioxide was low at 23.1 mmol/L (normal 24.0 to 31.0). Troponin-I was 0.04 ng/mL (normal 0.00 to 0.04); a repeat Troponin I was 0.01. Lactate was 1.4 mmol/L (normal 0.5 to 2.2). Blood ethanol level was <5 mg/dL. The rapid plasma reagin screening for syphilis (RPR) was nonreactive and an overdose drug screen panel was negative. A high sensitivity C-reactive protein was 0.13 mg/dL (normal <0.744), vitamin B12 was low at 140 pg/mL (160 to 911) and folate was normal (6.76 ng/mL, normal ≥3.4). Thyroid stimulating hormone (TSH) was normal at 3.157 uIU/mL (0.35 to 5.50). The homocysteine level was 24.36 umol/L (5.0 to 13.9). Lipids were as follows: total cholesterol 109 mg/dL (normal ≤200), triglycerides 57 mg/dL (normal 40 to 160), high density lipoprotein 44 mg/dL (normal ≥40), and low density lipoprotein 54 mg/dL (normal ≤130). The hemoglobin A1c was 5.2% (normal). An electrocardiogram was normal. Hydralazine was administered intravenously to reduce the blood pressure. Computed tomography (CT) of the head and an MRI/MRA of the head and neck were ordered, and emergency consultations with the eye clinic and neurology were also arranged for that day. The patient underwent the CT scan, but the MRI could not be completed because the patient became agitated and combative, and left the procedure room.

Upon examination at the eye clinic, the patient’s entering visual acuity was finger counting in each eye. The extraocular muscles were full and the pupils were normal. Gross visual field testing by finger counting was severely restricted OD and OS. There were otherwise no changes noted in anterior or posterior segment evaluations from the last visit. No evidence of hypertensive retinopathy or optic nerve abnormalities was present. With no ocular etiologies to contribute to the vision loss, and considering the hypertensive emergency and history of prior stroke, a new occipital lobe stroke was considered the most likely diagnosis. Bilateral optic neuropathy was considered an unlikely differential. The patient was sent back to the emergency department with a recommendation to consult with neurology to evaluate for stroke and with primary care to address the hypertension. He was admitted to the intensive care unit for blood pressure control and a full neurological evaluation. The differential diagnoses under consideration at the time of admission were PRES, which was supported by the findings of hypodensities in the posterior circulation on CT, specifically in the right occipital lobe, especially in the context of uncontrolled hypertension. It was noted that it was difficult to assess for hypodensity in the left occipital lobe due to the prior (old) infarcts in that region. Since the patient was unable to complete the MRI, better assessment of the right occipital lobe to rule out acute infarct was not possible. Other potential causes for the vision loss included hypertensive encephalopathy causing vasogenic edema and seizures. They noted that seizures are common at the presentation of PRES. The admitting diagnosis was hypertensive emergency versus stroke. Hourly neurological checks were conducted and administration of nicardipine to keep the systolic blood pressure within the 160 to 190 mmHg range. Additional laboratory tests were ordered with significant results as follows: A high sensitivity C-reactive protein was 0.13 mg/dL (normal <0.744), vitamin B12 was low at 140 pg/mL (160 to 911) and folate was normal (6.76 ng/mL, normal ≥3.4). Thyroid stimulating hormone (TSH) was normal at 3.157 uIU/mL (0.35 to 5.50). The homocysteine level was 24.36 umol/L (5.0 to 13.9). Lipids were as follows: total cholesterol 109 mg/dL (normal ≤200), triglycerides 57 mg/dL (normal 40 to 160), high density lipoprotein 44 mg/dL (normal >40), and low density lipoprotein 54 mg/dL (normal <130). The hemoglobin A1c was 5.2% (normal). The PT/INR/APTT, chemistry panel, and CBC were repeated, with similar results to those obtained when the patient was in the emergency department. Also recommended was to reattempt MRI following neurology’s “stroke protocol,” with diffusion-weighted images, GRE to rule out microhemorrhages, and FLAIR. This protocol was to help distinguish between stroke and hypertensive emergency.

The blood pressure goal if hypertensive emergency was established was 160 to 190 mmHg. However, the goal blood pressure if the patient had a stroke was about 200 mmHg systolic to help perfuse the ischemic penumbra. The neuroradiologist’s CT scan report indicated that there was hypodensity with blurring of the gray-white matter differentiation and sulcal effacement of the right occipital lobe. Also revealed was evidence of chronic infarct of the left occipital lobe, right parietal lobe, and right temporal lobes. Moderately severe microvascular ischemic changes of the cerebral white matter were evident. There were also small lacunes in the left cerebellum and left basal ganglia. The neurologist indicated there was no evidence on the CT scan of an acute stroke and attributed the sulcus effacement to edema likely secondary to the hypertension (Fig. 3). The report for the MRI/MRA/DWI indicated a recently completed infarct of the right medial posterior temporal and right medial occipital lobes. The neuroradiolgist stated that an “unusual appearance of severe PRES will be the differential in the proper clinical setting.” There was also a likely subacute infarct of the right parietal lobe with laminar necrosis and petechial blood products. Chronic infarcts involving the left posterior cerebral artery territory and right lateral temporal lobe were again identified, as well as interval progression since the last MRI of the microvascular ischemic changes in the cerebral white matter and pons. There was a relatively stable lacune of the left posterior thalamus with hemosiderin deposition and a slight increase in the number small lacunes in the left cerebellum compared to the last study (Fig. 4). The brain MRA demonstrated a lack of flow signal in the left posterior cerebral artery distal to the P1 segment which was thought to represent either occlusion or highgrade stenosis with slow flow. The other visualized major intracranial arteries were patent. Mild narrowing of the proximal left internal carotid artery was noted. On the morning after admission to the hospital, the patient was advised of the neurologist’s recommendation to repeat the MRI with the stroke protocol. However, the patient declined this examination. He stated that his vision had returned to normal gradually over the course of the previous day’s afternoon and evening, as his blood pressure was controlled. The patient was evaluated by the neurologist again, and he indicated that on this examination, the patient’s vision had indeed returned to baseline, with the pre-existing right homonymous hemianopsia. It was noted that his blood pressure was under better control, with current fluctuations between 140s to 180s systolic and 60s to 90s diastolic. The neurologist stated that the gradual manner in which his vision returned to baseline with control of the hypertension made PRES the most likely diagnosis. The patient explained that his refusal to repeat the MRI was

Posterior Reversible Encephalopathy Syndrome — Shim, Ilsen

Fig. 3A-3D: CT without contrast demonstrates hypodensity with blurring of the gray-white matter differentiation and sulcal effacement of the right occipital lobe. Chronic infarcts of the right parietal and temporal lobes and the left occipital lobe are evident.

due to claustrophobia. Thus, the diagnosis of PRES could not definitively be confirmed with MRI. The neurologist said there was also a possibility that the event was due to a left occipital lobe transient ischemic attack, but he felt this was not likely since total vision loss did not occur. He also indicated that localized seizure activity in the occipital lobe was an unlikely explanation since it is very rare and tends to produce positive symptoms.

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The recommendation by the neurologist was to continue control of the hypertension, including an angiotensin converting enzyme inhibitor for secondary stroke prevention; aspirin 81 mg daily was also recommended. The patient was advised not to drive. He was encouraged to undergo repeat MRI with the stroke protocol, but the neurologist indicated that although this would provide helpful information, it was unlikely to alter management.

Fig. 4A, 4B: MRI T2FLAIR and diffusion-weighted images reveal bilateral occipital lobe lesions.

The patient was discharged from the hospital the day after admission. Discharge medications included amlodipine, 81 mg aspirin, lisinopril, multivitamin/mineral, folic acid, and thiamine with PRES being the discharge diagnosis. Arrangements were made for him to be seen in neurology clinic after discharge. Other than returning about two months later for an electroencephalogram to further investigate for seizures (normal), he did not return to neurology as instructed. The patient returned to the eye clinic about seven months after discharge with a chief complaint of decreased distance and near vision, and a request for new glasses. His blood pressure was measured at 143/76 mmHg. The patientâ&#x20AC;&#x2122;s pupils and EOMs were normal, and gross confrontational visual fields was restricted in the temporal quadrant OD and the nasal quadrant OS, consistent with his previously diagnosed right hemianopsia. With subjective refraction, he was back at his baseline best corrected acuity of 6/9 (20/30) OD, OS. All other ocular health findings were consistent with the prior examinations. Over the course of the ten months from his initial presentation with PRES, the patient was readmitted to the hospital on three additional occasions for other medical problems. He subsequently developed vascular dementia and was admitted to a neuropsychiatric nursing home. He has continued to return for routine eye care, but his capacity to cooperate with testing has been quite limited.

DISCUSSION Since its introduction in 1996 by Hinchey et al, PRES has been presented under many different names, including: reversible posterior leukoencephalopathy syndrome, reversible posterior cerebral edema syndrome, posterior leukoencephalopathy syndrome, and hyperperfusion encephalopathy.1,2,7,19,38,41,43-45 The nomenclature of this syndrome has been long debated as none of the above names has accurately described the condition. The posterior region of the brain is predominantly affected in many but not all cases.1,11,19,20,46,47 Although cases often present with involvement of the posterior parieto-occipital region, many radiographic studies have shown that other areas such as the frontal lobes, basal ganglia, cerebellum, and brainstem may also atypically be involved.1,3,12,41,48-51 None of the cases studied by Roth and Ferbert were found to have an isolated brainstem or cerebellar lesion.14 However, brainstem lesions occurred in addition to hemispheric lesions in 30% of cases.14 Cerebellar lesions were found in conjunction with hemispheric lesions in 20% of cases.14 A possible correlation between pre-eclampsia/ eclampsia and predilection for the basal ganglia has been discussed,52-54 but any direct correlation between predisposing factors and location of the edema or its severity in imaging is yet to be discovered.6,52 Studies have shown that if not detected and treated promptly, this phenomenon is not always reversible, nor is the encephalopathy limited to the white matter.2,4,36,42,47,54-58

Posterior Reversible Encephalopathy Syndrome â&#x20AC;&#x201D; Shim, Ilsen

Table I PRES-associated conditions Hypertensive Encephalopathy Vasculitis/Autoimmune Disease: Systemic Lupus Erythermatosus80 Systemic sclerosis/Scleroderma56 Polyarteritis nodosa29 Thrombotic thrombocytopenic purpura26 Cushing’s syndrome97 Goodpasture’s disease98

Immunosuppressive Treatment Drugs/Treatment Cyclosporine86 Tacrolimus101 Cisplatin102 Oxaliplatin103 Ephedra overdose104 Triple-H therapy94

Toxemia of Pregnancy Preeclampsia34 Eclampsia35

Miscellaneous Glomerulonephritis32 Hypomagnesemia105 Hypercalcemia106 Hypocholesterolemia86 Guillain-Barré syndrome90 Infection/sepsis/shock13,100 Sickle Cell Disease25 Neuromyelitis Optica107 Tumor Lysis syndrome108

Post-transplantation Allo-Bone marrow transplantation99 Solid orgran transplantation99

Hence, it is suggested that the acronym should be changed from posterior to “potentially” reversible encephalopathy syndrome.41,59-62 Epidemiology With the youngest reported patient at 10 months and the oldest at 90 years of age,2,15 no particular age group has proven to be more predisposed to PRES. However, females have shown to be more susceptible than males despite adjusting for the large number of women who experience PRES in association with eclampsia/ preeclampsia.1,10,13,14 Roth and Ferbert reported a female:male ratio of 2.6:1.12 To date, no studies have been conducted to establish incidence or prevalence of PRES.12 Risk Factors and Associated Conditions Some authors suggest that posterior reversible encephalopathy syndrome is a variant of hypertensive encephalopathy.10,20,63 It has been found in patients experiencing acute transient hypertension more commonly than in those with chronic hypertension, since those patients with chronic hypertension have adapted to the longstanding hypertensive state over time.6,10,64 The blood pressure elevation may only be mild in cases where there is also sepsis or drug toxicity.10 In light of countless case reports involving acute hypertension as one of its main signs in the past decade, the influence of acutely elevated blood pressure in the pathogenesis of PRES cannot be denied.1,6,65-70 In a recent retrospective study by Roth and Ferbert, the mean systolic and diastolic blood pressure value for all of their patients was about 170 mmHg and 98 mmHg respectively.12 Hypertensive encephalopathy as a result of uncontrolled hypertension may possibly be the most common cause of PRES.10,20,53,63,65,71-79

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As clinicians have become increasingly aware of this syndrome, reports of other common predisposing factors have been reported for PRES. Some of the most common PRES inducing pathologic states besides acute hypertension include: autoimmune diseases such as systemic lupus erythematosus,9,80-82 eclampsia/preeclampsia,35-38,66 cytotoxic or immunosuppressive therapies such as cyclosporine,83-86 and connective tissue disorders.10,13,15,79,87,88 Other reported associations include: Guillain-Barré syndrome;89-91 pheochromocytoma,58,92 and other renal disease;30,32 bone marrow, stem cell, or solid organ transplantation;48 triple-H therapy;93,94 and sepsis or infection, among many.3,13,95 Posterior reversible encephalopathy syndrome in the pediatric population has similar etiologic factors as PRES in adults.62,88 However, there are some predisposing factors that are specific to the pediatric population, and these include: acute lymphocytic leukemia, Ewing sarcoma, juvenile lupus, acute glometrulonephritis, and treatment of enuresis with oxybutynin.32,88,96 The wide variety of associated conditions are listed in the Table I.13,25,26,29,32-35,56,80,86,90,94,97-108 Clinical Presentation and Evaluation One of the most frequent clinical manifestations of PRES is transient epileptic seizures or altered mentation such as confusion, stupor, lethargy, and even coma.1,10,47,102 In a study by Roth and Ferbert, generalized seizures occurred in 88% of PRES cases.14 Seizure was a presenting symptom in 87% of Lee’s patients.4 Another common manifestation is vision loss or disturbances primarily attributed to edema.5,23,40,96,104,109-111 Visual disturbances involve but are not limited to blurred vision, restricted fields, scotomas, visual hallucinations, or cortical blindness.102,105 Patients may also complain of headache and facial numbness;

aphasia, status epilepticus, and ataxia may be additional presenting signs.9,15,16,92, 105,112 Hinchey et al concluded that although one of the most common symptoms, PRES does not always involve headaches.1 Headache was a presenting symptom in 53% of the 38 cases studied by Lee et al.4 Rare disorders of motor functions include hemiparesis, dystonia, dysmetria.1,15,86,95 Dyspnea, anarthria, and dysphagia have been reported as possible manifestations of brain stem involvement.40,113 Mirza noted that seizures occurring in the context of PRES cause serum CO2 and lactate levels to increase.10 Visual compromise was reported in 40% of cases of HTN associated PRES in a recent study by Ogaki et al.65 Similarly, visual presenting symptoms occurred in 39% of the patients studied by Lee et al.4 Hypertensive retinal changes may also occur as a result of intracranial hypertension or associated with brainstem defect.62,114-116 Pathophysiology A center of controversy for PRES has been its pathophysiology, as the mechanism of PRES remains unclear. The opposing theories that currently exist are theories of hyperperfusion versus hypoperfusion.3,117 The hypoperfusion theory predicts vasoconstriction/vasospasm leading to hypoperfusion ultimately leading to cerebral edema.3,117-119 This is evidenced by magnetic resonance images that show decreased blood volume in PRES lesions.3,117-119 A more widely accepted theory involves vasogenic edema as a result of elevated blood pressure, loss of cerebral autoregulation, and blood-brain barrier compromise due to fluid extravasation from blood vessels.10,11,99,120 The hyperperfusion theory is supported by the vasogenic edema seen in MRI with restricted diffusion.6,29,120 Although much has been revealed concerning PRES since 1996, further investigation is necessary for a more complete picture of this syndrome. Clinical evaluation of PRES should include careful medical history and review of the patient’s medication list in search of any PRES inducing drugs. An exhaustive evaluation of the visual system with dilation is indicated to rule out ocular pathologies that may potentiate visual disturbance and all other predisposing factors that may underlie the manifest clinical symptoms.62 A comprehensive ophthalmic examination is indicated especially when a patient is experiencing visual disturbances to rule out any ocular causes of visual defect.62 Although signs of hypertension may not always be present, posterior segment examination is recommended to evaluate hypertensive changes such as retinal hemorrhages, cotton wool spots, exudates, arterior-venous nicking, macular edema, and papilledema.116 Pupils may also be involved with sluggish reflex and miosis.80,95,121 In hypertension associated PRES, occipital cortical disturbance has been speculated as the leading cause of vision impairment.65 Hence, cortical

defects should not be neglected as potential cause of vision loss and prompt imaging must be obtained.62 Multifactorial causation for vision loss such as PRES and concurrent retinal detachment may make it difficult for the clinician to assess vision loss secondary to edema.62 Differential Diagnosis Some of the differentials to be considered include neoplasms, encephalitis, encephalopathies, venous thrombosis, and vasculitis.7,95,120 One of the major differentials that must be ruled out is cerebral infarction/ischemic stroke.10 This differentiation is vital for the determination of treatment and management of the condition.2,7,10 In PRES, controlling the elevated blood pressure is the mainstay of treatment in addition to treatment of systemic causes or removal of offending agents whereas in cerebrovascular accidents, blood pressure is not aggressively controlled to prevent any damage in the watershed areas.2,10,122 Neuroimaging with MRI must be consulted to make the distinction between cerebral infarct versus PRES.2,7,10 MRI with FLAIR, Diffusion weighted imaging (DWI), and “apparent diffusion coefficient (ADC) map” should allow diagnosis with reasonable certainty.7,10,95,122,127 Other conditions such as central pontine myelinosis, multiple sclerosis and pontine glioma may rarely mimic PRES which should be distinguished with imaging and clinical correlation.10 Functional vision loss should be a diagnosis of exclusion and only considered after all other organic etiologies have been ruled out54,5 If this diagnosis is considered in the absence of appropriate work-up, the resulting treatment delay may ultimately induce worsening and irreversible symptoms, coma, or even death.54,57 Neuroimaging and Radiologic Presentation The neuroimaging presentation in PRES originally described by Hinchey et al was that of bilateral vasogenic edema with its presence primarily in the posterior region of the brain, more specifically, occipital or parietooccipital lobes of the cerebral hemispheres.1,11,47 This is partly attributed to lack of sympathetic innervation of vasculature emerging from the basilar artery which is thought to play a protective role.43,60,61,64,65,71,123 Vasogenic edema in the parietal or occipital lobes was discovered in 98% of the cases studied by Bartynski and Boardman.11 The characteristic neuroimaging pattern of PRES is one of vasogenic edema without infarction; discovering vasogenic edema with appropriate radiographic study is key for diagnosis of PRES.3,43,124 Magnetic resonance imaging (MRI) is the gold standard7,64,120 and technique of choice over computed tomography (CT) scan as CT scans lack sensitivity for the vasogenic edema prominent in PRES versus cytotoxic edema, a finding that accompanies ischemic complications, mass occupying lesions, or infarct.11,125,126 MRI is indicated emergently upon suspicion of PRES.4,7,64

Posterior Reversible Encephalopathy Syndrome — Shim, Ilsen

Posterior reversible encephalopathy lesions on MRI T2 views reveal hyperintensity and MRI T1 views reveals iso-hypointensity.4 A distinction must be made between vasogenic edema (consistent with PRES) and cytotoxic edema (consistent with infarction rather than PRES).5 Vasogenic edema can be demonstrated with diffusion weighted imaging (DWI).5,8 On DWI, vasogenic edema will produce a bright (hyperintense) signal; however, T2 signal may also produce hyperintensity on DWI.5,8 To determine if hyperintensity on DWI is caused by vasogenic edema, the contribution of T2 signal must be eliminated; this is accomplished by a modification of the DWI images called an “apparent diffusion coefficient (ADC) map.”4,5,8,21,123,127 The ADC map eliminates the T2 signal in diffusion-weighted images, so that any hyperintensity which appears on ADC mapping can be attributed solely to vasogenic edema.4,5,8,21,50,120,122,123,128,129 Cytotoxic edema due to acute infarction would appear dark on an ADC map.4,5,7,42,95,120,122 However, recent case reports have revealed that vasogenic and cytotoxic edema may coexist.47,51,126 With the advancement of radiographic imaging over the past decade, numerous reports have revealed that variations in extent and atypical presentations of PRES lesions exist. The edema may also involve the frontal lobe, temporal lobe, cortical gray matter, brain stem, basal ganglia, or cerebellum.1,3,11,47,51,122 Bartynski and Boardman found frontal lobe involvement to occur in 68% of the cases in their study, the inferior temporal lobes was affected in 40% of cases, and the cerebellum was involved in 30% of cases.11 They categorized three major patterns of PRES based on the MRI and CT appearance: first was the “holohemispheric watershed” type of pattern, occurring in almost 23% of cases, and demonstrating edema in a linear pattern mostly through the frontal, parietal, and occipital lobes and involving the watershed zones between the medial hemispheric blood supply and the lateral hemispheric blood supply; second was the “superior frontal sulcus” pattern, affecting about 27% of cases, and characterized by involvement primarily of the frontal lobe, with some involvement of the parietal and occipital lobes; third was the “dominant parietal-occipital” type of pattern, affecting about 22% of patients, where the parietal and occipital cortex was primarily affected, with variable involvement of the temporal lobe.3,11 Treatment and Management Upon diagnosis, the clinician must manage the underlying etiological factors such as hypertension, seizures, or coma.41,57,95,101, 107,130 Hypertensive emergencies must be managed aggressively. Mean arterial blood pressure should be decreased by 20% or diastolic BP of 100mmHg should be reached within the first hour whichever value is greater. Then, the

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blood pressure should be monitored every 15 minutes in the following 24 to 48 hour period to prevent brain hypoperfusion that may result in cerebral damage.10,41,131 For the parenteral anti-hypertensive treatment, most clinicians prefer sodium nitroprusside for its short acting property in vessel dilation despite the black box warning of cyanide toxicity.40,41,71,77 Other effective treatments used are intravenous labetolol and calcium channel blockers.40,41,71,77 However, clonidine with its CNS depressive property should be avoided as not to interfere with the neurologic evaluation of the patient.10,41 A neurologist should be consulted in patients with seizures. Phosphenotoyin, phenotoyin, and benzodiazepines (e.g., lorezepam, diazepam) may be indicated for seizure control.62,95,,124,132,133 However, in cases where seizures are subtle and are not convulsive, EEG is indicated.124 Likewise, the obstetrician should be involved in pregnant patients who present with eclampsia/ pre-eclampsia associated PRES as these patients should be considered for emergent delivery.10 These patients are treated differently from their non-pregnant cohorts due to the many contraindications in pregnancy.54,124 In eclampsia, treatment with magnesium parenterally will show drastic improvement in not only blood pressure, but also neurological signs.54,124 Hydralazine and labetolol are the antihypertensive used in eclampsia; however, nitroglycerin with its vasodilating property is contraindicated.2 Angiotensin converting enzyme (ACE) inhibitors are also contraindicated due to their teratogenic potential.10,54,124 Patients on cyclosporine therapy should have their magnesium checked as cyclosporine may cause hypomagnesemia which in turn can result in seizures and lead to cerebral edema.84,86 Effective communication and collaboration with critical care, neurology, radiology, and pediatrics and/or obstetrics is essential for prompt management of patient’s symptoms.2,6,10,62 Prognosis In a report published in 2008 on 38 patients with PRES, Lee et al reported an average of about 5 days for clinical symptoms to resolve.4 Five percent of their patients had a recurrence of PRES and 10% had irreversible damage demonstrated on neuroimaging.4 The only formal study conducted to evaluate the long-term prognosis of PRES was one by Roth and Ferbert which demonstrated an excellent short-term and long-term prognosis even in severe and acute cases.12,14 In general, resolution of symptoms are favorable and were apparent within 7.5 days on average.12,24,42,51,101,134,135 Although slower than clinical recovery, imaging abnormalities also demonstrated improvement in 72% of cases.12 It is interesting to note that recurrence of PRES is rare despite causative factors that may persist or recur in many of these same patients.1,12,18,41,42,65,71,76,135

CONCLUSION Posterior reversible encephalopathy syndrome has become an increasingly popular subject of study and case reports over the past decade. However, it remains a fairly unfamiliar territory for optometrists as PRES in our daily patient encounters are uncommon. On the other hand, optometrists may be consulted as part of the investigation in suspected cases of PRES, since cortical blindness is often one of the presenting manifestations. Optometrists should keep PRES in mind as one of the differential diagnosis for visual disturbances especially in patients with any of the predisposing risk factors. Hence, careful history and thorough evaluation of the eyes are indicated to rule out any ocular etiology of the symptoms. Then appropriate imaging and laboratory investigation should be obtained along with prompt referral to neurology or critical care. ❏

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86. Gijtenbeek JM, van den Bent MJ, Vecht CJ. Cyclosporine neurotoxicity: a review. J Neurol 1999; 246(5): 339-346. 87. Mellion ML, Rizvi S. Spontaneous bilateral carotid artery dissection and posterior reversible encephalopathy syndrome. Neurol 2005; 65(12): 1990. 88. Morris EB, Laningham FH, Sandlund JT, et al. Posterior reversible encephalopathy syndrome in children with cancer. Pediatric Blood Cancer 2007; 48(2): 152-159. 89. Van Diest D, Van Goethem JWM, Vercruyssen A, et al. Posterior reversible encephalopathy and Guillain-Barré syndrome in a single patient: coincidence or causative relation. Clin Neurol Neurosurg 2007; 109(1): 58-62. 90. Sutter R, Mengiardi B, Lyrer P, et al. Posterior reversible encephalopathy as the initial manifestation of a GuillainBarré syndrome. Neuromusc Disorders 2009; 19(10): 709-710. 91. Koichihara R, Hamano S, Yamashita S, et al. Posterior reversible encephalopathy syndrome associated with IVIG in a patient with Guillain-Barré syndrome. Pediatric Neurol 2008; 39(2): 123-125. 92. Kelley BJ, Samples S, Kunkel R. PRES following administration of DHE in a patient with unsuspected pheochromocytoma. Headache 2008; 48(8): 1237-1239. 93. Wartenberg KE, Parra A. CT and CT-perfusion findings of reversible leukoencephalopathy during triple-H therapy for symptomatic subarachnoid hemorrhage-related vasospasm. J Neuroimaging 2006; 16(2): 170-175. 94. Sanelli PC, Jacobs MA, Ougorets I, et al. Posterior reversible encephalopathy syndrome on computed tomography perfusion in a patient on “Triple H” therapy. Neurocritical Care 2005; 3(1): 46-50. 95. Pedraza R, Marik PE, Varon J. Posterior Reversible Encephalopathy Syndrome: A Review. Crit Care Shock 2009; 12(4): 135-143. 96. Branson JA, Dale RC. Transient bilateral blindness and posterior reversible encephalopathy syndrome: a rare complication of enuresis treatment. J Paediatrics Child Health 2008; 44(6): 380-382. 97. Lodish M, Patronas NJ, Stratakis CA. Reversible posterior encephalopathy syndrome associated with micronodular adrenocortical disease and Cushing syndrome. European J Pediatrics 2010; 169(1): 125-126. 98. Preul C, Gerth J, Lang S, et al. Cerebral involvement in a patient with Goodpasture's disease due to shortened induction therapy: a case report. J Med Case Reports 2009; 3: 120. 99. Bartynski WS, Boardman JF. Catheter angiography, MR angiography, and MR perfusion in posterior reversible encephalopathy syndrome. Am J Neuroradiol 2008; 29(3): 447-455. 100. Bartynski WS, Upadhyaya AR, Boardman JF. Posterior reversible encephalopathy syndrome and cerebral vasculopathy associated with influenza A infection: report of a case and review of the literature. J Computer Assisted Tomography 2009; 33(6): 917-922. 101. Yilmaz S, Gokben S, Arikan C, Calli C, et al. Reversibility of cytotoxic edema in tacrolimus leukoencephalopathy. Pediatric Neurol 2010; 43(5): 359-362. 102. Kwon EJ, Kim SW, Kim KK, et al. A case of gemcitabine and cisplatin associated posterior reversible encephalopathy syndrome. Cancer Research Treatment 2009; 41(1): 53-55.

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103. Skelton MR, Goldberg RM, O'Neil BH. A case of oxaliplatin-related posterior reversible encephalopathy syndrome. Clin Colorectal Cancer 2007; 6(5): 386-388. 104. Moawad FJ, Hartzell JD, Biega TJ, et al. Transient blindness due to posterior reversible encephalopathy syndrome following ephedra overdose. Southern Med J 2006; 99(5): 511-514. 105. Onder AM, Lopez R, Teomete U, et al. Posterior reversible encephalopathy syndrome in the pediatric renal population. Pediatric Nephrol 2007; 22(11): 1921-1929. 106. Kastrup O, Maschke M, Wanke I, et al. Posterior reversible encephalopathy syndrome due to severe hypercalcemia. J Neurol 2002; 249(11): 1563-1566. 107. Magana SM, Matiello M, Pittock S J, et al. Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders. Neurol 2009; 72(8): 712-717. 108. Kaito E, Terae S, Kobayashi R, et al. The role of tumor lysis in reversible posterior leukoencephalopathy syndrome. Pediatric Radiol 2005; 35(7): 722-727. 109. Nguyen-Lam J, Kiernan MC. Acute cortical blindness due to posterior reversible encephalopathy. J Clin Neuroscience 2008; 15(10): 1182-1185. 110. Puppala S, Hourihan MD. A pressing case of transient blindness. Br J Radiol 2005; 78(934): 967-968. 111. Soltes L, Schmalfuss IM, Bhatti MT. Cortical blindness due to reversible posterior leukoencephalopathy syndrome in a patient with thrombotic thrombocytopenic purpura and preeclampsia. Arch Ophthalmol 2004; 122(12): 1885-1887. 112. Gasco J, Rangel-Castilla L, Clark S et al. Hemorrhagic stroke with intraventricular extension in the setting of acute posterior reversible encephalopathy syndrome (PRES): case report. Neurocirugía 2009; 20(1): 57-61. 113. Prasad N, Gulati S, Gupta RK, et al. Spectrum of radiological changes in hypertensive children with reversible posterior leucoencephalopathy. Br J Radiol 2007; 80(954): 422-429. 114. Albini TA, Lakhanpal RR, Foroozan R, et al. Retinopathy and choroidopathy as the initial signs of hypertensive brainstem encephalopathy. Arch Ophthal 2004; 124(12): 1784-1786. 115. Seet RCS, Lim ECH. Images in cardiovascular medicine. Hypertensive brainstem encephalopathy. Circulation 2007; 115(9): e310-311. 116. Bakker RC, Verburgh C A, van Buchem MA, et al. Hypertension, cerebral oedema and fundoscopy. Nephrol Dialysis Transplantation 2003; 18(11): 2424-2427. 117. Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema. Am J Neuroradiol 2008; 29(6): 1043-1049. 118. Brubaker L M, Smith JK, Lee, Y Z, et al. Hemodynamic and permeability changes in posterior reversible encephalopathy syndrome measured by dynamic susceptibility perfusion-weighted MR imaging. Am J Neuroradiol 2005; 26(4): 825-830. 119. Tajima Y, Isonishi K, Kashiwaba T, et al. Two similar cases of encephalopathy, possibly a reversible posterior leukoencephalopathy syndrome: serial findings of magnetic resonance imaging, SPECT and angiography. Internal Med 1999; 38(1): 54-58.

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120. Doelken M, Lanz S, Rennert J et al. Differentiation of cytotoxic and vasogenic edema in a patient with reversible posterior leukoencephalopathy syndrome using diffusionweighted MRI. Diagnostic Interventional Radiol 2007; 13(3): 125-128. 121. Irvin W, MacDonald G, Smith JK, et al. Dexamethasoneinduced posterior reversible encephalopathy syndrome. J Clin Oncol 2007; 25(17): 2484-2486. 122. Covarrubias DJ, Luetmer PH, Campeau NG. Posterior reversible encephalopathy syndrome: prognostic utility of quantitative diffusion-weighted MR images. Am J Neuroradiol 2002; 23(6): 1038-1048. 123. Limaye S, Cooper J. The right scan at the right time: reversible posterior leukoencephalopathy syndrome mimicking bilateral occipital lobe infarcts. Age Ageing 2009; 38(4): 483-484. 124. Striano P, Striano S, Tortora F, et al. Clinical spectrum and critical care management of Posterior Reversible Encephalopathy Syndrome (PRES). Med Science Monitor 2005; 11(11): CR549-553. 125. Sweany JM, Bartynski WS, Boardman JF. “Recurrent” posterior reversible encephalopathy syndrome: report of 3 cases--PRES can strike twice. J Computer Assisted Tomography 2007; 31(1): 148-156. 126. Benziada-Boudour A, Schmitt E, Kremer S, et al. Posterior reversible encephalopathy syndrome: a case of unusual diffusion-weighted MR images. J Neuroradiol 2009; 36(2): 102-105. 127. Schaefer PW. Diffusion-weighted imaging as a problemsolving tool in the evaluation of patients with acute strokelike syndromes. Topics Magnetic Resonance Imaging 2000; 11(5): 300-309. 128. Efthimiou P, Petryna O, Kukar M, et al. Characteristic neuroimaging findings in posterior reversible encephalopathy syndrome (PRES) in systemic lupus erythematosus. Arthritis Rheumatism 2010; 62(6): 1692. 129. Ugurel MS, Hayakawa M. Implications of post-gadolinium MRI results in 13 cases with posterior reversible encephalopathy syndrome. European J Radiol 2005; 53(3): 441-449. 130. Ho C, Chan K. Posterior reversible encephalopathy syndrome with vasospasm in a postpartum woman after postdural puncture headache following spinal anesthesia. Anesthesia Analgesia 2007; 105(3): 770-772. 131. Patel AJ, Fox BD, Fulkerson DH, et al. Posterior reversible encephalopathy syndrome during posterior fossa tumor resection in a child. J Neurosurg Pediatrics 2010; 6(4): 377-380. 132. Hong J, Jee YS, Lee I H, et al. Posterior Reversible Encephalopathy Syndrome after Cesarean Section under Spinal Anesthesia—a case report. Korean J Anesthesiol 2007; 52(S): 86-90. 133. Pizon AF, Wolfson AB. Postpartum focal neurologic deficits: posterior leukoencephalopathy syndrome. J Emergency Med 2005; 29(2): 163-166. 134. Yamada SM, Kitagawa R, Teramoto A. A case of reversible posterior leukoencephalopathy syndrome with acute hypotension. Neurol Sciences 2011; 32(1): 165-168. 135. Mankad K, Hoey E, Yap KS. Reversible leukoencephalopathy syndrome. Am J Emergency Med 2010; 28(3): 386.e3-5.

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QUESTIONNAIRE Posterior Reversible Encephalopathy Syndrome Sarah E. Shim, OD; Pauline F. Ilsen, OD, FAAO 1. ❏ ❏ ❏ ❏

All of the following conditions are associated with PRES, EXCEPT: Lupus erythematosus Acute hypertensive events Reactive rheumatoid arthritis Renal disease

2. ❏ ❏ ❏ ❏

In the Case Report presented, what was the patient’s initial chief complaint? Decreased near vision Diplopia Decreased night vision Decreased vision at far

In the Case Report presented, the patient had all of the following clinical signs/symptoms at the three year and six months point, EXCEPT: He was unable to see faces He could distinguish between light and dark Headache above his left temple He saw floaters upon awakening

❏ ❏ ❏ ❏

Posterior Reversible Encephalopathy Syndrome — Shim, Ilsen

COPE-APPROVED CE CREDIT APPLICATION FORM

26:2, 15

4. ❏ ❏ ❏ ❏

In the Case Report presented, what did slit lamp examination reveal? 6/3 (20/10) OD 6/9 (20/30) OD 6/12 (20/40) OD 6/30 (20/1000) OD

5. ❏ ❏ ❏ ❏

In the Case Report presented, upon examination at the eye clinic the patient had all of the following clinical signs/symptoms, EXCEPT: The extraocular muscles were full Pupils were normal Hypertensive retinopathy No optic nerve abnormalities

6. ❏ ❏ ❏ ❏

All of the following statements about PRES are true, EXCEPT: If not detected and treated promptly, it is not always reversible It is reversible if detected and treated promptly Treatment success is partially dependent on the age of the patient Advanced cases have responded well to treatment

7. ❏ ❏ ❏ ❏

All of the following statements about PRES are true, EXCEPT: No particular age group has proven to be predisposed to PRES Males are more susceptible to the condition than females Ethnic background does not affect susceptibility to the condition Family history of the disease has not been shown to be a risk factor

8. ❏ ❏ ❏ ❏

Which of the following conditions is NOT associated with PRES? Polyarteritis nodosa Cushing’s syndrome Goodpasture’s disease Erythema nodosa

9. ❏ ❏ ❏ ❏

All of the following predispose children to PRES, EXCEPT: Juvenile lupus Ewing sarcoma Acute lymphocytic leukemia Ocular effects of juvenile diabetes

10. ❏ ❏ ❏ ❏

All of the following are frequent clinical manifestations of PRES, EXCEPT: Headache Memory loss Aphasia Facial numbness

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CLICK HERE TO PRINT THIS CE CREDIT ARTICLE AND TEST

Clinical & Refractive Optometry: Online Edition is pleased to present this continuing education (CE) article by Dr. Denise Goodwin and Dr. Tracy C. Doll entitled Differential Diagnosis and Management of Orbital Apex Syndrome. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 74 for complete instructions.

Denise Goodwin, OD, FAAO; Tracy C. Doll, OD, FAAO

present a case of an immunocompetent patient with latent tuberculosis infection and steroid responsive OAS, and we review the available literature associated with OAS.

ABSTRACT

CASE REPORT

Differential Diagnosis and Management of Orbital Apex Syndrome

Orbital apex syndrome (OAS) is a rare condition that presents with a set of symptoms that include visual loss, ophthalmoplegia, periorbital pain, ptosis, proptosis, and upper eyelid and forehead anesthesia. The condition is potentially sight and life threatening; therefore, prompt diagnosis and management is critical in order to obtain an improved prognosis. We report here on a case of a patient who presented with periorbital pain, ophthalmoplegia and acute visual loss in the setting of a latent tuberculosis infection. The etiology of OAS includes inflammatory, infectious, neoplastic, vascular, and traumatic causes. Careful history, ophthalmic examination, laboratory testing, and neuroimaging are essential in determining the diagnosis. A chest CT or biopsy of the lesion may be necessary. Management includes anti-infectious or anti-inflammatory agents, depending on the cause. Generally, proptosis and ocular motility improve with treatment, but permanent vision loss in not uncommon.

INTRODUCTION Orbital apex syndrome (OAS) is a rare condition that is characterized by optic nerve dysfunction in association with damage to the oculomotor, trochlear, abducens, or ophthalmic branch of the trigeminal nerve. The condition is potentially sight and life threatening; therefore, prompt diagnosis and management is critical in order to obtain an improved prognosis. OAS can result from infection, inflammation, neoplasm, vascular causes, or trauma. It is a known, but rare, manifestation of tuberculosis.1-3 We D. Goodwin — Professor, Pacific University College of Optometry, Forest Grove, OR; T.C. Doll — Assistant Professor, Pacific University College of Optometry, Forest Grove, OR Correspondence to: Dr. Denise Goodwin, Pacific University College of Optometry, 2043 College Way, Forest Grove, OR 97116; E-mail: goodwin@pacificu.edu This article has been peer-reviewed.

A 32-year-old Hispanic female presented with eye pain around the left eye for one week. Three days following the onset of the pain, she began to experience binocular, vertical double vision and nausea. In addition, an area of skin around her left temple, about an inch in size, felt numb. She did not report numbness or weakness of the extremities, dizziness, fever, or rash. This was her first eye examination. She reported no past eye problems. Her last medical exam, less than a year earlier, was reportedly unremarkable. She was taking birth control. Family history was non-contributory. Best corrected visual acuities were 6/6 (20/20) in the right eye (OD) and 6/12 (20/40) in the left eye (OS). A marked left hypertropia of greater than 30 prism diopters was present (Fig. 1). Extraocular muscle testing demonstrated marked restriction of the left eye in superior-nasal gaze and moderate restriction of the left eye in inferiornasal gaze (Fig. 2). She reported pain with eye movements, especially on inferior-nasal gaze. Pupils were round and reactive to light, and no relative afferent pupillary defect (RAPD) was present. A frequency doubling technique (FDT) Matrix Visual Field Screening N-24-5 showed no defects. As seen in the images, the patient experienced mild conjunctival injection following instillation of topical Fluress® (fluorescein sodium and benoxinate hydrochloride, Akorn Inc., Lake Forest, Illinois). Prior to instillation in each eye, there was no conjunctival injection. The anterior segment of both eyes was unremarkable. Intraocular pressures with Goldmann applanation tonometry were 20 mmHg in each eye. Examination of the posterior segments revealed healthy looking optic nerve heads with no edema, pallor, or hyperemia. Disc margins were distinct. Cup-to-disc ratios were 0.3/0.3 in both eyes. Due to the acute onset muscle restriction and decreased visual acuities, the patient was felt to have a condition involving the orbit. She was seen by a neuroophthalmologist a week later. At this visit, visual acuity

Differential Diagnosis and Management of Orbital Apex Syndrome — Goodwin, Doll

Fig. 1 A left hypertropia is present in primary gaze.

had dropped to 6/21 (20/70) in the left eye, and she had developed a 0.3 log unit RAPD. She obtained 9 out of 10 color plates OD and 0 out of 10 color plates OS with HHR pseudoisochromatic plates. With the Octopus 24 Visual Field Threshold, a small superior nasal and inferior temporal depression was present in the right eye. The left eye demonstrated an enlarged blind spot with a cecocentral defect greatest in the superior-temporal quadrant. Extraocular muscle restrictions had also worsened showing almost complete inability to move the left eye. Exophthalmometry was 17 mm in each eye. Cranial nerve evaluation showed symmetric responses for cranial nerves 5, 7, 8, 9, 10, 11, and 12. To ascertain the underlying cause, the patient was sent for an MRI of the orbits with and without contrast. This confirmed an enlarged left lateral rectus muscle extending into the orbital apex (Fig. 3). Based on these findings, a tentative diagnosis of orbital pseudotumor was given. The patient was started on intravenous (IV) methylprednisolone sodium succinate, 500 mg daily. Laboratory testing yielded an increase in white blood cells at 21.1 K/cu mm (normal 4.4-11.0 K/cu mm). Kidney and liver function, as well as angiotensin converting enzyme (ACE), blood glucose, and thyroid hormone levels, were within normal limits. Following three days of IV steroid use, the visual acuity had improved in the left eye to 6/6-2 (20/20-2). Her color vision returned, and extraocular muscle movement improved significantly. The IV steroids were discontinued, and she was prescribed oral prednisone 40 mg daily for one month. At the one-month follow-up visit, the vertical strabismus had completely resolved. Visual acuity was 6/6 (20/20) OD and OS, there were no extraocular motility restrictions, and no RAPD was present. However, the patient reported that she was again experiencing pain in and around her left eye. She was also placed on ibuprofen 800 mg every 6 hours for pain. A repeat MRI showed resolution of the previously enlarged left lateral rectus muscle. However, posterior pachymeningeal and leptomeningeal enhancement was detected, greater on the right side (Fig. 4).

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The patient was scheduled with infectious disease specialist who ordered additional testing. A chest x-ray did not show evidence of pulmonary disease. Laboratory testing, including antineutrophil cytoplasmic antibodies (pANCA and cANCA), antinuclear antibodies (ANA), extractable nuclear antigen antibodies (ENA), and Lyme disease titers came back within normal limits. However, QuantiFERON-TB Gold was positive. Based on these test results, the patient was questioned further. She reported that, as a teenager in Mexico, she was treated for tuberculosis. Cerebral spinal fluid (CSF) analysis for tuberculosis was found to be negative. The CSF contained 7 WBC/mm3 and 9 RBC/mm3. Protein and glucose levels were within the normal range. The VDRL, ACE, gram smear and stain, and acid fast bacilli smear were negative. The CSF cytology was negative for malignancy. About 10 months following the initial presentation, the patient developed a transient, right-sided cranial nerve 7 palsy and was referred to a neurologist. This palsy was felt to be related to the patientâ&#x20AC;&#x2122;s chronic inflammatory condition. However, the patient reported being pregnant at the onset of cranial nerve 7 palsy. After the pregnancy, she will be treated for latent tuberculosis infection.

DISCUSSION OAS affects the optic nerve as it passes through the optic canal and may involve the oculomotor, trochlear, abducens, or the ophthalmic branch of the trigeminal nerve as each passes through the superior orbital fissure. It is characterized by vision loss, ophthalmoplegia, proptosis, periorbital pain, and anesthesia of the upper eyelid and forehead. Signs of orbital inflammation, such as conjunctival hyperemia or swelling of the eyelids, may be present depending on the cause. Determining the underlying etiology of OAS can be challenging, but prompt diagnosis and proper management is critical to the prognosis. Numerous conditions have been implicated in the etiology of OAS, including inflammatory, infectious, neoplastic, vascular, or traumatic disorders. Specific causes of OAS that have been reported in the literature are listed in Table I. An interdisciplinary approach is typically necessary to make the diagnosis. Many infectious, inflammatory, and neoplastic conditions can mimic orbital inflammatory pseudotumor. However, orbital inflammatory pseudotumor is a diagnosis of exclusion, and care must be taken to rule out other causes prior to making this diagnosis. An inflammatory process such as sarcoidosis, Wegener granulomatosis, Churg-Strauss syndrome, or giant cell arteritis can cause acute onset OAS4,5,8,9 and should be ruled out prior to assuming a diagnosis of orbital inflammatory pseudotumor.

Fig. 2 Extraocular muscle movements demonstrating restriction of the left eye.

Fig. 3 Sagital (A) and axial (B) MRI of orbit with gadolinium demonstrating inflammation of left lateral rectus and orbital apex.

Bacterial, viral, fungal or parasitic infections involving the paranasal sinuses or orbit can result in OAS. There should be a heightened suspicion for fungal infections in immunocompromised patients, including those with diabetes, malignancy, acquired immunodeficiency syndrome, and drug induced immunosuppression.25-27 However, fungal infections have been reported in immunocompetent patients.20,23,30,32 Tuberculosis has been reported to affect the orbital apex1,68,69 and cavernous sinus.68,70,71 Systemic symptoms, including frontal headache, flu-like symptoms, weight loss, or night sweats, may be present in patients with tuberculosis-related orbital disease.1,68 Our patient had a positive QuantiFERON-TB Gold result. Both the chest x-ray and the CSF evaluation for tuberculosis were negative. She did not have a cough, fatigue, or unintentional weight loss. Hughes et al1 reported 7 patients with tuberculosis related optic neuropathy or orbital apex involvement. The diagnosis was determined by either a tuberculin test or a tissue culture in all cases. All cases had normal chest x-ray and CSF findings but abnormal tuberculin test. Likewise, in 1975, Mortada2 reported a 3-year-old girl

with OAS. Tuberculin test was positive. X-ray and CSF pressure, cell, protein, and chloride evaluation was normal. Histopathology showed tuberculous granulation. Unfortunately, the childâ&#x20AC;&#x2122;s condition worsened and she died. Autopsy showed a tuberculoma at the orbital apex. Tuli3 presented a 6-year-old boy with proptosis, vision loss, and ophthalmoplegia over one month. Following antituberculosis treatment, proptosis and ocular motility resolved and vision improved from finger counting to 6/9 (20/30). Neoplasm should be a differential diagnosis for all patients with OAS. As metastatic disease has been shown to cause OAS, those with a history of cancer should be at particularly high suspicion for tumor invasion being the cause of the OAS. Evaluation A complete history is essential in determining the cause of OAS. After ruling out trauma, evaluate the patient for vascular risk factors, sign or symptoms of infection, and history of cancer or autoimmune disease. Ask about symptoms of giant cell arteritis in those over age 60 years.

Differential Diagnosis and Management of Orbital Apex Syndrome â&#x20AC;&#x201D; Goodwin, Doll

Table I Causes of OAS reported in the literature. Inflammatory

Churg-Strauss syndrome4 Giant cell arteritis5 Orbital inflammatory pseudotumor6,7 Sarcoidosis8 Wegener granulomatosis9

Infectious

Herpes zoster10-14 Mycobacterium leprae15 Mycobacterium tuberculosis1-3 Staphylococcus aureus and Pseudomonas aeruginoisa16 Syphilis17 Aspergillosis18-24 Mucormycosis25-31 Pseudallescheria boydii32 Zygomycosis33 Gnathostomiasis34

Neoplasms

Adenoid cystic carcinoma35 Cavernous hemangioma36 Ciliary neurinoma37 Extramedullary hematopoises38 Lymphoma39 Meningioma40,41 Metastasized prostate cancer42,43 Metathesized hepatocellular carcinoma43 Metathesized renal carcinoma44 Mucoepidermoid carcinoma45 Rhabdomyosarcoma46,47 Sarcomatoid carcinoma48 Squamous cell carcinoma49-52

Fig. 4 T1 axial MRI with contrast demonstrating resolution of the orbital inflammation and the pachymeningeal and leptomeningeal enhancement (arrow).

Additionally, inquire regarding symptoms associated with dysfunction of the adjacent paranasal sinuses, as this is associated with orbital abscess.72 Patients frequently present with pain around the involved eye, but the condition may be painless.26,72 Diplopia and vision loss are other common presenting symptoms. Symptoms typically have an abrupt onset with progression over days to weeks.73 Optic neuropathy is a characteristic feature of OAS. The optic nerve often appears normal on ophthalmoscopy, although atrophy may develop over weeks to months.10,18,26,73 Decreased visual acuity, reduced color vision, and detection of a relative afferent pupillary defect will help detect the presence of optic neuropathy. Visual field testing may also be useful for assessing visual defects. Extraocular muscle restrictions may follow a pattern of a single cranial nerve palsy but commonly do not follow a pattern due to multiple cranial nerves being involved. Levator function, as well as corneal and facial sensation may be impaired. Exophthalmos is frequently present. The pupil may be fixed and dilated due to involvement of the parasympathetic innervation to the iris. Sensation of the cornea and periorbital region should be evaluated, as involvement of ophthalmic branch of the trigeminal nerve can result in either increased or diminished sensation. Exophthalmometry is useful to evaluate and follow proptosis. Finally, body temperature is helpful in ruling out infectious causes.

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Vascular causes Carotid-cavernous fisula53 Ischemia54 Other

Trauma55-60 Surgery to the orbital or face61-67

Depending on the suspected diagnosis, laboratory testing may include complete blood count (CBC) with differential, erythrocyte sedimentation rate (ESR), angiotensin converting enzyme (ACE), antinuclear antibodies (ANA), fasting blood glucose level, rapid plasma reagin (RPR), microhemagglutination assay for antibody to Treponema pallidum (MHA-TP), human immunodeficiency virus (HIV) antibodies, cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA), perinuclear antineutrophil cytoplasmic antibody (p-ANCA), and purified protein derivative (PPD).25,73 A chest CT is necessary to rule out conditions such as Wegener granulomatosis, sarcoidosis, or tuberculosis. Evaluation of the CSF may be warranted, particularly if meningitis symptoms are present.73 MRI of the brain and orbits with gadolinium contrast is essential in the evaluation of OAS. Extraocular muscle enlargement, infiltration of orbital fat, inflammation of the optic nerve, or a focal or diffuse inflammatory orbital mass may be present. The cavernous sinuses should be

carefully evaluated to assure they are not involved. Radiologic findings may be minimal or absent.25 Neurosarcoidosis, meningitis, or neoplasms that spread into the subarachnoid space may cause leptomeningeal enhancement.74,75 Pachymeningial enhancement is caused by intracranial hypotension, meningiomas, metastatic disease, central nervous system lymphoma, and granulomatous disease.74 Additional neuroimaging may be necessary depending on the suspected cause of OAS. CT scan is necessary if involvement of the paranasal sinuses or trauma present. An MRA or CTA should be performed if a vascular lesion is suspected. Repeat neuroimaging may be necessary to determine treatment efficacy. Occasionally, transnasal endoscopic exploration, biopsy, or culture may be necessary to make the diagnosis.25,72 Treatment/Management Management of OAS involves a multidisciplinary approach. Depending on the suspected cause, consultation with infectious disease specialists, endocrinology, otolaryngology, neurology, or neurosurgery may be necessary. Treatment of infectious OAS involves the use of antibiotic, antiviral, or antifungal agents, depending on the etiology. Debridement of necrotic tissue, as well intravenous amphotericin B, is warranted if mucormycosis or aspergillosis is present.18,25 Tuberculosis treatment includes rifampicin, isoniazid, pyrazinamide, ethambutol, moxifloxacin, and pyridoxine. Systemic steroids are helpful in reducing the inflammation. Corticosteroids may be useful in managing inflammation but should be used with caution as they can exacerbate an infection or delay a correct diagnosis.50,73 In the absence of a specific cause and if systemic infection is unlikely, corticosteroids under close observation is warranted.1,73 If the condition progresses despite corticosteroid treatment, repeat neuroimaging and biopsy may be necessary.73 Prognosis Due to the rarity of OAS, no large clinical trials have been performed to determine the prognosis of the condition. Ptosis and ocular motility generally improve with treatment.10,18,42,76,77 However, permanent vision loss is not uncommon despite complete recovery of the extraocular muscle motility.7,21,47,69 With prompt treatment complete visual recovery may be possible.12,78 Hughes et al1 found that six of seven patients with optic nerve involvement secondary to tuberculosis had visual acuity of 6/6 (20/20) after treatment. In those with traumatic OAS, eyesight was found to recover if surgery was performed within 24 to 48 hours of the injury.76 On the other hand, delayed treatment of OAS can result in blindness6 or even death.24,25

CONCLUSION OAS is a rare condition involving the optic nerve, as well as the nerves passing through the superior orbital fissure. The many potential causes make the diagnosis difficult. Prompt treatment with a multidisciplinary approach is essential to improve the chances of restoration of vision and eye movements. Tuberculosis should be suspected in patients from endemic areas. ❏ Acknowledgement: We would like to thank Cameron D. Horch for his assistance in this case.

REFERENCES 1. 2. 3. 4. 5. 6.

8. 9. 10. 11. 12. 13.

14. 15. 16.

Hughes EH, Petrushkin H, Sibtain NA, et al. Tuberculous orbital apex syndromes. Br J Ophthalmol 2008; 92(11): 1511-1517. Mortada A. Orbital apex syndrome with contra-lateral hemiplegia due to tuberculoma of orbital apex. Mod Probl Ophthalmol 1975; 14: 657-659. Tuli N. Orbital tuberculosis in childhood with intracranial extension: A case report. Cases J 2010; 3: 38. Tokumaru AM, Obata T, Kohyama S, et al. Intracranial meningeal involvement in Churg-Strauss syndrome. AJNR Am J Neuroradiol 2002; 23(2): 221-224. Islam N, Asaria R, Plant GT, et al. Giant cell arteritis mimicking idiopathic orbital inflammatory disease. Eur J Ophthalmol 2003; 13(4): 392-394. Eftekhari K, Chikwava KR, Katowitz WR. Idiopathic orbital inflammation leading to unilateral blindness over a 2-day presentation in a child. Ophthal Plast Reconstr Surg 2011; 27(2): e46-47. Tay E, Gibson A, Chaudhary N, et al. Idiopathic orbital inflammation with extensive intra- and extracranial extension presenting as 6th nerve palsy — a case report and literature review. Orbit 2008; 27(6): 458-461. Segal EI, Tang RA, Lee AG, et al. Orbital apex lesion as the presenting manifestation of sarcoidosis. J Neuroophthalmol 2000; 20(3): 156-158. Chua J, Lim L. Systemic Wegener’s granulomatosis with severe orbito-ocular involvement. Singapore Med J 2008; 49(10): e259-262. Arda H, Mirza E, Gumus K, et al. Orbital apex syndrome in herpes zoster ophthalmicus. Case Rep Ophthalmol Med 2012; 2012: 854503. Shirato S, Oshitari T, Hanawa K, et al. Magnetic resonance imaging in case of cortical apex syndrome caused by varicella zoster virus. Open Ophthalmol J 2008; 2: 109-111. Kurimoto T, Tonari M, Ishizaki N, et al. Orbital apex syndrome associated with herpes zoster ophthalmicus. Clinical Ophthalmology 2011; 5: 1603-1608. Saxena R, Phuljhele S, Aalok L, et al. A rare case of orbital apex syndrome with herpes zoster ophthalmicus in a human immunodeficiency virus-positive patient. Indian J Ophthalmol 2010; 58(6): 527-530. Ugarte M, Dey S, Jones CA. Ophthalmoplegia secondary to herpes zoster ophthalmicus. BMJ Case Rep 2010; 2010. El Beltagi AH, El-Nil H, Alrabiah L, et al. Orbital apex syndrome due to trigeminal perineural spread of sinonasal leprosy: A case report. Clin Imaging 2012; 36(2): 142-145. Colson AE, Daily JP. Orbital apex syndrome and cavernous sinus thrombosis due to infection with staphylococcus aureus and pseudomonas aeruginosa. Clin Infect Dis 1999; 29(3): 701-702.

Differential Diagnosis and Management of Orbital Apex Syndrome — Goodwin, Doll

17. Currie JN, Coppeto JR, Lessell S. Chronic syphilitic meningitis resulting in superior orbital fissure syndrome and posterior fossa gumma. A report of two cases followed for 20 years. J Clin Neuroophthalmol 1988; 8(3): 145-159. 18. Cho SH, Jin BJ, Lee YS, et al. Orbital apex syndrome in a patient with sphenoid fungal balls. Clin Exp Otorhinolaryngol 2009; 2(1): 52-54. 19. Yip CM, Hsu SS, Liao WC, et al. Orbital apex syndrome due to aspergillosis with subsequent fatal subarachnoid hemorrhage. Surg Neurol Int 2012; 3: 124. 20. Yamanoi T, Shibano K, Soeda T, et al. Intracranial invasive aspergillosis originating in the sphenoid sinus: A successful treatment with high-dose itraconazole in three cases. Tohoku J Exp Med 2004; 203(2): 133-139. 21. Kaeser PF, Borruat FX. Aspergillosis: An unusual case of orbital apex syndrome. Klin Monatsbl Augenheilkd 2010; 227(4): 326-327. 22. Lim SC, Choi JU, Bae SH. Rapid development of an infectious aneurysm of the internal carotid artery from orbital apex syndrome. Otolaryngol Head Neck Surg 2010; 142(2): 294-295. 23. Oâ&#x20AC;&#x2122;Toole L, Acheson JA, Kidd D. Orbital apex lesion due to aspergillosis presenting in immunocompetent patients without apparent sinus disease. J Neurol 2008; 255(11): 1798-1801. 24. Fernandes YB, Ramina R, Borges G, et al. Orbital apex syndrome due to aspergillosis: Case report. Arq Neuropsiquiatr 2001; 59(3-B): 806-808. 25. Auerbach DB, Bilyk JR. Lung cancer, proptosis, and decreased vision. Surv Ophthalmol 1999; 43(5): 405-412. 26. Balch K, Phillips PH, Newman NJ. Painless orbital apex syndrome from mucormycosis. J Neuroophthalmol 1997; 17(3): 178-182. 27. Dooley DP, Hollsten DA, Grimes SR, et al. Indolent orbital apex syndrome caused by occult mucormycosis. J Clin Neuroophthalmol 1992; 12(4): 245-249. 28. Ali S, Ahmad I. Mucormycosis causing palatal necrosis and orbital apex syndrome. J Coll Physicians Surg Pak 2005; 15(3): 182-183. 29. Bray WH, Giangiacomo J, Ide CH. Orbital apex syndrome. Surv Ophthalmol 1987; 32(2): 136-140. 30. Varghese A, Thomas S. Orbital apex syndrome secondary to mucormycosis after a tooth extraction in an immunocompetent patient. Ear Nose Throat J 2010; 89(4): e24-26. 31. Turunc T, Demiroglu YZ, Aliskan H, et al. Eleven cases of mucormycosis with atypical clinical manifestations in diabetic patients. Diabetes Res Clin Pract 2008; 82(2): 203-208. 32. Thiagalingam S, Fernando GT, Tan K, et al. Orbital apex syndrome secondary to pseudallescheria boydii fungal sinusitis in an immunocompetent patient. Clin Experiment Ophthalmol 2004; 32(5): 545-547. 33. Schuster MG, Stern J. Zygomycosis orbital apex syndrome in association with a solitary lung carcinoma. J Med Vet Mycol 1995; 33(1): 73-75. 34. Preechawat P, Wongwatthana P, Poonyathalang A, et al. Orbital apex syndrome from gnathostomiasis. J Neuroophthalmol 2006; 26(3): 184-186. 35. McDonald HR, Char DH. Adenoid cystic carcinoma presenting as an orbital apex syndrome. Ann Ophthalmol 1985; 17(12): 757-759. 36. Kashkouli MB, Imani M, Tarassoly K, et al. Multiple cavernous hemangiomas presenting as orbital apex syndrome. Ophthalmic Plast Reconstr Surg 2005; 21(6): 461-463.

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37. Vassilikos C, Pepe P, Christopoulos C. Ciliary neurinoma: A very rare intraorbital extraocular tumor causing orbital apex syndrome. Plast Reconstr Surg 2003; 112(5): 1504-1505. 38. Pless M, Rizzo JF,3rd, Shang J. Orbital apex syndrome: A rare presentation of extramedullary hematopoiesis: Case report and review of literature. J Neurooncol 2002; 57(1): 37-40. 39. Hayashi T, Watanabe K, Tsuura Y, et al. Sight-threatening optic neuropathy is associated with paranasal lymphoma. Clinical Ophthalmology 2010; 4: 143-146. 40. Ikawa F, Uozumi T, Kiya K, et al. Cavernous sinus meningioma presenting as orbital apex syndrome. diagnostic methods of dynamic MRI, spoiled GRASS (SPGR) image. Neurosurg Rev 1995; 18(4): 277-280. 41. Scott A, Sharkawi E, Micallef C, et al. Chordoid meningioma presenting as painful orbital apex syndrome in pregnancy. Int Ophthalmol 2008; 28(5): 355-357. 42. Chua CN, Gibson AR, Frank J. An unusual cause of orbital apex syndrome. Eye 2001; 15(Pt 3): 342-343. 43. Hirunwiwatkul P, Tirakunwichcha S, Meesuaypong P, et al. Orbital metastasis of hepatocellular carcinoma. J Neuroophthalmol 2008; 28(1): 47-50. 44. Mehelas TJ, Kosmorsky GS. Painful ophthalmoplegia syndrome secondary to metastatic renal cell carcinoma. J Neuroophthalmol 1996; 16(4): 289-290. 45. Gore HL, Corin SM, Klussmann KG, et al. Mucoepidermoid carcinoma presenting as an orbital apex syndrome. Ophthalmic Surg 1992; 23(1): 59-61. 46. Machleder DJ, Banik R, Rosenberg RB, et al. An unusual case of rhabdomyosarcoma presenting as orbital apex syndrome. Int J Pediatr Otorhinolaryngol 2005; 69(2): 249-254. 47. Shindler KS, Liu GT, Womer RB. Long-term follow-up and prognosis of orbital apex syndrome resulting from nasopharyngeal rhabdomyosarcoma. Am J Ophthalmol 2005; 140(2): 236-241. 48. Sadaba LM, Garcia-Layana A, Garcia-Gomez PJ, et al. Sarcomatoid carcinoma and orbital apex syndrome. Eur J Ophthalmol 2006; 16(4): 608-610. 49. Alonso PE, Bescansa E, Salas J, et al. Perineural spread of cutaneous squamous cell carcinoma manifesting as ptosis and ophthalmoplegia (orbital apex syndrome). Br J Plast Surg 1995; 48(8): 564-568. 50. Nieto Enriquez J, Medel Jimenez R, Huguet Redecilla P. Undiagnosed squamous cell carcinoma of the forehead presenting as a tolosa-hunt syndrome. Orbit 2009; 28(5): 290-292. 51. Srinivasan S, Fern AI, Wilson K. Orbital apex syndrome as a presenting sign of maxillary sinus carcinoma. Eye 2001; 15(Pt 3): 343-345. 52. Veness MJ, Biankin S. Perineural spread leading to orbital invasion from skin cancer. Australas Radiol 2000; 44(3): 296-302. 53. de Keizer R. Carotid-cavernous and orbital arteriovenous fistulas: Ocular features, diagnostic and hemodynamic considerations in relation to visual impairment and morbidity. Orbit 2003; 22(2): 121-142. 54. Jabs DA, Miller NR, Green WR. Ischaemic optic neuropathy with painful ophthalmoplegia in diabetes mellitus. Br J Ophthalmol 1981; 65(10): 673-678. 55. Acarturk S, Sekucoglu T, Kesiktas E. Mega dose corticosteroid treatment for traumatic superior orbital fissure and orbital apex syndromes. Ann Plast Surg 2004; 53(1): 60-64.

56. Gawley SD, McAvoy CE, Best RM, et al. Traumatic self-induced orbital apex syndrome. Eye 2007; 21(11): 1451-1452. 57. Zachariades N, Vairaktaris E, Papavassiliou D, et al. Orbital apex syndrome. Int J Oral Maxillofac Surg 1987; 16(3): 352-354. 58. Lubbe DE, Gardiner I, Fagan JJ. An unusual orbital foreign body resulting in the orbital apex syndrome: Report of a case. Arch Otolaryngol Head Neck Surg 2005; 131(6): 526-528. 59. Peter NM, Pearson AR. Orbital apex syndrome from blunt ocular trauma. Orbit 2010; 29(1): 42-44. 60. Stuzin JM, Cutting CB, McCarthy JG, et al. Radiographical documentation of direct injury of the intracanalicular segment of the optic nerve in the orbital apex syndrome. Ann Plast Surg 1988; 20(4): 368-373. 61. Eo S, Kim JY, Azari K. Temporary orbital apex syndrome after repair of orbital wall fracture. Plast Reconstr Surg 2005; 116(5): 85e-89e. 62. Yeh S, Yen MT, Foroozan R. Orbital apex syndrome after ethmoidal artery ligation for recurrent epistaxis. Ophthal Plast Reconstr Surg 2004; 20(5): 392-394. 63. Jaison SG, Bhatty SM, Chopra SK, et al. Orbital apex syndrome: A rare complication of septorhinoplasty. Indian J Ophthalmol 1994; 42(4): 213-214. 64. Lax T, Ng JD. Cavernous sinus/orbital apex syndrome associated with indwelling orbital catheter use. Ophthal Plast Reconstr Surg 2006; 22(5): 389-391. 65. Vassallo P, Tranfa F, Forte R, et al. Ophthalmic complications after surgery for nasal and sinus polyposis. Eur J Ophthalmol 2001; 11(3): 218-222.

66. Rene C, Rose GE, Lenthall R, et al. Major orbital complications of endoscopic sinus surgery. Br J Ophthalmol 2001; 85(5): 598-603. 67. Maharshak I, Hoang JK, Bhatti MT. Complications of vision loss and ophthalmoplegia during endoscopic sinus surgery. Clin Ophthalmol 2013; 7: 573-580. 68. Al Soub H, Al Alousi FS, Al-Khal AL. Tuberculoma of the cavernous sinus. Scand J Infect Dis 2001; 33(11): 868-870. 69. Dewan T, Sangal K, Premsagar IC, et al. Orbital tuberculoma extending into the cranium. Ophthalmologica 2006; 220(2): 137-139. 70. Bafna S, Lee AG. Presumed tuberculosis presenting as a cavernous sinus syndrome. J Neuroophthalmol 1997; 17(3): 207-208. 71. Phookan G, Towns GM. Tuberculoma of the cavernous sinusâ&#x20AC;&#x201D;a case report. Br J Neurosurg 1995; 9(2): 205-207. 72. Chee E, Looi A. Onodi sinusitis presenting with orbital apex syndrome. Orbit 2009; 28(6): 422-424. 73. Yeh S, Foroozan R. Orbital apex syndrome. Curr Opin Ophthalmol 2004; 15(6): 490-498. 74. Smirniotopoulos JG, Murphy FM, Rushing EJ, et al. Patterns of contrast enhancement in the brain and meninges. Radiographics 2007; 27(2): 525-551. 75. Ginat DT, Dhillon G, Almast J. Magnetic resonance imaging of neurosarcoidosis. J Clin Imaging Sci 2011; 1: 15. 76. Li Y, Wu W, Xiao Z, et al. Study on the treatment of traumatic orbital apex syndrome by nasal endoscopic surgery. Eur Arch Otorhinolaryngol 2011; 268(3): 341-349. 77. Kander PL, Leaver PK. Orbital apex syndrome complicating frontal pyocoele. J Laryngol Otol 1974; 88(6): 551-557. 78. Kumagai M, Hashimoto S, Suzuki H, et al. Orbital apex syndrome caused by sphenoethmoid mucocele. Auris Nasus Larynx 2003; 30(3): 295-297.

Differential Diagnosis and Management of Orbital Apex Syndrome â&#x20AC;&#x201D; Goodwin, Doll

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QUESTIONNAIRE Differential Diagnosis and Management of Orbital Apex Syndrome Denise Goodwin, OD, FAAO; Tracy C. Doll, OD, FAAO 1. ❏ ❏ ❏ ❏

All of the following are symptoms of orbital apex syndrome (OAS), EXCEPT: Periorbital pain Ptosis Sinus pain Proptosis

2. ❏ ❏ ❏ ❏

All of the following are etiologies of OAS, EXCEPT: Traumatic causes Infectious causes Hereditary causes Vascular causes

3. ❏ ❏ ❏ ❏

All of the following statements about OAS are true, EXCEPT: Ocular motility generally improves with treatment Permanent vision loss is common Proptosis generally improves with treatment Permanent vision loss is rare

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4. ❏ ❏ ❏ ❏

In the Case Report presented, all of the following describe the patient’s condition at first presentation, EXCEPT: Dizziness Eye pain around the left eye Nausea Vertical double vision

5. ❏ ❏ ❏ ❏

In the Case Report presented, all of the following describe the patient at initial presentation, EXCEPT: Optic nerve head pallor Unremarkable anterior segment Distinct disc margins Normal intraocular pressure

6. ❏ ❏ ❏ ❏

In the Case Report presented, which of the following test findings were abnormal? Elevated white blood cell count Normal kidney function Elevated blood glucose levels Normal liver function

7. ❏ ❏ ❏ ❏

All of the following are possible causes of OAS, EXCEPT: Sarcoidosis Ciliary neurinoma Basal cell carcinoma Trauma

8. ❏ ❏ ❏ ❏

All of the following conditions point to heightened suspicion for fungal infections, EXCEPT: Malignancy Diabetes Drug induced immunosuppression Leukemia

9. ❏ ❏ ❏ ❏

All of the following systemic symptoms may be present in patients with tuberculosis-related orbital disease, EXCEPT: Migraine Weight loss Frontal headache Flu-like symptoms

10. ❏ ❏ ❏ ❏

All of the following statements about OAS are true, EXCEPT: The condition may be painless Vision loss is a common presenting symptom In most cases vision is restored with proper treatment Diplopia is a common presenting symptom

Differential Diagnosis and Management of Orbital Apex Syndrome — Goodwin, Doll

News and Notes Dr. George Woo Receives Distinguished Asian Pacific American Alumni Award Venerated retired Waterloo faculty member Dr. George Woo is the most recent recipient of Indiana University’s “Distinguished Asian Pacific American Alumni Award,” presented earlier this spring. Dr. Woo graduated from the College of Optometry of Ontario in 1964, and after completing his graduate work at Indiana University, he dedicated 26 years of his career to the University of Waterloo. During his time here, Dr. Woo co-founded the Low Vision Clinic and was the Founding Director of the Centre for Sight Enhancement which is now world renowned. His research on contrast sensitivity and low vision is well known across many cities and many continents. He has had an expansive career which allowed him to provide vision care through the Red Cross and take on leadership roles at Hong Kong Polytechnic University, the World Council of Optometry, and on allied health research committees. Additionally, Dr. Woo has published more than 170 papers in scholarly journals and has given many invited presentations. Dr. Woo is also a recipient of one of the University of Waterloo 50th Anniversary Awards and is a leadership donor to the School's clinic transformation campaign. The award from Indiana University honours Asian/Pacific American alumni “who impact their local communities and the greater Asian/Pacific American community, exhibit excellence and achievement in their careers, and inspire future IU alumni.” Johnson & Johnson Vision Care to be Headline Sponsor of the 1st World Congress of Optometry Organizers of the 1st World Congress of Optometry are delighted to announce that Johnson & Johnson Vision Care Companies is to be the event’s headline sponsor. The Congress, organized by the World Council of Optometry (WCO) and the Colombian Federation of Optometrists (FEDOPTO), takes place August 14-16, 2015 in Medellin, Colombia. It will be the first global event to encompass all aspects of optometry in order to share knowledge, explore clinical and technological innovation and establish an agreed holistic policy for the sector and for the future of accessible eye health care. During the Congress, Johnson & Johnson Vision Care will deliver a keynote lecture and will also address the Presidents’ Forum, which takes place on August 13, 2015. Registration Now Open for International Vision Expo West International Vision Expo & Conference has opened attendee registration for Vision Expo West at the Sands Expo and Convention Center in Las Vegas, Nev. (Education: Sept. 16 –19, 2015 Exhibition: Sept. 17 – 19, 2015.) Registration for education courses is now open. are Technologies, a VM Live Presentation, and specialty programming for lab owners and managers at The Optical Lab Division Meeting. In response to requests from attendees, International Vision Expo will host its first job fair in conjunction with Local Eye Site. Attendees who register by August 20, 2015 will benefit from early bird pricing: a $25 discount on registration fees. Customizable education packages are available with a la carte options and total office pricing offers discounts for practice groups. To learn more or to register, visit www.VisionExpoWest.com.

Indications and clinical use: LOTEMAX® Gel (loteprednol etabonate ophthalmic gel 0.5% w/w) is indicated for the treatment of postoperative inflammation and pain following cataract surgery. • The safety and efficacy of LOTEMAX® have not been studied in pediatric patients (<18 years of age) and the product should not be used in these populations. Contraindications: • Suspected or confirmed infection of the eye: viral diseases of the cornea and conjunctiva including epithelial herpes, simplex keratitis (dendritic keratitis), vaccinia, and varicella; untreated ocular infection of the eye; mycobacterial infection of the eye and fungal diseases of ocular structures. • Hypersensitivity to LOTEMAX® or any ingredient in the formulation or container, or to other corticosteroids. Relevant warnings and precautions: • LOTEMAX® Gel is indicated for short-term treatment only (up to 14 days). If LOTEMAX® Gel is used for 10 days or longer, intraocular pressure (IOP) should be closely monitored. • The use of steroids after cataract surgery may delay wound healing. • Prolonged use of corticosteroids may result in cataract and/or glaucoma formation. Should not be used in the presence of glaucoma or elevated IOP, unless absolutely necessary and close ophthalmologic monitoring is undertaken. • LOTEMAX® Gel includes benzalkonium chloride. • Should not be used in pregnant or lactating women unless the benefit to the mother clearly outweighs the risk to the infant/child. For more information: Please consult the Product Monograph at http://www.bausch.ca/en-ca/our-products/ rx-pharmaceuticals/lotemax-gel-loteprednoletabonate-ophthalmic-gel-05-w-w for complete dosing instructions, warnings, precautions, adverse events and patient selection criteria. The Product Monograph is also available by calling 1-888-459-5000.

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