SUPPLEMENT TO April 15, 2010

www.revoptom.com

Twelfth Edition

Joseph W. Sowka, O.D., FAAO, Dipl. Andrew S. Gurwood, O.D., FAAO, Dipl. Alan G. Kabat, O.D., FAAO

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Eyelids & Adnexa & & Vitreous & Neuro-Ophthalmic Disease Oculosystemic Disease

EYELIDS & ADNEXA VITREOUS & RETINA

Floppy Syndrome ...... 6 Macular Hole ...... 35

Herpes Zoster Ophthalmicus ...... 7 Branch Retinal Vein Occlusion ...... 37

Canaliculitis ...... 9 Central Retinal Vein Occlusion...... 40

Dacryocystitis ...... 11 Acquired ...... 43

CONJUNCTIVA & SCLERA NEURO-OPHTHALMIC DISEASE

Acute Allergic ...... 13 Melanocytoma of the ...... 45

Pterygium ...... 16 Demyelinating (,

Subconjunctival Hemmorrhage ...... 18 Retrobulbar Optic Neuritis) ...... 47

Traumatic Optic Neuropathy ...... 50 CORNEA Pseudotumor Cerebri ...... 52 Corneal Abrasion and Recurrent Corneal Erosion ..20 ...... 54 Dry Syndrome ...... 22

Thygeson’s Superficial Punctate Keratopathy ...... 26 OCULOSYSTEMIC DISEASE

Cat Scratch Disease ...... 56 UVEA & GLAUCOMA Sjögren’s Syndrome ...... 57 Anterior ...... 28 Hypertension ...... 60 Iridocorneal Endothelial Syndromes (ICE) ...... 30 Diabetes Mellitus ...... 62 Phacolytic Glaucoma ...... 31

Primary Chronic Angle Closure Glaucoma ...... 33

A Peer-Reviewed Supplement The articles in this supplement were subjected to Review of Optometry ’s peer-review process. The maga- zine employs a double-blind review system for clinical manuscripts. Two referees review each manuscript before publication. This supplement was edited by the editors of Review of Optometry .

©2010. Reproducing editorial content and photographs require permission from Review of Optometry.

001_ro0410_hndbkv7.indd 4 4/5/10 8:47 AM FROM THE AUTHORS

To Our Colleagues:

The publication of the Twelfth edition of The Handbook of Ocular Disease Management coincides with many changes within the profession of optometry. Optometry has evolved from what was once a purely visual correction and refractive profession to an integrated member of the healthcare team. There has been increased specialization within optometry to the point that optometrists now utilize intra-professional referrals rather than strictly using inter-professional referrals. We need to embrace the concept that eye care, patient care, and optometry have become so advanced that it is difficult for any single practitioner to be everything to every patient. Optometric societies have developed to cater to and foster interest in specialized areas of optometry. Sub-specialization has become a real part of optometry. Referral to optometric colleagues for glaucoma and ocular disease management, vision therapy, low vision, and specialty contact fittings is now common place.

Common to all of these changes is the need for optometrists to remain current and enhance their knowledge and education. Optometrists must commit to lifelong learning. Reading high quality peer-reviewed publications is necessary. Attending continuing education conferences that are free of commercial bias allows optometrists to keep current and interact, both socially and professionally, with colleagues. We have always felt that the best way to begin this commitment to lifelong learning is through the completion of an accredited residency. Residency training not only provides increased clinical experience, it opens doors and initiates the lifelong learning process. To all optometry stu- dents (and practitioners) reading this manuscript, we strongly encourage you to pursue residency training.

Joe Andy Al

Joseph W. Sowka, O.D., F.A.A.O., Dipl., is a professor of optometry at Nova Southeastern University College of Optometry, where he teaches Glaucoma and Retinal Disease. He is the director of the Glaucoma Service and chief of the Advanced Care Service. He is a diplomate of the Disease Section of the American Academy of Optometry (Glaucoma Subsection) and a founding member of the Optometric Glaucoma Society and the Optometric Retina Society. He can be reached at (954) 262-1472 or at [email protected].

Andrew S. Gurwood, O.D., F.A.A.O., Dipl., is a member of the attending staff of The Albert Einstein Medical Center Department of . Involved in direct patient care, he also precepts students and medical residents teaching clinical practice, clinical The authors have medicine and its relationship to the eye and ocular urgencies and emergencies. He is a diplomate of the American Academy of Optometry’s Primary Care Section, a found- no financial inter- ing member of the Optometric Retina Society, a member of the Optometric Glaucoma est in any product Society and a member of the Optometric Dry Eye Society. He serves on the American Academy of Optometry’s Program Committee and is the Chairperson of the American mentioned. Academy of Optometry’s Disease Section Written Examination for Retinal Disease Diplomate. He can be reached at (215) 276-6134 or at [email protected].

Alan G. Kabat, O.D., F.A.A.O., is an associate professor at Nova Southeastern University College of Optometry where he teaches several didactic courses and serves as an attending physician in The Eye Care Institute. He is a founding member of the Optometric Dry Eye Society and the Ocular Surface Society of Optometry. Dr. Kabat is also the newly appointed Diplomate Chair for the Disease Section (Anterior Segment ] Disease Subsection) of the American Academy of Optometry. He can be reached at (954) 262-1440 or at [email protected].

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FLOPPY EYELID SYNDROME Pathophysiology surface. Others have suggested that the The exact etiology of FES is not underlying mechanism is simply poor Signs and Symptoms thoroughly understood. Research has apposition of the upper eyelid to the Floppy eyelid syndrome , instigating an inadequate (FES), first described in 1981 tear distribution and subsequent by Culbertson and Ostler, is a desiccation of the ocular surface relatively uncommon ocular tissues.9 condition characterized by flac- cid, easily everted upper lids.1 Management It is usually seen in overweight, In the majority of cases, middle-aged males, although it diagnosis is made by the clas- may occasionally be encountered sic appearance and effortless or in women, children and non- spontaneous eversion of the eye- obese individuals. A fair per- lids. There are few ancillary tests centage of patients with FES to consider beyond the normal also suffer from obstructive sleep ocular evaluation, though vital apnea (OSA), a disorder marked Floppy eyelid syndrome. dye staining (e.g., sodium fluo- by partial collapse of the phar- rescein, rose bengal and/or lis- ynx during inspiration while sleeping, demonstrated that tarsal elastin is sig- samine green) may help to assess the resulting in loud snoring and gasping nificantly diminished in these patients, severity of any associated keratopathy. for air.2-4 such that the tarsal plate of the eye- Treatment for FES consists primar- Symptoms generally consist of ocular lid no longer displays its customary ily of lubricating the ocular surface and irritation, itching and stringy mucous rigidity.6 A recent study of patients safeguarding the eye from nocturnal discharge, particularly upon awaken- with FES identified elevated matrix damage. Artificial , used liberally ing.1-4 The symptoms may appear to metalloproteinase (MMP) activity in throughout the day, help to eliminate be largely unilateral or asymmetric. subjects’ eyelids; MMPs in these cases mucous debris and promote corneal Patients with OSA characteristical- have been shown to degrade local elas- healing. In cases of moderate or pro- ly complain of erratic sleep patterns, tin fibers and may ultimately lead to found epitheliopathy, consider more chronic somnolence, fatigue and morn- eyelid laxity and instability in this dis- enduring lubricants such as Systane ing headaches. ease process.7 The authors postulated Ultra (Alcon Laboratories) or Blink Examination of patients with FES that nocturnal mechanical factors may Tears (Abbott Medical Optics) on a typically reveals chronic papillary con- result in local eyelid ischemia, which q.i.d. basis. At bedtime, the patient junctivitis with mild to moderate bul- upregulates these elastin-degrading should instill either a bland ophthal- bar hyperemia, often lateralizing to the enzymes to produce the tissue laxity.7 mic ointment (e.g., Systane Nighttime, patient’s habitual sleeping side (i.e., Another publication suggested that from Alcon Laboratories or Refresh if they sleep on their LEFT side, the elevated plasma leptin (a hormone that PM from Allergan) or mild antibi- presentation is more evident OS).5 produces satiety symptoms) in FES otic ointment and apply a protective Punctate corneal epitheliopathy and patients may play a role in the sys- eye shield, or simply tape the lids mucous strands in the tear film and temic up-regulation of the MMPs that in a closed position. Another option fornices may also be apparent. The lids degrade elastin within the eyelid.8 involves the use of removable eyelid themselves routinely display pseudo- Along with the etiopathology, the weights (e.g., Blinkeze External Lid and an odd “rubbery” consisten- precise mechanism by which this dis- Weights, by MedDev Corporation) cy.5 Eversion of the upper lids can be order becomes manifested also remains at bedtime.10 Severe, recalcitrant cases accomplished with minimal manipula- disputed.1,6-9 The most widely held that do not respond to primary ther- tion; in fact, it may occur spontaneously theory suggests that, because of the lid apy may require surgical intervention. during normal ocular examination. Past laxity and tendency of these patients Most commonly, this involves an eye- ocular history may include , to lie on their sides or in a “face- lid tightening procedure at the lateral dysfunction, derma- down” position, spontaneous lid ever- canthus, or a horizontal lid shortening tochalasis, and seasonal sion occurs during sleep.1 This results procedure by full-thickness resection .5 in mechanical abrasion of the ocular of the lateral one-third of the lid mar-

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11 10(1)1:174-81. gin. Lateral tarsorrhaphy has been 7.Schlötzer-Schrehardt U, Stojkovic M, Hofmann- mendously symptomatic, even when suggested for noncompliant patients Rummelt C, et al. The pathogenesis of floppy eye- the rash is minimal.1-3 A number of 12 lid syndrome: involvement of matrix metalloprotein- with severe disease. ases in elastic fiber degradation. Ophthalmology. patients will continue to experience As important as managing the ocu- 2005;112(4):694-704. pain known as post-herpetic neuralgia lar sequela of FES is addressing the 8. Taban M, Taban M, Perry JD. Plasma leptin levels long after resolution of the acute out- in patients with floppy eyelid syndrome. Ophthal Plast 3 associated problem of obstructive sleep Reconstr Surg. 2006; 22:375-377. break. apnea. OSA is a potentially fatal condi- 9. Schwartz LK, Gelender H, Forster RK. Chronic Ocular involvement in herpes zoster conjunctivitis associated with “floppy eyelids.” Arch tion that has been linked to pulmonary Ophthalmol. 1983;101(12):1884-8. occurs in 20–50% of cases and is by 4,5 hypertension, congestive heart failure 10. Mastrota KM. Impact of floppy eyelid syndrome no means invariable. However, in and cardiac arrhythmia. Weight loss in ocular surface and dry . Optom Vis Sci. patients with vesicular eruptions at 2008;85(9):814-6. and consultation with a sleep physi- 11. Periman LM, Sires BS. Floppy eyelid syndrome: A the tip of the nose indicating nasocili- cian for appropriate studies are highly modified surgical technique. Ophthal Plast Reconstr ary nerve involvement (Hutchinson’s Surg. 2002;18(5):370-2. recommended, considering the signifi- 12. Bouchard CS. Lateral tarsorrhaphy for a non- sign), the patient has a nearly 100% cant comorbidities of both obesity and compliant patient with floppy eyelid syndrome. Am J likelihood of ocular involvement.1,4-6 OSA. At least one study has demon- Ophthalmol. 1992;114(3):367-9. Severe vesicular eruptions are also pre- 13. McNab AA. Reversal of floppy eyelid syndrome with strated notable improvement of FES treatment of obstructive sleep apnoea. Clin Experiment dictive of ocular involvement, uveitis, when OSA is properly addressed.13 Ophthalmol 2000;28(2):125-6. reduced visual outcome and incidence of post-herpetic neuralgia.5 In addition Clinical Pearls HERPES ZOSTER to nasociliary nerve involvement, lac- • Many patients with FES mani- OPHTHALMICUS rimal nerve involvement is also highly fest attendant blepharitis, particularly predictive of ocular manifestations.5 meibomian gland dysfunction. Signs and Symptoms Ocular involvement is highly var- has also been found in association with Herpes zoster ophthalmicus (HZO) ied and may involve anterior struc- both FES and OSA. In the course of typically begins with nondescript facial tures, retina and , as well as treating these patients, strongly con- pain, fever, and general malaise.1-3 the (optic, oculomotor, sider a trial of oral doxycycline 50mg to About four days after onset of symp- trochlear, abducens).5-17 The common 100mg b.i.d. for six to 12 weeks. toms indicative of an outbreak, a skin presentations include subconjunctival • In the course of interviewing rash appears along the distribution of hemorrhage, follicular conjunctivitis, patients with FES, always remember the fifth cranial nerve (trigeminal). epithelial and/or interstitial , to inquire about prominent snoring Patients then develop a painful unilat- nummular keratitis, keratouveitis with or gasping episodes during sleep. In eral dermatomal rash in the distribution secondary inflammatory glaucoma, this regard, realize that a spouse or of one or more branches of the trigemi- or , , family member may actually prove to nal nerve (the ophthalmic division, V1, acute retinal necrosis, optic neuritis, be a more reliable resource than the or the maxillary division, V2) with each and ophthalmoplegia with cranial patient! Any such findings consistent being able to support lesions amongst nerve III, IV, and VI palsy.5-17 with OSA warrant consultation with its branches. Frequently V1 with its Corneal involvement may appear as a a sleep physician, otolaryngologist, or supraorbital, lacrimal, and nasociliary non-descript epitheliopathy or pseudo- pulmonologist. nerves is affected.1 A characteristic dendritic keratopathy. Occasionally, respect for the midline, consistent with superficial epithelial deposits repre- 1. Culbertson WW, Ostler HB. The floppy eyelid syn- the distribution of the affected nerves senting necrotic epithelial cells will drome. Am J Ophthalmol. 1981;92(4):568-75. 1,2 2. Pham TT, Perry JD. Floppy eyelid syndrome. Curr will be evident. The skin manifesta- manifest. Opin Ophthalmol. 2007;18(5):430-3. tions begin as an erythematous macu- Patients experiencing HZO are typ- 3. Abdal H, Pizzimenti JJ, Purvis CC. The eye in sleep apnea syndrome. Sleep Med. 2006;7(2):107-15. lar rash, which progresses over several ically elderly, with most cases occurring 4. Karger RA, White WA, Park WC, et al. days into papules, vesicles, and then in patients over age 50 due to natu- Prevalence of floppy eyelid syndrome in obstruc- tive sleep apnea-hypopnea syndrome. Ophthalmology. pustules. The vesicles emanate a fluid ral weakening of the immune system. 2006;113(9):1669-74. discharge and begin to form scabs after However, the condition does occur in 5. Ezra DG, Beaconsfield M, Collin R. Floppy eyelid about one to three weeks in immu- children as well.18-20 In adults under syndrome: stretching the limits. Surv Ophthalmol. 2010; 1,2 55(1):35-46. nocompetent individuals. During the age of 50, HIV co- should 6. Netland PA, Sugrue SP, Albert DM, et al. this inflammatory stage, the pain is always be considered.21 Histopathologic features of the floppy eyelid syndrome. Involvement of tarsal elastin. Ophthalmology. 1994; extremely severe, and patients are tre- In a rare subset of patients, there

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001_ro0410_hndbkv7.indd 7 4/5/10 8:47 AM will be unilateral neuropathic pain able.3,10,22,23 Timing is crucial, and with other characteristics of HZO, if these agents are started within but without the attendant rash. 72 hours of the onset of the acute This has been termed zoster sine rash, they will significantly shorten herpete.15 the period of pain, viral shedding, rash, and anterior segment com- Pathophysiology plications.23 Valacyclovir and fam- Herpes zoster is the second man- ciclovir may better reduce the inci- ifestation of the Varicella zoster dence and severity of post-herpetic virus (VZV), which typically causes neuralgia compared with acyclovir. chickenpox.2,4 This virus typically However, oral antiviral agents can- enters the human system through not totally prevent post-herpetic the conjunctiva and/or nasal or oral neuralgia.23 mucosa, and then occupies sensory Oral may be uti- ganglia throughout the body. The lized as adjuvant therapy to alleviate herpes zoster rash most commonly pain and associated facial edema; resides in the facial and mid-tho- 40mg to 60mg of prednisone daily, racic-to-upper lumbar dermatomes. tapered slowly over ten days is rec- Characteristic dermatological manifestations in a patient An active immune system suppress- with herpes zoster and inflammatory glaucoma. ommended. Topical care of the skin es the virus, which lies dormant in lesions may be afforded by applying dorsal ganglia. Should the body’s an or antibiotic-steroid immunity fail from natural aging, or will most likely entail ocular inflam- ointment to the affected areas twice other triggers such as mation, typically affecting the tissues daily. Ocular management is depen- or severe systemic disease occur, the of the anterior segment. Contiguous dent upon the severity and tissues con- virus actively replicates along the route spread of the virus may lead to involve- cerned. In most cases involving uveitis of the ganglia. Due to the widespread ment of other cranial nerves, resulting or keratitis, ( exposure to the virus, nearly 100% of in optic neuropathy (CN II) or isolated 5% t.i.d.-q.i.d. or scopolamine ¼% the population develops antibodies to cranial nerve palsies (CN III, IV, or b.i.d. to q.i.d.) is warranted. Topical the disease by age 60.4 Cell-mediated VI).13,14,16,17 The numerous manifes- steroids (prednisolone acetate 1% q2h immunity keeps the VZV suppressed tations in HZO are likely due to the to q3h) may be utilized in addition to and periodic re-exposure helps prevent varied pathophysiologic processes initi- oral antiviral agents. Prophylaxis with a the VZV from activating as herpes ated by the VZV. There are features broad-spectrum antibiotic is also usu- zoster. Declining VZV-specific cell- of viral infection, vascular and neural ally advisable for any compromised mediated immune response account , immune and general cornea. Finally, palliative treatment for the increased frequency of herpes inflammatory reactions. These numer- may consist simply of cool compresses; zoster seen in older adults. Periodic ous reactions partially explain the suc- however some patients may require subclinical reactivation of VZV serves cess and failure of anti-viral medication oral analgesics in severely painful cases. as immune boosters increasing the cell- in cases of HZO.4 Tricyclic antidepressants, antiseizure mediated immunity and reducing the drugs, opioids, and topical analgesics likelihood of the patient experiencing a Management are pain relief options.23 Cimetidine full herpes zoster outbreak.5 The systemic component of this (H2-histamine receptor blocker) HZO results when the trigeminal disorder as well as the myriad of condi- 400mg p.o. b.i.d. may afford some ganglion is invaded by the herpes zos- tions occurring in HZO is best treated additional relief from the neuralgia, ter virus. Neuronal spread of the virus by initiating oral antiviral therapy as though the mechanism by which this occurs along the ophthalmic (1st) and soon as the condition is diagnosed. occurs is not entirely understood.24 less frequently the maxillary (2nd) divi- Oral acyclovir, 600mg to 800mg 5x/ It may well be that the best treatment sion of cranial nerve five. Vesicular day for seven to ten days is standard. for HZO is prevention through vacci- eruptions occur at the terminal points Alternately, famciclovir (500mg p.o. nation.25-27 The Shingles Prevention of sensory innervation, causing extreme t.i.d.) and valacyclovir (1000mg b.i.d. Study Group demonstrated that a vac- pain. Nasociliary nerve involvement to t.i.d.) for a 10-day course are accept- cine against VZV boosted VZV cell-

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mediated immunity and significantly are key diagnostic findings in patients 20. Binder NR, Holland GN, Hosea S, et al. Herpes zoster ophthalmicus in an otherwise-healthy child. J reduced the morbidity due to HZ and with unusual corneal presentations, AAPOS. 2005;9(6):597-8. post-herpetic neuralgia in older adults other peculiar ocular involvement or 21. Yoganathan K. Herpes zoster ophthalmicus. Don’t forget HIV. BMJ. 2009 Sep 14;339. without causing or inducing an actual headaches without other signs. 22. Opstelten W, Eekhof J, Neven AK, et al. Treatment herpes zoster outbreak.25 Overall, VZV of herpes zoster. Can Fam Physician. 2008;54(3):373- vaccine reduced the incidence of post- 1. Catron T , Hern HG. Herpes zoster ophthalmicus. 7. West J Emerg Med. 2008; 9(3):174–6. 23. Pavan-Langston D. Herpes zoster antivirals and herpetic neuralgia by 66.5% and the 2. McCrary ML, Severson J, Tyring SK. Varicella zoster pain management. Ophthalmology. 2008;115(2 incidence of HZ outbreak was also virus. J Am Acad Dermatol. 1999;41(1):1–14. Suppl):S13-20. 25 3. Stankus SJ, Dlugopolski M, Packer D. Management 24. Miller A, Harel D, Laor A, et al. Cimetidine as an reduced by 51.3%. of herpes zoster (shingles) and postherpetic neuralgia. immunomodulator in the treatment of herpes zoster. J Am Fam Physician. 2000;61(8):2437–48. Neuroimmunol. 1989;22(1):69-76. 4. Liesegang TJ. Herpes zoster ophthalmicus natural 25. Holcomb K, Weinberg JM. A novel vaccine Clinical Pearls history, risk factors, clinical presentation, and morbidity. (Zostavax) to prevent herpes zoster and postherpetic • This disorder has a great propen- Ophthalmology. 2008;115(2 Suppl):S3-12. neuralgia. J Drugs Dermatol. 2006;5(9):863-6. sity for those over the age of seventy. 5. Nithyanandam S, Dabir S, Stephen J, et al. Eruption 26. Gnann JW Jr. Vaccination to prevent herpes zoster severity and characteristics in herpes zoster ophthal- in older adults. J Pain. 2008;9(1 Suppl 1):S31-6. Also, those who are immunocompro- micus: correlation with visual outcome, ocular com- 27. Oxman MN, Levin MJ; Shingles Prevention Study mised due to lymphoma, HIV and plications, and postherpetic neuralgia. Int J Dermatol. Group. Vaccination against herpes zoster and posther- 2009;48(5):484-7. petic neuralgia. J Infect Dis. 2008;197 Suppl 2:S228- AIDS, are at significantly increased 6. Zaal MJ, Völker-Dieben HJ, D’Amaro J. Prognostic 36. risk of developing HZO. value of Hutchinson’s sign in acute herpes zoster • Ocular involvement is extremely ophthalmicus. Graefes Arch Clin Exp Ophthalmol. CANALICULITIS 2003;241(3):187–91. variable and often confusing in the 7. Sellitti TP, Huang AJ, Schiffman J, et al. Association early stages. Extreme care must be of herpes zoster ophthalmicus with acquired immuno- Signs and Symptoms deficiency syndrome and acute retinal necrosis. Am J taken in differentiating this condition Ophthalmol. 1993 15;116(3):297-301. Canaliculitis is a relatively rare dis- from virus (HSV), par- 8. Najjar DM, Youssef OH, Flanagan JC. Palpebral order that typically affects older adults. ticularly when there is corneal involve- subconjunctival hemorrhages in herpes zoster ophthal- In one recent series, patients ranged micus. Ophthal Plast Reconstr Surg. 2008;24(2):162-4. 1 ment—one key consideration is that 9. Dhingra S, Williams G, Pearson A. Severe, perma- from 43 to 90 years of age. An older the dendriform keratitis which occurs nent orbital disease in herpes zoster ophthalmicus. study suggests that canaliculitis is more . 2008;27(4):325-7. 2 in HZO is infiltrative, while the HSV 10. Shaikh S, Ta CN. Evaluation and management common in postmenopausal women. dendrites are ulcerative. of herpes zoster ophthalmicus. Am Fam Physician. Most cases are unilateral, though 2002;66(9):1723-30. • In pseudo-dendritic keratitis in 11. Lin P, Yoon MK, Chiu CS. Herpes zoster keratou- bilateral phenomena have been docu- 3 HZO, there are no terminal end-bulbs veitis and inflammatory 8 years mented. Complaints tend to center on the lesion whereas true dendritic after varicella vaccination. Ocul Immunol Inflamm. around a chronic, recalcitrant 2009;17(1):33-5. keratitis in HSV will have terminal 12. Ying XH, Wagle AM, Tan L, et al. A rare case of her- and focal swelling of the medial can- end-bulbs. pes zoster ophthalmicus with complete ophthalmople- thus. , or excessive tearing to gia. J Am Geriatr Soc. 2008;56(11):2160-2. • The practitioner must also recog- 13. Im M, Kim BJ, Seo YJ, et al. Complete ophthal- the point of overflow, is often reported. nize the possibility of more involved moplegia after herpes zoster. Clin Exp Dermatol. The discharge may range from a sim- and complex ocular sequelae (cho- 2007;32(2):162-4. ple watery consistency to full-blown 14. Delengocky T, Bui CM. Complete ophthalmoplegia rioretinitis, optic neuropathy, cranial with pupillary involvement as an initial clinical presenta- mucopurulence. In many cases, the nerve palsies, uveitic glaucoma) and tion of herpes zoster ophthalmicus. J Am Osteopath patient will report previous therapy Assoc. 2008;108(10):615-21. apply appropriate management strate- 15. Kido S, Sugita S, Horie S, et al. Association of with topical , but to no avail. gies in these cases. varicella zoster virus load in the aqueous humor with Recurrent episodes are not uncommon. • Herpetic keratouveitis is a com- clinical manifestations of anterior uveitis in herpes zoster The classic biomicroscopic sign ophthalmicus and zoster sine herpete. Br J Ophthalmol. mon manifestation of HZO where the 2008;92(4):505-8. associated with canaliculitis is a “pout- patient demonstrates elevated intra- 16. Shin MK, Choi CP, Lee MH. A case of her- ing punctum,” although it may not be pes zoster with abducens palsy. J Korean Med Sci. 1,4,5 ocular pressure in the face of mild 2007;22(5):905-7. seen in all cases. This terminol- anterior segment inflammation. This 17. Shin HM, Lew H, Yun YS. A case of complete oph- ogy refers to the fact that the punc- thalmoplegia in herpes zoster ophthalmicus. Korean J is best managed according to standard Ophthalmol. 2005;19(4):302-4. tal orifice is red, swollen and turned treatments for anterior uveitis with the 18. De Freitas D, Martins EN, Adan C, et al. Herpes outward, resembling a pair of pouting addition of oral antiviral medication. In zoster ophthalmicus in otherwise healthy children. Am J lips. The involved area is often tender Ophthalmol. 2006;142(3):393-9. diagnosing this entity, look also for 19. Bhatnagar A, Tomlins P, Parulekar MV. Role to the touch. Discharge and/or concre- stromal atrophy and mild . of polymerase chain reaction in early diagnosis of tions may be expressed with digital herpes zoster ophthalmicus in children. J AAPOS. • Malaise and neuralgic prodrome 2009;13(2):213-4. manipulation of the punctum and/

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001_ro0410_hndbkv7.indd 9 4/5/10 8:47 AM or canaliculi. Other important signs which the infection flourishes. In these tions and thick stagnant secretions include erythema and swelling of the “pockets” the organisms are not sub- impede the penetrance of topical eye lid and adnexal tissue, and a conjuncti- ject to the antimicrobial properties drops to the site of the infection. vitis that is more pronounced inferiorly of the precorneal tear film.4 Foreign Definitive management of cana- and nasally. Diagnostic signs can also objects that reside within the cana- liculitis involves surgical excavation be encountered with lacrimal probing, liculus, such as intracanalicular punctal of the canaliculus, or canaliculoto- although this should never be attempt- plugs, can produce a similar presenta- my, with plating of extruded mate- ed by a novice. The clinician will tion. Indeed, a significant number of rial for the purpose of determining encounter a “soft stop” while probing published cases have been associated the correct pharmacologic course.4,7,19 the canaliculus. This blockage indicates with the SmartPLUG (Medennium, Canaliculotomy is performed under the presence of concretions within the Irvine, CA), a thermoacrylic polymer local anesthesia; a probe is inserted drainage system. Concurrent with this designed for lacrimal occlusion therapy through the punctum and an incision finding is the so-called “wrinkle sign”; in patients with dry eye.3,15-17 is made through the adjacent conjunc- as the clinician’s probe meets resis- tiva into the dilated canaliculus, tance, the overlying skin of the effectively dissecting the nasal lid medial canthus may be seen to from the punctal orifice down to compress and wrinkle.6 the level of the common cana- liculus (approximately 10mm).1 Pathophysiology Next, a small curette is Canaliculitis represents a prima- used to remove any concretions ry infection and inflammation of or dacryoliths. Post-operatively, the lacrimal outflow system, at the broad spectrum topical and sys- level of the canaliculus. Multiple temic antibiotics are indicated. The pathogens have been associated preferred agent for Actinomyces is with the condition, including penicillin, and penicillin G solution , fungi and some viruses.7 may be used for canalicular irriga- Canaliculitis has been most closely tion. Systemic antibiosis with oral associated with Actinomyces israelii, penicillin or ampicillin should be a cast-forming, Gram-positive Canaliculitis presents with canalicular inflammation and continued for several weeks follow- anaerobe that is difficult to isolate punctal dacryoliths. ing surgical recovery.1 Canaliculitis and identify.8 Actinomyces spe- secondary to herpetic or fungal eti- cies are prone to causing of Management ologies should be addressed with the the hollow spaces via the formation Many cases of canaliculitis are diag- appropriate agents (e.g., trifluridine 1% of canaliculiths.8 Other bacteria that nosed only after a seemingly benign case solution five times daily for two to three have been associated with canaliculitis of blepharoconjunctivitis fails to resolve weeks, and nystatin 1:20,000 ophthal- include Arcanobacterium haemolyticum, following topical antibiotic therapy. mic solution t.i.d., respectively). In Mycobacterium chelonae, Arachnia propi- Cases often persist in a recurrent fash- extreme cases, patients may have such onica, Nocardia asteroides, Fusobacterium, ion for long periods of time with clini- severely scarred nasolacrimal systems Lactococcus lactis cremoris, Eikenella cor- cians failing to observe the hallmark that they must undergo intubation via rodens and .4,7,9-12 sign of dacryoliths. In one series, an to successfully Fungal pathogens include Candida and average duration of 36 months was reestablish lacrimal outflow. Aspergillus species.13 Herpetic etiolo- noted before the correct diagnosis was gies should be suspected when cana- made.1 Topical antibiotics are generally Clinical Pearls liculitis is encountered in a younger ineffective alone because many of the • Canaliculitis must always be dif- patient (i.e., under 40 years of age).14 offending organisms are not bacterial; ferentiated from , as the Canaliculitis is associated with the in addition, the bacteria Actinomyces treatment modalities differ signifi- formation of dacryoliths, which are demonstrates limited susceptibility to cantly. Dacryocystitis typically presents small stones or concretions that fur- some of the more common ophthalmic more acutely and with greater pain ther impede lacrimal drainage. These drugs (e.g., tobramycin or ciprofloxa- and swelling in the canthal region; concretions help to form pockets in cin).18 Moreover, canalicular concre- it is treated with systemic antibiotics

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Plast Reconstr Surg. 2008;24(1):54-5. and generally does not require surgical 10. Bharathi MJ, Ramakrishnan R, Meenakshi R, et ity of cases seen in infants and those 1 intervention. al. Nocardia asteroides canaliculitis: A case report over 40 years of age. Postmenopausal • Herpetic canaliculitis often fol- of uncommon aetiology. Indian J Med Microbiol. women represent approximately 75% 2004;22(2):123-5. 1 lows herpes simplex blepharoconjunc- 11. Jordan DR, Agapitos PJ, McCunn PD. Eikenella of cases. Untreated, dacryocystitis fre- tivitis. This should be considered in corrodens canaliculitis. Am J Ophthalmol. 1993 quently progresses to preseptal cel- 15;115(6):823-4. 1,2 cases that manifest persistent epiphora 12. Leung DY, Kwong YY, Ma CH, et al. Canaliculitis lulitis. is far less after resolution of the herpes vesicles. associated with a combined infection of Lactococcus common, but has been documented in • Should treatment fail to eradicate lactis cremoris and Eikenella corrodens. Jpn J the literature.1,2 Ophthalmol. 2006;50(3):284-5. the problem or if canalicular patency 13. Tower RN. Dacryocystitis and dacrolith. In: Roy FH, cannot be restored with a simple cana- Fraunfelder FT. Roy and Fraunfelder’s Current Ocular Pathophysiology Therapy, 6th Edition. Philadelphia: Elsevier Saunders, liculotomy, dacryocystorhinostomy 2007.538-40. The nasolacrimal apparatus drains may be required. 14. Harley RD, Stefanyszyn MA, Apt L, et al. the tears and tear constituents from the • Smears and cultures are usually Herpetic canalicular obstruction. Ophthalmic Surg. into the nose. The system consists 1987;18(5):367-70. obtained from the extruded canalicu- 15. SmartPlug Study Group. Management of com- of inferior and superior puncta, their lar material. However, in the typical plications after insertion of the SmartPlug punctal respective 10mm canaliculi, the 7mm plug: a study of 28 patients. Ophthalmology. scenario of an older, otherwise healthy 2006;113(10):1859.e1-6. to 10mm , and a common individual with canuliculitis, culture 16. Fowler AM, Dutton JJ, Fowler WC, et al. 17mm interosseous/intermembrane- Mycobacterium chelonae canaliculitis associated and pathology of the specimen may with SmartPlug use. Ophthal Plast Reconstr Surg. ous that drains into not be necessary. Empirical canalicu- 2008;24(3):241-3. the nose through the valve of Hasner lotomy is extremely effective in both 17. Hill RH 3rd, Norton SW, Bersani TA. Prevalence of beneath the inferior turbinate.3 The pri- canaliculitis requiring removal of SmartPlugs. Ophthal Actinomyces and non-Actinomyces infec- Plast Reconstr Surg. 2009;25(6):437-9. mary etiology of dacryocystitis is naso- tions.19 Furthermore, since Actinomyces 18. Smith AJ, Hall V, Thakker B, et al. Antimicrobial obstruction, prompt- susceptibility testing of Actinomyces species with 4 is difficult to identify, many studies fail 12 antimicrobial agents. J Antimicrob Chemother. ing secondary infection. Most cases of to yield definitive results. 2005;56(2):407-9. nasolacrimal duct obstruction are found • Interestingly, while Actinomyces is 19. Anand S, Hollingworth K, Kumar V, et al. in the older population, resulting from Canaliculitis: the incidence of long-term epiphora fol- not susceptible to many commercial lowing canaliculotomy. Orbit. 2004;23:19-26. chronic mucosal degeneration, ductile topical antibiotics, agents to which it stenosis, stagnation of tears and bacterial may be sensitive include several older DACRYOCYSTITIS overgrowth.5 The most frequently isolat- drugs, such as chloramphenicol, sulfa- ed pathogens are Gram-positive bacte- cetamide and erythromycin. Signs and Symptoms ria, particularly Staphylococcus aureus and An inflammation of the nasolacri- Streptococcus; common Gram-negative 1. Briscoe D, Edelstein E, Zacharopoulos I, et al. mal sac, dacryocystitis typically pres- organisms include Pseudomonas aeru- Actinomyces canaliculitis: diagnosis of a masquer- ading disease. Graefes Arch Clin Exp Ophthalmol. ents with focal pain, redness and swell- ginosa, Fusobacterium and Haemophilus 2004;242(8):682-6. ing over the nasal aspect of the lower influenza.6 2. Vécsei VP, Huber-Spitzy V, Arocker-Mettinger E, et al. Canaliculitis: difficulties in diagnosis, differential diag- eyelid. In some cases, the pain may Infantile or congenital dacryocystitis nosis and comparison between conservative and surgi- extend to the nose, cheek, or teeth is less common than the adult form, cal treatment. Ophthalmologica. 1994;208(6):314-7. 3. Scheepers M, Pearson A, Michaelides M. Bilateral on the involved side. Epiphora and/ and results primarily from incomplete canaliculitis following SmartPLUG insertion for dry eye or ocular discharge is also frequently canalization of the nasolacrimal duct, syndrome post LASIK surgery. Graefes Arch Clin Exp reported. Examination reveals ery- specifically at the valve of Hasner.3 Ophthalmol. 2007;245(6):895-7. 4. Fulmer NL, Neal JG, Bussard GM, et al. Lacrimal thematous swelling over the lacrimal Neonatal infection may be a contribu- canaliculitis. Am J Emerg Med. 1999;17(4):385-6. sac, and mucopurulent discharge may tory element.3 5. Liyanage SE, Wearne M. Lacrimal canaliculitis as a cause of recurrent conjunctivitis. Optometry. be expressed from the inferior punctum 2009;80(9):479-80. when pressure is applied. The condi- Management 6. Reed KK. Diseases of the lacrimal system. In: Bartlett tion may be recurrent, and in severe Because dacryocystitis represents a JD, Jaanus SD, eds. Clinical Ocular Pharmacology, 5th Edition. Boston:Butterworth-Heinemann, 2007. 415- cases associated with fever. While deep tissue infection, systemic antibiot- 36. vision may be subjectively blurred ics are indicated. Options for children 7. Varma D, Chang B, Musaad S. A case series on chronic canaliculitis. Orbit. 2005;24(1):11-4. due to discharge, acuity is not acutely include oral amoxicillin/clavulanate 8. McKellar MJ, Aburn NS. Cast-forming Actinomyces impacted in most instances.1-6 or cefaclor 20mgs/kg/day to 40mgs/ israelii canaliculitis. Aust N Z J Ophthalmol. Dacryocystitis demonstrates a kg/day in three divided doses, along 1997;25(4):301-3. 9. Moscato EE, Sires BS. Atypical canaliculitis. Ophthal bimodal distribution, with the major- with topical antibiotic drops (e.g., 0.5%

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001_ro0410_hndbkv7.indd 11 4/5/10 8:47 AM moxifloxacin or 1% azithromycin). the concretions with which it is asso- Amoxicillin and cephalosporins (e.g., ciated from the canaliculi. cephalexin 500mg p.o. q.i.d.) are also • Prompt, decisive and aggressive popular choices for adult therapy.7,8 management is essential in cases of Supportive treatment includes the use dacryocystitis. Hospitalization with of warm compresses several times a intravenous antibiotics should be con- day, and oral analgesics (e.g., acet- sidered in severe, febrile or recalci- aminophen, aspirin or ibuprofen) as trant presentations. needed for pain and inflammation. • Punctal dilation and nasolac- Management of the febrile patient rimal irrigation is ABSOLUTELY must be handled with extreme cau- CONTRAINDICATED in the tion. In these instances hospitaliza- acute stages of dacryocystitis, as iatro- tion should be considered along with genic trauma can facilitate the spread IV antibiotics such as cefazolin q8h.5 of infection beyond the confines of In cases that are atypical or suspect, Dacryocystitis, with characteristic inflammation of the the nasolacrimal system, potentially neuroimaging (CT or MRI) should nasolacrimal sac. resulting in life-threatening conse- be considered to rule out potential quences. malignancies and other invasive dis- from six weeks to six months.12 orders. Alternatives to DCR include balloon 1. Henney SE, Brookes MJ, Clifford K, Banerjee A. Dacryocystitis presenting as post-septal cellulitis: a Surgical management of dacryocys- dacryoplasty and recanalizaton using case report. J Med Case Reports. 2007;1:77. titis serves to reduce recurrence rates a high frequency lacrimal probe.13,14 2. Maheshwari R, Maheshwari S, Shah T. Acute dac- ryocystitis causing orbital cellulitis and abscess. Orbit. as well as symptomatic epiphora, and Balloon dacroplasty employs an inflat- 2009;28(2-3):196-9. likely helps to normalize the conjunc- able probe, inserted through the punc- 3. Kapadia MK, Freitag SK, Woog JJ. Evaluation and 9 management of congenital nasolacrimal duct obstruc- tival flora. The treatment of choice tum, to essentially stretch the lacrimal tion. Otolaryngol Clin North Am. 2006;39(5):959-77, vii. is dacryocystorhinostomy (DCR), a duct and canaliculus; this technique has 4. Morgan S, Austin M, Whittet H. The treatment procedure that creates a direct commu- been shown to work well for incom- of acute dacryocystitis using laser assisted endo- nasal dacryocystorhinostomy. Br J Ophthalmol. nication between the lacrimal drainage plete, non-acute nasolacrimal duct 2004;88(1):139-41. system and the nasal cavity, bypass- obstruction.13 The recanalization tech- 5. Mueller JB, McStay CM. Ocular infection and inflam- mation. Emerg Med Clin North Am. 2008;26(1):57-72, ing the nasolacrimal sac. Historically, nique described by Chen and associates vi. DCR was performed as an exter- involves a probe that can discharge a 6. Mills DM, Bodman MG, Meyer DR, et al. ASOPRS nal surgical procedure, approaching power current (50 to 150 watts) at 150 Dacryocystitis Study Group. The microbiologic spec- trum of dacryocystitis: a national study of acute ver- through the skin overlying the nose. kHz frequency to cauterize blocked sus chronic infection. Ophthal Plast Reconstr Surg. More recently, however, surgeons have tissue in the nasolacrimal duct, which 2007;23(4):302-6. 7. Cahill KV, Burns JA. Management of acute dac- begun using an endonasal technique, ultimately dissipates the blockage and ryocystitis in adults. Ophthal Plast Reconstr Surg. which can be performed by the use of a allows for enhanced lacrimal drain- 1993;9(1):38-41; discussion 42. long-handled scalpel or laser.4,10,11 The age.14 8. Bertino JS. Impact of antibiotic resistance in the management of ocular infections: the role of current technique begins with the creation of and future antibiotics. Clin Ophthalmol. 2009;3:507-21. a mucosal flap over the anterior por- Clinical Pearls 9. Owji N, Khalili MR. Normalization of conjunctival flora after dacryocystorhinostomy. Ophthal Plast Reconstr tion of the middle turbinate, exposing • Obstruction of the tear drainage Surg. 2009;25(2):136-8. the lacrimal fossa at the juncture of system can occur at any age, but is most 10. Hong JE, Hatton MP, Leib ML, et al. Endocanalicular laser dacryocystorhinostomy analysis of 118 consecu- the maxillary and lacrimal bones. This common in young children and older tive surgeries. Ophthalmology. 2005;112(9):1629-33. bony area is drilled out to expose the adults. 11. Mandeville JT, Woog JJ. Obstruction of the nasoacrimal sac, which is then incised. • Dacryocystitis must always be dif- lacrimal drainage system. Curr Opin Ophthalmol. 2002;13(5):303-9. A neo-ostium is created so that tears ferentiated from canalicultis, as the 12. McDonogh M, Meiring JH. Endoscopic trans- can drain from the canaliculus directly treatment modalities differ significant- nasal dacryocystorhinostomy. J Laryngol Otol. 1989;103(6):585-7. into the nose through the middle tur- ly. Canaliculitis tends to run a more 13. Couch SM, White WL. Endoscopically assisted bal- binate. This ostium is kept open with a chronic and indolent course, with less loon dacryoplasty treatment of incomplete nasolacrimal silicone tube placed through the puncta significant pain and swelling near the duct obstruction. Ophthalmology. 2004;111(3):585-9. 14. Chen D, Ge J, Wang L, et al. A simple and evolution- into the sac and out the nose. The punctal orifice. Canaliculitis typically al approach proven to recanalise the nasolacrimal duct tubes are kept in place for anywhere requires surgical intervention to remove obstruction. Br J Ophthalmol. 2009;93(11):1438-43.

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ACUTE ALLERGIC tory of allergies. Concurrent symptoms recruitment and activation of addi- CONJUNCTIVITIS of allergic rhinitis, post-nasal drip, or tional inflammatory cells, leading to sinus congestion may be present, espe- what has come to be known as the “late Signs and Symptoms cially in SAC.3 phase” of the allergic response. Allergic conjunctivitis is the most The late phase reaction typically common manifestation of ocular aller- Pathophysiology commences between four and six hours gy, affecting between 20% and 40% of The allergic response is classically following sustained mast cell degranu- the U.S. population.1-10 Acute allergic considered to be an over-reaction of the lation.8,11 T-lymphocyte activation and conjunctivitis describes the abrupt and body’s immune system to substances infiltration of the conjunctival mucosa immediate response seen in sensitized perceived as foreign (allergens), despite by eosinophils, neutrophils, monocytes individuals after exposure to a particu- the fact that said substances are not and basophils are the hallmark of the lar allergen or sensitizing agent. Two inherently pathogenic.4 This response late phase.9,12 Leukocytic infiltration is forms are recognized: seasonal allergic can be innate or acquired. The key com- not necessarily inherent to all cases of conjunctivitis (SAC), which coincides ponent of the ocular allergic response is acute allergic conjunctivitis; in fact, the with pollen blooms such as ragweed, the mast cell; mast cells are widely late phase response is much more char- and perennial (or persistent) allergic distributed, especially in connective acteristic of chronic allergic disorders conjunctivitis (PAC), in which expo- tissue and mucosal surfaces, particular- like atopic and vernal keratoconjuncti- sure may occur at any time throughout ly the conjunctiva.1 Immunoglobulin vitis, which constitute less than 2% of the year (e.g., allergies to animal dan- (IgE and IgG) receptors, which are cases seen in clinical practice.1,5 der or dust mite feces).4,5 In the major- sensitized to specific allergens, are ity of cases, allergic conjunctivitis is a expressed on mast cell surfaces. When Management bilateral phenomenon, although the allergens are encountered at the cellu- The management of ocular allergic presentation may be asymmetric. lar level, an antigen-antibody response reactions is primarily aimed at reducing The allergic response classically ensues, in turn triggering mast cell symptomology and quelling any sig- involves several signs and symptoms, degranulation; this process releases nificant inflammation while attempt- all of which may vary in intensity. pre-formed pro-inflammatory media- ing to discover, remove and avoid the Ocular itching remains the hallmark tors, and spurs the secretion of che- offending agent, although this may symptom; tearing is also an exceed- mokines and cytokines.4,8 The primary not always be possible or practical. ingly common complaint, particularly chemical mediator released during Artificial tear solutions provide a bar- after rubbing the eyes in response to degranulation is histamine, which rier function, serving to flush or dilute itching.1-7 More severe reactions may is responsible for increased vascular the antigens from the ocular surface prompt symptoms of ocular burning, permeability, vasodilation, bronchial while soothing and lubricating the irri- foreign body sensation, or photopho- contraction and increased secretion of tated ocular surface; these may be used bia, though these are relatively rare.1 mucus.9 Heparin, chymase and trypt- on an as-needed basis. Cold com- Clinical evaluation reveals variable ase are also released from mast cells, presses and topical decongestants help conjunctival hyperemia and . as well as several chemotactic fac- to produce vasoconstriction, reduc- Ocular discharge is watery, though tors. Degranulation also stimulates the ing hyperemia, chemosis and other mucus may accumulate in the forni- production of newly formed media- symptoms by retarding the release of ces or collect on the lash margin in tors through the activation of phos- the inflammatory cells into the tis- the form of “crusts,” especially during pholipase-A2 on membrane phospho- sues from the vasculature. Numerous sleep. Eversion of the eyelids may lipids, releasing arachidonic acid and decongestant solutions (containing one reveal a fine papillary response, par- platelet-activating factor. Arachidonic of the following: naphazoline, antazo- ticularly along the upper tarsal plate. acid is further degraded via the cyclo- line, tetrahydrozaline, phenylephrine) Externally, the eyelids may be red, oxygenase pathway to form, among are available as over-the-counter prep- swollen and edematous, with a pseudo- other chemicals, prostaglandins and arations, either alone or in combina- ptosis in pronounced cases. A palpable thromboxanes, and via the lipoxy- tion with a mild topical antihistamine preauricular lymph node is noticeably genase pathway into leukotrienes.8,10 (e.g., pheniramine maleate or antazo- absent. If questioned, the patient will These newly formed mediators drive line phosphate). These agents tend to often reveal a personal or family his- the inflammatory reaction and incite be the preferred treatment modality for

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001_ro0410_hndbkv7.indd 13 4/5/10 8:47 AM those patients who self-medicate those patients with more severe their allergies. Unfortunately, cases of acute allergic conjunc- such OTC preparations have tivitis. While there are well- been associated with significant known risks associated with tachyphylaxis as well as chron- long-term use ic follicular conjunctivitis and (e.g., cataractogenesis, ocular eczematoid blepharoconjuncti- hypertension), short-term thera- vitis when used chronically.13,14 py with steroids can be extreme- The pharmacologic options ly effective. Also, studies have for managing ocular allergy are shown Alrex to have an excellent extremely diverse. In fact, there safety profile in the treatment of are more commercially available ocular allergy, even with therapy 16 topical medications for allergic Profound conjunctival chemosis in a patient with allergic conjunc- of up to four years’ duration. conjunctivitis today than there tivitis. Topical NSAIDs are likely the are for glaucoma. Overall, five least effective option for ocular distinct classes or categories of topical was granted over-the-counter status allergy. While they may provide mild drugs are recognized; these include: in October 2006. In the wake of that symptomatic relief, they do not directly 1. Antihistamines, e.g., Emadine approval, ketotifen has been released address mast cell degranulation or the (0.05% emedastine difumarate, Alcon commercially under a variety of other histamine response, and inhibit only a Laboratories); trade names, including Alaway (Bausch portion of the inflammatory cascade. 2. Mast cell stabilizers, e.g., + Lomb), Refresh Eye Itch Relief In the last few years, there has been Crolom (4% cromolyn sodium, (Allergan), Claritin Eye (Schering- a good deal of discussion regarding the Bausch & Lomb), Alomide (0.1% Plough) and Zyrtec Itchy Eye Drops use of nasal allergy preparations and lodoxamide tromethamine, Alcon (McNeil Consumer Healthcare). their potential for alleviating ocular Laboratories), Alocril (2% nedocro- In general, all of these medications allergy symptoms. The literature does mil sodium, Allergan), and Alamast are beneficial to a degree by themselves demonstrate that nasal corticosteroid (0.1% pemirolast postassium, Vistakon and in combinations. Topical antihis- sprays can have a direct and beneficial Pharmaceuticals); tamines provide prompt symptomatic impact on ocular allergy.18-23 Studies 3. Antihistamine/mast cell stabilizer relief, but their effects can be short- have consistently shown that medica- combinations, e.g., Patanol and Pataday lived––on the order of just four to tions like Flonase (0.05mg flutica- (0.1% and 0.2% olopatadine hydrochlo- six hours. Mast cell stabilizers prevent sone propionate, GlaxoSmithKline), ride, respectively, Alcon Laboratories), degranulation and hence eliminate the Veramyst (0.0275 mg fluticasone Optivar (0.05% azelastine hydro- allergic response, but they lack the furoate, GlaxoSmithKline) and chloride, Meda Pharmaceuticals), capacity to alleviate itching rapidly. Nasonex (0.05mg mometasone furoate, Zaditor (0.025% ketotifen fumarate, In addition, mast cell stabilizers may Schering-Plough) help to ameliorate Novartis Pharmaceuticals), Elestat take several days to a week in order to concurrent ocular symptoms when used (0.05% epinastine hydrochloride, achieve full efficacy, and require pre- to treat nasal rhinitis.18-23 However, it Inspire Pharmaceuticals) and Bepreve loading to be effective when the expo- is important to understand that topical (1.5% bepotastine besilate, ISTA sure takes place. Antihistamine/mast agents still offer faster, safer and more Pharmaceuticals); cell stabilizer combinations provide the complete relief of ocular symptoms 4. Corticosteroids, e.g., Alrex benefits of both of these categories and than any other form of therapy, as (0.2% loteprednol etabonate, Bausch are by far the most common choice demonstrated in head-to-head studies + Lomb); among eye care practitioners; these for ocular itching, redness, chemosis 5. Non-steroidal anti-inflammatory drugs also have the advantage of b.i.d. and eyelid swelling associated with agents (NSAIDs), e.g., Acular (0.5% dosing, except for Pataday which is the allergic conjunctivitis.24-26 ketorolac tromethamine, Allergan). only topical allergy medication cur- Oral antihistamines are rarely These medications are available only rently approved for once-daily dosing.15 required for the treatment of acute by prescription in the United States, Topical corticosteroids may serve to allergic conjunctivitis, unless there is with the exception of Zaditor, which quell inflammation and offer relief to associated rhinitis, sinusitis, urticaria

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or other manifestations of systemic the same time each year, and may last Louis: Mosby, 1996. 50-70. 12. Bacon AS, Ahluwalia P, Irani AM, et al. Tear and allergy. Some of the older, over-the- for only a month or two. Therefore, conjunctival changes during the allergen-induced early- counter antihistamines, such diphen- patients who present for their annual and late phase responses. J Allergy Clin Immunol. 2000;106(5):948-54. hydramine hydrochloride and chlor- examination during other times of the 13. Durham SR. The inflammatory nature of allergic pheniramine maleate, are effective but year may go undiagnosed. It is impor- disease. Clin Exp Allergy. 1998;28 Suppl 6:20-4. can induce drowsiness and functional tant to ask not only whether the patient 14. Soparkar CN, Wilhelmus KR, Koch DD, et al. Acute and chronic conjunctivitis due to over-the- 27,28 impairment. Loratadine, deslorata- is experiencing symptoms at the time counter ophthalmic decongestants. Arch Ophthalmol. dine, fexofenadine, cetirizine and levo- of the exam, but also if they EVER 1997;115(1):34-8. 15. Tappeiner C, Sarra GM, Abegg M. Abuse of vaso- cetirizine are second generation anti- suffer from red, itchy, watery eyes. The constrictive eyedrops mimicking an ocular pemphigoid. histamines; the sedative effect of these safety and efficacy of today’s medica- Eur J Ophthalmol. 2009;19(1):129-32. 16. Uchio E. Treatment of allergic conjunctivitis with drugs is greatly diminished, though tions allows for proactive prescribing, olopatadine hydrochloride eye drops. Clin Ophthalmol. it is not entirely eliminated. In addi- even months before symptoms arise. 2008;2(3):525-31. tion, all of these oral medications have • Livostin (0.05% levocabastine 17. Ilyas H, Slonim CB, Braswell GR, et al. Long-term safety of loteprednol etabonate 0.2% in the treatment the capacity for anticholinergic effects, hydrochloride), a topical antihistamine of seasonal and perennial allergic conjunctivitis. Eye causing dryness of the mucosal mem- introduced by Novartis in 1993, was Contact Lens. 2004;30(1):10-3. 29 18. DeWester J, Philpot EE, Westlund RE, et al. The branes of the mouth, nose and eyes. discontinued in the U.S. and U.K. efficacy of intranasal fluticasone propionate in the relief several years ago. It is still available, of ocular symptoms associated with seasonal allergic Clinical Pearls however, in Canada, several European rhinitis. Allergy and Asthma Proc. 2003;24(5):331-7. 19. Bernstein DI, Levy AL, Hampel FC, et al. Treatment • When evaluating patients with countries and Australia/New Zealand. with intranasal fluticasone propionate significantly presumed allergic conjunctivitis, pay • Despite marketing efforts to the improves ocular symptoms in patients with seasonal allergic rhinitis. Clin Exp Allergy. 2004;34(6):952-7. special attention to the inferior fornix contrary, most allergy experts agree that 20. Kaiser HB, Naclerio RM, Given J, et al. Fluticasone and medial canthus. In many cases, topical ophthalmic medications are the furoate nasal spray: A single treatment option for the the caruncle and plica semiluminaris best means to manage the symptoms symptoms of seasonal allergic rhinitis. J Allergy Clin Immunol. 2007;119(6):1430-7. may demonstrate marked hyperemia of ocular allery; nasal sprays are best 21. Fokkens WJ, Jogi R, Reinartz S, et al. Once daily or inflammation. This is presumably for nasal symptoms, and oral antihista- fluticasone furoate nasal spray is effective in sea- sonal allergic rhinitis caused by grass pollen. Allergy. because of the accumulation of his- mines should be used as an adjunct to 2007;62(9):1078-84. tamine-laden tears in the area of the these therapies when necessary. 22. Baroody FM, Shenaq D, DeTineo M, et al. Fluticasone furoate nasal spray reduces the nasal- lacrimal puncta. Also, eyelid eversion ocular reflex: a mechanism for the efficacy of topical 1. Bielory L, Friedlaender MH. Allergic conjunctivitis. is recommended to assess the status of steroids in controlling allergic eye symptoms. J Allergy Immunol Allergy Clin North Am. 2008;28(1):43-58, vi. Clin Immunol. 2009;123(6):1342-8. the superior tarsus. 2. Ono SJ, Abelson MB. Allergic conjunctivitis: update 23. Anolik R, Nathan RA, Schenkel E, et al. Intranasal on pathophysiology and prospects for future treatment. • In differentiating allergic conjunc- mometasone furoate alleviates the ocular symptoms J Allergy Clin Immunol. 2005;115(1):118-22. associated with seasonal allergic rhinitis: results tivitis from other forms of ocular sur- 3. Butrus S, Portela R. Ocular allergy: diagnosis and of a post hoc analysis. Int Arch Allergy Immunol. treatment. Ophthalmol Clin North Am. 2005;18(4):485- face disease, an extremely helpful ques- 2008;147(4):323-30. 92, v. 24. Rosenwasser LJ, Mahr T, Abelson MB, et al. A tion may be, “What happens when you 4. Chigbu DI. The management of allergic eye dis- comparison of olopatadine 0.2% ophthalmic solution rub your eyes?” Most itchy surface dis- eases in primary eye care. Cont Lens Anterior Eye. versus fluticasone furoate nasal spray for the treat- 2009;32(6):260-72. orders such as dry eye and blepharitis ment of allergic conjunctivitis. Allergy Asthma Proc. 5. del Cuvillo A, Sastre J, Montoro J, et al. Allergic 2008;29(6):644-53. generally improve with digital manipu- conjunctivitis and H1 antihistamines. J Investig Allergol 25. Spangler DL, Abelson MB, Ober A, et al. Clin Immunol. 2009;19 Suppl 1:11-8. lation because it stimulates the flow of Randomized, double-masked comparison of olopata- 6. Bielory L. Ocular allergy overview. Immunol Allergy dine ophthalmic solution, mometasone furoate mono- additional tears. However, rubbing in Clin North Am. 2008;28(1):1-23, v. hydrate nasal spray, and fexofenadine hydrochloride allergy can cause further degranulation 7. Uchio E, Kimura R, Migita H, et al. Demographic tablets using the conjunctival and nasal allergen chal- aspects of allergic ocular diseases and evaluation of of mast cells, releasing more histamine lenge models. Clin Ther. 2003;25(8):2245-67. new criteria for clinical assessment of ocular allergy. 26. Horak F, Stuebner P, Zieglmayer R, et al. Efficacy and other chemokines into the ocular Graefes Arch Clin Exp Ophthalmol. 2008;246(2):291-6. and safety of ketotifen eye drops as adjunctive therapy 8. Chigbu DI. The pathophysiology of ocular allergy: a tissues and resulting in greater sympto- to mometasone nasal spray in subjects with sea- review. Cont Lens Anterior Eye. 2009;32(1):3-15. 30,31 sonal allergic rhinoconjunctivitis. Clin Drug Investig. mology. Hence, patients with true 9. Abelson MB, Smith L, Chapin M. Ocular allergic dis- 2003;23(9):597-604. ease: mechanism, disease sub-types, treatment. Ocul allergies almost always say that their 27. Gengo F, Gabos C, Miller JK. The pharmacody- Surf. 2003;1(3):127-49. symptoms worsen when they rub their namics of diphenhydramine-induced drowsiness and 10. Leonardi A, Motterle L, Bortolotti M. Allergy and changes in mental performance. Clin Pharmacol Ther eyes. the eye. Clin Exp Immunol. 2008;153 Suppl 1:17-21. 1989; 45(1):15-21. 11. Cousins SW, Rouse BT. Chemical mediators • Remember that seasonal allergic 28. Bower EA, Moore JL, Moss M, et al. The effects of ocular inflammation. In: Pepose JS, Holland GN, of single-dose fexofenadine, diphenhydramine, and conjunctivitis usually occurs around Wilhelmus KR, Eds. Ocular Infection and Immunity. St.

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001_ro0410_hndbkv7.indd 15 4/5/10 8:47 AM placebo on cognitive performance in flight personnel. and formation.2-4 The use vascular endothelial cells.7 The detec- Aviat Space Environ Med 2003; 74(2):145-52. 29. Welch D, Ousler GW 3rd, Nally LA, et al. Ocular of UV-blocking sunglasses has been tion of T-lymphocyte infiltration in drying associated with oral antihistamines (loratadine) seen to reduce the incidence of pte- pterygium epithelium strongly supports in the normal population - an evaluation of exaggerated 4 dose effect. Adv Exp Med Biol 2002; 506(Pt B):1051-5. rygia. One study showed that pterygia the suggestion that cellular immunity 30. Greiner JV, Peace DG, Baird BS, et al. Effects of occurred three times more frequently plays an important role in pterygium eye rubbing on the conjunctiva as a model of ocular in patients of African descent than in formation.8 Epidermal growth factors inflammation. Am J Ophthalmol. 1985;100(1):45-50. 4 31. Raizman MB, Rothman JS, Maroun F, et al. Effect whites. Men are affected somewhat have been localized in pterygium tissue, of eye rubbing on signs and symptoms of allergic con- more frequently than women.4 and are significantly induced by UV-B junctivitis in cat-sensitive individuals. Ophthalmology. 2000;107(12):2158-61. in pterygium-derived epithelial cells. Pathophysiology This may be the means by which UV Ultraviolet light exposure (both irradiation causes the pathogenesis of PTERYGIUM UV-A and, especially, UV-B) appears pterygium.9 to be the most significant contributory Histologically, pterygium develop- Signs and Symptoms factor in the development of pterygia.5 ment resembles actinic degeneration In most cases, pterygia are discov- This may explain why the incidence is of the skin. Surface cells in pterygi- ered upon routine ocular evaluation vastly greater in populations near the um exhibit squamous metaplasia with in asymptomatic individuals, or in equator and in persons who spend a increased goblet cell density. These patients who present with a cosmetic great deal of time outdoors.6 Other changes are most pronounced directly concern about a tissue “growing over agents that may contribute to the for- over the pterygium surface.10 Stocker’s the eye.” In some instances, the vas- mation of pterygia include allergens, line represents corneal linear iron cularized pterygium may become red noxious chemicals, and irritants (e.g., deposition, derived from tear film lac- and inflamed, motivating the patient wind, dirt, dust, air pollution). Heredity toferrin and presumably due to abnor- to seek immediate care. In other cases, may also be a factor.5 While the etiolo- mal iron metabolism. The presence of the irregular ocular surface can interfere gy is varied, pterygia represent a degen- Stocker’s line along the advancing head with the stability of the precorneal tear eration of the conjunctival stroma with of the pterygium may signify a lack of film, creating a symptomatic dry eye replacement by thickened, tortuous growth potential.11 Pterygia often per- syndrome. Occasionally, the pterygium elastotic fibers. Activated fibroblasts sist after surgical removal; these lesions may induce irregular corneal warp- in the leading edge of the pterygium appear as a fibrovascular arising age and , or even obscure invade and fragment Bowman’s layer from the excision site. These “recurrent the visual axis of the eye, resulting in as well as a variable amount of the pterygia” probably have no relationship diminished acuity.1-4 superficial corneal stroma. It has been to ultraviolet radiation, but rather may Clinical inspection of pterygia suggested that multipotential stem and be likened to keloid development in reveals a raised, whitish, triangular- progenitor cells may be involved in the skin. shaped wedge of fibrovascular tissue, the pathogenesis of pterygium through whose base lies within the interpalpe- their differentiation into fibroblasts and Management bral conjunctiva and whose apex Before initiating management, encroaches on the cornea. The the clinician must be certain that leading edge of this tissue often the diagnosis is correct. A clear displays a fine, reddish-brown iron distinction needs to be made deposition line (Stocker’s line). between the potentially progres- More than 90% of pterygia occur sive pterygium and the less threat- nasally.1 These lesions are more ening . When large, commonly encountered in warm, pingueculae may be very difficult dry climates, or in patients who are to differentiate from pterygia. otherwise chronically exposed to Pingueculae are more yellow in outdoor elements or smoky/dusty color and lie within the inter- environments. There is a striking- palpebral space, but generally do ly significant association between not encroach beyond the limbus.12 outdoor work, sunlight exposure Nasal pterygium encroaching on the visual axis. Pingueculae also lack the wing-

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shaped appearance of pterygia, corneal degradative effects of a the former being more oval or pterygium extend approximately amoeboid in appearance. three millimeters beyond the lead- Because pterygium development ing edge, or head, of the lesion. and proliferation appears to be This means that the pterygium linked to environmental exposure, need not cover the visual axis to management for asymptomatic or inflict significant visual compro- mildly irritative pterygia involves mise. Clinicians have discovered UV-blocking spectacles and liberal that seemingly benign pterygia ocular lubrication. Patients should at least two millimeters off the be advised to avoid smoky or dusty visual axis have induced in excess areas as much as possible. More of 10 diopters of irregular corneal inflamed or irritated pterygia may Close-up view of pterygium; note the pronounced vascularity. astigmatism and resulted in a best be treated with topical cortico- corrected acuity of 20/80. steroids (e.g., 1% prednisolone high rate of recurrence.16 Medical • It is not wise to wait until a acetate or 0.5% loteprednol etabonate adjuncts in the form of the antimetab- pterygium impacts the visual axis or q.i.d. for several days). olites mitomycin C and 5-Fluorouracil vision before recommending surgical Surgical excision of pterygia is indi- may be used in order to reduce pte- excision. Since healthy corneal tissue cated for unacceptable cosmesis, sig- rygia recurrence.19-22 However, these beyond the leading edge of the pteryg- nificant induced astigmatism, threats antimetabolites can have attendant ium must be resected during excision, to peripheral corneal hydration and complications and are frequently used waiting until the visual axis is affected stability and/or significant threat by in cases of previous surgical failure. virtually guarantees permanent visual ingrowth to the visual axis. Surgical Beyond medical adjuncts, single-dose reduction. excision involves dissection and remov- beta-irradiation remains the simplest • Follow-up on medium to large al of the fibrous tissue down to the procedure following bare sclera sur- sized pterygia should be performed at level of Tenon’s capsule. Conjunctival gery. It is an effective and safe treat- least once or twice yearly. It should autograft—a technique that involves ment that reduces the risk of primary include a manifest refraction, corneal excision of the pterygium and cover- pterygium recurrence.23 Removal of topography, evaluation with ing of the resulting bare sclera with large pterygia can greatly reduce the measurement of the pterygium and a free conjunctival graft harvested amount of induced corneal astigma- photodocumentation if possible. from an uninvolved site of the ocular tism and preserve limbal health.24 surface—is typically used to prevent 1. Ebana Mvogo C, Bella-Hiag A, Ngosso A, et al. Pterygium: epidemiological, clinical and therapeuti- 6,13,14 recurrence. The use of fibrin glue Clinical Pearls cal aspects at the Douala General Hospital. Rev Int has advanced the use of conjunctival • Pterygia represent a benign clini- Trach Pathol Ocul Trop Subtrop Sante Publique. 1995;72:151-61. autografts by eliminating the need for cal entity in most cases. 2. Al-Bdour M, Al-Latayfeh MM. Risk factors for pteryg- suturing, hence reducing both operat- • Another clinical entity that must ium in an adult Jordanian population. Acta Ophthalmol Scand. 2004;82(1):64-7. ing time and postoperative pain and be ruled out in the diagnosis of pterygia 3. Gazzard G, Saw SM, Farook M, et al. Pterygium in 15 inflammation. An alternative to is conjunctival intraepithelial neoplasia Indonesia: prevalence, severity and risk factors. Br J conjunctival autograft involves use of (CIN). CIN is a precursor of conjunc- Ophthalmol. 2002;86(12):1341-6. 4. Luthra R, Nemesure BB, Wu SY, et al. Barbados an amniotic membrane transplanta- tival squamous cell carcinoma. This Eye Studies Group. Frequency and risk factors for pte- tion.16-18 Amniotic transplants typical- lesion is generally unilateral, elevated rygium in the Barbados Eye Study. Arch Ophthalmol. 2001;119(12):1827-32. ly are reserved for patients with recur- and gelatinous, with deep irregular vas- 5. Di Girolamo N, Chui J, Coroneo MT, et al. rence following conjunctival autograft cularization and an amoeboid shape. Pathogenesis of pterygia: role of cytokines, growth and those with insufficient viable con- CIN is an invasive ocular cancer with factors, and matrix metalloproteinases. Prog Retin Eye Res. 2004;23(2):195-228. junctival tissue, or those with glaucoma the capacity to inflict significant mor- 6. Todani A, Melki SA. Pterygium: current concepts who may need the superior conjunctiva bidity. Biopsy should be obtained if in pathogenesis and treatment. Int Ophthalmol Clin. 2009;49(1):21-30. preserved for future trabeculectomy. CIN is suspected. 7. Ye J, Song YS, Kang SH, et al. Involvement of bone Unfortunately, amniotic membrane • Pterygia do have the capacity to marrow-derived stem and progenitor cells in the patho- transplantation is associated with a affect vision if left unchecked. The genesis of pterygium. Eye. 2004;18(8):839-43. 8. Beden U, Irkec M, Orhan D, et al. The roles of

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001_ro0410_hndbkv7.indd 17 4/5/10 8:47 AM T-lymphocyte subpopulations (CD4 and CD8), intercel- is a common presenting clinical prob- most frequently diagnosed in the sum- lular adhesion molecule-1 (ICAM-1), HLA-DR receptor, 1–11 and mast cells in etiopathogenesis of pterygium. Ocul lem for eye care practitioners. The mer months, those induced by contact Immunol Inflamm. 2003;11(2):115-22. condition is marked by a well defined, lenses were in younger populations, 9. Nolan TM, DiGirolamo N, Sachdev NH, et al. The role of ultraviolet irradiation and heparin-binding epidermal well circumscribed area of coalesced and those associated with systemic growth factor-like growth factor in the pathogenesis of blood between the bulbar conjunctiva hypertension were noted most often in pterygium. Am J Pathol. 2003;162(2):567-74. and the sclera. The hemorrhage may older patients.6,10-12,14 10. Chan CM, Liu YP, Tan DT. Ocular surface changes in pterygium. Cornea. 2002;21(1):38-42. be flat or slightly elevated depend- 11. Detorakis ET, Spandidos DA. Pathogenetic mecha- ing on the volume trapped. While Pathophysiology nisms and treatment options for ophthalmic pterygium: trends and perspectives (Review). Int J Mol Med. they are impressive to observe and The etiopathology of SCH is vascu- 2009;23(4):439-47. often a source of worry or panic for lar compromise of capillaries under the 12. Dong N, Li W, Lin H, et al. Abnormal epithelial dif- 1-10 ferentiation and tear film alteration in pinguecula. Invest patients, they rarely produce symptoms conjunctiva. This may result from 1-10 Ophthalmol Vis Sci. 2009;50(6):2710-5. or disabilities of any kind. Although exposure to mechanical forces such as 13. Frau E, Labetoulle M, Lautier-Frau M, et al. Corneo- SCH is usually benign, it can be caused excessive increase in blood or plasma conjunctival autograft transplantation for pterygium surgery. Acta Ophthalmol Scand. 2004;82(1):59-63. by a variety of entities, each with their volume, shearing forces, rapid accel- 14. Chaidaroon W, Wattananikorn S. Conjunctival own important sequelae.3-11 When the eration/deceleration exposure or from autograft transplantation for primary pterygium. J Med Assoc Thai. 2003;86(2):111-5. condition is induced by traumatic vec- hemo-perfusive abnormalities such as 15. Bahar I, Weinberger D, Gaton DD, et al. Fibrin glue tors, no additional work-up is required. blood flow stasis or impaired blood tis- versus vicryl sutures for primary conjunctival closure SCH has an established relationship sue composition.1-15 in pterygium surgery: long-term results. Curr Eye Res. 2007;32(5):399-405. with loose, free moving conjunctival The largest subset of SCH patients 16. Tananuvat N, Martin T. The results of amni- tissue.10 Here, suffer from acute trauma.3-7 Here, otic membrane transplantation for primary pterygi- um compared with conjunctival autograft. Cornea. permits the conjunctival surfaces that something as complicated as rapid 2004;23(5):458-63. are redundant to be in frictional con- acceleration, deceleration and expo- 17. Sangwan VS, Murthy SI, Bansal AK, et al. Surgical tact with one another, resulting in sure to blunt forces or as simple as treatment of chronically recurring pterygium. Cornea. 10 2003;22(1):63-5. small vessel and rupture. This a sneeze or Valsalva’s maneuver can 18. Huang Y, Li H, Huang Z, et al. Application of amnion also explains why the phenomenon is result in threshold vascular stresses membrane transplantation combined with mitomycin C in the treatment of pterygium. Yan Ke Xue Bao. observed more frequently in persons sufficient to overcome vessel cellular 2004;20(2):74-6. of older age and in persons who wear barriers. Jarring physical contact, the 19. Segev F, Jaeger-Roshu S, Gefen-Carmi N, et 11,12 al. Combined mitomycin C application and free flap contact lenses. act of vomiting, coughing, singing, conjunctival autograft in pterygium surgery. Cornea. In the event a subconjunctival bleed playing an air-driven musical instru- 2003;22(7):598-603. cannot be explained by mechanical ment, raising of the voice, lifting heavy 20. Akarsu C, Taner P, Ergin A. 5-Fluorouracil as che- moadjuvant for primary pterygium surgery: preliminary means or redundant tissue sources, a weights and attempting to overcome report. Cornea. 2003;22(6):522-6. comprehensive history and ancillary constipation are all reported sources 21. Nabawi KS, Ghonim MA, Ali MH. Evaluation of lim- 1-11 bal conjunctival autograft and low-dose mitomycin C in testing is indicated to rule out infection of SCH. Hypertension, diabetes, the treatment of recurrent pterygium. Ophthalmic Surg or adverse effects from systemic medi- various anemias (such as polycythemia, Lasers Imaging. 2003;34(3):193-6. cations or systemic disease.3,13 for example), disorders (Von 22. Anduze AL. Pterygium surgery with mitomy- cin-C: ten-year results. Ophthalmic Surg Lasers. Epidemiologic studies prospective- Willebrand’s disease, hemophilia, 2001;32(4):341-5. ly examined 8,726 and 161 patients, those caused by medication side effects 23. Jurgenliemk-Schulz IM, Hartman LJ, Roesink JM, et al. Prevention of pterygium recurrence by postopera- respectively, in outpatient eye clin- or anticoagulation therapy), Behcet’s tive single-dose beta-irradiation: a prospective random- ics.6,14 In one study, a total of 225 disease and malignancies (tumors of ized clinical double-blind trial. Int J Radiat Oncol Biol patients (2.9%) presented with a sub- the conjunctiva and blood–leukemia) Phys. 2004;59(4):1138-47. 6 24. Bahar I, Loya N, Weinberger D, et al. Effect of pte- conjunctival hemorrhage. No sexual are all capable of adding to the blood rygium surgery on corneal topography: a prospective or age predilection was found in either volume, increasing blood viscosity, cre- study. Cornea. 2004;23(2):113-7. cohort.6,14 The most common causes ating an inability to clot, raising blood for SCH found in both studies were pressure, producing abnormal perfu- SUBCONJUNCTIVAL minor local trauma, systemic hyperten- sion, altering blood flow and creat- HEMORRHAGE sion and acute hemorrhagic conjuncti- ing vascular stasis and/or leakage––all vitis.6,14 There were some interesting processes capable of contributing to the Signs and Symptoms cohorts identified. In both reports, processes that generate SCH.13,16 Subconjunctival hemorrhage (SCH) SCH resulting from local trauma were Evidence suggests that anatomi-

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cal and system-wide abnormali- ined in patients with subconjunc- ties may induce SCH to occur tival hemorrhages, particularly in in lesion specific locations.1 older patients. Researchers examining location of • Any 360° subconjunctival SCH and underlying pathologic hemorrhage following trauma causes found that traumatic SCH should invoke a suspicion and were smaller in their extent com- investigation to rule out ruptured pared with SCH related to hyper- globe. tension, diabetes, hyperlipidemia • Recurrent events may sug- or those that were idiopathic.1 gest a situation of abuse, tumor Further, SCH in all groups was or excessive anticoagulation ther- significantly more common in the apy (Requiring an International inferior aspect as compared to A subconjunctival hemmorrhage. This resulted from ocular Normalized Ratio [INR] evalu- trauma. superior.1 In patients with SCH ation to determine the patient’s secondary to trauma or diabetes, done. This includes, but is not lim- sensitivity to clotting). there was a tendency to find temporal ited to, a complete blood count with areas affected more often than the nasal differential and platelets, prothrombin 1. Mimura T, Yamagami S, Usui T, et al. Location and extent of subconjunctival hemorrhage. Ophthalmologica. 1 areas. time, activated partial thromboplastin 2009;224(2):90-95. time, fasting blood sugar, blood pres- 2. Snell RS, Lemp MA. The Ocular Appendages. In: Snell RS, Lemp MA. Clinical Anatomy of the Eye, 2nd Management sure evaluation, echocardiogram, lipid Ed. Malden MA; Blackwell Science Inc., 1998: 90–131. The management for subconjunc- profile, homocysteine levels, antipho- 3. Wilson RJ. Subconjunctival hemorrhage: overview and management. J Am Optom Assoc 1986;57(5):376-80. tival hemorrhage begins with appro- solipid antibodies, protein s, protein 4. Curl A. Seeing red. A review of subconjunctival hem- priate patient education. Frightened c, antithrombin III, factor V Leiden, orrhage. Adv Nurse Pract. 1999;7(3):77-8. individuals can be reassured and com- beta-glycoprotein, sickle cell prepara- 5. Fishbaugh J. Subconjunctival hemorrhage––some- thing more you should know. Insight 1995;20(1):20-1. forted regarding the source and benign tion and human immunodeficiency 6. Fukuyama J, Hayasaka S, Yamada K, et al. Causes nature (in most cases) of the bleed- virus titres.15,16 of subconjunctival hemorrhage. Ophthalmologica. 1990;200(2):63-7. ing. Counseling regarding resolution In most cases, SCH episodes are not 7. Chi MJ, Ku M, Shin KH, et al. An Analysis of 733 and expected course also can add lay- so severe that they warrant cessation of surgically treated blowout fractures. Ophthalmologica. ers of assurance. Cold compress, hot a patient’s necessary systemic medica- 2009;224(3):167-175. 8. Sodhi PK, Jose R. Subconjunctival hemorrhage: the compress, artificial tears and possibly tions. However, in cases where the first presenting clinical feature of idiopathic thrombocy- bed rest are other palliative strategies. occurrence is substantial, communica- topenic purpura. Jpn J Ophthalmol. 2003;47(3):316-8. 9. Castellarin A, Lipskey S, Sternberg P Jr. Iatrogenic While the hemorrhage itself does not tion and discussion with the internist open globe eye injury following sinus surgery. Am J require direct medication to promote is advised. As a rule SCH is rarely Ophthalmol. 2004;137(1):175-6. its resolution, an underlying cause, if evacuated.1-11 10. Mimura T, Usui T, Yamagami S, et al. Subconjunctival hemorrhage and conjunctivochalasis. Ophthalmology. it exists, may. If the etiology is trauma, 2009;116(10):1880-6. cycloplegia and topical anti-inflamma- Clinical Pearls 11. Mimura T, Yamagami S, Usui T, et al. Changes of conjunctivochalasis with age in a hospital-based study. tory therapy may be indicated for any • Given the common nature of this Am J Ophthalmol. 2009;147(1):171-177. concurrent uveitis. If the cornea or entity, so long as there are obvious 12. Mimura T, Usui T, Yamamoto H, et al. Conjunctivochalasis and contact lenses. Am J conjunctiva are abraded or infected, a mechanical vectors and the injury is Ophthalmol. 2009;148(1):20-5. topical antibiotic is required. not recurrent, no further work up is 13. Sahin OG. Conjunctival microvascular abnormali- Management of any discomfort must required. ties in two cases with Behcet’s disease. Ocul Immunol Inflamm. 2009;17(5):345-7. be accomplished through means that do • Since the space between the sclera 14. Mimura T, Usui T, Yamagami S, et al. Recent causes not promote anti-platelet activity. This and conjunctiva is infinitely thin, the of subconjunctival hemorrhage. Ophthalmologica. 2009;224(3):133-137. means aspirin and ibuprofen derivatives smallest amount of blood can produce a 15. Chang C, Sheu M, Chern C, et al. Epidemic kerato- must be used with caution if they are striking lesion. conjunctivitis caused by a new genotype of adenovirus used at all. In highly recurrent cases, • Arresting patient fear is often more type 8 (Ad8)-a chronological review of Ad8 in Southern Taiwan. Jpn J Ophthalmol 2001; 45 (2):160–6. testing for blood-tissue abnormali- significant than the actual post incident 16. Burden G, Bryant SA. Hemolytic Anemia. In: Burden ties, clotting disorders, hypertension, care. G, Bryant SA. Laboratory and Radiologic Tests for Primary Eye Care. Boston; Butterworth-Heinemann, diabetes and malignancies should be • Blood pressures should be exam- 1997: 88-96.

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not rupturing Descemet’s membrane). from the trauma. CORNEAL ABRASION and Abrasions may result from foreign Ophthalmic treatment is initiated by RECURRENT CORNEAL bodies, contact lenses, chemicals, fin- using adequate cycloplegia (determined EROSION gernails, hair brushes, tree branches, on a case by case basis; 1% dust and numerous other etiologies.1-11 q.d. - t.i.d., for the worst and scopol- Signs and Symptoms The cornea has remarkable healing amine, cyclogel or homatropine in the Corneal abrasion is one of the com- properties. The epithelium adjacent to office only for the mildest) and topical mon urgent clinical entities that pres- any insult expands in size to fill in the broad spectrum antibiotics.12,13 Bed ent in practice.1 Patients usually pres- defect, usually within 24 to 48 hours.11 rest, inactivity, cold compresses, arti- ent with some or all of the following: Lesions that are purely epithelial often ficial tear drops and over-the-counter acute pain, , pain upon heal quickly and completely without analgesics can be used to relieve acute blinking and extraocular muscle move- intervention or subsequent scarring. pain. In cases where pain is severe, ment, lacrimation, blepharospasm, for- Lesions that extend below Bowman’s topical nonsteroidal anti-inflammato- eign body sensation, blurry vision and membrane possess an increased risk for ry medications or a thin, low-water- a history of contact lens wear or being leaving a permanent scar.11 content bandage contact lens can be struck in the eye.2-10 Biomicroscopy of prescribed.2-7,10 Pressure patching is the injured area often reveals diffuse Management not contraindicated (except perhaps for corneal edema and epithelial disrup- Treatment for corneal abrasion contact len wearing patients); however, tion. In severe cases, when edema is begins with history. The time, place it is no longer considered standard- excessive, folds in Descemet’s mem- and activity surrounding the injury of-care.1,3,5,7,8,14,15 Patients should be brane may be visible. Cobalt blue light should be recorded for both medi- reevaluated every 24 hours until the inspection, with the instillation of cal and legal purposes. Visual acuity abrasion is reepithelialized.2–8 sodium fluorescein dye, will illumi- (VA) should be recorded before any Riboflavin-ultraviolet A (UVA) nate the damaged segment. The newly procedures or drops are given. If the treatment is a new procedure that created wound appears as a bright blepharospasm is sufficiently intense induces collagen cross-linking to stiff- green area compared to the rest of the to preclude an acuity measurement, en the corneal stroma.16 Inducing a cornea because the dye accumulates in one drop of topical anesthetic can reduction in stromal swelling and an the divot, adding density.4,6 In severe be administered with the VA mea- increased resistance to microbial and cases, a mild anterior chamber reaction sured immediately thereafter (pinhole, enzymatic degradation, the procedure may be present. if necessary). The shows promise for corneal of should proceed in a logical fashion all types that demonstrate increased Pathophysiology from external adnexa to funduscopic healing times.16 The cornea has five distinct lay- examination. The eyelids should be Reports have recognized the oral ers. Below the tear film lays the cor- everted and fornices scrutinized to rule antibiotic class of the tetracyclines neal epithelium. The corneal epithe- out the presence of foreign material. for their ability to protect the cor- lium is actually composed of three Fluorescein dye (without anesthetic) nea against proteolytic degradation tissues: the stratified surface epithe- should be instilled to identify the cor- after moderate to severe ocular chem- lium, the wing cell layer (containing neal defects. The Seidel test (paint- ical injury.17,18 Here, oral prepara- the corneal nerves) and the mitotically ing of the wound with fluorescein tions inhibit matrix metalloprotein- active basement membrane. Next is dye observing for aqueous leakage) is ases (MMP) via mechanics that are the Bowman’s membrane (a whirling used when full-thickness injuries are independent of the agent’s antimi- structure designed to prevent penetrat- suspected. The abrasion should be crobial properties. These compounds, ing injuries), the organized lamellar documented for size, shape, location primarily through restriction of gene sheets of stroma, the Descemet’s mem- and depth. It should be cleaned and expression of neutrophil collagenase brane and finally the endothelium.11 scrutinized for foreign matter. The and epithelial gelatinase suppression There are two categories of cor- anterior chamber should be observed of alpha1-antitrypsin degradation and neal abrasion: superficial, (not involv- for any evidence of inflammation. A scavenging of reactive oxygen spe- ing Bowman’s membrane) and deep dilated examination should be com- cies, are able to limit production of (penetrating Bowman’s membrane, but pleted to rule out any posterior effects the inflammatory mediator MMP.17,18

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Oral tetracyclines can be used along ent superficial layers of the cornea by eyelids are temporarily sutured togeth- with other therapeutic agents to inhib- ablating the corneal surface with an er, providing a complete form of patch- it collagenolytic degradation of the excimer laser. Complications of this ing.26 Tarsorrhaphy provides complete cornea. Topical steroids can also be procedure include excessive pain, per- immobilization of the eyelid, which employed following early stage repair foration and exposure to infection.23 yields more efficient healing.26 Often, of superficial ocular injuries to increase Anterior stromal puncture is the sutures are left tied but not knot- the efficiency of corneal wound heal- another option.25 Anterior stromal ted and then taped to the forehead, so ing by suppressing inflammatory puncture involves repeatedly punctur- they can be tightened and loosened for enzymes.17,18 Using 50mg of dox- the purpose of opening the lids to ycycline b.i.d. orally and topical instill medications. Partial tarsor- fluorometholone 0.1% t.i.d. for at rhaphy can be accomplished when least four weeks has demonstrated complete closure is not required. efficacy in patients with recurrent While a tarsorrhaphy is simple, corneal erosion syndrome who safe and effective, it can be some- have failed other forms of treat- what unsightly and create cosmet- ment.18 This non-invasive treat- ic concern for the patient. This ment modality can be effective is typically only done in extreme in concordance with conservative cases, such as neurotrophic kera- ocular lubricant management.18 titis. Patients with a history of cor- Amniotic membrane trans- neal abrasions are more prone plantation (AMT) is a surgical to recurrent corneal erosions Epithelial debridement and NaFl staining in a corneal abrasion. modality used to create a tempo- secondary to altered formation rary “tissue” patch for non-healing of the hemidesmosomes of the epi- ing the Bowman’s layer, penetrating corneal lesions. The membrane can thelial basal cell layer.9-21 When the into the anterior 1/3 of the corneal serve as a reconstructive graft for both hemidesmosomal anchoring fibers are stroma either with a 27 1/2 gauge the cornea and conjunctiva.27 AMT not established properly, a “peeling” needle on a tuberculin syringe or via is primarily used to treat conditions off of the epithelium can result. This a neodymium:yttrium-aluminum-gar- where the normal corneal reparative most frequently occurs upon awaken- net (Nd:YAG) laser.25 When applied process is either faulty or cannot gain ing.9-16,19-21 Patients who have no his- to loosened epithelium or the recur- momentum.27 In a new procedure, tory of a corneal abrasion but who suf- rent epithelial defect area, both options AMT is accomplished using fibrin fer from corneal dystrophies (Cogan’s serve to produce purposeful scarring, glue instead of sutures. The procedure microcystic dystrophy, map-dot-fin- which strengthens the adherence of was reported as a safe and effective gerprint dystrophy, Meesmann’s cor- the overlying superficial epithelium method for restoring the corneal epi- neal dystrophy, Reis–Bucklers dystro- to the Bowman’s layer.25 While the thelium. It also had the added benefit phy, honeycomb dystrophy, granular complications of the needle-based of not requiring a transplantation of and lattice dystrophies) are also more procedure include pain, infection, limbal epithelial stem cells.27 susceptible to recurrent corneal ero- reduced acuity secondary to excessive New and on the horizon is a den- sions.9,22 In cases such as these, pal- scarring and accidental penetration, dritic polymer known as a dendrimer. liative treatment should include a new laser-based practice has been This molecule seems to have applica- hyperosmotic solutions and lubricants. evaluated in small studies to reduce the tions as a nano-adhesive to improve When recurrent erosion does occur, frequency of attacks while only pro- corneal wound repair.28 The agent is patching and bandage lenses may be ducing mild post procedural discom- composed entirely of the biocompat- employed.2,4,5,10,21,23 fort.25 Epithelial debridement and ible products, glycerol and succinic When these modalities fail to pro- diamond burr polishing of Bowman’s acid.28 The adhesive has advantages mote adequate corneal healing, super- membrane is also an option. over sutures in the repair of corneal ficial phototherapeutic laser keratecto- Tarsorrhaphy is the management lacerations, securing unstable LASIK my (PTK) may prove to be of benefit.24 option that is used primarily for recal- flaps and closing leaky surgi- PTK attempts to remove poorly adher- citrant epithelial defects.26 Here, the cal incisions.28-30 Other applications

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001_ro0410_hndbkv7.indd 21 4/5/10 8:47 AM al. Treatment of traumatic corneal abrasion with con- treatment of corneal abrasions. Ann Emerg Med. for potential usage of the adhesive tact lens associated with topical nonsteroidal anti- 2000;35(2):131-7. include ocular emergencies involving inflammatory agent (NSAID) and antibiotic: a safe, 21. Patterson J, Fetzer D, Krall J, et al. Eye patch perforation of tissues due to trauma or effective and comfortable solution. J Fr Ophtalmol. treatment for the pain of corneal abrasion. South Med 2001;24(10):1025-33. J. 1996;89(2):227-9. infection. The substance may also be 3. Michael JG, Hug D, Dowd MD. Management of 22. Reidy JJ, Paulus MP, Gona S. Recurrent erosions applied to strengthen or build up weak corneal abrasion in children: a randomized clinical trial. of the cornea: epidemiology and treatment. Cornea. Annals Ann Emerg Med. 2002;40(1):67-72. 2000;19(6):767-71. tissues that have been compromised 4. Kunimoto DY, Kanitkar, KD, Makar MS. Trauma: 23. Le Sage N, Verreault R, Rochette L. Efficacy of eye by the destructive processes associated Corneal Abrasion. In: Kunimoto, D.Y., Kanitkar, patching for traumatic corneal abrasions: a controlled with inflammation.28-30 K.D., Makar, M.S. The Wills Eye Manual: Office and clinical trial. Ann Emerg Med. 2001;38(2):129-34. Emergency Room Diagnosis and Treatment of Eye 24. Rapuano, C J. PTK Effective therapy for select Disease. Philadelphia, PA: Lippincott Williams & Wilkins group of patients. Ophthalmology Times.1998:2-3. Clinical Pearls 2004;17-9. 25. Tsai TY, Tsai TH, Hu FR, et al. Recurrent cor- 5. Willoughby CE, Batterbury M, Kaye SB. Collagen neal erosions treated with anterior stromal punc- • To promote healing, prevent corneal shields. Surv Ophthalmol. 2003;48(2):241. ture by neodymium: yttrium-aluminum-garnet laser. recurrent erosion and reduce corneal 6. Zhao J, Nagasaki T. Mechanical damage to Ophthalmology. 2009;116(7):1296-300. edema, a hypertonic solution or oint- corneal stromal cells by epithelial scraping. Cornea 26. Robinson C, Tantri A, Shriver E, et al. Temporary 2004;23(5):497-502. eyelid closure appliqué. Arch Ophthalmol. ment may be prescribed along with the 7. Willcox MD, Holden BA. Contact lens related corneal 2006;124(4):546-9. other medications or after re-epitheli- infections. Biosci Rep. 2001;21(4):445-61. 27. Kheirkhah A, Casas V, Raju VK, et al. Sutureless 8. Kaiser PK. A comparison of pressure patching ver- amniotic membrane transplantation for par- alization has occurred. The minimum sus no patching for corneal abrasions due to trauma tial limbal stem cell deficiency. Am J Ophthalmol. period of recommended application or foreign body removal. Corneal Abrasion Patching 2008;145(5):787-94. Study Group. Ophthalmology. 1995;102(12):1936-42. 28. Luman NR, Kim T, Grinstaff MW. Dendritic for this type of therapy is one month; 9. Fujikawa LS, Nussenblatt RB. Recurrent and polymers composed of glycerol and succinic acid: however, unusual cases may require Chronic Corneal Epithelial Defects. In : Abbott, R.L. Synthetic methodologies and medical applications. months or even permanent use. Surgical Intervention in Corneal and External Diseases. Pure Appl Chem. 2004;76(7-8):1375-85. New York; Grune & Stratton, Inc. 1987:59-67. 29. Wathier M, Jung PJ, Carnahan MA, et al. Dendritic • In cases where excess epithelium 10. Gilad E, Bahar I, Rotberg B, et al. Therapeutic con- macromers as in situ polymerizing biomaterials for impairs regrowth, a cotton-tipped tact lens as the primary treatment for traumatic corneal securing cataract incisions. J Am Chem Soc. 2004 erosions. Isr Med Assoc J. 2004;6(1):28-9. 13;126(40):12744-5.. applicator saturated with anesthetic 11. Binder PS, Wickham GM, Zavala EY, et al. Corneal 30. Kang PC, Carnahan MA, Wathier M, et al. Novel may be used to debride the loose or Anatomy and Wound Healing. In: Barraquer JI, Binder tissue adhesives to secure laser in situ keratomileusis excessive tissue.5 PS, Buxton JN, et al. Symposium on Medical and flaps. J Cataract Refract Surg. 2005;31(6):1208-12. Surgical Diseases of the Cornea. St. Louis; CV Mosby • When a significant inflammation Company 1980:1-35. is present or if subepithelial infiltration 12. Ta CN, Chan I, Dhatt HS, et al. Prospective com- parison of topical moxifloxacin in eliminating conjuncti- occurs during the reparative process, val bacterial flora following a one-day or one-hour appli- topical steroids may be required. They cation. J J Ocul Pharmacol Ther. 2008;24(4):427-31. Signs and Symptoms must be used judiciously as they can 13. Moshirfar M, Chew J, Werner L, et al. Comparison Dry eye syndrome may occur in a of the effects of fourth-generation fluoroquinolones on retard corneal healing and raise intra- corneal re-epithelialization in rabbit eyes. Graefes Arch wide range of individuals, although it ocular pressure. Clin Exp Ophthalmol. 2008;246(10):1455-61. is more frequently seen in women and 14. Calder L, Balasubramanian S, Stiell I. Lack of con- • Worsening subepithelial infil- sensus on corneal abrasion management: results of a older adults (i.e., those 50 years of age tration, increased pain and increased national survey. CJEM. 2004;6(6):402-7. and above).1-7 A higher incidence has 15. Kaiser PK, Pineda II R. A study of topical non- injection in the setting of an epithe- steroidal anti-inflammatory drops and no pressure also been noted in those with connec- lial break may be a sign of ulceration patching in the treatment of corneal abrasions. Corneal tive tissue disorders (e.g., rheumatoid secondary to infection. Lesions such Abrasion Patching Study Group. Ophthalmology. arthritis, Sjögren’s syndrome), diabetes 1997;104(8):1353-9. as these should be considered vision 16. Ehlers N, Hjortdal J, Nielsen K, et al. Riboflavin- mellitus, HIV infection and numerous threatening, warranting immediate UVA treatment in the management of edema and other systemic conditions.1,8,9 Patients nonhealing ulcers of the cornea. J Refract Surg. treatment with a fourth-generation 2009;25(9):S803-6. with dry eye commonly present with fluoroquinolone antibiotic drops (if 17. Ralph RA. Tetracyclines and the treatment of complaints of ocular irritation or dis- one is not already employed) and con- corneal stromal ulceration: a review. Cornea. comfort. As the name implies, dryness 2000;19(3):274-7. sideration for culture to determine the 18. Wang L, Tsang H, Coroneo M. Treatment of recur- is the most frequently cited problem; presence of an underlying microbial rent corneal erosion syndrome using the combination patients may further report itching, of oral doxycycline and topical corticosteroid. Clin organism. Experiment Ophthalmol. 2008;36(1):8-12. burning, or a “sandy/gritty” foreign 19. Meek B, Speijer D, de Jong PT, et al. The ocular body sensation. Symptoms may be 1. Kumar NL, Black D, McClellan K. Daytime presenta- humoral immune response in health and disease. Prog exacerbated by poor air quality, low tions to a metropolitan ophthalmic emergency depart- Retin Eye Res. 2003;22(3):391-415. ment. Clin Experiment Ophthalmol. 2005;33(6):586-92. 20. Szucs PA, Nashed AH, Allegra JR, et al. Safety humidity or extreme heat and tend 2. Vandorselaer T, Youssfi H, Caspers-Valu LE, et and efficacy of diclofenac ophthalmic solution in the to be more prominent later in the

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day.10 Occasionally, patients will report ondary to meibomian gland dysfunc- or other surface disorders (e.g., ocular excess lacrimation, or epiphora, in tion (MGD), so another vital aspect allergy) comprise the evaporative cat- association with the discomfort, a con- of examination includes assessment of egory. Additional contributory factors dition known as paradoxical tearing. the lid margin and meibomian glands. may include contact lenses, low envi- Upon gross inspection, the majority In these cases, the clinician may notice ronmental humidity and a number of of dry eye patients demonstrate a rela- lid erythema, (loss of lash- medications.12 tively white and quiet eye. However, es), (inward turning of the Over the last 15 years, a great deal key slit lamp findings may include a lashes), and meibomian gland inspis- of research has been conducted in meager tear meniscus at the lower lid, sation (plugging). Foamy, frothy tears the area of dry eye and ocular sur- as well as a reduced tear film break-up are one of the earliest signs of mei- face disease, yielding new informa- time (TFBUT) of 10 seconds or tion and concepts regarding the less. Sodium fluorescein stain- pathophysiology of this disease ing may be evident as punctate process. Much of this research epithelial keratopathy from the was summarized in the recent interpalpebral region to the lower report of the International Dry third of the cornea. In more Eye Workshop (DEWS).1,10,11,15- severe cases, rose bengal or lissa- 17 DEWS represents the most mine green staining of the cornea current and complete consensus and/or conjunctiva may be seen in regarding dry eye. According to the same area. Filaments, which the DEWS report, “Dry eye is a are tags composed of mucus, epi- multifactorial disease of the tears thelial cells and tear debris, may and ocular surface that results in also stain with these vital dyes. symptoms of discomfort, visual Additional clinical tests for dry Severe dry eye syndrome. disturbance, and tear film insta- eye syndrome are quite numerous. bility with potential damage to Tear volume assessment is used quite bomian gland dysfunction, represent- the ocular surface. It is accompanied commonly, and may be ascertained ing saponification of tear film lipids. by increased osmolarity of the tear by use of Schirmer tear test strips Digital expression of the meibomian film and inflammation of the ocular (5mm x 35mm strips of Whatman #41 glands may demonstrate thickened, surface.”10 The report further suggests or other unbonded, porous paper) or turbid and/or diminished oil secretion. that dry eye, while having numerous the Zone-Quick test (70mm strands contributory and etiologic factors, is of yellow cotton thread impregnated Pathophysiology ultimately the result of “core mecha- with phenolsulfonphthalein or “phenol Dry eye syndrome has tradition- nisms,” which can initiate, amplify and red” dye, a pH indicator). Diminished ally been viewed as a quantitative or potentially change the character of dry wetting of these test media over a set qualitative reduction of the tear film, eye over time. These are tear hyperos- period of time (five minutes for the with a multitude of etiologies and con- molarity and tear film instability.10 Schirmer and 15 seconds for the Zone- tributory factors. The condition tends Osmolarity refers to the concentra- Quick test) is indicative of tear vol- to be categorized as either “aqueous tion of particles in the tear film; it is ume deficiency and dry eye syndrome. deficient” or “evaporative,” based upon akin to the concept of salinity when Additional diagnostic methodologies a comprehensive classification scheme referring to the concentration of salt in for dry eye include tear film osmo- that was developed in 1995, and later a sample of seawater. In a dry eye state, larity, lysozyme analysis, lactoferrin reiterated in 2007.1,12 Those condi- the tear film becomes hyperosmotic as a assay, lipocalin assay, impression cytol- tions that contribute to diminished result of diminished aqueous tear flow, ogy and tear ferning; however, these tear production, such as Sjögren’s excessive evaporation, or a combina- tests have seen their greatest utilization syndrome or acquired lacrimal gland tion of these events. Hyperosmolarity within the research community, being disease, constitute the aqueous defi- (more particles per sample) stimu- too complex, expensive or time con- cient variety. Conditions involving lates a cascade of inflammatory events, suming for practical clinical use.11 meibomian oil deficiency, poor lid resulting in the production of inflam- Dry eye also commonly occurs sec- congruity and altered blink dynamics matory cytokines (e.g., interleukin-1a,

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001_ro0410_hndbkv7.indd 23 4/5/10 8:47 AM interleukin-1b, tumor necrosis factor well as their respective active and inac- to 44% of patients and improve basal alpha) and matrix metalloproteinases, tive ingredients. tear production (as demonstrated by which in turn activate inflammatory In theory, artificial tears may be Schirmer testing) in up to 59% of cells at the ocular surface.14,18,19 These used as often as necessary. When patients after six months of therapy.27 inflammatory events lead to apoptotic beginning therapy however, lubricants The use of topical corticosteroids (e.g., death of surface epithelial cells and should be dosed more frequently and 0.5% loteprednol etabonate q.i.d. for goblet cells.20 Other factors, such as regularly; later, this therapy can be two to four weeks) in conjunction with autoimmune targeting of the ocular tapered based upon patient response Restasis therapy may hasten recovery surface and noxious environmen- and further diminish symptoms tal stimuli, can amplify these ini- associated with dry eye.16,25,28 tiating inflammatory events. Long-term use of topical steroids Tear film instability may also is not recommended however, initiate a dry eye state in the due to the potential for cataracto- absence of or preceding tear genesis and ocular hypertension. hyperosmolarity. Tear instabil- Oral medications and nutri- ity results from local deficien- tional supplements are another cies which causes the tear film potential therapy for patients to break up too rapidly, thereby with dry eye syndrome secondary minimizing the protective effect to meibomian gland disease. The to the ocular surface; usually this use of oral tetracycline therapy is described as a TFBUT that is (e.g., doxycycline 50mg -100mg 21 less than the blink interval. This Sodium fluorescein in dry eye: note areas of negative staining, daily for six to 12 weeks) may be phenomenon induces local dry- mucus filaments and diffuse epitheliopathy. beneficial in patients who fail to ing of the exposed surface, which improve with lubricating drops can result in surface epithelial damage and compliance. Highly symptomatic and lid hygiene. Tetracyclines dem- and disturbance of the glycocalyx and patients may benefit from products onstrate a host of anti-inflammatory goblet cell mucins.10 Like osmolarity, that demonstrate enhanced ocular sur- effects, which have proven beneficial tear instability can be spurred by a face residence time, such as Systane in those with various forms of blepha- host of factors, including allergic eye Ultra (Alcon Laboratories), which ritis.29,30 Omega-3 fatty acid supple- disease, chronic use of preserved topi- provide relief with less frequent instil- ments may provide similar benefits in cal medications (particularly those with lation. Solutions have a distinct advan- restoring meibomian gland function benzalkonium chloride) and contact tage over ointments, as they tend to and tear stability, though the body lens wear.22-24 induce less . In addi- of evidence for such therapy is still tion, experts recommend that patients emerging.31 Management with more advanced diseases employ Oral secretagogues are sometimes Historically, management of dry eye non-preserved artificial tear products, used to manage advanced cases of syndrome has been aimed at replenish- to avoid any potential for toxicity.16,25 aqueous deficient dry eye, such as those ing the eyes’ moisture and/or delaying Patients who do not respond to tear encountered in Sjögren’s syndrome. evaporation of the patient’s natural rehabilitative/lubrication therapy alone Salagen (pilocarpine HCl 5mg, MGI tears. The first line of defense typi- may require treatment with topical Pharma) and Evoxac (cevimeline HCl cally involves the use of ophthalmic immunomodulatory agents, such as 30mg, SnowBrand Pharmaceuticals) lubricants or “artificial tears.” The Restasis (0.05% cyclosporine A oph- are muscarinic agonists, which stimu- purpose of these agents is to allevi- thalmic emulsion, Allergan) or topi- late non-selective secretion from exo- ate symptoms and, in some cases, to cal steroids. Cyclosporine works by crine glands via autonomic pathways, promote healing of the ocular surface suppressing T-cells and inhibiting resulting in enhanced tear produc- and corneal epithelium. A great deal their activation, while downregulat- tion.32,33 It should be noted that these of diversity exists within this market, ing T-cell mediated cytokine produc- agents are specifically indicated for and practitioners should familiarize tion.26 In clinical trials, Restasis was xerostomia (dry mouth) associated themselves with the various options as shown to ameliorate symptoms in up with Sjögren’s syndrome or certain

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1. The epidemiology of dry eye disease: report of the forms of cancer, and their use in based on subjective complaints than Epidemiology Subcommittee of the International Dry dry eye is considered off-label. Also, on ocular inspection. Eye WorkShop (2007). Ocul Surf. 2007;5(2):93-107. because of the potential for a mul- • Many common systemic drugs 2. Munoz B, West SK, Rubin GS, et al. Causes of blindness and visual impairment in a population of titude of systemic side-effects, it is can transiently decrease lacrimal secre- older Americans: The Salisbury Eye Evaluation Study. recommended that these agents only tions, creating or exacerbating a dry Arch Ophthalmol. 2000;118(6):819-25. 3. Moss SE, Klein R, Klein BE. Prevalence of and be employed after consultation with an eye state. These may include anti- risk factors for dry eye syndrome. Optom Vis Sci. experienced rheumatologist. histamines, oral contraceptives, beta- 2008;85(8):668-74. Occlusion of nasolacrimal outflow blockers, diuretics, phenothiazine 4. Chia EM, Mitchell P, Rochtchina E, et al. Prevalence and associations of dry eye syndrome in an older pop- with punctal or intracanalicular plugs antianxiety preparations and atropine ulation: the Blue Mountains Eye Study. Clin Experiment offers a different management strategy derivatives. As part of the manage- Ophthalmol. 2003;31(3):229-32. 5. Moss SE, Klein R, Klein BE. Long-term incidence for dry eye: preventing drainage of ment for dry eye patients, a thorough of dry eye in an older population. Optom Vis Sci. the tear film and maximizing con- medication history–including both 2008;85(8):668-74. tact duration with the ocular surface. prescriptive and over-the-counter 6. Schaumberg DA, Sullivan DA, Buring JE, et al. Prevalence of dry eye syndrome among US women. While the theory is sound, a signifi- agents–is mandatory. Am J Ophthalmol. 2003;136(2):318-26. cant percentage of plugs may be spon- • Likewise, numerous systemic 7. Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence of dry eye disease among US men: taneously expelled, and it has been conditions can be associated with dry estimates from the Physicians’ Health Studies. Arch observed that many patients notice a eye. Beyond directed ocular treatment, Ophthalmol. 2009;127(6):763-8. 8. Kaiserman IN, Kaiserman N, Nakar S, et al. subjective decrease in improvement it is essential that clinicians obtain a Dry eye in diabetic patients. Am J Ophthalmol. 34- of symptoms with plugs over time. detailed medical history on patients 2005;139(3):498-503. 36 Some individuals have actually with dry eye to determine if there is 9. Jeng BH, Holland GN, Lowder CY, et al. Anterior segment and external ocular disorders associated cautioned against occlusion therapy any underlying or undiagnosed dis- with human immunodeficiency virus disease. Surv in many cases, citing the potential ease. Conditions to consider include Ophthalmol. 2007;52(4):329-68. 10. The definition and classification of dry eye dis- inflammatory aspects of dry eye; they connective tissue disorders (e.g., ease: report of the Definition and Classification suggest that the use of punctal plugs rheumatoid arthritis, systemic lupus Subcommittee of the International Dry Eye WorkShop may create a “cesspool” of cytokines erythematosus, Sjögren’s syndrome), (2007). Ocul Surf. 2007;5(2):75-92. 11. Methodologies to diagnose and monitor dry and promote, rather than alleviate, diabetes mellitus, HIV infection, sar- eye disease: report of the Diagnostic Methodology damage to the ocular surface.25 This coidosis, thyroid disease and hepatitis Subcommittee of the International Dry Eye WorkShop 1 (2007). Ocul Surf. 2007;5(2):108-52. is why experts highly recommend that C. 12. Lemp MA. Report of the National Eye Institute/ any inflammatory aspects related to • Before initiating any form of Industry Workshop on Clinical Trials in Dry Eyes. CLAO dry eye be addressed prior to the inser- therapy, practitioner and patient alike J. 1995;21(4):221-32. 13. Mathers WD. Why the eye becomes dry: A cor- 10,25 tion of punctal plugs. must understand one basic tenet of nea and lacrimal gland feedback model. CLAO J. The most severe forms of dry eye dry eye management: namely, that 2000;26(3):159-65. 14. Baudouin C. The pathology of dry eye. Surv may require more radical forms of this is a CHRONIC disease, marked Ophthalmol. 2001;45 Suppl 2:S211-20.. therapy; some options include topical by exacerbations and remissions. The 15. Design and conduct of clinical trials: report of the Clinical Trials Subcommittee of the International Dry acetylcysteine, punctal cautery, system- only way for patients to achieve con- Eye WorkShop (2007). Ocul Surf. 2007;5(2):153-62. ic anti-inflammatory therapies, ban- trol of their symptoms and discom- 16. Management and therapy of dry eye disease: dage contact lenses, oral cyclosporine, fort is through active participation report of the Management and Therapy Subcommittee 25 of the International Dry Eye WorkShop (2007). Ocul moisture goggles, or surgery. Patients in the prescribed treatment regimen Surf. 2007;5(2):163-78. at this level of severity are probably and periodic reevaluation. There is no 17. Research in dry eye: report of the Research Subcommittee of the International Dry Eye WorkShop best referred to an experienced, board- “magic bullet” cure, and appropriate (2007). Ocul Surf. Ocul Surf. 2007;5(2):179-93. certified corneal specialist. care requires patience, perseverance 18. Niederkorn JY, Stern ME, Pflugfelder SC, et al. and a willingness to try new (and Dessicating stress induces T-cell mediated Sjogren’s syndrome-like lacrimal sicca. J Clinical Pearls sometimes unconventional) options. Immunol. 2006;176(7):3950-7. • The symptoms of dry eye syn- Strong consideration must be made 19. Brignole F, Pisella PJ, Goldschild M, et al. Flow cytometric analysis of inflammatory markers in con- drome tend to be quite variable. Often, for the improvement of lid hygiene junctival epithelial cells of patients with dry eyes. Invest patients seem to be more symptom- through scrubs or other methods to Ophthalmol Vis Sci. 2001;42(1):90-5. atic than their clinical signs would reduce the impact of poor meibomian 20. Yeh S, Song XJ, Farley W, et al. Apoptosis of ocular surface cells in experimentally induced dry eye. indicate. Astute clinicians realize that secretions in the development of dry Invest Ophthalmol Vis Sci. 2003;44(1):124-9. the diagnosis of dry eye is more often eye. 21. Ousler GW 3rd, Hagberg KW, Schindelar M, et al. The Ocular Protection Index. Cornea. 2008;27(5):509-

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001_ro0410_hndbkv7.indd 25 4/5/10 8:47 AM 13. 22. Fujishima H, Toda I, Shimazaki J, Tsubota K. first described by Phillips Thygeson in No established cause for the disease 1 Allergic conjunctivitis and dry eye. Br J Ophthalmol. 1950. It is characterized by an insidi- is known; however, allergic, viral and 1996;80(11):994-7. ous onset of corneal inflammation with toxic mechanisms that interrupt the 23. Ishibashi T, Yokoi N, Kinoshita S. Comparison of the short-term effects on the human corneal surface of a long duration of exacerbations and keratinization process (tissue drying) topical timolol maleate with and without benzalkonium remissions. The clinical presentation is have been proposed.6,9 The clinical chloride. J Glaucoma. 2003;12(6):486-90. 24. Pisella PJ, Malet F, Lejeune S, et al. Ocular sur- characterized by recurrent episodes of manifestations of TSPK resemble a face changes induced by contact lens wear. Cornea. photophobia, tearing, ocular burning combination of findings that meld the 2001;20(8):820-5. and foreign body sensation, typically signs of viral keratitis with the reaction 25. Behrens A, Doyle JJ, Stern L, et al. Dysfunctional 1,2 tear syndrome study group. Dysfunctional tear syn- in both eyes. Physical examination that is observed following an exposure drome: a Delphi approach to treatment recommenda- reveals whitish fine granular “asterisk- to a noxious agent. 2,3,6,10 The TSPK tions. Cornea. 2006;25(8):900-7. 26. Pflugfelder SC. Anti-inflammatory therapy for dry shaped” or “dendriform” intraepithelial lesions seem to possess the ability to eye. Am J Ophthalmol. 2003;1(1):31-6. opacities, sometimes creating an eleva- gain access to the deeper corneal epi- 27. Sall K, Stevenson OD, Mundorf TK, et al. Two tion of the overlying corneal epitheli- thelial layers.2,3,6,10 An altered immune multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate um. Characteristically, no conjunctival response to an unknown exogenous or to severe dry eye disease. CsA Phase 3 Study Group. inflammation is associated with the endogenous antigen may explain the Ophthalmology. 2000;107(4):631-9. 28. Byun YJ, Kim TI, Kwon SM, et al. Efficacy of com- keratitis, and the eye is otherwise white characteristic exacerbations and remis- bined 0.05% cyclosporine and 1% methylprednisolone and quiet. sions of the disease.8,10,11 In some treatment for chronic dry eye. Cornea. 2009. [Epub ahead of print]. Most lesions are central; however, patients, an increase in HLA-Dw3 and 29. Dougherty JM, McCulley JP, Silvany RE, et al. The peripheral lesions do occur and may HLA-DR3 expression, both of which role of tetracycline in chronic blepharitis. Inhibition of be associated with delicate, peripheral are HLA loci associated with immune lipase production in staphylococci. Invest Ophthalmol 11,12 Vis Sci. 1991;32(11):2970-5. vascularization in chronic cases. Fine response genes, has been detected. 30. Shine WE, McCulley JP, Pandya AG. Minocycline filaments also may be associated with Recently, researchers were able effect on meibomian gland lipids in meibomianitis 1-3 patients. Exp Eye Res. 2003;76(4):417-20. the keratitis. The disease may per- to determine that the number of 31. Macsai MS. The role of omega-3 dietary supple- sist from one month to decades, with Langerhans cells (antigen-presenting mentation in blepharitis and meibomian gland dys- an average episodic duration of eight cells) in the cornea, normally located function (an AOS thesis). Trans Am Ophthalmol Soc. 4 2008;106:336-56. years or longer. Visual acuity may be in the peripheral cornea and to a less- 32. Papas AS, Sherrer YS, Charney M, et al. Successful decreased by the subepithelial opaci- er extent, the central regions of the treatment of dry mouth and dry eye symptoms in Sjögren’s syndrome patients with oral pilocarpine: ties, but generally it returns to normal healthy cornea, were greatly increased a randomized, placebo-controlled, dose-adjustment following resolution of the keratitis.3 within the basal cell layer of the corneal study. J Clin Rheumatol. 2004;10(4):169-77. Corneal sensation is usually normal, epithelium and within Bowman’s layer 33. Ono M, Takamura E, Shinozaki K, et al. Therapeutic 12 effect of cevimeline on dry eye in patients with Sjögren’s but the physiologic climate for mild of affected eyes. Most of the corneal syndrome: a randomized, double-blind clinical study. hypoesthesia exists.5 abnormalities in the eyes affected by Am J Ophthalmol. 2004;138(1):6-17. 34. Balaram M, Schaumberg DA, Dana MR. Efficacy The onset of TSPK is most common TSPK are confined to the basal cell and tolerability outcomes after punctal occlusion with in the second and third decades with an layer of the corneal epithelium, the silicone plugs in dry eye syndrome. Am J Ophthalmol. 5 2001;131(1):30-6. age range of 2.5 to 70 years. No clear subepithelial nerve plexus, Bowman’s 13 35. Yen MT, Pflugfelder SC, Feuer WJ. The effect of sexual predilection exists, although a membrane and the anterior stroma. punctal occlusion on tear production, tear clearance, female preponderance has been sug- The middle and deep regions of the and ocular surface sensation in normal subjects. Am J 1-5 Ophthalmol. 2001;131(3):314-23. gested. Recurrence has been associ- stroma, Descemet’s membrane and 36. Koh S, Maeda N, Ninomiya S, et al. Paradoxical ated with corneal surgical procedures.7,8 endothelial cells are spared from path- increase of visual impairment with punctal occlusion 13 in a patient with mild dry eye. J Cataract Refract Surg. ological changes. 2006;32(4):689-91. Pathophysiology Corneal scrapings of the lesions Classically, there are five charac- demonstrate nonspecific findings, THYGESON’S SUPERFICIAL teristic features of TSPK: chronic, which include atypical and degener- PUNCTATE KERATOPATHY bilateral punctate inflammation; long ated epithelial cells and a mild mono- duration with remissions and exacerba- nuclear and polymorphonuclear cell Signs and Symptoms tions; healing without significant scar- infiltrate.13 Focal cell destruction Thygeson’s superficial punctate ring; absent clinical response to topical without the cell-to-cell pattern, typical keratopathy (TSPK) is a bilateral, epi- antibiotics and striking symptomatic of , has been thelial keratitis of unknown etiology, response to topical corticosteroids.3 reported. However, the presence of

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specific viral particles has not been • No specific systemic associa- documented.13 tions have been reported for this disease. Management • Proper counseling regarding The diagnosis of TSPK is gener- the exacerbations and remissions ally made from the clinical history that occur with this disease can and biomicroscopic examination. It help patients understand what is confirmed by the unusually rapid will be required with this some- and successful response to topical times frustrating and often both- corticosteroids.1-3,6,11 Topical cor- ersome clinical entity. ticosteroids decrease the signs and symptoms of TSPK and are most 1. Thygeson P. Superficial punctate keratitis J Am Med Assoc. 1950;144(18):1544-9. effective during acute exacerba- 2. Oudová PM. Thygeson’s keratitis--clinical tions.3,11 A rapid taper of the dose Stellate lesions in Thygeson’s SPK. characteristics and therapy. Cesk Slov Oftalmol. 2004;60(1):17-23. to maintain control of the symp- 3. Nagra PK, Rapuano CJ, Cohen EJ, et al. toms is recommended.3 Some evidence cal antiviral compound trifluridine in Thygeson’s superficial punctate keratitis: ten years’ 16 experience. Ophthalmology. 2004;111(1):34-7. suggests that the course of the disease unresponsive cases of TSPK. In five of 4. van Bijsterveld OP, Mansour KH, Dubois FJ. may be prolonged with the chronic use the six trifluridine-treated-eyes, a favor- Thygeson’s superficial punctate keratitis. Ann of corticosteroids. Such use should be able response was elicited. Symptoms Ophthalmol. 1985;17(2):150-3.. 5. Tabbara KF, Ostler HB, Dawson C, et al. avoided, especially given the well-doc- and signs of the disease disappeared, but Thygeson’s superficial punctate keratitis. Ophthalmol. umented complications of long-term more slowly than in cases treated with 1981;88(1):75-7. 16 6. Del Castillo JM, Del Castillo JB, Garcia-Sanchez topical corticosteroid therapy. A recent topical corticosteroids. One patient J. Effect of topical cyclosporin A on Thygeson’s report outlining the efficacy of topical with an 11-year history of topical corti- superficial punctate keratitis. Doc Ophthalmol. 1996- 2% cyclosporine in the treatment of costeroid dependence for clearing TSPK 1997;93(3):193-8.. 7. Jabbur NS, O’Brien TP. Recurrence of keratitis after TSPK may provide direction toward an was treated successfully with trifluridine, excimer laser keratectomy. J Cataract Refract Surg. equally effective treatment associated with his eyes remaining clear for over 2003;29(1):198-201. 3,15 8. Seo KY, Lee JB, Jun RM, et al. Recurrence of with fewer side effects. one year without any therapy once the Thygeson’s superficial punctate keratitis after photore- Published evidence suggests that course was finished.16 Mild irritation fractive keratectomy. Cornea. 2002;21(7):736-7. topical 2% cyclosporine A (CsA) placed and transient limbal follicle formation 9. Connell PP, O’Reilly J, Coughlan S, et al. The role of common viral ocular pathogens in Thygeson’s 16 into in an olive oil vehicle may be are recognized side effects. superficial punctate keratitis. Br J Ophthalmol. an effective and safe topical treatment Therapeutic bandage contact lenses, 2007;91(8):1038-41. 10. Tabery HM. Corneal surface changes in Thygeson’s for Thygeson’s superficial punctate extended wear contact lenses and patch- superficial punctate keratitis: a clinical and non-contact keratitis when topical steroids fail or ing have been used to improve visual photomicrographic in vivo study in the human cornea. Eur J Ophthalmol. 2004;14(2):85-93. when topical steroidal therapy has the acuity, as well as to reduce the irritative 11. Duszak RS. Diagnosis and management of 3,11,17 potential to induce high risk complica- symptoms in suffering patients. Thygeson’s superficial punctate keratitis. Optometry. tions secondary to long-term use.14 It is Scraping of the lesions is not effective 2007;78(7):333-8. 12. Darrell RW. Thygeson’s superficial punctate keratitis: not clear if the commercially available and may stimulate scarring or recur- natural history and association with HLA DR3. Trans Am concentrations of cyclosporine (0.05%) rence.7,8 Ophthalmol Soc. 1981;79:486-516. 13. Kawamoto K, Chikama T, Takahashi N, et al. In is effective in this condition, but an Most patients who have TSPK vivo observation of Langerhans cells by laser confocal off-label trial would not be unwar- recover completely with no loss of visual microscopy in Thygeson’s superficial punctate keratitis. ranted in cases where steroids are ill- acuity, although some patients may be Mol Vis. 2009;15:1456-62. 14. Cheng LL, Young AL, Wong AK, et al. In vivo confo- 3 advised. Considering the chronicity of left with faint subepithelial opacities. cal microscopy of Thygeson’s superficial punctate kera- Thygeson’s superficial punctate kerati- titis. Clin Experiment Ophthalmol. 2004;32(3):325-7. 15. Hasanreisoglu M, Avisar R. Long-term topical tis, CsA alone or in combination with Clinical Pearls cyclosporin A therapy in Thygeson’s superficial punctate other topical treatments, may offer an • The granular epithelial findings keratitis: a case report. Cases J. 2008;1(1):415. advantage and synergy for cases requir- of TSPK occasionally may be confused 16. Nesburn AB, Lowe GH 3rd, Lepoff NJ, et al. Effect of topical trifluridine on Thygeson’s superficial punctate 15 ing chronic long-term intervention. with other causes of epithelial keratitis. keratitis. Ophthalmology. 1984;91(10):1188-92. In a classic paper published in 1984, However, conjunctival inflammation is 17. Goldberg DB, Schanzlin DJ, Brown SI. Management of Thygeson’s superficial punctate keratitis. Am J researchers experimented with the topi- absent in TSPK. Ophthalmol. 1980;89(1):22-4.

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ANTERIOR UVEITIS trauma to widespread systemic infec- tion (e.g., tuberculosis) to generalized Signs and Symptoms ischemic disorders (e.g., giant cell arteri- Uveitis is most commonly encoun- tis).4-6 Some other well-known systemic tered in persons between 20 and 59 etiologies include ankylosing spondylitis, years of age.1 Children and the elderly rheumatoid arthritis, psoriatic arthritis, are rarely affected, except in cases of , inflammatory bowel disease, blunt ocular trauma. Anterior uveitis does multiple sclerosis, , Lyme disease, not tend to favor either gender, nor is and histoplasmosis.4-6 Of course, not there any particular racial predilection. all forms of uveitis are associated with Cells and flare––the classic anterior chamber Patients with anterior uveitis typically signs of uveitis. systemic illness. Localized present with a triad of pain, photophobia may occur as well, either by iatrogenic or and hyperlacrimation. The pain is charac- kocytes (white blood cells) liberated from idiopathic means. Some primary uveitic teristically described as a deep, dull ache, the iris vasculature in response to inflam- syndromes include Fuch’s heterochro- which may extend to the surrounding mation, observable and freely floating in mic iridocyclitis and Posner-Schlossman orbit. Associated sensitivity to lights may the convection currents of the aqueous. syndrome. be severe; often, these patients present Flare is the term used to describe liber- While the precise pathophysiology of wearing dark sunglasses. Excessive tear- ated proteins from the inflamed iris or anterior uveitis has not been entirely ing results secondary to increased neural . When present, flare gives the elucidated, we do have a basic under- stimulation of the lacrimal gland, and is aqueous a particulate, or smoky, appear- standing of the cascade of events involved not associated with a foreign body sensa- ance. Iris findings may include adhesions during this inflammatory state. In the tion. In terms of visual acuity, there is to the lens capsule (posterior ) normal , the anterior cham- variable impact. In the earliest stages of or, less commonly, to the peripheral ber remains free of cells and plasma anterior uveitis, visual acuity is minimally cornea (peripheral anterior synechia— proteins by virtue of the blood-aqueous compromised; however, as the condition PAS). Synechiae are the cause of irregular barrier. The blood-aqueous barrier is persists over days to weeks, accumulation and/or fixed in cases of uveitis. comprised of tight junctions between the of cellular debris in the anterior chamber Additionally, granulomatous nodules are endothelial cells of the iris vasculature, and along the corneal and lenticular sur- sometimes seen at the pupillary border and between the apico-lateral surfaces faces may result in subjectively blurred (Koeppe nodules) and within the iris of the nonpigmented epithelium of the vision. Accommodative tasks may be dif- stroma (Bussaca nodules) in cases of ciliary body.7 In an inflammatory ocular ficult or painful due to ciliary spasm. uveitis associated with systemic disease.2,3 state, cytokines mediate numerous tissue The patient with anterior uveitis may is often impacted changes, among them vasodilation and display a sluggish, fixed, and/or irregular in anterior uveitis, though it may be increased vasopermeability.8,9 When the on the involved side. Ocular motil- depressed, normal or elevated depend- uveal vessels dilate, exudation of plas- ity is generally intact. Gross observation ing on the stage at which it is measured ma, white blood cells and proteins into may reveal a pseudoptosis, secondary to and the duration of the disease process. the extravascular spaces (e.g., the ante- photophobia; there is not typically any In early stages, IOP is characteristically rior chamber) becomes possible. Small notable lid edema. reduced due to secretory hypotony of the molecular weight proteins may cloud Clinical inspection of patients with inflamed ciliary body. However, as the the ocular media, but have little impact uveitis typically reveals a deep perilimbal reaction persists, inflammatory by-prod- otherwise; however, as larger molecu- injection of the conjunctiva and epi- ucts may accumulate in the trabeculum, lar weight proteins like fibrinogen accu- sclera, although the palpebral conjunctiva which can cause first, normalization, and mulate in the aqueous and/or vitreous, remains unaffected. The cornea displays later elevation of intraocular pressure. pathological sequelae follow. Fibrinogen mild stomal edema upon biomicroscopy, In severe cases, sustained IOP elevation is ultimately converted into fibrin, an and in more severe or protracted reac- signals the presence of uveitic glaucoma insoluble protein involved in the blood tions keratic precipitates may be noted on with increased potential for PAS. clotting process. In the anterior chamber, the endothelium. In non-granulomatous fibrin acts as a glue, binding with cellular cases, these small, irregular gray to brown Pathophysiology debris to form keratic precipitates; more deposits with a predilection for the cen- Uveitis should be thought of not as importantly, fibrin facilitates the adhe- tral or inferior cornea can be observed a singular ocular disorder, but rather sion of adjacent ocular structures, forming without large depositions (“mutton fat” as a diverse collection of pathological synechiae. With synechiae come the risk keratic precipitate). The hallmark signs conditions with similar, clinically observ- of secondary , particular angle of non-granulomatous anterior uveitis able signs. A vast multitude of etiologies closure with or without pupillary block. are “cells and flare.” Cells represent leu- may induce uveitis, ranging from blunt Additionally, chronic uveal inflamma-

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001_ro0410_hndbkv7.indd 28 4/5/10 8:47 AM tion results in an increased concentration medical workup is particularly relevant UVEA AND GLAUCOMA of vasoproliferative mediators, promot- when the history or associated symptoms ing angiogenesis or neovascularization.8,9 are suggestive of a particular etiology. Neovascular changes in the iris and angle Laboratory testing is not always produc- can further predispose an individual to tive, though the results may be helpful secondary glaucoma. when considered in terms of the com- plete clinical picture. Some of the more Management common and important tests to consider The primary goals in managing ante- include: complete blood count (CBC) rior uveitis are threefold: first, immobilize with differential and platelets; erythrocyte the iris and ciliary body to decrease the Posterior synechiae in acute anterior uveitis. sedimentation rate (ESR); antinuclear pain and prevent exacerbation of the antibody (ANA); human leukocyte test- condition; second, quell the inflammatory barrier. Likewise, most physicians tend to ing (HLA-B27); rheumatoid factor (RF); response to avert detrimental sequelae; avoid topical prostaglandin analogs, after angiotensin-converting enzyme (ACE); and third, identify the underlying cause. early reports that these IOP-lowering purified protein derivative (PPD) with Cycloplegia is a crucial step in achieving agents showed limited efficacy in the anergy panel; fluorescent treponemal the first goal. This may be accomplished face of inflammation, and perhaps even antibody absorption (FTA-ABS) and using a variety of topical medications. exacerbated the uveitic response.13 More rapid plasma reagin (RPR); and Lyme Depending upon the severity of the reac- recent studies suggest, however, that immunoassay (ELISA).19 Imaging stud- tion, physicians may employ 5% homat- prostaglandin analogs are indeed both ies are also part of the medical workup, ropine t.i.d. to q.i.d., 0.25% scopolamine safe and effective in cases of uveitic glau- particularly when the clinical picture b.i.d. to q.i.d, or 1% atropine q.d. to t.i.d. coma, with their principle disadvantage is suggestive of ankylosing spondylitis, Cyclopentolate is typically not potent being length of time to adequate pharma- tuberculosis or sarcoidosis. X-rays of the enough to achieve adequate cycloplegia cologic effect.14,15 sacroiliac joint are useful in the diagnosis in the inflamed eye. Topical cortico- After treatment is initiated, patients of ankylosing spondylitis, while a chest steroids are used to address the inflam- should be reevaluated every one to seven radiograph helps to identify tuberculosis matory response. The “gold standard” days, depending on the severity of the and/or sarcoidosis infiltration into the for uveitis management has historically reaction. As resolution becomes evident, pulmonary system.19 been 1% prednisolone acetate, though cycloplegics may be discontinued and newer options such as 0.5% loteprednol topical steroids may be tapered to q.i.d. Clinical Pearls etabonate (Lotemax, Bausch + Lomb) or t.i.d.. Generally, it is better to taper • Most cases of acute anterior uveitis and difluprednate 0.05% (Durezol, slowly rather than abruptly, and patients in the optometric setting are the result of Sirion) have shown equivalent utility.10-12 may need to remain on steroid drops blunt ocular trauma. These cases gener- Steroids should be administered in a daily or every other day for several weeks ally resolve without incident and do not commensurate fashion with the severity to ensure treatment success. Recalcitrant recur when properly managed. of the inflammatory response. In pro- cases of anterior uveitis that are unre- • A comprehensive, dilated fundus nounced cases, dosing every 15 minutes sponsive to conventional therapy may evaluation is mandatory in all cases of may be appropriate; at minimum how- necessitate the use of injectible periocular uveitis, and is particularly important ever, steroids should be instilled every or intraocular depot steroids, oral cortico- when visual acuity is markedly dimin- three to four hours initially. When in steroids (e.g., prednisone 0.5 to 1.0 mg/ ished. Many cases of suspected anterior doubt, it is usually better to overtreat kg), oral nonsteroidal anti-inflammatory uveitis actually constitute collateral dam- than to undertreat. If posterior synechia preparations or systemic immunosup- age from intermediate or posterior uve- is present, attempts should be made to pressants, such as cyclophosphamide, itis. Such is the case with toxoplasmosis, break the adhesions using 1% atropine in methotrexate, azathioprine, cyclosporine, for example, where the cells observed conjunction with 10% phenylephrine, in tacrolimus, interferon or infliximab.16-18 in the anterior chamber actually repre- office. Secondary elevations in IOP that These systemic drugs should only be pre- sent “spillover” from posterior segment are significant (i.e., >26mm Hg) may be scribed when the etiology is recognized inflammation. addressed by using standard anti-glau- by clinicians who are well-trained in their • In cases of endogenous uveitis (i.e., coma agents, such as 0.5% timolol b.i.d. use and able to manage their side effects. those cases secondary to infectious or or 0.1% brimonidine t.i.d. Pilocarpine Medical testing is indicated in cases ), management may should be avoided in uveitic glaucoma, of bilateral uveitis (unrelated to trauma), be difficult and lengthy. Indeed, patients as it will only serve to worsen the inflam- granulomatous uveitis, or recurrent uni- with endogenous uveitis often require matory response by mobilizing the uveal lateral or bilateral uveitis—defined as months of therapy, and some individuals tissues and disrupting the blood-aqueous three or more unexplained incidents. A may need to use topical corticosteroids

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001_ro0410_hndbkv7.indd 29 4/5/10 8:47 AM indefinitely to control the inflammation. IRIDOCORNEAL ENDOTHELIAL Recent reports have additionally noted Physicians who are uncomfortable with SYNDROMES (ICE) striking similarities between the ICE such long-term management are advised syndromes and posterior polymorphous to refer patients to a specialist with expe- Signs and Symptoms dystrophy, suggesting that the conditions rience in treating uveitis. The patient with ICE syndrome is may be variants of the same disease pro- • While most eye care practitioners typically a younger female. It is most cess.7,8 The corneal endothelium has a are capable of ordering laboratory tests for common in whites, with typically no fine beaten-silver appearance. This, along uveitis directly, it is often more productive family history of the disease. It is most with ensuing corneal edema, is a cause of to communicate with the patient’s prima- commonly a unilateral phenomenon, but vision reduction in these patients. The ry care physician before proceeding, such bilateral cases have been documented.1,2 It endothelium is most affected in essential that all aspects of the systemic history tends to manifest in early to middle adult- iris atrophy. Some endothelial changes may be taken into account. Should the hood.3 However, it has also been reported such as migration and reparative processes patient be diagnosed with a contributory to develop in children.4 Common find- are identifiable, as is the presence of cell systemic disease, comanagement with the ings include a beaten bronze appearance necrosis and chronic inflammation.9 It primary care physician becomes para- to the corneal endothelium with concur- appears that the endothelial cells undergo mount. rent corneal edema, iris atrophy and iris a metaplastic transformation into “epithe- hole formation, corectopia, prominent lial-like” cells that migrate as a membrane 1. Wakefield D, Chang JH. Epidemiology of uveitis. Int Ophthalmol Clin. 2005;45(2):1-13. iris nevus, peripheral anterior synechia over the anterior chamber angle to the 2. Myers TD, Smith JR, Lauer AK, et al. Iris nod- with progressive angle closure and sec- iris.9,10 Confocal biomicroscopy indicates ules associated with infectious uveitis. Br J Ophthalmol. 2002;86(9):969-74. ondary closed angle glaucoma. Vision that ICE syndromes are characterized by 3. Moschos MM, Guex-Crosier Y. Anterior segment granu- may be unaffected or may be reduced pleomorphic epithelioid-like endothelial loma and involvement as the presenting signs 11 of systemic sarcoidosis. Clin Ophthalmol. 2008;2(4):951-3. due to endotheliopathy with or without cells with hyper-reflective nuclei. 4. Zeboulon N, Dougados M, Gossec L. Prevalence resultant corneal edema or glaucoma. The migration of the abnormal cor- and characteristics of uveitis in the spondyloarthropa- thies: a systematic literature review. Ann Rheum Dis. The patient may occasionally complain neal endothelial cell membrane across 2008;67(7):955-9. of monocular secondary to an the anterior chamber angle and on to the 5. Hooper C, McCluskey P. Intraocular inflammation: its causes and investigations. Curr Allergy Asthma Rep. exposed area of full thickness iris atrophy anterior surface of the iris is responsible 2008;8(4):331-8. creating another entrance for light to for corneal edema (due to subsequent 6. Smith JR. HLA-B27-associated uveitis. Ophthalmol Clin North Am. 2002;15(3):297-307. enter the eye (polycoria). dysfunction of the endothelial sodium- 7. Freddo TF. Shifting the paradigm of the blood-aqueous potassium pump responsible for corneal barrier. Exp Eye Res. 2001;73(5):581-92. 8. Casey R, Li WW. Factors controlling ocular angiogen- Pathophysiology dehydration), secondary glaucoma, nevi, esis. Am J Ophthalmol. 1997;124(4):521-9. The ICE syndromes represent a con- atrophy of the iris, and pupillary distor- 9. Kuo IC, Cunningham ET Jr. Ocular neovascularization in patients with uveitis. Int Ophthalmol Clin. 2000;40(2):111- tinuum of disease involving three distinct tion. The contraction of the migrated 26. entities: essential iris atrophy, Chandler membrane-like ICE tissue produces 10. Loteprednol Etabonate US Uveitis Study Group. Controlled evaluation of loteprednol etabonate and pred- syndrome, and Cogan-Reese (iris nevus) holes in the iris. Subsequent contraction nisolone acetate in the treatment of acute anterior uveitis. syndrome. Essential iris atrophy is charac- of the membrane pulls the iris toward Am J Ophthalmol. 1999;127(5):537-44. 11. Jamal KN, Callanan DG. The role of difluprednate terized by progressive iris atrophy and iris the cornea inducing a chronic progres- ophthalmic emulsion in clinical practice. Clin Ophthalmol. hole formation, corectopia, and marked sive synechial closure of the angle. This 2009;3:381-90. 12. Mochizuki M, Ohno S, Usui M, et al. A phase III open- peripheral anterior synechia. The iris and results in secondary angle closure without label clinical study of difluprednate ophthalmic emulsion pupil are pulled in the direction of the pupil block. The cellular membrane may 0.05% in the treatment of severe refractory anterior uveitis. Invest Ophthalmol Vis Sci. 2007 48: E-Abstract 3905. peripheral anterior synechia. Chandler also cause aqueous outflow blockage in 13. Saccà S, Pascotto A, Siniscalchi C, et al. Ocular syndrome, the most common of the the absence of peripheral anterior syn- complications of latanoprost in uveitic glaucoma: three 12,13 case reports. J Ocul Pharmacol Ther. 2001;17(2):107-13. three, manifests greater corneal changes echia. 14. Markomichelakis NN, Kostakou A, Halkiadakis I, and edema, but fewer iris abnormalities. et al. Efficacy and safety of latanoprost in eyes with uveitic glaucoma. Graefes Arch Clin Exp Ophthalmol. Cogan-Reese syndrome presents with iris Management 2009;247(6):775-80. atrophy, corneal endotheliopathy, corneal Management of ICE syndromes is 15. Fortuna E, Cervantes-Castañeda RA, Bhat P, et al. Flare-up rates with bimatoprost therapy in uveitic glau- edema and prominent iris nevi. Patients case specific and should be dictated by coma. Am J Ophthalmol. 2008;146(6):876-82. with Chandler’s syndrome typically have the degree of corneal edema and severity 16. Smith JR. Management of uveitis. Clin Exp Med. 2004;4(1):21-9. worse corneal edema than the other two of the secondary glaucoma. Topical aque- 17. Lustig MJ, Cunningham ET. Use of immunosup- entities, while its secondary glaucoma is ous suppressants are the medical mainstay pressive agents in uveitis. Curr Opin Ophthalmol. 5 2003;14(6):399-412. more severe. for management of glaucoma secondary 18. Murphy CC, Ayliffe WH, Booth A, et al. Tumor necrosis All of the ICE syndromes share a to ICE syndromes. Medications that factor alpha blockade with infliximab for refractory uveitis and scleritis. Ophthalmology. 2004;111(2):352-6. common underlying pathophysiology increase aqueous outflow are typically less 19. Kabat AG. Uveitis. In: Bartlett JD, Jaanus SD, and can all be considered to be primary effective and are not the drugs of choice. eds. Clinical Ocular Pharmacology, 5th Ed. Boston: 6 Butterworth-Heinemann, 2007: 587-600. proliferative endothelial degenerations. Also, laser trabeculoplasty is not seen as

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001_ro0410_hndbkv7.indd 30 4/5/10 8:47 AM 18. Alvim PT, Cohen EJ, Rapuano CJ, et al. Penetrating

effective. In severe cases, trabeculectomy UVEA AND GLAUCOMA keratoplasty in iridocorneal endothelial syndrome. Cornea. may be necessary, though there is a risk 2001;20(2):134-40. of closure of the sclerotomy site by the 19. Huang T, Wang Y, Ji J, et al. Deep lamellar endothelial keratoplasty for iridocorneal endothelial syndrome in pha- abnormal membranes with subsequent kic eyes. Arch Ophthalmol. 2009;127(1):33-6. surgeries required.14,15 Trabeculectomy 20. Price MO, Price FW Jr. Descemet stripping with endo- thelial keratoplasty for treatment of iridocorneal endothelial with adjunctive antimetabolite or glau- syndrome. Cornea. 2007;26(4):493-7. coma surgical implant devices may be 21. Bahar I, Kaiserman I, Buys Y, et al. Descemet’s 16 stripping with endothelial keratoplasty in iridocorneal necessary for this reason. Despite ade- endothelial syndrome. Ophthalmic Surg Lasers Imaging. quate IOP control, corneal edema may 2008;39(1):54-6. persist due to the endotheliopathy. In Correctopia and iris atrophy in essential iris these cases, penetrating keratoplasty may atrophy. PHACOLYTIC GLAUCOMA be necessary to restore vision, though this procedure will not affect abnor- totally visually handicapped. Signs and Symptoms malities in the iris or anterior chamber • The iris is dragged in the direction The patient with phacolytic glaucoma angle.17 Favorable visual outcomes can of the prominent peripheral anterior syn- is typically elderly with a history of pro- be achieved through keratoplasty proce- echiae. gressively worsening vision from pre- dures for patients with ICE syndrome; existing . There appears to be no 1. Huna R, Barak A, Melamed S. Bilateral iridocorneal however, multiple corneal and glaucoma endothelial syndrome presented as Cogan-Reese and gender predilection with varying reports procedures may be necessary.18 Chandler’s syndrome. J Glaucoma. 1996;5(1):60-2. supporting contradictory findings in this 2. Gupta V, Kumar R, Gupta R, et al. Bilateral iridocorneal 1,2 More recently, the trend has moved endothelial syndrome in a young girl with Down’s syn- regard. Vision typically is reduced to away from full thickness procedures, drome. Indian J Ophthalmol. 2009;57(1):61-3. light perception, but the patient may 3. Shields MB. Progressive essential iris atrophy, such as penetrating keratoplasty, toward Chandler’s syndrome, and the iris nevus (Cogan-Reese) have no light perception either due to the selective removal and replacement only syndrome: a spectrum of disease. Surv Ophthalmol. presence of a hypermature cataract or an 1979;24(1):3-20. 1 of the defective layers of the cornea. 4. Salim S, Shields MB, Walton D. Iridocorneal endothelial advanced, related glaucomatous process. Deep lamellar endothelial keratoplasty syndrome in a child. J Pediatr Ophthalmol . The patient will often be experiencing 2006;43(5):308-10. (DLEK) has been seen as an effica- 5. Wilson MC, Shields MB. A comparison of the clinical ocular pain. During the acute process, cious surgical procedure in phakic eyes variations of the iridocorneal endothelial syndrome. Arch there will be anterior segment inflamma- 19 Ophthalmol. 1989;107(10):1465-8. with ICE syndromes. More common- 6. Langova A, Praznovska Z, Farkasova B. Progressive tion with an anterior chamber reaction. ly, Descemet’s stripping with endothe- essential atrophy of the iris as a form of the iridocor- A hypermature lens is invariably present. neal endothelial (ICE) syndrome. Cesk Slov Oftalmol. lial keratoplasty (DSEK) is being used to 1997;53(6):371-80. The intumescence of the lens prevents treat corneal edema associated with ICE 7. Anderson NJ, Badawi DY, Grossniklaus HE, et al. observation of the fundus ophthalmo- 20,21 Posterior polymorphous membranous dystrophy with syndrome. Selective replacement of overlapping features of iridocorneal endothelial syndrome. scopically. Intraocular pressure (IOP) dysfunctional endothelium with DSEK Arch Ophthalmol. 2001;119(4):624-5. may be quite elevated, often exceeding 8. Lefebvre V, Sowka JW, Frauens BJ. The clinical 1,2 has been seen to successfully treat corneal spectrum between posterior polymorphous dystrophy 50mm Hg to 70mm Hg. The resultant edema and associated visual loss caused and iridocorneal endothelial syndromes. Optometry. glaucoma is typically unilateral or asym- 2009;80(8):431-6. by ICE syndrome. Visual recovery is 9. Alvarado JA, Murphy CG, Maglio M, et al. Pathogenesis metric, depending upon the degree of much more rapid and rejection rates of Chandler’s syndrome, essential iris atrophy and the cataractogenesis. Synechiae, either ante- Cogan-Reese syndrome. I. Alterations of the corneal endo- minimized compared with replacement thelium. Invest Ophthalmol Vis Sci. 1986;27(6):853-72. rior or posterior, is uncommon. of the full corneal thickness with tradi- 10. Howell DN, Damms T, Burchette JL Jr, et al. Endothelial metaplasia in the iridocorneal endothelial syndrome. Invest tional penetrating keratoplasty. However, Ophthalmol Vis Sci. 1997;38(9):1896-901. Pathophysiology separate procedures or medical therapy 11. Le QH, Sun XH, Xu JJ. In-vivo confocal micros- Upon cataract hypermaturation, the copy of iridocorneal endothelial syndrome. Int Ophthalmol. may still be required if patients suffer 2009;29(1):11-8. lens cortex undergoes spontaneous lysis from glaucoma because these procedures 12. Herde J. Iridocorneal endothelial syndrome (ICE-S): and absorption with secondary lens classification, clinical picture, diagnosis. Klin Monatsbl do not address peripheral anterior syn- Augenheilkd. 2005;222(10):797-801. nucleus shrinkage and capsule wrin- echiae formation and angle closure. 13. Denis P. Iridocorneal endothelial syndrome and glau- kling.3,4 This allows internal lens proteins coma. J Fr Ophtalmol. 2007;30(2):189-95. 14. Halhal M, D’hermies F, Morel X, et al. Iridocorneal to leak out through an intact though Clinical Pearls endothelial syndrome. Series of 7 cases. J Fr Ophtalmol. permeable lens capsule.1 While the inter- 2001;24(6):628-34. • Essential iris atrophy, Chandler’s 15. Kidd M, Hetherington J, Magee S. Surgical results nal lens proteins are the host’s own body syndrome and Cogan-Reese syndrome in iridocorneal endothelial syndrome. Arch Ophthalmol. tissue, they have never been exposed 1988;106(2):199-201. are all within the same clinical disease 16. Doe EA, Budenz DL, Gedde SJ, et al. Long-term to the anterior chamber due to their spectrum termed the ICE syndromes. surgical outcomes of patients with glaucoma secondary envelopment by the lens capsule. Thus, to the iridocorneal endothelial syndrome. Ophthalmology. • Progression is unpredictable and 2001;108(10):1789-95. when the body detects these internal lens many patients have a good outcome. 17. Buxton JN, Lash RS. Results of penetrating kera- proteins, it interprets them as foreign and toplasty in the iridocorneal endothelial syndrome. Am J Due to unilaterality, few patients become Ophthalmol. 1984;98(3):297-301. antigenic. Subsequently, a lens-induced

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001_ro0410_hndbkv7.indd 31 4/5/10 8:47 AM inflammatory reaction ensues.3 The che- degree of discomfort. Typically, hom- The addition of trabeculectomy to cata- motactic activity produced by the internal atropine and scopolamine are adequate ract extraction is typically unnecessary lens proteins contributes to the invasion choices.11,12 In many cases of phacolytic in the control of IOP in patients with of the anterior chamber by inflamma- glaucoma, there may be loss of zonular phacolytic glaucoma who are operated on tory cells in an antigen-antibody immune support to the lens, often manifesting within two to three weeks of the onset response.4 There is a pronounced macro- as phacodonesis. In cases where there is of symptoms. Light perception without phage response occurring in the anterior poor zonular support, cycloplegia with projection is not a contraindication for chamber.5 Numerous macrophages con- attendant pupil dilation may result in cataract surgery in phacolytic glaucoma taining phagocytized degenerated lens anterior dislocation of the lens, possibly as postoperative visual recovery to some material (phacolytic cells) can be found in into the anterior chamber. If poor zonular degree is possible.17 the anterior chamber. support to the lens is suspected, cyclople- Phacolysis can be considered an innate White patches consisting of aggre- gia should be avoided. evolutionary response to cataractogenesis. gated macrophages may be seen on the The secondary glaucoma accompany- Prior to the advent of surgical lens remov- lens surface and often indicate the site ing phacolysis is often improved by the al, many individuals would become blind of lens protein leakage.6,7 Other con- reduction in inflammation with topical from cataract formation. The subsequent stituents of the anterior chamber in pha- steroid therapy. However, if additional lytic process and inflammatory degrada- colysis have been demonstrated to include pressure reduction is necessary, aque- tion would effectively remove the visual free floating degenerated lens material, obstruction. Unfortunately, the eye would erythrocytes, and ghost erythrocytes.6 be left aphakic and often irreparably Lipofuscin granules and phagocytic vacu- damaged from glaucoma. Spontaneous oles containing lens proteins have also absorption of cataracts through the pha- been found.5 colytic process have been reported, which Additionally, extremely high levels of supports this evolutionary role of pha- high molecular weight (HMW) soluble colysis.18,19 It should be emphasized that proteins of sufficient size to block trabec- while the cataract maturation process ular aqueous outflow have been found in is typically quite slow, once a lens has patients with phacolytic glaucoma. It has become hypermature, the phacolytic pro- been demonstrated that HMW soluble Phacolytic lens. cess can develop quite rapidly.7 proteins can directly obstruct aqueous outflow.8,9 It may be that macrophages ous suppressants are advocated, pending Clinical Pearls are scavenger cells that attempt to remove no systemic contraindications. Miotics • Phacolytic glaucoma develops only lens material and re-establish normal should be avoided due to their propensity in eyes with hypermature cataracts. aqueous outflow.8 Further, during the to aggravate the disease.11,12 Vision typically ranges from counting uveitic process, breakdown of the blood- In most cases, it is necessary to remove fingers to light perception. If vision is bet- ocular barrier occurs with subsequent the antigenic lens in order to fully manage ter than 20/400, consider another cause influx of proteins as well as inflammatory phacolytic glaucoma. Commonly, extra- for the glaucoma. cells. These constituents are considered to capsular and even intracapsular cataract • Be careful to assess lens zonular have a major impact on IOP elevation as extraction is used to remove the antigenic integrity before employing a cycloplegic well. Obstruction of the trabecular mesh- lens. Either anterior or posterior chamber in the management of phacolytic glau- work by inflammatory cells and proteins, intraocular lens implantation can be an coma. as well as trabeculitis (inflammation of option.13 Manual small incision cataract • The benefits of inflammation the trabecular meshwork), likely contrib- surgery with trypan blue staining of the control in phacolytic glaucoma greatly ute to the secondary glaucoma.10 anterior capsule is a safe and effective outweigh the potential risks of steroid- method of cataract extraction for patients induced pressure complications. Management with phacolytic glaucoma.14 In cases of • Ultimately, phacolytic glaucoma is The first step in the management long duration prior to surgery, trabeculec- a surgically managed condition, though of phacolytic glaucoma involves qui- tomy may additionally be needed in order medical therapy may be initially employed eting the acute inflammatory reaction to control IOP.15 Removal of the anti- to reduce inflammation and IOP. and ameliorating the elevated IOP.11,12 genic lens and control of the glaucoma • In eyes with phacolytic glaucoma Topical corticosteroids are indicated just should be done quickly. One study found that have no visual recovery potential, as they would be for any anterior uve- that patients over 60 years and in whom and pain and inflammation can be man- itis. Cycloplegics are also indicated. The the glaucoma was present for more than aged with topical corticosteroids, aque- choice should be dictated by the severity five days had a significantly higher risk ous suppressants and cycloplegics, then of the uveitic response and the patient’s of poor visual outcome postoperatively.16 lensectomy can potentially be deferred.

32A REVIEW OF OPTOMETRY APRIL 15, 2010

001_ro0410_hndbkv7.indd 32 4/5/10 8:47 AM 1. Podhorecki J, Munir A. Result of operations for hyper-

this condition. White patients are affected angle becomes compromised. Peripheral UVEA AND GLAUCOMA mature cataract complicated with phacolytic glaucoma. Klin Oczna. 2002;104(5-6):350-3. to a lesser extent, and patients of African anterior synechia may occur after acute or 2. Rijal AP, Karki DB. Visual outcome and IOP control after descent are affected even less. subacute attacks of angle closure. cataract surgery in lens induced glaucomas. Kathmandu Univ Med J (KUMJ). 2006;4(1):30-3. Biomicroscopically, there will be a While in most cases, there is asym- 3. Oprescu M. The etiopathology of phacoantigenic uveitis shallow anterior chamber and narrow metric closure involving, first, the superior and phacolytic glaucoma. Oftalmologia 1992; 36(3):207-13. 4. Rosenbaum JT, Samples JR, Seymour B, et al. angles by Van Herick estimation method. angle, there can also be an even circum- Chemotactic activity of lens proteins and the patho- However, the chamber depth is typically ferential process that slowly progresses genesis of phacolytic glaucoma. Arch Ophthalmol 1987;105(11):1582-4. deeper in PCACG than primary acute to symmetrical closure. This has been 5. Filipe JC, Palmares J, Delgado L, et al. Phacolytic angle closure glaucoma. There will be termed creeping angle closure and appears glaucoma and lens-induced uveitis. Int Ophthalmol. 1993;17(5):289-93. characteristic glaucomatous damage to as an angle that becomes progressively 6. Ueno H, Tamai A, Iyota K, et al. Electron microscopic the optic disc and . The distin- more shallow over time.5 observation of the cells floating in the anterior chamber in a case of phacolytic glaucoma. Jpn J Ophthalmol. guishing characteristic is the absence of 1989;33(1):103-13. visible anterior chamber angle structures Management 7. Sowka J, Vollmer L, Falco L. Rapid onset phacolysis. Optometry. 2004;75(9):571-6. upon the performance of . All cases of primary angle closure 8. Epstein DL, Jedziniak JA, Grant WM. Identification of The angle may be appositionally closed resulting from pupil block need to under- heavy molecular weight soluble protein in aqueous humor in human phacolytic glaucoma. Invest Ophthalmol Vis Sci and opened upon manual pressure on the go laser peripheral iridotomy (LPI) as 1978; 17(5):398-402. four-miror goniolens or the angle may soon as possible after diagnosis. This 9. Epstein DL, Jedziniak JA, Grant WM. Obstruction of aqueous outflow by lens particles and by heavy molecular be synechially closed with broad areas of allows a communication for aqueous to weight soluble lens proteins. Invest Ophthalmol Vis Sci peripheral anterior synechia (PAS). The flow from the posterior chamber to the 1978; 17(3):272-7. 10. Pleyer U, Ruokonen P, Heinz C, et al. Intraocular pres- superior and temporal quadrants of the anterior chamber bypassing any pupil sure related to uveitis. Ophthalmologe. 2008;105(5):431-7. anterior angle may be the earliest sites of block that may be present. This can allow 11. Sung VC, Barton K. Management of inflammatory glau- comas. Curr Opin Ophthalmol. 2004;15(2):136-40. the synechial angle closure, gradual exten- for the backward relaxation of the iris and 12. Epstein DL, Jedziniak JA, Grant WM. Obstruction of sion on the nasal quadrant, until the angle a deepening of the chamber and opening aqueous outflow by lens particles and by heavy molecular 2 weight soluble lens proteins. Invest Ophthalmol Vis Sci may close at the inferior quadrant. Other of the angle. This is a safe method to 1978; 17(3):272-7. features of PCACG include a smaller open the angle following chronic clo- 13. Singh G, Kaur J, Mall S. Phacolytic glaucoma--its treat- 6,7 ment by planned extracapsular cataract extraction with corneal diameter, shorter axial length, sure. However, while LPI can alter the posterior chamber intraocular lens implantation. Indian J shallower anterior chamber, thicker lens, anatomic status of the angle, a significant Ophthalmol. 1994;42(3):145-7. 14. Venkatesh R, Tan CS, Kumar TT, et al. Safety and effi- more relative anterior location of lens, number of these patients manifest residual cacy of manual small incision cataract surgery for phacolytic swelling of ciliary process and anterior angle closure after LPI.6 Additionally, glaucoma. Br J Ophthalmol. 2007;91(3):279-81. 3 15. Braganza A, Thomas R, George T, et al. Management rotation of ciliary body. there often will be elevated IOP despite of phacolytic glaucoma: experience of 135 cases. Indian J a laser-induced open anterior chamber Ophthalmol. 1998;46(3):139-43. 8 16. Prajna NV, Ramakrishnan R, Krishnadas R, et al. Lens Pathophysiology angle. This is most likely due to damage induced glaucomas--visual results and risk factors for final Anatomical features act in concert to to the trabecular meshwork from apposi- visual acuity. Indian J Ophthalmol. 1996;44(3):149-55. 17. Mandal AK, Gothwal VK. Intraocular pressure control cause shallowing of the anterior chamber. tional and synechial closure. In PCACG and visual outcome in patients with phacolytic glau- As a patient ages, thickening of the crystal- eyes, the trabecular architecture has lost coma managed by extracapsular cataract extraction with or without posterior chamber intraocular lens implantation. line lens leads to a relative pupil block that its regular arrangement, with fewer and Ophthalmic Surg Lasers. 1998;29(11):880-9. exacerbates the condition. This acts to put narrower trabecular spaces and fusion of 18. Blaise P, Duchesne B, Guillaume S, et al. Spontaneous recovery in phacolytic glaucoma. J Cataract Refract Surg. the iris into apposition with the trabecular the trabecular beams in areas. In addition, 2005;31(9):1829-30. meshwork or cornea. In the absence of there is evidence of loss of endothelial cells 19. Mohan M, Bartholomew RS. Spontaneous absorp- 9 tion of a cataractous lens. Acta Ophthalmol Scand. secondary causes, this is considered to be and reactive repair processes. Despite 1999;77(4):476-7. a primary angle closure. Due to the fact the presence of a patent LPI, most eyes that the closure is slow, there is an absence with PCACG present with elevated IOP, PRIMARY CHRONIC ANGLE of symptoms that would typify an acute optic disc and visual field damage, indi- CLOSURE GLAUCOMA angle closure. Thus, patients are unaware cating they require further treatment to of the process.4 Chronic angle closure control IOP, including trabeculectomy Signs and Symptomst denotes an angle with areas that are closed and medical therapy.10 The patient with primary chronic permanently with PAS. In angles that Medical therapy that has been seen to angle closure glaucoma (PCACG) typi- have closure without the formation of be successful in ameliorating the IOP in cally is older and asymptomatic.1 Women PAS, the term chronic appositional clo- eyes with PCACG include beta blockers, are more commonly affected than men. sure is often used. However, appositional miotics, alpha-2 adrenergic agonists, and Hyperopia is commonly encountered. closure often will lead to PAS if untreated. prostaglandins.11,12 However, in recent Patients of Asian descent are the most In chronic angle closure, the intraocular years, it has come to light that prosta- predisposed to PCACG, with Eskimos pressure (IOP) may be initially low and glandin analogs seem to work especially being the most represented group with elevates asymptomatically as more of the well in eyes with PCACG that need IOP

APRIL 15, 2010 REVIEW OF OPTOMETRY 33A

001_ro0410_hndbkv7.indd 33 4/5/10 8:47 AM 13-16 of Nd:YAG laser iridotomy in Asian eyes. Ophthalmic Surg reduction both before and after LPI. extraction alone can significantly reduce Lasers Imaging. 2003;34(4):291-8. These medications are thought to lower both IOP and the requirement for topical 8. Chen MJ, Cheng CY, Chou CK, et al. The long-term 23,24 effect of Nd:YAG laser iridotomy on intraocular pressure IOP by increasing matrix metalloprotein- therapy. It has been suggested that in Taiwanese eyes with primary angle-closure glaucoma. J ase activity, which subsequently reduces phacoemulsification may be a primary Chin Med Assoc. 2008;71(6):300-4. 9. Sihota R, Lakshmaiah NC, Walia KB, et al. The tra- the amount of extracellular matrix mate- treatment for eyes with PCACG. In becular meshwork in acute and chronic angle closure rial surrounding the ciliary muscle fiber PCACG medically controlled with co- glaucoma. Indian J Ophthalmol. 2001;49(4):255-9. 17 10. Rosman M, Aung T, Ang LP, et al. Chronic angle-clo- bundles. Once-daily dosing of any of existent cataract, there appears to be no sure with glaucomatous damage: long-term clinical course the commercially available prostaglandin difference in IOP control with cataract in a North American population and comparison with an Asian population. Ophthalmology. 2002;109(12):2227-31. analogs (, bimatoprost, latano- extraction by phacoemulsification alone 11. Ruangvaravate N, Kitnarong N, Metheetrairut A, et prost) reduces IOP in eyes with PCACG versus the combined procedure phacotra- al. Efficacy of brimonidine 0.2 per cent as adjunctive 25 therapy to beta-blockers: a comparative study between that have residually elevated IOP follow- beculectomy. However, in eyes where POAG and CACG in Asian eyes. J Med Assoc Thai. ing LPI. The degree of pressure lowering preoperative IOP control with medica- 2002;85(8):894-900. 12. Aung T, Wong HT, Yip CC, et al. Comparison of the seems to be similar to that seen in primary tions is not acceptable, then a combined intraocular pressure-lowering effect of latanoprost and open angle glaucoma. procedure with phacotrabeculectomy is timolol in patients with chronic angle closure glaucoma: a preliminary study. Ophthalmology. 2000;107(6):1178-83. While the method of IOP reduction superior in restoring vision and postoper- 13. How AC, Kumar RS, Chen YM, et al. A randomised from prostaglandin analogs is enhanced atively controlling IOP than phacoemul- crossover study comparing bimatoprost and latanoprost 26 in subjects with primary angle closure glaucoma. Br J uveoscleral outflow, it seems contradic- sification alone. In another study, it was Ophthalmol. 2009;93(6):782-6. tory that these medications would have recommended that for an angle closed 14. Chen MJ, Chen YC, Chou CK, et al. Comparison of the effects of latanoprost and bimatoprost on intraocular pres- an effect in eyes where the uveoscleral 180 degrees continually or more, that sure in chronic angle-closure glaucoma. J Ocul Pharmacol meshwork is physically blocked by the phacotrabeculectomy be employed while Ther. 2007;23(6):559-66. 15. Chen MJ, Chen YC, Chou CK, et al. Comparison of the iris. However, Aung and associates noted phacoemulsification alone was sufficient effects of latanoprost and travoprost on intraocular pres- that the IOP-reducing efficacy of latano- for angles closed less than 180 degrees.27 sure in chronic angle-closure glaucoma. J Ocul Pharmacol Ther. 2006;22(6):449-54. prost was not affected by the degree of 16. Gupta V, Srinivasan G, Sharma A, et al. Comparative angle narrowing or extent of synechial Clinical Pearls evaluation of bimatoprost monotherapy in primary chronic 18 angle closure and primary open angle glaucoma eyes: a angle closure. More interestingly, in a • After the anterior chamber angle three-year study. J Ocul Pharmacol Ther. 2007;23(4):351- study of 14 eyes with PCACG and ultra- has been successfully opened by LPI, 8. 17. Lindsey JD, Kashiwagi K, Kashiwagi F, et al. sound-biomicroscopically-proven-total- the IOP may still be elevated. Many will Prostaglandins alter extracellular matrix adjacent to human occlusion of the angle by 360 degrees erroneously think that the patient has now ciliary muscle cells in vitro. Invest Ophthalmol Vis Sci 1997;38:2214-23. secondary to PAS with no visible ciliary developed primary open angle glaucoma. 18. Aung T, Chan YH, Chew PT; EXACT Study Group. body face, once-daily dosing with latano- In actuality, the trabecular meshwork has Degree of angle closure and the intraocular pressure-low- ering effect of latanoprost in subjects with chronic angle- prost achieved a significant reduction in been damaged by the chronic appositional closure glaucoma. Ophthalmology. 2005;112(2):267-71. IOP.18 Clearly, the mechanism of action closure. This situation is like the trabecu- 19. Kook MS, Cho HS, Yang SJ, et al. Efficacy of latano- prost in patients with chronic angle-closure glaucoma and of prostaglandin analogs in eyes with lar dysfunction seen in angle recession no visible ciliary-body face: a preliminary study. J Ocul complete angle closure is not completely glaucoma. Pharmacol Ther. 2005;21(1):75-84. 20. Zou J, Zhang F, Zhang L, et al. A clinical study on laser understood. Possibly, uveoscleral tissues • Gonioscopy must be done on all peripheral iridoplasty for primary angle-closure glaucoma other than the ciliary muscle are tar- open angle glaucoma patients at least with positive provocative tests after iridectomy. Chung Hua Yen Ko Tsa Chih. 2002;38(12):708-11. geted or these agents reach the uveoscleral annually to ascertain that the patient is 21. Ritch R, Tham CC, Lam DS. Argon laser periph- meshwork by way of the peripheral iris.19 not developing a concurrent angle closure eral iridoplasty (ALPI): an update. Surv Ophthalmol. 2007;52(3):279-88. Argon laser iridoplasty has been seen mechanism. 22. Pachimkul P, Intajak Y. Effect of lens extraction on as another option for the management of primary angle closure in a Thai population. J Med Assoc 1. Bonomi L, Marchini G, Marraffa M, et al. Epidemiology Thai. 2008;91(3):303-8. PCACG as it can affect the shape of the of angle-closure glaucoma: prevalence, clinical types, and 23. Lai JS, Tham CC, Chan JC. The clinical outcomes peripheral iris and prevent this condition association with peripheral anterior chamber depth in of cataract extraction by phacoemulsification in eyes 20,21 the Egna-Neumarket Glaucoma Study. Ophthalmology. with primary angle-closure glaucoma (PACG) and co- from deteriorating. 2000;107(5):998-1003. existing cataract: a prospective case series. J Glaucoma. In that the crystalline lens can con- 2. Mok KH, Lee VW. Synechial angle closure pattern in 2006;15(1):47-52. Chinese chronic primary angle-closure glaucoma patients. 24. Hata H, Yamane S, Hata S, et al. Preliminary outcomes tribute to the development of PCACG, J Glaucoma. 2001;10(5):427-8. of primary phacoemulsification plus intraocular lens implan- lensectomy remains a viable option for 3. Wang T, Liu L, Li Z, et al. Studies of mechanism of tation for primary angle-closure glaucoma. J Med Invest. primary angle closure glaucoma using ultrasound biomi- 2008;55(3-4):287-91. some eyes. Phacoemulsification and croscope. Zhonghua Yan Ke Za Zhi. 1998;34(5):365-8. 25. Tham CC, Kwong YY, Leung DY, et al. intraocular lens implantation can lower 4. Tarongoy P, Ho CL, Walton DS. Angle-closure glau- Phacoemulsification versus combined phacotrabeculecto- coma: the role of the lens in the pathogenesis, prevention, my in medically controlled chronic angle closure glaucoma IOP, reduce or remove the critical ana- and treatment. Surv Ophthalmol. 2009;54(2):211-25. with cataract. Ophthalmology. 2008;115(12):2167-73. tomical characteristics that produce 5. Lowe RF. Primary creeping angle closure glaucoma. Br 26. Tham CC, Kwong YY, Leung DY, et al. J Ophthalmol 1964;48:544. Phacoemulsification versus combined phacotrabeculecto- pupillary block, and subsequently increase 6. He M, Friedman DS, Ge J, et al. Laser periph- my in medically uncontrolled chronic angle closure glauco- angle width.22 It has been demonstrated eral iridotomy in primary angle-closure suspects: biomet- ma with cataracts. Ophthalmology. 2009;116(4):725-31. ric and gonioscopic outcomes: the Liwan Eye Study. 27. Zhang X, Teng L, Li A, et al. The clinical outcomes in eyes with PCACG and co-existing Ophthalmology. 2007;114(3):494-500. of three surgical managements on primary angle-closure cataract that phacoemulsification cataract 7. Hsiao CH, Hsu CT, Shen SC, et al. Mid-term follow-up glaucoma. Yan Ke Xue Bao. 2007;23(2):65-74.

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001_ro0410_hndbkv7.indd 34 4/5/10 8:47 AM VITREOUS AND RETINA VITREOUS AND RETINA MACULAR HOLE secondary to the lifted and displaced times called cellophane , foveal retinal tissue. The increased red or vitreoretinal Signs and Symptoms coloration is derived from the unob- interface maculopathy), vitreo-papapil- Macular holes may range from the structed visualization of the rich choroi- lary adhesion is associated with intra- incipient stages where the chief pre- dal blood supply of the choriocapillaris retinal cysts that have the ability to senting sign is a macular cyst with without interference from the retinal exert vectors of force at the vitreo-retinal serous foveal detachment, resulting in structures. interface, inducing both full thickness only minor visual disturbances, to full macular holes and macular cysts.33 thickness lesions with catastrophic end- Pathophysiology In his classic publications, Gass points.1-6 While the epidemiology of Macular holes may be induced sec- devised the standard for classifying and macular holes may vary depending on ondary to idiopathic factors, partial mac- characterizing macular holes, which the diversity of the population, has essentially been proven correct as a rule, some characteristics are recently through optical coherence universally accepted: macular holes tomography.2,9,10,14,34,35 He sepa- occur more frequently in women rated the progression of macular over the age of 65, occur more holes into four stages: frequently in women than men at Stage 1 (macular cyst) is defined all ages and are typically unilateral by a serous detachment of the with an incidence of bilaterality in fovea. In early stage 1 holes (stage less than 29% of cases.1,7-17 Visual 1-A) the concavity of the fovea is symptoms vary depending upon lost and a yellow spot representing the hole’s staging and severity, increased visibility of the xantho- ranging from normal vision func- phyll pigment appears in the center tion (20/20) without symptoms of the macular area. Later (stage to mild metamorphopsia to visual 1-B), the pigment is displaced out- loss correlating to the size, location Fibrotic traction causing full thickness macular hole. ward, towards the circumference and injury to the macular tissue of the impending hole causing it (20/400).1-28 ular tissue avulsion secondary to poste- to appear ring-shaped.2,9,10,13,14 This The prevalence of macular holes is rior vitreous detachment or tractional change in pigment appearance, from 3.3 per 1,000 persons.5,12,16 Other asso- forces produced by epiretinal membrane a spot to a ring is uniquely peculiar to ciated causes of macular hole include formation.1-8 Chronic cystoid macular macular hole development. In 50% of trauma, solar , degenera- edema, choroidal vascular insufficiency cases the process spontaneously aborts.2 tive/pathologic , and intravitreal and anteroposterior vitreoretinal trac- Stage 2 (early macular hole) is defined triamcinolone used in the management tion (which is different than tangential by full-thickness retinal dehiscence. of other vitreoretinal events.10,11,29,30 traction) have all been implicated as Biomicroscopically, it appears as an oval, The majority of macular holes are idio- provoking elements in macular hole for- crescent, or horseshoe shaped retinal pathic in nature, and this is especially mation.1,2,10,13,15,31 defect on the inside edge of the xantho- true in older patients (6th-7th decade New ultrastructural evidence from phyll ring. It can emerge as a central, of life).1,9,13-18 flat-mounted, post-mortem preparations round retinal defect surrounded by a rim Macular microholes are small lamel- have revealed that some macular holes of elevated retina with or without an lar defects in the outer retina or retinal are caused, at least in part, by forces overlying pre-foveal opacity. Secondary pigment epithelium that occur through delivered through the insertion of the to centrifugal movement of retinal recep- mechanisms which include spontaneous cortical vitreous into the foveal internal tors, these macular holes may enlarge.18 vitreoretinal interface changes, trauma, limiting membrane.32 It appears that Up to 70% of stage 2 holes progress to phototoxicity as well as through mecha- vitreous collagen fibers exert traction stage 3.10 nisms that are not well defined or under- on the vitreofoveal region, resulting in Stage 3 full thickness macular stood.31 They rarely induce symptoms decompensation of the tissue leading hole (FTMH) is defined by its size and are recognized as a condition that to foveal tearing.32,33 This is the char- (400µm-600µm diameter hole), and is is non-progressive, occurring in patients acteristically reported tangential trac- usually surrounded by a rim of elevated of all ages, with a stable and good visual tion.2,9,10,11,14,32,33 Vitreo-papillary adhe- retina. The vitreous becomes separated prognosis.31 A classic, full-thickness sion increases the risk of full-thickness from the fovea and a pre-foveal opacity, macular hole appears as a symmetric, macular hole formation. When present representing this separation, may or may round, red lesion with a definable border in the form of macular pucker (some- not be visible. Posterior vitreous detach-

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001_ro0410_hndbkv7.indd 35 4/5/10 8:47 AM ment (PVD) is not present.2,9 a macular hole of any stage in one eye, toxicity and safety.39 The dyes include Stage 4 macular holes are FTMH that there is up to 29% risk of macular hole Evans blue and light green for staining demonstrate a detachment of the pos- developing in the fellow eye.5 Risk fac- the internal limiting membrane with terior vitreous.2 A pseudo-operculum, tors for developing macular hole in the options for fast green and indigo car- if present, is usually found near the fellow eye include pigment epithelial mine.39 Bromophenol blue and Brilliant temporal border of Weis’s ring (the free defects and macular retinal thinning.10 blue are newer agents with purported floating oval ring representing the previ- However, the presence of a PVD in the increased safety profiles.39 The dyes cur- ous site of attachment at the optic disc unaffected fellow eye lowers the risk to rently in use for the procedure known known as the area of Martigiani).2 almost 0%.10,22-24 as chromovitrectomy include triamcino- Patients with stage 1 and 2 mac- The current standard of treatment lone acetonide for vitreous identification, ular holes present with symptoms of for early full-thickness macular holes is indocyanine green, infracyanine green decreased visual acuity/metamorphop- early intervention rather than observa- and Brilliant blue for internal limiting sia.10-12 Stage 3 usually finds visual acuity tion.1-3,36-38 Surgical procedures have membrane identification and Trypan significantly more depressed. Acuities been shown to decrease the incidence blue for epiretinal membrane identifica- for eyes with FTMH range from 20/40 of hole enlargement and can result in tion.39 These adjuncts enhance visualiza- to 5/200 with an average of 20/200.9 improvement of visual acuity.1-3 tion of fragile microscopic structures, but Central corresponding to the Stage 1 holes should be observed they also increase the risk of toxicity.39 macular hole can be demonstrated using for progression. Stage 2 holes should As an alternative, autologous heparin- scanning laser ophthalmoscope micro- be treated promptly by a retinologist ized whole blood can be used to coat the perimetry.8,9 experienced in vitreomacular procedures. internal limiting membrane to facilitate Fluorescein angiography is usually Current modalities include pars plana visibility during peeling.40 Recent work normal with impending macular holes, vitrectomy with gas tamponade using in this area has demonstrated promise as

stage 1a. Early hyperfluorescence has SF6 (sulfahexafluoride) or C3F8 (per- a cost-effective and useful tool for assist- occasionally been reported in cases of late fluoropropane) with subsequent 80%- ing macular hole surgery with less risk of stage 1b lesions.9,15 This phenomenon 90% face-down positioning.36,37 Because toxicity.40 is thought to be secondary to absence the face-down positioning represents The most recent development in of xanthophyll pigment.9 Fluorescein the most unpalatable portion of the macular surgery is the intraoperative use angiography of stage 2-4 macular holes reparative process to a significant por- of a handheld spectral domain optical reveals an area of distinct early hyper- tion of eligible candidates, new research coherence tomographer (SD-OCT).41 fluorescence.2,9,10,15 has examined the benefits of vitrectomy Here, imaging of macular tissues pro- Macular holes may coexist with other with internal limiting membrane peeling vides an efficient method for visualizing retinal pathologies.21 The presence of a along with expansive gas tamponade the macular pathology and related sur- macular hole with any subclinical reti- using minimal-to-no face-down posi- rounding anatomy. The technology per- nal detachment increases the risk of tioning.36,37 Data have demonstrated mits surgeons to confirm the existence hypotony and choroidal detachment promise in selected cases for minimal of lesions, identify additional pathologies especially when accompanied by other face-down posturing with favorable ana- and probe the region for the boundar- ocular pathologies, such as high myopia, tomical and functional results.36,37 Some ies and limits of macular diseases all , pseudophakia or rhegmatog- researchers have experimented with while being in the setting of the action enous in the pres- optical coherence tomography (OCT) of repair.41 It is recognized that some ence of advancing age.21 In this light, as a method for visualizing postopera- macular holes hold a poor prognosis management of the macular hole may be tive macular hole closure.38 Consistent for visual recovery.42 Old macular holes required as a first step toward complete with new thinking, surgeons have been (generally of greater than 1.5 years dura- repair.21 reevaluating the necessity of extensive tion), large holes (greater than 400µm) face-down positioning, trying to estab- and holes whose genesis is secondary to Management lish guidelines for using the technol- another retinal pathology are regarded The prognosis for recent onset macu- ogy, as soon as the day after surgery, to as those which are least likely to have lar holes not complicated by additional determine when to stop this posturing repairable function.42 concurrent macular or ocular patholo- for patients.38 Classic complications following gies or caused by trauma is good.36,37 The application of vital dyes to macular hole surgery include cataract Fifty percent of stage 1 macular holes facilitate delicate removal of intraocu- formation, RPE alterations, raised intra- progress to stages 2 and 3.8-10 Seventy lar membranes during vitreoretinal ocular pressure, additional retinal breaks/ percent of holes reaching stage 2 prog- surgery is another evolving practice.39 detachment, macular hole enlargement, ress to stage 3.10 If a patient develops Controversy still remains regarding hole reopening, vascular occlusion,

36A REVIEW OF OPTOMETRY APRIL 15, 2010

001_ro0410_hndbkv7.indd 36 4/5/10 8:47 AM miology, natural history and treatment. Acta Ophthalmol papillary adhesion in macular hole and macular pucker. VITREOUS AND RETINA chronic CME, choroidal neovascular- Scand. 2002;80(6):579-87. Retina. 2009;29(5):644-50. ization, visual field loss and endophthal- 12. Gass JD. Macular dysfunction caused by vitreous 34. Ko TH, Fujimoto JG, Schuman JS, et al. Comparison and vitreoretinal interface abnormalities. In: Gass JDM. of ultrahigh- and standard-resolution optical coher- 4,27,28 mitis. Ed. Stereoscopic Atlas of Macular Diseases: Diagnosis ence tomography for imaging macular pathology. and Treatment. St. Louis, Missouri; Mosby-Year Book Ophthalmology. 2005;112(11):1922.e1-15. 1997:903-73. 35. Mirza RG, Johnson MW, Jampol LM. et al. Optical Clinical Pearls 13. Alexander LJ. Exudative and nonexudative macular coherence tomography use in evaluation of the vitreoreti- • Pars plana vitrectomy with gas disorders. In: Alexander LJ, Ed. Primary Care of the nal interface: a review. Surv Ophthalmol. 2007;52(4):397- tamponade followed by one or more Posterior Segment. East Norwalk, Connecticut; Appleton 421. & Lange 1994:277-344. 36. Carvounis PE, Kopel AC, Kuhl DP, et al. 25-gauge vit- weeks of face-down positioning almost 14. Kanski JJ. Degenerations and dystrophies of the rectomy using sulfur hexafluoride and no prone position- always achieves anatomical hole closure. fundus. In: Kanski JJ, Ed. Clinical Ophthalmology: ing for repair of macular holes. Retina. 2008;28(9):1188- a Systematic Approach, 3rd edition. Boston, 92. Functional improvement may not be Massachusetts; Butterworth-Heinemann 1994:381-425. 37. Yagi F, Sato Y, Takagi S, et al. Idiopathic macular hole complete even in the face of hole closure. 15. Margherio AR, Margherio RR. Macular holes and vitrectomy without postoperative face-down positioning. epiretinal macular membranes. In: Tasman, W., Jaeger, Jpn J Ophthalmol. 2009;53(3):215-8. • Acuity improvement of two or E.A. Eds. Duane’s Clinical Ophthalmology. Philadelphia, 38. Farah ME, Maia M, Rodrigues EB. Dyes in ocular more lines is almost always realized. Pennsylvania; Lippincott-Raven 1996:6(61):1-18. surgery: principles for use in chromovitrectomy. Am J • Pars plana vitrectomy performed 16. Benson WE. Surgery for Macular Holes. In: Laibson Ophthalmol. 2009;148(3):332-40. PR. Ed. The Year Book of Ophthalmology 1992, 39. Masuyama K, Yamakiri K, Arimura N, et al. Posturing within two months of the onset of symp- Philadelphia, Pennsylvania, Mosby-Year Book 1992:273- time after macular hole surgery modified by optical toms indicating hole formation allows 78. coherence tomography images: a pilot study. Am J 17. Gass JD. Idiopathic senile macular hole: its early Ophthalmol. 2009;147(3):481-8. for the best outcome. stages and pathogenesis. Archives of Ophthalmology 40. Lai CC, Hwang YS, Liu L, et al. Blood-assisted inter- • In general, surgical solutions are 1988;106(5):629-39. nal limiting membrane peeling for macular hole repair. optimally investigated within two years 18. McDonnell, JM. Ocular embryology and anatomy. Ophthalmology. 2009;116(8):1525-30. In: Ryan S. Ed. Retina. St. Louis, Missouri, Mosby-Year 41. Dayani PN, Maldonado R, Farsiu S, et al. of the discovery. Book 1994:5-17. Intraoperative use of handheld spectral domain optical • Larger holes and those associated 19. Aaberg TM. Macular holes: a review. Survey of coherence tomography imaging in macular surgery. Ophthalmology 1970;15(3):139-58. Retina. 2009;29(10):1457-68. with concurrent retinal pathology indi- 20. Akiba J, Ishiko S, Hikichi T, et al. Imaging of Epiretinal 42. Susini A, Gastaud P. Macular holes that should not be cate a poorer prognosis. Membranes in Macular Holes by Scanning Laser operated. J Fr Ophtalmol. 2008;31(2):214-20. • In patients with older holes that . American Journal of Ophthalmology 1996;121(2):177-80. would not be optimal for surgical revi- 21. Kang JH, Park KA, Shin WJ, et al. Macular hole BRANCH RETINAL VEIN sion, patient education and low vision as a risk factor of choroidal detachment in rhegmatog- OCCLUSION enous retinal detachment. Korean J Ophthalmol. rehabilitation offer potential assistance. 2008;22(2):100-3. 22. Lewis H, Cowan GM, Straatsma BR. Apparent Signs and Symptoms 1. Androudi S, Stangos A, Brazitikos PD. Lamellar macu- disappearance of a macular hole associated with devel- Branch retinal vein occlusion (BRVO) lar holes: tomographic features and surgical outcome. opment of an epiretinal membrane. American Journal of Am J Ophthalmol. 2009;148(3):420-6. Ophthalmology 1986;102(2):172-75. is a commonly encountered intrareti- 2. Gass JD. Reappraisal of biomicroscopic classification 23. Lewis M, Cohen SM, Smiddy WE, et al. Bilaterality nal vascular event.1-3 Reports on retinal of stages of development of a macular hole. American of idiopathic macular holes. Graefe’s Archives for Clinical Journal of Ophthalmology 1995;119(9):752-59. and Experimental Ophthalmology 1996;234(4):241-45. vasculopathy recognize its prevalence 3. Kim JW, Freeman, WR, Azen SP, et al. Prospective 24. Kelly NE, Wendel RT. Vitreous surgery for idio- second only to .2,3 randomized trial of vitrectomy or observation for stage pathic macular holes. Results of a pilot study. Archives of 2 macular holes. American Journal of Ophthalmology Ophthalmology 1991;109(5):654-59. Patients who are symptomatic typically 1996;121(6):605-14. 25. de Bustros S. Vitrectomy for prevention of macular present with a chief complaint of pain- 4. Banker AS, Freeman WR, Kim JW, et al. Vision- holes: results of a randomized multicentered clinical trial. less blurry vision in one eye, although Ophthalmology 1994;101(6):1055-60. threatening complications of surgery for full-thickness 1-4 macular holes. Ophthalmology 1997;104(9):1442-53. 26. Willis AW, Garcia-Cosio JF. Macular hole surgery. vein occlusion can occur bilaterally. In 5. Nao-i N. Pearls in the management of macular holes. Comparison of longstanging versus recent macular holes. some cases, BRVO may present asymp- Seminars in Ophthalmology 1998;13(1):10-19. Ophthalmology 1996;103(4):1811-14. 6. Minihan M, Goggin M, Cleary PE. Surgical Management 27. Paques M, Massin PY, Santiago P, et al. Late reopen- tomatically and be found at a routine of macular holes: results using gas tamponade alone, ing of successfully treated macular hoes. British Journal of examination. Because the disease itself or in combination with autologous platelet concentrat, Ophthalmology 1997;81(8):658-62. is often the result of the systemic and VY [YHUZMVYTPUN NYV^ [O MHJ[VY    ) YP[PZO 1V\YUHS VM 28. Hutton WL, Fuller DG, Snyder WB, et al. Visual Ophthalmology 1997;81(12):1073-79. field defects after macular hole surgery. A new finding. local genetic factors that induced the 7. Ezra E, Wells JA, Gray RH, et al. Incidence of idio- Ophthalmology 1996;103(12):2152-59. event, there is no gender predilection, pathic full-thickness macular holes in fellow eyes. A 5 29. Lattanzio R, Ramoni A, Scotti F, et al. Macular hole - year prospective natural history study. Ophthalmology and intravitreal injection of triamcinolone acetonide for there is no racial preference and there 1998;105(2):353-9. due to central retinal vein occlusion. Eur are no concrete epidemiologic data as 8. Tsujikawa M, Ohji M, Fujikado T, et al. Differentiating J Ophthalmol. 2007;17(3):451-3. that information is subcategorized to the full thickness macular holes from impending macu- 30. Hirasawa M, Noda K, Shinoda H, et al. Secondary 5 lar holes and macular pseudoholes. British Journal of macular hole associated with central retinal vein occlusion specific diseases that increase its risk. Ophthalmology 1997;81(2):117-22. treated with corticosteroid injection. Jpn J Ophthalmol. Branch retinal vein occlusions are 9. McDonnell PJ, Fine SL, Hillis AI. Clinical features of 2009;53(3):279-81. idiopathic macular cysts and holes. American Journal of 31. Emerson GG, Spencer GR, Klein ML. Macular micro- categorized as those that permit vascular Ophthalmology 1982(6);93:777-86. holes. Retina. 2007;27(5):595-600. perfusion (non-ischemic, or perfused) 10. McCannel CA, Ensminger JL, Diehl NN, et al. 32. Gandorfer A, Scheler R, Haritoglou C, et al. Pathology Population-based incidence of macular holes. of the macular hole rim in flat-mounted internal limiting and those that produce vascular sta- Ophthalmology. 2009;116(7):1366-9. membrane specimens. Retina. 2009;29(8):1097-105. sis, limiting blood circulation (ischemic, 11. la Cour M, Friis J. Macular holes: classification, epide- 33. Wang MY, Nguyen D, Hindoyan N, et al. Vitreo- or non-perfused). Patients who present

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001_ro0410_hndbkv7.indd 37 4/5/10 8:47 AM with large, ischemic BRVO may where the large caliber retinal present with an afferent pupillary veins reside.3,7 This produces an defect. Patients with ischemic inflammatory and immunologi- branch retinal vein occlusions cal reaction in the affected tis- where the macula is infarcted sue.1,6 The discontinuation of have significantly reduced visual venous blood flow also interrupts acuity with a poorer prognosis the arterial blood flow; blocked then their non-ischemic coun- venous egress leaves no direct terparts.6 In contradistinction, pathway for the venous blood patients presenting with non- or arterial blood to proceed.3-7 ischemic branch retinal vein The overall flow in both systems occlusions may have minimal to becomes sluggish as the blood is no functional interruptions. In forced through other anastomoses general, non-ischemic BRVO Ischemic BRVO. around the formed thrombus.1-11 has a good prognosis.1-6 The deoxygenated blood intro- The retinal observations duced into retinal tissues—along seen in BRVO include dilated, with other chemokines, cytokines tortuous retinal veins, sectoral, and cellular players—initiates tis- flame-shaped intraretinal hem- sue damage in preparation for orrhages, variable local patches repair.1,5,6,-9 These active sub- of retinal ischemia (cotton wool stances as well as the setting of infarcts), intraretinal exudates, an ischemic environment can and variable retinal and macular provoke the release of vasopro- edema.3,6 The site of the occlu- liferative messengers known as sion can typically be observed vascular endothelial growth fac- at or just adjacent to the site of tors (VEGF).12,13 This category an arteriovenous crossing where of substances stimulates new ves- retinal arteries and veins share sel growth by inducing neovas- a common adventitial sheath.1 Non-ischemic BRVO. cular “budding” off of existing Here, an increased (broadened) arterial tissues. These new vessels retinal arteriolar reflex can be seen con- vein occlusions resolve without sequelae, lack normal architecture, become “scaf- noting ongoing general vascular arterio- requiring no treatment, the most impor- folded” to the vitreous body and have lar decompensation along with venous tant initial step in formulating a manage- the potential to cause pre-retinal or vit- nicking, representing the mechanical ment plan is to commit to discovering an reous hemorrhage and tractional retinal forces applied by the overlying vessel.3,7 underlying cause.1-9 detachment.14 Additionally, VEGF is Complications which can be observed associated with breakdown of the blood- following a branch retinal vein occlusion Pathophysiology retinal barrier, which results in increased include variable retinal edema, macular The provoking mechanism of branch vascular permeability and fluid leakage edema, and, in the face of significant retinal vein occlusion is classically related and the resultant retinal and macular ischemia, capillary non-perfusion, reti- to disorders of the blood tissue (blood edema. nal neovascularization, vitreous hem- dyscrasias) which incite platelet aggrega- Because the pathophysiology of the orrhage and tractional retinal detach- tion through coagulopathy syndromes event itself is painless, the symptomatol- ment.7 and/or hyperviscosity syndromes, or ogy in these cases is typically visual. In Upwards of 50%-60% of eyes recover by mechanical mechanisms (venous the initial stages, this is the direct effect a final visual acuity of 20/40 or bet- compression secondary to an overlying of the light being blocked from reach- ter without treatment.8 The entity artery’s expansion and hardening via ing the photoreceptors. In cases where rarely occurs idiopathically; rather it atheromatous formation) which impedes chronic, inner-retinal ischemia develops, is frequently associated with systemic venous drainage.3,7 This causes the capillary occlusion can result secondary coagulopathy, hyperviscosity, infection, venous wall to be overcome by the forces to failed vascular “push.” Here increased inflammation, hypertension, diabetes of an abnormal volume within its lumen. hydrostatic (back) pressure in the vessels mellitus, dyslipidemia, antiphospholipid As the walls of the vessel decompensate, becomes transmitted to the capillary antibody syndromes, cardiac and carotid deoxygenated venous blood gains access bed causing affected areas of the retina etiologies.1-9 Since most branch retinal to the retina via the nerve fiber layer, to become malnourished and hypoxic.

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001_ro0410_hndbkv7.indd 38 4/5/10 8:47 AM VITREOUS AND RETINA This creates an environment conducive in eyes with persistent macular edema Clinical Pearls to retinal cellular death and persistent following branch retinal vein occlusion • Optical coherence tomography edema, both deleterious to function.7 where vision was 20/40 or worse fol- (OCT) is an excellent adjunct to obser- lowing the resolution of the event.21,22 vation for diagnosing intraretinal edema Management Importantly, pan retinal laser photoco- and to monitor for resolution. All vein occlusion patients should be agulation was found to be of benefit once • While neovascularization of the iris, assessed both ocularly and systemically. neovascularization was observed, signifi- angle, and retina are rare, non-ischemic While intraretinal neovascular forma- cantly reducing the likelihood of vitreous BRVO should be monitored every four tion is uncommon in cases involving hemorrhage by 30 %.21 This modality of to six weeks for the first four months to non-ischemic BRVO, ischemic conver- treatment remains the standard of care. rule out late complications. sion over time is plausible, requiring the The SCORE study was designed to • While elevated intraocular pres- patient to be observed through complete compare the effectiveness and safety sure (IOP), especially in patients with resolution.1 Systemic laboratory testing between the standard care of BRVO undiagnosed or poorly controlled glau- may include depending upon patient (grid and focal laser photocoagulation) coma, has been reported as a risk factor profile: blood pressure evaluation, com- and intravitreal injection of triamcino- for developing central and hemiretinal plete blood count (CBC), fluorescent lone (two different concentrations) for venous occlusion, it seems to be less of a treponemal antibody absorption (FTA- treating macular edema associated with risk factor in the development BRVO. Abs), rapid plasma reagin (RPR), lipid both branch and central retinal vein • Variations of branch retinal vein profile, antiphospholipid antibody titres, occlusion (CRVO).23 The results of occlusion include occlusion of smaller fasting blood sugar (FBS), homocys- this trial found that there was equal venous tributaries (twig vein occlusion), teine levels, protein S and protein C, final outcome for improving visual acu- an occlusion of one side of a bifurcated lupus , electrocardiogram ity for the steroid groups compared central retinal vein (hemiretinal vein and carotid imaging.11 Infectious and to the standard care group in cases of occlusion) and occlusion of the entire inflammatory diseases have also been BRVO.22 However, rates of adverse central retinal vein (central vein occlu- reported as sources for branch vein events (particularly elevated intraocular sion). occlusion. Testing for sarcoidosis, tuber- pressure and cataract) were increased • The main condition to be evaluated culosis, rheumatoid arthritis and Lyme in the steroid group.22 This study con- in patients with BRVO is hypertension. infection should be considered when cluded that grid or focal photocoagula- vascular risks are absent and initial evalu- tion should remain the standard of care 1. Hayreh SS. Prevalent misconceptions about acute retinal vascular occlusive disorders. Prog Retin Eye Res. 15-17 ation fails to elicit a cause. for the treatment of macular edema 2005;24(4):493-519. While rare with BRVO, clinicians secondary to BRVO.23 2. Hamid S, Mirza SA, Shokh I. Branch retinal vein occlu- sion. J Ayub Med Coll Abbottabad. 2008;20(2):128-32. should monitor intraocular pressure and New treatment possibilities are being 3. Opremcak EM, Bruce RA. Surgical decompression of iris and angle for neovascularization.18 explored with anti-VEGF medications. branch retinal vein occlusion via arteriovenous crossing sheathotomy: a prospective review of 15 cases. Retina. The retinal treatment for all forms of vein A recently published report investigated 1999;19(1):1-5. occlusion is aimed at minimizing the loss 12-month follow-up results of intravit- 4. Hayreh SS, Zimmerman MB, Beri M, et al. Intraocular of acuity from macular edema and pre- real bevacizumab therapy for macular pressure abnormalities associated with central and 19-23 hemicentral retinal vein occlusion. Ophthalmology. venting neovascularization. Clinical edema secondary to branch retinal vein 2004;111(1):133-41. management for BRVO is guided by the occlusion.24 With a mean number of 5. Steinbrugger I, Haas A, Maier R, et al. Analysis of inflammation- and atherosclerosis-related gene poly- classic works of The National Institutes injections at two, ranging from one to morphisms in branch retinal vein occlusion. Mol Vis. of Health, National Eye Institute. four, the study demonstrated a benefit 2009;15(3):609-18. These include the Branch Retinal Vein for all patients, with younger patients 6. Margolis R, Singh RP, Kaiser PK. Branch retinal vein occlusion: clinical findings, natural history, and manage- Occlusion Study (BRVOS) and The having the best visual acuity improve- ment. Compr Ophthalmol Update. 2006;7(6):265-76. Standard Care versus Corticosteroid for ment during and after the 12-month 7. Funk M, Kriechbaum K, Prager F, et al. Intraocular con- 24 centrations of growth factors and cytokines in retinal vein Retinal Vein Occlusion (SCORE) stud- follow-up period. Better pretreatment occlusion and the effect of therapy with bevacizumab. ies.21-23 visual acuity was associated with better Invest Ophthalmol Vis Sci. 2009;50(3):1025-32. Results from the eight-year BRVOS visual acuity at 12 months but with less 8. Bek T. Inner retinal ischaemia: current understanding and needs for further investigations. Acta Ophthalmol. demonstrated that prophylactic scatter overall improvement of the visual acu- 2009;87(4):362-7. argon laser photocoagulation would not ity.24 This has opened the door for con- 9. Rehak J, Rehak M. Branch retinal vein occlusion: pathogenesis, visual prognosis, and treatment modalities. prevent the development of neovascular- sidering intravitreal bevacizumab alone Curr Eye Res. 2008;33(2):111-31. ization or vitreous hemorrhage in cases or in combination with other accepted 10. Noma H, Funatsu H, Sakata K, et al. Macular micro- circulation and macular edema in branch retinal vein of BRVO, and that macular argon laser treatments as a long-term effective occlusion. Br J Ophthalmol. 2009;93(5):630-3. photocoagulation (grid or focal photo- treatment for macular edema secondary 11. Mahoney BP, Constantine V. Retinal and Retinal coagulation) could improve visual acuity to branch retinal vein occlusion.24 Vascular Emergencies. In: Nyman, J. Problems

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001_ro0410_hndbkv7.indd 39 4/5/10 8:47 AM in Optometry; Ocular Emergencies. Philadelphia: JB Lippincott Co, 1989:123-48. (under age 50, or 40 depending upon blood flow or blood constituents, ath- 12. Chappell JC, Taylor SM, Ferrara N, et al. Local guid- reports) tend to less often have the erosclerosis, vessel anomalies, or a com- ance of emerging vessel sprouts requires soluble Flt-1. above-mentioned systemic associations. bination of these factors. Essentially, Dev Cell. 2009;17(3):377-86. 13. Pournaras CJ, Rungger-Brändle E, Riva CE, et al. In younger patients with CRVO, there properties of blood and the vein itself act Regulation of retinal blood flow in health and disease. is a greater likelihood of encountering in concert to cause thrombus formation Prog Retin Eye Res. 2008;27(3):284-330. 14. Ho TY, Chung YM, Lee AF, et al. Severe vaso- thrombophilic conditions and hyper- with subsequent impedance of venous occlusive retinopathy as the primary manifestation in a coagulopathies from blood dyscrasias blood flow from the retina.1-4,14,25 patient with systemic lupus erythematosus. J Chin Med such as antiphospholipid antibody syn- There are numerous ways that a Assoc. 2008;71(7):377-80. 15. DeRosa AJ, Margo CE, Orlick ME. Hemorrhagic reti- drome, hyperhomocysteinemia and low thrombus forms within the central reti- nopathy as the presenting manifestation of sarcoidosis. plasma folate.7-15 Typically, CRVO is nal vein. Blood flow combined with ves- Retina. 1995;15(5):422-7. 16. O’Hearn TM, Fawzi A, Esmaili D, et al. Presumed a unilateral phenomenon. Occasionally, sel wall abnormalities can stimulate vein ocular tuberculosis presenting as a branch retinal vein patients will experience bilateral CRVO. thrombosis. Additionally, changes in occlusion in the absence of retinal vasculitis or uveitis. Br J Ophthalmol. 2007;91(7):981-2. This should be considered very suspect blood constituents, such as hypercoagu- 17. Mikkilä HO, Seppälä IJ, Viljanen MK, et al. The for underlying systemic disease, such as lability states, elevated viscosity and sys- expanding clinical spectrum of ocular lyme borreliosis. Waldenström’s macroglobulinemia and temic states of decreased thrombolysis, Ophthalmology. 2000;107(3):581-7. 16-18 18. Nahberger D, Meyer-Schwickerath R, Saygili O, et al. chronic myeloid leukemia. promote thrombus formation. In that Development of neovascularization of the optic papilla, Patients often will complain of a sud- the central retinal artery and vein share a retina and iris. Dependence on site and extent of retinal ischemia. Ophthalmologe. 2000;97(6):422-8. den painless loss of vision and/or visual common adventitial sheath, compression 19. Heyreh SS. So-called “Central Retinal Vein field in the involved eye(s). The patient of the vein by a sclerotic artery can cause Occlusion” II. venous stasis retinopathy. Ophthalmologica may also complain of a sudden onset of turbulent blood flow causing throm- 1976;172:14-35. 20. Heyreh SS, Heyreh MS. Hemi-Central Retinal Vein floating spots or flashing lights. Visual bus formation at the lamina cribrosa, Occlusion. Pathogenesis, clinical features, and natural acuity may range from 20/20 to finger where the intraluminal pressure of the history. Arch Ophthalmol 1980;98:1600-9. 21. Branch Vein Occlusion Study Group. Argon laser counting in ischemic cases. If vision loss vein is lowest, rendering it susceptible scatter photocoagulation for the prevention of neovascu- is severe (a sign of an ischemic event), to collapse. External factors, such as larization and vitreous hemorrhage in branch vein occlu- there often will be a relative afferent (causing increased pressure sion. Arch Ophthalmol 1986; 104:34-41. 19-23 22. Branch Vein Occlusion Study Group. Argon Laser pupillary defect. in the optic nerve sheath), may cause Photocoagulation for Macular Edema in Branch Vein Ophthalmoscopically, there will be further compression and contribute to Occlusion. Am J Ophthalmol 1984; 98:271-82. 23. Scott IU, Ip MS, VanVeldhuisen PC, et al. A random- retinal edema, superficial flame-shaped occlusion. Other entities that can induce ized trial comparing the efficacy and safety of intravitreal and deep blot hemorrhages, disc edema, compression of the vessel include: orbital triamcinolone with standard care to treat vision loss asso- ciated with macular Edema secondary to branch retinal cotton wool spots, and tortuous and tumor and abscesses, cavernous sinus vein occlusion: the Standard Care vs Corticosteroid for dilated retinal veins encompassing all thrombosis, and retrobulbar intranerve Retinal Vein Occlusion (SCORE) study report 6. Arch four retinal quadrants. The hemorrhag- sheath injection, and optic disc dru- Ophthalmol. 2009;127(9):1115-28. 24. Kondo M, Kondo N, Ito Y, et al. Intravitreal injection ing in any case may be so severe that sen. Further, systemic diseases influence of bevacizumab for macular edema secondary to branch all features of the underlying retina are thrombus formation through external retinal vein occlusion: Results After 12 Months and multiple regression analysis. Retina 2009; 29(7):913-25. obscured. The presence of multiple cot- compression, primary thrombus forma- ton wool spots, poor visual acuity and tion through stasis, and degenerative relative afferent pupillary defect is highly or inflammatory disorders of the vein CENTRAL RETINAL VEIN indicative of retinal ischemia and cap- itself.1-4,14,25 OCCLUSION illary non-perfusion.19-23 In ischemic Thrombotic occlusion of the central cases, anterior and posterior segment retinal vein impedes venous blood flow Signs and Symptoms neovascularization may occur later in the from the retina. This backup will result Patients experiencing central retinal course of the disease. Neovascularization in leakage from the retinal capillary beds, vein occlusion (CRVO) are typically occurs more commonly on the iris and accounting for the blood, retinal edema over the age of 50 having concurrent angle with attendant neovascular glau- and disc congestion seen in this condi- systemic diseases such as atherosclero- coma (NVG) than it does on the retina tion. The capillary beds may be irrevers- sis, hyperlipidemia, diabetes and hyper- and optic disc with subsequent tractional ibly damaged by this process, resulting tension.1-5 In regards to these com- retinal detachement.24 in perpetual non-perfusion of the retinal monly associated systemic conditions, tissue. If a significant area of capillary diabetes has the least impact as a risk Pathophysiology non-perfusion is present, then the occlu- factor for CRVO.2 However, those The etiology of CRVO is a throm- sion is considered ischemic. patients with concurrent diabetes tend botic obstruction of the central retinal Loss of retinal capillary beds with to have more ischemic CRVO than vein as it constricts through the lamina subsequent retinal non-perfusion will non-diabetic patients.6 Younger patients cribrosa. This may involve abnormal lead to retinal hypoxia and the subse-

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001_ro0410_hndbkv7.indd 40 4/5/10 8:47 AM VITREOUS AND RETINA quent release of vascular endo- Recently, the SCORE study thelial growth factors (VEGF), compared the outcome of stan- which will then stimulate the dard therapy for vision loss from proliferation of neovasculariza- macular edema in CRVO (in this tion from nearby viable capil- case, observation without thera- lary beds. In CRVO, the closest peutic intervention) to intravit- viable capillary network from real injection of two doses (1mg which neovascularization will and 4mg) of intravitreal injected form is the posterior iris. This triamcinolone. The conclusion can lead to rubeosis irides, and of this study was that intravit- neovascular glaucoma as the ves- real triamcinolone was superior sels move across the posterior to observation for treating vision and anterior iris into the angle.24 loss associated with macular Additionally, VEGF increases Ischemic CRVO. edema secondary to CRVO and vascular permeability leading to that the 1mg dose safety pro- increased retinal edema.26 file was superior to that of the In all cases of venous occlu- 4mg dose.31 Studies comparing sion, the main cause of vision intravitreal injected triamcino- decrease is macular edema. lone with intravitreal injections However, if retinal capillary of bevacizumab have seen similar non-perfusion involves the peri- improvements with each treat- foveal region, then vision is dra- ment, though bevacizumab did matically and irreversibly lost. not have the complicating factors The other main cause of severe, of cataract and intraocular pres- irreversible vision loss in CRVO sure (IOP) elevation as seen in is neovascular glaucoma.24 the steroid group.32,33 However, it should be noted that in the Management SCORE study, there was equal When managing patients Non-ischemic CRVO. incidence of IOP elevation and experiencing CRVO, it is cataractogenesis in both the 1mg important to consider the natural history information about retinal capillary perfu- triamcinolone group and the untreated of the disease as well as related systemic sion and whether the occlusion is isch- observation group.31 implications. Non-ischemic CRVO has emic, and thus more likely to develop It is well demonstrated that patients a much better visual prognosis than does neovascular complications.1,21 However, with ischemic CRVO developing anteri- ischemic CRVO.19,27 Typically, patients early in the course of the occlusion when or segment neovascularization and NVG with good presenting visual acuity the retina is extremely hemorrhagic, flu- benefit from pan-retinal photocoagula- (>20/40) have the best visual prognosis orescein details may be blocked. tion to stimulate vessel regression. Eyes and those eyes with initial acuity worse It has been well documented that with ischemic CRVO do not benefit than 20/200 have the greatest likelihood argon laser grid photocoagulation for from prophylactic pan-retinal photo- of poor final acuity. The initial level of macular edema in CRVO has no ben- coagulation prior to the development vision often correlates well with retinal eficial visual effect. Thus, this proce- of neovascularization.34 This procedure non-perfusion and is a discriminator dure is not indicated in management.28 should be withheld until the patient of ischemia. It must be noted that eyes However, intravitreal injections of develops frank neovascularization of the with intermediate level acuity are often anti-VEGF drugs such as ranibizumab iris, disc, or retina.34 Recently, it has been classified as “indeterminate” in regards to (Lucentis, Genentech) and bevacizumab shown that intravitreal injected bevaci- ischemia and have a guarded prognosis (Avastin, Genentech) have proven effec- zumab dramatically regressed anterior for final acuity. Indeed, many of these tive in reducing macular edema and segment neovascularization and assisted eyes (as well as eyes that are initially improving visual acuity in eyes with in the management of NVG associated considered non-ischemic or perfused) CRVO and vision loss occurring mainly with CRVO.35,36 This treatment has convert to non-perfused, ischemic eyes from macular edema.29,30 Indeed, these become very popular in the management with a subsequent propensity to develop are popular treatments today, though of NVG, both alone and in conjunction NVG.19,27 there are few controlled studies guiding with pan-retinal photocoagulation. Fluorescein angiography can provide their usage. In that CRVO is a perfusion imbal-

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001_ro0410_hndbkv7.indd 41 4/5/10 8:47 AM ance with significant congestion, this ic and coagulation disorders, such as rior segment neovascularization. The condition has been considered a com- antiphospholipid antibody syndrome absence of iris neovascularization does partment syndrome. Thus attempts have and hyperhomocysteinemia. There is not preclude the possibility of angle neo- been made to reduce congestion and not strong evidence to support an exten- vascularization. Gonioscopy must still be increase perfusion with an optic nerve sive work-up for thrombophilic and performed even in the face of a pristine decompression procedure known as coagulation diseases for the vast majority iris. radial optic neurotomy (RON). In this of patients with CRVO. However, when • Dilated and tortuous retinal veins procedure, the nasal aspect of the optic tests for common cardiovascular risk fac- are a sign of outflow obstruction and disc in eyes with CRVO is surgically tors for CRVO are negative, evaluation possibly an impending CRVO. cut to reduce congestive pressure. There for potential coagulation disorders may have been numerous reports demon- be indicated. This is especially important 1. Wang GL, Zhang F, Peng XY, et al. The study of clinical characteristic of nonischemic central retinal vein occlu- strating an improvement in visual func- for young patients, those with bilateral or sion. Zhonghua Yan Ke Za Zhi. 2008;44(2):152-6. tion and a reduction in macular edema, recurrent CRVO, and those with a his- 2. O’Mahoney PR, Wong DT, Ray JG. Retinal vein occlu- sion and traditional risk factors for atherosclerosis. Arch but there have also been contradictory tory of previous thromboses in other sys- Ophthalmol. 2008;126(5):692-9. reports.37-40 Due to the invasiveness and tems or a family history of thrombosis.25 3. Klatt C, Purtskhvanidze K, Hasselbach H, et al. Retrospective case analysis of ophthalmological and the advent of other successful intravitreal systemic risk factors in patients with retinal vascular drugs, it is unclear if RON has any place Clinical Pearls occlusion. Ophthalmologe. 2009. [Epub ahead of print]. in the contemporary management of • The management of CRVO 4. Di Capua M, Coppola A, Albisinni R, et al. Cardiovascular risk factors and outcome in patients with CRVO. involves monitoring for resolution or retinal vein occlusion. J Thromb Thrombolysis. 2009. The patient with CRVO should be late complications, laser intervention [Epub ahead of print]. 5. Klein R, Moss SE, Meuer SM, et al. The 15-year cumu- monitored with serial ophthalmoscopy, if neovascular complications develop, lative incidence of retinal vein occlusion: the Beaver Dam fundus photography, and gonioscopy intravitreal therapy for non-remitting Eye Study. Arch Ophthalmol. 2008;126(4):513-8. on a monthly basis until resolution is macular edema, and systemic comanage- 6. Mansour AM, Walsh JB, Goldberger S, et al. Role of diabetes mellitus on the natural history of central retinal evident. The patient should be closely ment with an internist. vein occlusion. Ophthalmologica. 1992;204(2):57-62. monitored for neovascularization of the • Ischemic CRVOs typically pres- 7. Sottilotta G, Oriana V, Latella C, et al. Role of hyper- homocystinemia in retinal vascular occlusive disease. Clin disc, retina, iris and angle. If neovas- ent with acuity worse than 20/200. Appl Thromb Hemost. 2007;13(1):104-7. cularization develops, then pan-retinal Those eyes with initial acuity better 8. Gao W, Wang YS, Zhang P, et al. Hyperhomocysteinemia photocoagulation is indicated. If the than 20/200 are at low risk of develop- and low plasma folate as risk factors for central retinal vein occlusion: a case-control study in a Chinese population. patient has unremitting macular edema, ing severe vision loss, and are likely to Graefes Arch Clin Exp Ophthalmol. 2006;244(10):1246-9. then referral for intravitreal injective spontaneously improve. 9. Kuhli C, Hattenbach LO, Scharrer I, et al. High prevalence of resistance to APC in young patients with therapy is indicated. Patients with poor • Ischemic CRVOs are likely to pres- retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol. initial acuity should be monitored more ent with a relative afferent pupillary 2002;240(3):163-8. 10. Lahey JM, Kearney JJ, Tunc M. Hypercoagulable closely and will most likely need special- defect. states and central retinal vein occlusion. Curr Opin Pulm ty consultation and tertiary treatment. • CRVO is a dynamic phenomenon. Med. 2003;9(5):385-92. Patients with good initial acuity should There exists the possibility that non- 11. Kuhli-Hattenbach C, Scharrer I, Lüchtenberg M, et al. Selective thrombophilia screening of young patients not be recommended for intravitreal ischemic CRVO with good acuity and with retinal vein occlusion. Klin Monatsbl Augenheilkd. injections without a period of observa- perfusion can progress to an ischemic 2009;226(9):768-73. 12. Popa A, Voinea L, Pop M, et al. Primary antiphospho- tion as there is a chance for spontaneous situation with subsequently poor per- lipid syndrome. Oftalmologia. 2008;52(1):13-7. improvement. fusion and bad outcome. Eyes with 13. Rehak M, Müller M, Scholz M, et al. Antiphospholipid Due to the association of systemic CRVO with intermediate levels of vision syndrome and retinal vein occlusion. Meta-analysis of Published Studies. Ophthalmologe. 2009;106(5):427-34. disease with vein occlusions, the patient loss (between 20/50 and 20/200) and are 14. Turello M, Pasca S, Daminato R, et al. Retinal vein should be comanaged with an inter- neither ischemic nor non-ischemic and occlusion: evaluation of “classic” and “emerging” risk factors and treatment. J Thromb Thrombolysis. 2009. nist. There seems to be a relationship are hence considered to be “indetermi- [Epub ahead of print]. between CRVO, mortality and increased nate” are more likely to progress on to 15. Janssen MC, den Heijer M, Cruysberg JR, et cardiovascular risk factors, such as smok- fully ischemic occlusions. al. Retinal vein occlusion: a form of venous throm- bosis or a complication of atherosclerosis? A meta- ing, diabetes and macrovascular disease. • When diabetes is present in patients analysis of thrombophilic factors. Thromb Haemost. There is the possibility of an association with CRVO, closer observation is neces- 2005;93(6):1021-6. 41 16. Chanana B, Gupta N, Azad RV. Case report: between CRVO and . Older sary as this seems to be a risk factor bilateral simultaneous central retinal vein occlusion patients should be examined for isch- dictating late onset ischemia. in Waldenström’s macroglobulinemia. Optometry. 2009;80(7):350-3. emic vascular diseases, such as hyper- • Undilated iris evaluation and goni- 17. Alexander P, Flanagan D, Rege K, et al. Bilateral tension, diabetes, hyperlipidemia, and oscopy is necessary at each progress simultaneous central retinal vein occlusion secondary to atherosclerosis while younger patients evaluation for eyes with CRVO in order hyperviscosity in Waldenstrom’s macroglobulinaemia. Eye. 2008;22(8):1089-92. should be examined for thrombophil- to properly detect the onset of ante- 18. El Fekih L, Hmaied W, Elhif S, et al. Chronic myeloid

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001_ro0410_hndbkv7.indd 42 4/5/10 8:47 AM VITREOUS AND RETINA leukemia revealed by bilateral occlusion of the retinal nal vein occlusion: effects on visual acuity and mac- central vein. Tunis Med. 2008;86(10):937-9. ular anatomy. Graefes Arch Clin Exp Ophthalmol. vision or visual field loss, occur if fluid 19. The Central Retinal Vein Study Group. Natural history 2005;243(5):397-405. from the retinoschisis cavity accesses an and clinical management of central retinal vein occlusion. 38. Gribomont AC, Charlier L. Does radial optical neu- outer layer retinal hole to induce a rheg- Arch Ophthalmol. 1997;115(4):486-91. rotomy have a place in the treatment of central retinal vein 20. The Central Retinal Vein Study Group. Baseline and occlusion? Bull Soc Belge Ophtalmol. 2007;(305):13-9. matogenous retinal detachment. Only early natural history report. The Central Vein Occlusion 39. Callizo J, Kroll P, Mennel S, et al. Radial optic neuroto- rarely will patients report a sharp visual Study. Arch Ophthalmol. 1993;111(8):1087-95. my for central retinal vein occlusion: long-term retinal per- 21. Lang GE, Händel A. Clinical and fluorescein angiog- fusion outcome. Ophthalmologica. 2009;223(5):313-9. field defect corresponding to the area of 1 raphy changes in patients with central retinal vein occlu- 40. Fortunato P, Pollazzi L, Baroni M, et al. Venous retinal the retinoschisis. sion. A unicenter study of 125 patients. Klin Monatsbl flow reperfusion mechanisms following radial optic neu- Ophthalmoscopy will reveal a smooth, Augenheilkd. 1992;201(5):302-8. rotomy with adjunctive intraocular triamcinolone in central 22. Lu N, Wang GL, Zhang F, et al. Long-term follow- retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol. stationary, bullous elevation of either the up study of nonischemic central retinal vein occlusion. 2009. [Epub ahead of print]. inferior-temporal or superior-temporal Zhonghua Yan Ke Za Zhi. 2006;42(6):488-91. 41. Tsaloumas MD, Kirwan J, Vinall H, et al. Nine year 1-5 23. Zhang H, Xia Y. Analysis of visual prognosis and cor- follow-up study of morbidity and mortality in retinal vein retina. The greatest prevalence appears relative factors in retinal vein occlusion. Zhonghua Yan Ke occlusion. Eye. 2000;14(Pt 6):821-7. to be the inferior temporal retina. Nasal Za Zhi. 2002;38(2):98-102. involvement is very rare.1 The elevation 24. Hayreh SS. Neovascular glaucoma. Prog Retin Eye Res. 2007 Sep;26(5):470-85. may extend beyond the equator, and 25. Yau JW, Lee P, Wong TY, et al. Retinal vein occlu- ACQUIRED RETINOSCHISIS may rarely invade the posterior pole. sion: an approach to diagnosis, systemic risk factors and management. Intern Med J. 2008;38(12):904-10. However, the posterior border of the 26. Pe’er J, Folberg R, Itin A, et al. Vascular endothelial Signs and Symptoms majority of these lesions remains pre- growth factor upregulation in human central retinal vein occlusion. Ophthalmology 1998;105(3):412-6. Acquired retinoschisis is historically equatorial. The dome of the elevation is 27. Hayreh SS. Management of central retinal vein occlu- known as senile retinoschisis and, as the smooth and translucent. Blood vessels sion. Ophthalmologica. 2003;217(3):167-88. name implies, is typically found in the will traverse the dome and cast shadows 28. The Central Retinal Vein Occlusion Study Group. 1 Evaluation of grid pattern photocoagulation for macu- eyes of elderly patients. In one large on the underlying structures. In many lar edema in central vein occlusion. The Central Vein population based study, the mean age of cases, the smooth dome of the lesion Occlusion Study Group M report. Ophthalmology. 1995;102(10):1425-33. patients with acquired retinoschisis was demonstrates inner and outer layer holes. 1 29. Iturralde D, Spaide RF, Meyerle CB, et al. Intravitreal 69 years. In this study, the prevalence of In some cases, these lesions permit liquid bevacizumab (Avastin) treatment of macular edema in acquired retinoschisis was 3.9% for per- vitreous fluid to leak under the photo- central retinal vein occlusion: a short-term study. Retina. 2006;26(3):279-84. sons aged 60 to 80 years. There appears receptors separating the neurosensory 30. Rouvas A, Petrou P, Vergados I, et al. Intravitreal to be no gender predilection.1 There retina from the retinal pigment epithe- ranibizumab (Lucentis) for treatment of central retinal vein occlusion: a prospective study. Graefes Arch Clin Exp also do not appear to be any associated lium (RPE) creating a rhegmatogenous Ophthalmol. 2009 Jul 16. [Epub ahead of print]. conditions, though one report of three retinal detachment.6-8 A pigmentation 31. Ip MS, Scott IU, VanVeldhuisen PC, et al. SCORE cases noted acquired retinoschisis in line inferring some coexistent irritation Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with to the RPE connotes the observation to treat vision loss associated with macu- presence subretinal fluid lar edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein from a concurrent or old Occlusion (SCORE) study report 5. Arch Ophthalmol. chronic rhegmatogenous 2009;127(9):1101-14. 9,10 32. Guthoff R, Meigen T, Hennemann K, et al. process. There will be Comparison of Bevacizumab and Triamcinolone for no RPE hyperplasia in the Treatment of Macular Edema Secondary to Central form of a pigment demarca- Retinal Vein Occlusion - A Matched-Pairs Analysis. Ophthalmologica. 2009;224(2):126-32. tion line from an acquired 33. Tao Y, Hou J, Jiang YR, et al. Intravitreal bevacizumab retinoschisis lesion alone. vs triamcinolone acetonide for macular oedema due to central retinal vein occlusion. Eye. 2009. [Epub ahead of print]. Pathophysiology 34. The Central Retinal Vein Occlusion Study Group. Every aging eye mani- A randomized clinical trial of early panretinal photoco- agulation for ischemic central vein occlusion. The Central fests peripheral cystic Vein Occlusion Study Group N report. Ophthalmology. changes in the inner nuclear 1995;102(10):1434-44.     ) H[PV S\ -   ( Z[HT  5   6 aT LY[ ,   9HWPK PTWYV] LT LU[ VM and outer plexiform layers retinal and iris neovascularization after a single intravitreal Bullous acquired retinoschisis. of the retina. These spaces bevacizumab injection in a patient with central retinal vein coalesce to form interlacing occlusion and neovascular glaucoma. Int Ophthalmol. 2 2008;28(1):59-61. nanophthalmic eyes. Most commonly, tunnels. If enough cystic spaces coalesce, 36. Wakabayashi T, Oshima Y, Sakaguchi H, et al. acquired retinoschisis is bilateral, though the retina will form a retinoschisis, split- Intravitreal bevacizumab to treat iris neovasculariza- 1 tion and neovascular glaucoma secondary to ischemic unilaterality has been noted. ting into an inner and outer layer cavity. retinal diseases in 41 consecutive cases. Ophthalmology. Patients with acquired retinoschi- The superficial retinal layers comprise 2008;115(9):1571-80. 37. Zambarakji HJ, Ghazi-Nouri S, Schadt M, et al. sis are nearly always asymptomatic. the inner layer, while the deeper layers Vitrectomy and radial optic neurotomy for central reti- Typically, symptoms, in the form of of the retina and RPE represent the

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001_ro0410_hndbkv7.indd 43 4/5/10 8:47 AM outer layer of the acquired retinoschisis retinoschisis cavity and progression to progression is extremely slow and may cavity. The split typically occurs in the rhegmatogenous retinal detachment, take months to years to threaten vision. outer plexiform layer, or less often, in there are other changes that can occur. • Because the RPE is not disrupted the inner nuclear layer.2,3 These lesions, The development of acquired retinos- by acquired retinoschisis, the RPE does with their intraretinal separations, can be chisis in the fellow eye of unilateral cases not become hyperplastic and a pigment clearly demonstrated with optical coher- will occasionally occur during long-term demarcation line will not form. If a pig- ence tomography.11 follow up. Additionally, acquired reti- ment demarcation line is present in a There are technically two types of noschisis has been noted to spontane- retinoschisis, it should be taken as a sign acquired retinoschisis. There is the ously disappear in up to 2.3%-8.8% of that there is or was a concomitant retinal typical degenerative retinoschisis, cases over time.1,5,9 This may possibly detachment. which presents as a shallow elevation occur in cases where the retinal pigment • The acquired retinoschisis is firm of the inner retinal layers. There is epithelium pumps fluid out of the reti- and will show no movement or undu- also reticular degenerative retinoschi- noschisis cavity. However, this mecha- lation upon eye movement or scleral sis, which presents in the traditional nism is merely speculative. indentation, whereas a retinal detach- appearance of a bullous elevation. In all ment will. Furthermore, scleral indenta- types of acquired retinoschisis, there is Management tion will show preservation of the schisis the potential for either the inner layer The risk of acquired retinoschisis pro- cavity, as opposed to retinal detachment. or the outer layer, or both layers, to gressing to involve central vision or devel- • Should a visual field defect be develop holes.6-8 oping a rhegmatogenous retinal detach- detectable by standard threshold perim- Progression of acquired retinoschisis, ment (even with double layer holes) is etry, it will have a steep and sharply either by continued separation of the two low. There is no treatment for stable demarcated border. In contrast, the layers or the concurrent development of cases beyond routine monitoring every defect will not be as sharp with a retinal rhegmatogenous retinal detachment, is six to 12 months.8,12,13 In fact, in one detachment. uncommon.1,9,12,13 The risk of acquired long-term population-based study, there retinoschisis progression to concurrent was more disappearance of lesions than 1. Buch H, Vinding T, Nielsen NV. Prevalence and long-term natural course of retinoschisis among 1 rhegmatogenous retinal detachment progression to retinal detachment. This, elderly individuals: the Copenhagen City Eye Study. ranges from 0.07% – 2.2%.1,9 Those combined with the fact that prophylactic Ophthalmology. 2007;114(4):751-5. 2. Dhrami-Gavazi E, Schiff WM, Barile GR. cases that have been noted to progress treatment complications exceed the risk Nanophthalmos and acquired retinoschisis. Am J to rhegmatogenous retinal detachment of visual loss from progressive retinal Ophthalmol. 2009;147(1):108-10. 3. Astakhov IuS, Lukovskaia NG. Retinoschisis. often have additional complicating fac- detachment from acquired retinoschisis Diagnosis, classification, examination methods. Vestn tors, such as cataract surgery or a family clearly indicate that these lesion should Oftalmol. 2004;120(1):26-9. history of retinal detachment. Cases of be observed rather than treated. If possi- 4. Dotrelová D. Surgical treatment of progressive and symptomatic retinal detachment in senile retinoschisis. acquired retinoschisis most at risk for ble, the acquired retinoschisis should be Sb Lek. 2002;103(2):109-31. progression to retinal detachment are photodocumented to increase the abil- 5. Byer NE. Long-term natural history study of senile retinoschisis with implications for management. those that have outer layer breaks closest ity to detect progression or regression. Ophthalmology. 1986;93(9):1127-37. 1,4,5-8 to the retinal pigment epithelium. Because acquired retinoschisis results in 6. Sulonen JM, Wells CG, Barricks ME, et al. Degenerative Should holes develop within the a sharply demarcated visual field defect, retinoschisis with giant outer layer breaks and retinal detachment. Am J Ophthalmol. 1985;99(2):114-21. inner layers of the retina (inner layer the stability can be monitored with a 7. Hoerauf H, Joachimmeyer E, Laqua H, et al. Senile holes), the patient with acquired reti- threshold visual field as well. Acquired schisis detachment with posterior outer layer breaks. Retina. 2001;21(6):602-12. noschisis may have liquid vitreous retinoschisis lesions that manifest outer 8. Baron D, Randriamora T. Senile retinoschisis with potentially egress into the retinal tissue layer holes should be monitored more tearing of the deep layer--classification and pathogenic cavity. This will have no prognostic closely. hypotheses. Oftalmologia. 2006;50(2):77-86. 9. DiSclafani M, Wagner A, Humphrey W, et al. significance. However, if there are also Should any retinal detachment or Pigmentary changes in acquired retinoschisis. Am J outer layer holes, liquid vitreous will high risk retinal breaks develop from Ophthalmol. 1988;105(3):291-3. 10. Byer NE. Perspectives on the management of have the potential to gain access to the acquired retinoschisis, standard therapies the complications of senile retinoschisis. Eye. subretinal space, causing a rhegmatog- such as barrier laser photocoagulation, 2002;16(4):359-64. 11. Kamppeter BA, Jonas JB. Optical coherence enous retinal detachment. To this end, gas bubble tamponade and scleral buck- tomography of a peripheral retinal schisis with an 4,6,9,10 acquired retinoschisis with both inner ling procedures are appropriate. outer retinal layer break. Acta Ophthalmol Scand. and outer layer holes simultaneously 2004;82(5):574-5. 12. Byer NE. The natural history of senile retinos- (double layer holes) have greater poten- Clinical Pearls chisis. Trans Sect Ophthalmol Am Acad Ophthalmol tial to progress to rhegmatogenous reti- • While acquired retinoschisis has Otolaryngol. 1976;81(3 Pt 1):458-71. 4,12,13 13. Messmer EP. Prevention of retinal detachment and nal detachment. the potential to enlarge and extend pos- treatment of retinoschisis. Fortschr Ophthalmol. 1990;87 Beyond increased size of the acquired teriorly and threaten the macula, its Suppl:S62-9.

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001_ro0410_hndbkv7.indd 44 4/5/10 8:47 AM NEURO-OPHTHALMIC DISEASE NEURO-OPHTHALMIC DISEASE

MELANOCYTOMA OF THE loss, field loss, relative afferent pupil Bilateral optic disk melanocytoma OPTIC DISC defect, choroidal neovascularization) via is uncommon and associated with optic a variety of mechanisms.1,8-11 Visual disc hypoplasia and central nervous sys- Signs and Symptoms symptoms can be anticipated in up to tem abnormalities, such as Melanocytomas of the optic nerve 24% of patients.2 and .11 head (magnocellular nevus, melanocytic Potential associated ocular findings nevus) are slightly elevated, benign, include invasion into the choroid from Pathophysiology darkly pigmented tumors that classi- the retina, optic disc edema, retinal Melanocytoma is one of five dis- cally occur in or about the optic disk, edema, localized subretinal fluid, retinal orders of cells originating from the sometimes with contiguous involve- exudation, retinal hemorrhage and reti- neural crest (choroidal nevi, choroi- ment of the adjacent retina or cho- nal vein obstruction.1,2,10,12 dal melanoma, melanocytoma, ocular roid.1-3 They have been known to occur Associated ocular vascular abnormal- melanosis and oculodermal melano- most commonly in the disc and sis).17 Melanocytoma are derived peripapillary area, but can be found from uveal dendritic melanocytes anywhere melanocytes reside (iris, which also form uveal nevi and uvea, sclera, episclera, meninges).4,5 malignant melanoma.18,19 The pre- Classically, they appear as unilat- dominant cell in nevi and melano- eral black or dark brown lesions mas are of the spindle cell type.20 (other variations in color are pos- Characteristically, melanocytoma sible) with non-feathery margins display a static growth pattern; involving the disc and adjacent however, enlargement by a very retina.1-3 Variations in size can small degree over long periods occur; however, they are usually no of time has been documented as more than a few disc diameters in normal.1,8-11,18 Growth of mela- size.2,6 They have the potential to nocytoma produces locally invasive obscure the optic disc. The tumor behaviors.1-21 Tumors that extend rarely extends more than 2mm into Melanocytoma of the optic disc and adjacent RPE. down the optic nerve through the pre-retinal space.2 In most cases, lamina cribrosa become secluded less than half of the disc is typically ities may include arterial attenuation, from direct observation but can produce obscured.1 perivascular sheathing, superficial hem- vision losses ranging from 20/50 to hand In a study of 115 patients (116 eyes) orrhages and vascular occlusions.1,12 motion, vascular compression and axo- with melanocytoma of the optic disc, Nerve fiber layer hemorrhages and vit- nal swelling.12,19,20 the mean age at diagnosis was 50 years, reous hemorrhage are atypical and may Anterior segment changes associ- with a slight preponderance for female cause confusion in the diagnosis.14,15 ated with melanocytoma are mostly predilection.2 The lesion was unilat- Disruptions in the ocular circulation related to the unlikely migration of eral in 99% of patients, with whites or direct compression may also cause pigment to structures, which include affected more commonly than African secondary necrosis of the optic disc. the posterior lens capsule, anterior hya- Americans.2 Asian, Hispanic, Indian Circumpapillary subretinal fluid is not loid of the vitreous, iris, zonule fibers and Arabic races are significantly less uncommon and often produces retinal and anterior chamber angle.18,21-23 affected than the Caucasian or African striae, optic disc swelling and peripapil- Melanocytomalytic glaucoma is a sec- races.2 While many regard optic disc lary swelling.14 Subretinal or intraretinal ondary open angle pigmentary glaucoma melanocytomas as congenital lesions exudates, intraretinal thickening, and uncommonly encountered with mela- which mature over time, there is pub- even serous detachment of the macula nocytoma of the optic disc. It typically lished evidence supporting the potential have been associated with this lesion.14 occurs in selected cases of necrotic iris for spontaneous development in adult- Melanocytoma has also been associ- melanocytoma.22,23 hood.7 ated with increased levels of catechol- In general, these tumors are regarded While most lesions remain stable amine in the body.16 The relationship as benign and stationary, with little pre- throughout life, minor enlargement stems from the common neural crest ponderance for undergoing malignant can occur in 10%-15% of cases.1,8-11 origin of melanocytes, adrenal medul- transformation.1-20 Melanocytomas may Adjacent portions of the tumor have lary cells and chromaffin cells.16 As transform into malignant melanomas, the capability of damaging nerve fiber a result, systemic hypertension has but this is rare.6 Other unusual features bundles and major vessels with resul- recently been added to the list of pos- may include quickened growth pattern, tant variable visual complications (sight sible concurrent findings.16 infiltration of the macular region, and

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001_ro0410_hndbkv7.indd 45 4/5/10 8:47 AM the presence of retinal hemorrhages and mine the extent of penetration into the nocytoma are rare before puberty. exudates.1,2,6 optic nerve.21 A-scan ultrasonography, • Reactive hyperplasia of the RPE though less useful diagnostically, can can also masquerade as a melanocytoma. Management deliver the height of the lesion (typically These often stem from past eye injuries Specific diagnostic tests are useful in less than 2.0mm).6 or disease and can be differentiated the identification and clinical manage- Fluorescein and indocyanine green by their diffuse, rather than localized ment of melanocytoma.24-26 When a angiography demonstrate persistent appearance. lesion is first detected, careful fundus hypo fluorescence of the lesion.2 In most • Melanocytoma must also be differ- photodocumentation is necessary to give instances there is no leakage.2 entiated from choroidal nevi. These flat, later inspection a valid comparison data- Computerized tomography (CT grey-brown lesions with definite borders base.1-22 Baseline automated threshold scanning) and magnetic resonance have a small malignant potential. perimetry can permit accurate quanti- imaging (MRI) may aid in the localiza- • Bilateral melanocytomas are a tative tracking over time and is indi- tion and classification of the tumor.26 rare phenomenon. Because they have cated regardless of visual symptoms. The P32 test may be positive if a malig- documented associations with central Nerve fiber bundle defects, enlarged nancy exists. The P32 test is a phospho- nervous system dysfunctions, systemic blind spot, central and paracentral sco- rus uptake test designed to seed tumors evaluation is warranted in such cases. tomas or peripheral field constriction of this type.26 • Baseline visual fields and photo- are all potential visual field findings. Today, management of melanocy- documentation are reasonable data to Optical coherence tomography (OCT) toma is conservative, with long term gather. has been shown to be of excellent value observation and meticulous documenta- in these cases.22 On OCT imaging, tion.1-26 Treatment for vision threat- 1. Shields JA, Demirci H, Mashayekhi A, et al. Melanocytoma of the optic disk: a review. Surv melanocytomas display a gradual slop- ening non-rhegmatogenous lesions, Ophthalmol. 2006;51(2):93-104. ing transition from normal retina into extending toward the macula is vari- 2. Shields JA, Demirci H, Mashayekhi A, et 1,2,27 al. Melanocytoma of optic disc in 115 cases: the the mass, with hyper-reflectivity at the able. Leber’s neuroretinitis, a find- 2004 Samuel Johnson Memorial Lecture, part 1. anterior tumor surface with posterior ing associated with cat scratch disease, Ophthalmology. 2004;111(9):1739-46. 22 3. LoRusso FJ, Boniuk M, Font RL. Melanocytoma shadowing. Thicker tumors display has also been associated with melanocy- (magnocellular nevus) of the ciliary body: report of 10 thinner anterior hyper-reflective borders toma of the optic nerve head. It should cases and review of the literature. Ophthalmology. with denser shadowing.22 Given the be included in the differential diagnosis 2000;107(4):795-800. 27 4. Rahimi-Movaghar V, Karimi M. Meningeal melano- catastrophic consequences of misdiag- of neuroretinitis. cytoma of the brain and oculodermal melanocytosis nosis, all questionable lesions should The management for melanocyto- (nevus of Ota): case report and literature review. Surg Neurol. 2003;59(3):200-10. be referred for evaluation by a retinal mas converting to malignant melanoma 5. Biswas J, D’Souza C, Shanmugam MP. Seven 1,2,20 specialist or ocular oncologist. is limited typically to enucleation. diffuse melanotic lesion of the iris as a presenting Melanocytoma that do not show Photodynamic therapy can be used feature of ciliary body melanocytoma: report of a case and review of the literature. Surv Ophthalmol. enlargement over a 24-month observa- effectively for treating choroidal neovas- 1998;42(4):378-82. tional period are considered benign by cularization secondary to melanocytoma 6. Sharma PM, Sangal K, Malik P, et al. Malignant 1-10 transformation of optic disc melanocytoma? A clinical circumstantial evidence. Amsler grid, involving the peripapillary area and pap- dilemma at presentation with a review of the literature. observing for alterations once or twice illomacular bundle.28 Submacular sur- Ophthalmologica. 2002;216(4):292-5. monthly, can be used for home moni- gery may be considered for large choroi- 7. Shields JA, Shields CL, Piccone M, et al. Spontaneous appearance of an optic disk melanocy- toring. The patient should be instructed dal neovascular membranes associated toma in an adult. Am J Ophthalmol. 2002;134(4):614-5. to return should any changes in visual with a melanocytoma of the optic disc.9 8. Shields JA, Shields CL, Ehya H, et al. Total blind- ness from presumed optic nerve melanocytoma. Am J acuity or grid appearance occur. Ophthalmol. 2005;139(6):1113-4. Ultrasonography, particularly color Clinical Pearls 9. Tran HV, Bovey EH, Uffer S, et al. Peripapillary cho- roidal neovascularization associated with melanocy- Doppler imaging, can help to differen- • Malignant melanoma appears grey- toma of the optic disc: a clinicopathologic case report. tiate a melanocytoma from a choroidal brown (versus the typical brown or black Graefes Arch Clin Exp Ophthalmol. 2006;244(10):1367- melanoma and is indicated if visual appearance of an optic nerve head mela- 9. 10. Besada E, Shechtman D, Barr RD. Melanocytoma symptoms do not correspond with the nocytoma). inducing compressive optic neuropathy: the ocular fundus presentation.21,25 B-scan ultra- • Melanomas rarely infiltrate the morbidity potential of an otherwise invariably benign lesion. Optometry. 2002;73(1):33-8. sonography will identify a melanocy- NFL, so they are generally not feathery. 11. Demirci H, Shields CL, Shields JA. Bilateral optic toma as a smooth surface solid mass • Hamartomas of the RPE may disk melanocytoma in a 10-month-old infant. Am J with a high amplitude of internal reflec- extend into the optic nerve head and Ophthalmol. 2003;136(1):190-2. 12. Shields JA, Shields CL, Eagle RC Jr, et al. tivity (high spike), without underlying peripapillary retina and clinically resem- Central retinal vascular obstruction secondary to scleral excavation, subretinal fluid or ble melanocytoma. Hamartomas fre- melanocytoma of the optic disc. Arch Ophthalmol. 21 2001;119(1):129-33. retinal detachment. It can also deter- quently occur in children, whereas mela- 13. Hajji Z, Charif Chefchaouni M, Chaoui Z, et

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al. Diagnostic difficulties in pigmented tumor of the is commonly used to connote an acute with an acute attack of optic neuritis optic nerve head. A case report. J Fr Ophtalmol. 2005;28(6):614-7. unilateral optic neuropathy from any eti- will typically, at 10 years, have good 14. Zou Y, Ni C. Clinical and histopathological studies ology, the discussion here will be limited vision with 74% retaining 20/20 acu- of melanocytoma of the optic disc. Yan Ke Xue Bao. 7 2000;16(2):112-5. to demyelinating neuropathy associated ity. Recently it has been reported at the 15.Puri P, Prasad S, Rennie IG. Organized vitreous with multiple sclerosis. final follow up for the Optic Neuritis hemorrhage masquerading as an optic disc melanocy- Optic neuritis is often the initial pre- Treatment Trial (ONTT) that the pres- toma. Eur J Ophthalmol. 2003;13(2):215-7. 1-3 16. Kaliaperumal S, Gupta A, Nongrum B, et al. sentation of MS. After five years, ence of brain MRI abnormalities at Case reports of three patients showing optic nerve clinically definite multiple sclerosis the time of an optic neuritis attack is head melanocytoma and systemic hypertension. Ophthalmologica. 2007;221(1):62-4. (CDMS) develops in 30% of patients a strong predictor of the 15-year risk 17. Ellis FD. Selected pigmented fundus lesions of who present with ON, though the of MS.6 The overall risk of developing children. J AAPOS. 2005;9(4):306-14. 18. Shields JA, Shields CL, Eagle, et al. Malignant degree of neurological impairment is MS by 15 years after onset of optic 4 Melanoma Associated with Melanocytoma of the Optic generally mild. Brain magnetic res- neuritis was 50% and strongly related Disc. Ophthalmology 1990;97(2):225-30. onance imaging (MRI) performed at to the presence of brain MRI lesions. 19. Shuey TF, Blacharki PA. Pigmented Tumor and . Surv Ophthalmol. 1988;33(2):121-6. study entry into the Optic Neuritis Only 25% of patients with no lesions on 20. Meyer D, Ge J, Blinder KJ, et al. Malignant Treatment Trial (ONTT) was a strong baseline brain MRI have developed MS transformation of an optic disk melanocytoma. Am J Ophthalmol. 1999;127(6):710-4. predictor of CDMS, with the five-year during 15 year study follow-up com- 21. Mansour AM, Zimmerman LE, La Piana FG, et al. risk of CDMS, ranging from 16% in pared with 72% of patients with one or Clinicopathological Findings in a Growing Optic Nerve patients with no MRI lesions to 51% more lesions.8 The typical patient with Melanocytoma. Br J Ophthalmol. 1989;73(6):410-5. 22. Fineman MS, Eagle RC Jr, Shields JA, et al. in patients with three or more MRI demyelinating optic neuritis is a young Melanocytomalytic glaucoma in eyes with necrotic iris lesions.4 female, often between the ages of 20 melanocytoma. Ophthalmology. 1998;105(3):492-6. 23. el Baba F, Hagler WS, De la Cruz A, et al. However, even a normal brain MRI and 40 years. In the ONTT, 72% of the Choroidal Melanoma with Pigment Dispersion in does not preclude the development of patients were female and the median age Vitreous and Melanomalytic Glaucoma. Ophthalmology CDMS.4 Most patients who develop of onset was 32 years.9 In 92% of cases, 1988;95(3):370-7. 24. Shields CL, Perez B, Benavides R, et al. Optical clinically definite MS following an ini- the vision loss is painful with increased coherence tomography of optic disk melanocytoma in tial episode of optic neuritis will have a pain upon eye movement.9 A retrobul- 15 cases. Retina. 2008;28(3):441-6. 25. Yang W, Hu S, Wang J. Color Doppler imaging relatively benign course for at least 10 bar neuropathy with a normal appearing diagnosis of ocular tumor. Zhonghua Yan Ke Za Zhi. years.5 Patients with rapid succession optic disc occurs in 65% of cases with a 1997;33(4):272-6. 9 26. Dégi R, Szabó A, Janáky M. Experience in 13-year of severe ON events are more likely papillitis manifesting in the remainder. follow-up of a melanocytoma of the optic nerve head. to develop a generalized demyelinating There will be associated dyschromatop- Magy Onkol. 2005;49(1):31-4. disease.3 sia, decreased brightness sense and a 27. García-Arumí J, Salvador F, Corcostegui B, et al. 1,9 Neuroretinitis associated with melanocytoma of the The 10-year risk of MS following an relative afferent pupil defect. Without optic disk. Retina. 1994;14(2):173-6. initial episode of acute optic neuritis is treatment, vision typically begins to 28. Chalam KV, Gupta SK, Shah GY, et al. Successful management of melanocytoma-associated choroidal significantly higher if there is a single recover by approximately one month neovascularization with photodynamic therapy. Eur J brain MRI lesion; higher numbers of and the recovery is often rapid, pro- Ophthalmol. 2006;16(5):776-8. lesions do not appreciably increase that gressing over the course of a year’s time. risk. However, even when brain lesions Severe vision loss at time of onset seems DEMYELINATING OPTIC are seen on MRI, more than 40% of the to be associated with a poorer final NEUROPATHY (Optic Neuritis, patients will not develop clinical mul- outcome, though even patients with Retrobulbar Optic Neuritis) tiple sclerosis after 10 years.6 Patients poor initial vision recover quite well.10 Visual field defects are varied, but Signs and Symptoms seem to affect central vision more Optic neuritis (ON) is a broadly- than far . Central used term that technically implies and cecocentral scotomas are com- acute inflammation of the optic mon, as are generalized depres- nerve. While numerous etiologies sions and altitudinal defects.11-14 include infection (syphilis, mumps, Chiasmal and retrochiasmal lesions measles), infiltrative/inflammatory also may occur.11 Over the first disease (sarcoidosis, lupus) and year of follow-up, the majority of ischemic vascular disease (diabe- patients with visual field defects tes, hypertension), the most com- from acute optic neuritis returned mon etiology is the demyelinating to normal.11,13 Systemic signs and disease multiple sclerosis (MS). symptoms indicative of MS may While it is acknowledged that ON Papillitis in a patient with multiple sclerosis. include headache, nausea, Uhtoff’s

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001_ro0410_hndbkv7.indd 47 4/5/10 8:47 AM sign (decreased vision with or without ments in the understanding of the loss is a feature of multiple sclerosis.21 limb weakness following exposure to pathophysiologic process of optic neu- Numerous studies seem to indicate increased temperatures i.e., bath or exer- ritis, and it seems that there may be there is axonal loss as opposed to demy- cise), Romberg’s sign (patient falls when changes beyond demyelination that elination alone underlying the visual they close their eyes), Pulfrich’s stereo account for the visual features and disability seen in MS.22 phenomenon (beer barrel appearance disabilities that patients experience. An expert panel consensus examin- to the environment), L’Hermitte’s sign Advancements in understanding have ing the role of RNFL analysis with (tingling of the extremities upon chin come from automated diagnostic imag- OCT determined that OCT is valid down posture) and fever. ing using optical coherence tomography and reproducible and yields important (OCT) and scanning laser polarimetry information regarding patients with Pathophysiology (SLP), and have illuminated axonal ON and MS, but more studies are Multiple sclerosis is defined as an loss in both optic neuritis and MS.16- required to correlate OCT results with acquired, multifactorial, inflammatory 22 In one study using both OCT and other measures of MS disease activity. demyelinating disease, which affects SLP, the average peripapillary retinal However, it was also felt that OCT the white matter located in the cen- nerve fiber layer (RNFL) thickness was may evolve into an important primary tral nervous system. Myelin is respon- reduced in patients with MS compared or secondary outcome metric for MS sible for insulating the nerves of the with controls. Both modalities were clinical trials and patient care.20 peripheral and central nervous system, in agreement and the results support permitting transmission of electrical RNFL thickness as a marker for axonal Management impulses along nervous tissues. Loss degeneration and use of these tech- In the past, controversy existed as of myelin greatly slows nervous con- niques in clinical diagnosis and clinical to whether or not patients with ON duction and leads to the neurological trials.16 should be treated with corticosteroids deficits seen in MS. It has long been Another study examining the rela- and in which form. The ONTT sup- believed that demyelination in ON tionship between visual function and ports the administration of intrave- damages the fibers in both the visual RNFL thickness, as measured by OCT, nous methylprednisolone sodium suc- and pupillary pathways. This damage found that low-contrast letter acuity cinate (Solu-medrol) 250mg every six interrupts nerve impulses within the and contrast sensitivity correlated well hours for three days followed by oral pathways, producing decreased vision, a with RNFL thickness. It was seen prednisone (1mg/kg, per day) for 11 corresponding afferent pupillary defect that eyes with a history of acute optic days for the purposes of accelerating and sluggish pupilomotor activity. neuritis demonstrated greater reduc- visual recovery.23-25 This therapy did Although the exact cause of MS tions in RNFL thickness, but patients not improve visual outcome after one is presently unknown, many theories with MS, without a history of ON, also year but was found to increase the rate regarding its etiology exist. The most had less RNFL thickness than controls. at which patients recover. The ONTT common theories involve the immune This implied that the occurrence of also determined that the use of oral system. Evidence suggests that the cel- chronic retinal axonal loss occurred as prednisone (1mg/kg, per day) alone for lular immune response contributes to separate events and not just from acute 14 days is contraindicated.23 Patients the degradation of myelin. This patchy attacks in MS patients.17 In a major receiving this therapy had a higher demyelination is thought to be caused literature review, it was seen in all rate of new attacks of ON in both by a deposition of mononuclear cells, studies that there is a significant reduc- the initially affected and fellow eyes such as macrophages and B-cells in tion in RNFL in eyes affected by ON than did the intravenous/oral group perivascular regions.2 compared with fellow eyes and eyes of and placebo group, and overall the Changes in the brain on magnet- healthy controls. This further supports intervention contributed to a poorer ic resonance images are common in the contention that OCT may be used outcome systemically.23 As recorded in patients with optic neuritis, even when as a promising new tool for evaluating the three-year follow-up of patients in there is no other clinical evidence of retinal axonal atrophy in patients with the ONTT, treatment with intravenous multiple sclerosis.15 The brain lesions ON and MS. Jeanjean and associates methylprednisolone followed by oral of multiple sclerosis are commonly also demonstrated that retinal axonal corticosteroid regimens reduced the seen as T2 ovoid high-signal white loss following optic neuritis can be two-year rate of development of clini- matter lesions on MRI scans of the detected with OCT. They noted that cal MS, particularly in patients with brain, located in perivenular regions the RNFL of MS patients without signal abnormalities consistent with perpendicular to ventricles with variable optic neuritis was also thinner than demyelination on MRI of the brain enhancement.1 disease-free controls recognizing that at the time of study entry.26 Serious There have been recent advance- chronic, on-going optic nerve axonal side effects of glucocorticoid therapy

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the optic neuritis treatment trial. Optic Neuritis Study are infrequent. Therefore, outpatient should be considered an ocular finding Group. Arch Ophthalmol. 1993;111(2):231-4. administration of high-dose intrave- from a systemic disease. It is imperative 13. Fang JP, Lin RH, Donahue SP. Recovery of visual nous glucocorticoids may be recom- to identify patients with ON who are at field function in the optic neuritis treatment trial. Am J Ophthalmol. 1999;128(5):566-72. mended. Patients should be counseled risk for development of CDMS so that 14. Keltner JL, Johnson CA, Spurr JO, et al. as to the benefits and disadvantage of they may receive appropriate immuno- Comparison of central and peripheral visual field 24,27 properties in the optic neuritis treatment trial. Am J this treatment. modulatory therapy. Ophthalmol. 1999;128(5):543-53. Patients with typical acute mono- • In cases of optic neuropathy pre- 15. Beck RW, Arrington J, Murtagh FR, et al. Brain magnetic resonance imaging in acute optic neuritis. symptomatic demyelinating optic sumably secondary to demyelinating dis- Experience of the Optic Neuritis Study Group. Arch neuritis should receive gadolinium- ease, MRI can assist in systemic diag- Neurol. 1993;50(8):841-6. enhanced magnetic resonance imag- nosis by identifying both old and acute 16. Zaveri MS, Conger A, Salter A, et al. Retinal imaging by laser polarimetry and optical coherence tomography ing (MRI) of the brain and orbits to demyelinating plaques within periven- evidence of axonal degeneration in multiple sclerosis. determine if they are at high risk for the tricular white matter. Arch Neurol. 2008;65(7):924-8. 17. Fisher JB, Jacobs DA, Markowitz CE, et al. Relation subsequent development of CDMS. • Significant pain with eye move- of visual function to retinal nerve fiber layer thickness in A subset of patients with monosymp- ment is present in nearly every case of multiple sclerosis. Ophthalmology. 2006;113(2):324- tomatic optic neuritis manifested nei- demyelinating optic neuropathy. Eye 32. 18. Kallenbach K, Frederiksen J. Optical coherence ther clinical signs nor MRI evidence pain may precede visual dysfunction. tomography in optic neuritis and multiple sclerosis: a of demyelination after more than 10 • The course of ON is predictable review. Eur J Neurol. 2007;14(8):841-9. 19. Sergott RC. Optical coherence tomography: mea- years of follow-up. In other cases fol- with nearly full recovery. However, the suring in-vivo axonal survival and neuroprotection lowed for this length of time, the MRI course and development of CDMS is in multiple sclerosis and optic neuritis. Curr Opin signal abnormalities could be shown less certain. Some patients will experi- Ophthalmol. 2005;16(6):346-50. 20. Sergott RC, Frohman E, Glanzman R, et al. The role to accumulate; however, no new clini- ence a rapid decline while others, even of optical coherence tomography in multiple sclerosis: cal manifestations of multiple sclerosis with MRI abnormalities, will not. This expert panel consensus. J Neurol Sci. 2007;263(1- 28 2):3-14. developed. It is important to ascertain must all be considered when counseling 21. Jeanjean L, Castelnovo G, Carlander B, et al. the risk of progressing to CDMS in patients regarding prognosis. Retinal atrophy using optical coherence tomogra- phy (OCT) in 15 patients with multiple sclerosis and patients with ON, as there are systemic comparison with healthy subjects. Rev Neurol (Paris). 1. Chan JW. Optic neuritis in multiple sclerosis. Ocul immunomodulatory therapies available. 2008;164(11):927-34. Immunol Inflamm. 2002;10(3):161-86. 22. Plant GT. Optic neuritis and multiple sclerosis. Patients with an initial clinical episode 2. Soderstrom M. Optic neuritis and multiple sclerosis. Curr Opin Neurol. 2008;21(1):16-21. Beck RW, Cleary Acta Ophthalmol Scand. 2001;79(3):223-7. of optic neuritis and at least two char- PA, Anderson MM Jr, et al. A randomized, controlled 3.Pirko I, Blauwet LK, Lesnick TG, et al. The natu- trial of corticosteroids in the treatment of acute optic acteristic demyelinating lesions within ral history of recurrent optic neuritis. Arch Neurol. neuritis. The Optic Neuritis Study Group. N Engl J Med. 2004;61(9):1401-5. the brain who are treated with inter- 1992;326(9):581-8. 4. Optic Neuritis Study Group. The 5-year risk of MS 23. Cleary PA, Beck RW, Anderson MM Jr, et al. feron beta-1a (Avonex, Biogen Idec) after optic neuritis. Experience of the optic neuritis Design, methods, and conduct of the Optic Neuritis after initial treatment with intrave- treatment trial. . 1997;49(5):1404-13. Treatment Trial. Control Clin Trials. 1993;14(2):123-42. 5. Beck RW, Smith CH, Gal RL, et al. Optic Neuritis nous corticosteroids showed a 50% less 24. Beck RW. The optic neuritis treatment trial: Study Group. Neurologic impairment 10 years after 29-32 three-year follow-up results. Arch Ophthalmol. risk of progression to CDMS. The optic neuritis. Arch Neurol. 2004;61(9):1386-9. 1995;113(2):136-7. 6. Beck RW, Trobe JD, Moke PS, et al; Optic Neuritis Controlled High Risk Avonex Multiple 25. Balcer LJ, Galetta SL. Treatment of acute demyelin- Study Group. High- and low-risk profiles for the devel- ating optic neuritis. Semin Ophthalmol. 2002;17(1):4- Sclerosis Study (CHAMPS) supports opment of multiple sclerosis within 10 years after optic 10. the efficacy of Avonex therapy in sig- neuritis: experience of the optic neuritis treatment trial. 26. Optic Neuritis Study Group. Long-term brain mag- Arch Ophthalmol. 2003;121(7):944-9. nificantly reducing the three-year like- netic resonance imaging changes after optic neuritis 7. Beck RW, Gal RL, Bhatti MT, et al. Optic Neuritis in patients without clinically definite multiple sclerosis. lihood of future neurological events and Study Group. Visual function more than 10 years after Arch Neurol. 2004;61(10):1538-41. optic neuritis: Experience of the optic neuritis treatment worsening of the brain MRI in patients 27. Foroozan R, Buono LM, Savino PJ, et al. Acute trial. Am J Ophthalmol. 2004;137(1):77-83. 29 demyelinating optic neuritis. Curr Opin Ophthalmol. with a first episode of optic neuritis. 8. Brodsky M, Nazarian S, Orengo-Nania S, et al. Optic 2002;13(6):375-80. Neuritis Study Group. Multiple sclerosis risk after optic Currently, the most commonly 28. Galetta SL. The controlled high risk Avonex multiple neuritis: final optic neuritis treatment trial follow-up. employed immunomodulatory therapies sclerosis trial (CHAMPS Study). J Neuroophthalmol. Arch Neurol. 2008;65(6):727-32. 2001;21(4):292-5. for patients with MS include: Avonex 9. Optic Neuritis Study Group. The clinical profile 29. CHAMPS Study Group. Interferon beta-1a for optic of optic neuritis. Experience of the Optic Neuritis (interferon beta-1a, Biogen Idec); Rebif neuritis patients at high risk for multiple sclerosis. Am J Treatment Trial. Arch Ophthalmol. 1991;109(12):1673- Ophthalmol. 2001;132(4):463-71. (interferon beta-1a, EMD Serono, 8. 30. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular 10. Beck RW, Cleary PA, Backlund JC. The course Inc.); Betaseron (interferon beta-1b, interferon beta-1a therapy initiated during a first demy- of visual recovery after optic neuritis. Experience of elinating event in multiple sclerosis. CHAMPS Study Bayer Healthcare Pharmaceuticals); the Optic Neuritis Treatment Trial. Ophthalmology. Group. N Engl J Med. 2000;343(13):898-904. and Copaxone (glatiramer acetate, 1994;101(11):1771-8. 31. Minagara A, Murray TJ; PROOF Study Investigators. 36,37 11. Keltner JL, Johnson CA, Spurr JO, et al. Visual Teva Pharmaceuticals).. Efficacy and tolerability of intramuscular interferon beta- field profile of optic neuritis. One-year follow-up in 1a compared with subcutaneous interferon beta-1a in the Optic Neuritis Treatment Trial. Arch Ophthalmol. relapsing MS: results from PROOF. Curr Med Res Opin. 1994;112(7):946-53. Clinical Pearls 2008;24(4):1049-55. 12. Keltner JL, Johnson CA, Spurr JO, et al. Baseline 32. Simpson D, Noble S, Perry C. Glatiramer acetate: • Optic neuritis associated with MS visual field profile of optic neuritis. The experience of

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001_ro0410_hndbkv7.indd 49 4/5/10 8:47 AM a review of its use in relapsing-remitting multiple sclero- sis. CNS Drugs. 2002;16(12):825-50. speed penetration of the globe by for- nerve, hematoma of the nerve sheath, 33. Mikol DD, Barkhof F, Chang P, et al. REGARD 1-10 study group. Comparison of subcutaneous interferon eign material. optic nerve compression secondary to beta-1a with glatiramer acetate in patients with relaps- Examination of these patients reveals bony fracture of the orbital apex or ing multiple sclerosis (the REbif vs Glatiramer Acetate in variably reduced acuity and/or visual penetrating orbital foreign body.1-12 Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. field defects, which may be central, Most commonly, however, concussive 2008;7(10):903-14. paracentral, arcuate or altitudinal in shock waves are implicated; trans- 34. Murdoch D, Lyseng-Williamson KA. Spotlight on 1-10 subcutaneous recombinant interferon-beta-1a (Rebif) nature. An afferent pupillary defect mission of these forces to the bones in relapsing-remitting multiple sclerosis. BioDrugs. is characteristic and tell-tale for sever- and meninges of the orbit results in 2005;19(5):323-5. ity with varying degrees of dyschro- contusion of the intracanalicular optic 35. Murdoch D, Lyseng-Williamson KA. Subcutaneous 1-11 5-15 recombinant interferon-beta-1a (Rebif): a review of its matopsia noted. Ophthalmoscopic nerve. Subsequently, the axons and use in relapsing-remitting multiple sclerosis. Drugs. evaluation will vary greatly depend- microvasculature are compromised by 2005;65(9):1295-312. 36. Wang AG, Lin YC, Wang SJ, et al. Early relapse ing on the nature and severity of the ischemia secondary to reactive edema, in multiple sclerosis-associated optic neuritis following injury. Initially, practitioners may note as well as the generalized compressive the use of interferon beta-1a in Chinese patients. Jpn J a completely normal fundus without forces.14 In rare instances, the neu- Ophthalmol. 2006;(6):537-42. 37. Chen YM, Yang CC, Wang IH, et al. The effect any signs of disc edema, ischemia, or ropathy may develop months after the of interferon beta-1a on optic neuritis relapse in other abnormalities.12,13 In other cases, initial trauma, a consequence of scar- patients with multiple sclerosis. Graefes Arch Clin Exp Ophthalmol. 2009 Oct 6. [Epub ahead of print] a grossly edematous optic nerve head, ring within the optic canal that leads to vitreous hemorrhage, venous conges- secondary nerve compression.13,15 tion or retinal edema may be seen.1-12 Trauma that precipitates an optic TRAUMATIC OPTIC In the vast majority of cases, optic disc nerve injury almost always results in NEUROPATHY pallor ensues within several weeks to retinal ganglion cell axon damage.14 months after the injury.1-4,12-14 Neurotrophin deprivation secondary to Signs and Symptoms direct shear, edema, bleeding or other Patients with traumatic optic neu- Pathophysiology neurochemotactic factors induce death ropathy have experienced sudden, Traumatic optic neuropathy results of the retinal ganglion cells (RGCs).14 severe, vision loss following blunt inju- from injury sustained during trauma to These cells give rise to the axons that ry to the head or face.1-3 The condition the globe, orbital rim or frontal area.12- compose the optic nerve. Externally may manifest immediately or within 15 In adults, the etiology is typically a released agents that block mitochon- hours or days following the trauma.4 bicycle or motor vehicle accident, but drial electron transport have been used The vision loss may be insidi- in the laboratory to show that ous, with some cases the patient superoxide radicals generated in being unaware of any visual defi- the mitochondrial electron trans- cit until it is detected by routine port chain also induce cell death examination. The epidemiology after axonal injury.14 of traumatic optic neuropathy is non specific; however, it can Management be extrapolated world-wide, as High resolution imaging of the following trends consistent with head is critical in any case of blunt those individuals most likely to trauma to ensure that no life- sustain both eye injuries and gen- threatening intracranial damage eral blunt ocular trauma.5-10 The has been sustained.15 Particular patient demographic that is most attention should be given to the prone to ocular trauma includes orbital apex, optic canal and cav- young males (average ratio of Optic disc pallor in a patient who suffered traumatic optic ernous sinus if vision is compro- 4:1 over females), in their teens neuropathy. mised. A complete neurological or twenties, participating in out- assessment is also indicated in door or work-related activities during may also include physical assault, falls, these cases, especially if there was loss seasonal warm weather.5-10 Women sports-related injuries or (rarely) orbital of consciousness, as the optic neuropa- who sustain serious ocular injury tend surgery.1-11 There are a variety of ways thy is just one among other injuries to be involved in activities around the in which the optic nerve can be dam- resulting from the trauma. In many home.7 The history often includes a aged. In some cases, the pathophysiol- cases, patients with traumatic optic blow to the head severe enough to ogy may be multifactorial. Mechanisms neuropathy enter the medical system induce loss of consciousness or high include transection or avulsion of the through the emergency department

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prior to optometric or ophthalmo- survival of RGC and optic nerve regen- may likewise be minimally affected or logic consultation. In this instance, it eration through stimulation via neuro- severely compromised. The key to diag- is likely imaging studies have already trophic factors (NTF) either directly nosis lies in a thorough history and been ordered and interpreted by the or indirectly through retinal astrocyte/ meticulous ocular evaluation. ER physician.1-11 However, it may be Müller cell intermediary activation are • In evaluating for possible bony frac- necessary to later order more appropri- underway.21 NTF induce disinhibi- tures of the orbit or skull, computed ate imaging studies in some cases. tion of axon growth through regulated tomography (CT) is the vastly preferable Ocular treatment presents three intramembranous proteolysis.21 The technique. In addition to being far less options: 1) observation, 2) system- concomitant release of metalloprotein- expensive than MRI, CT offers much ic corticosteroid therapy, or 3) optic ases (MMP) and plasminogen activa- better resolution of bone, and also can nerve decompression surgery. While a tors from RGC axons as well as tissue demonstrate orbital hemorrhage in the fair number of patients with traumat- inhibitors of metalloproteinases from early stages following trauma. ic optic neuropathy experience some optic nerve glia, suppress scarring.19 • In those cases that involve pen- spontaneous improvement of vision, MMP also degrade myelin-derived etrating orbital injury or fracture of the there is great variability in the out- inhibitory messengers along regener- sinus walls, systemic antibiotic therapy come.16-18 Negative prognostic fac- ating axon trajectories, encouraging is mandatory to prevent secondary cel- tors include blood in the posterior growth. The combination of blocking lulitis. ethmoid cells, loss of consciousness, axon-growth inhibition while stimulat- older age (i.e., > 40) and complete loss ing axon growth promoters may be the 1. Carta A, Ferrigno L, Salvo M, et al. Visual prognosis after indirect traumatic optic neuropathy. J Neurol 1,2 of vision at the initial presentation. therapeutic formula for sustained axon Neurosurg Psychiatry 2003;74(2):246-8. In the 1990’s, researchers quoting the regeneration.21 2. Wang BH, Robertson BC, Girotto JA, et al. Traumatic optic neuropathy: A review of 61 patients. Plast Second National Acute Spinal Cord For now, medical and/or surgical Reconstr Surg 2001;107(7):1655-64. Injury Study recommended megadose intervention remains of questionable 3. Matschke J, Püschel K, Glatzel M. Ocular pathol- 22 ogy in shaken baby syndrome and other forms of systemic intravenous corticosteroid value. It has been suggested that infantile non-accidental head injury. Int J Legal Med. therapy on all patients with traumatic patients without negative prognostic 2009;123(3):189-97. optic neuropathy within eight hours indicators be effectively managed with 4. Wu N, Yin ZQ, Wang Y. Traumatic optic neuropathy 12,16 1,17,22 therapy: an update of clinical and experimental studies. of injury. While this approach is careful monitoring. Research has J Int Med Res. 2008;36(5):883-9. controversial (due to insufficient clini- shown that there is no significant dif- 5. Podbielski DW, Surkont M, Tehrani NN, et al. Pediatric eye injuries in a Canadian emergency depart- cal research demonstrating conclusive ference in final visual acuity relating ment. Can J Ophthalmol. 2009;44(5):519-22. effectiveness) the therapy is considered to dose of corticosteroid therapy, and 6. Soliman MM, Macky TA. Pattern of ocular trau- worth attempting given the poten- that there is no significant difference in ma in Egypt. Graefes Arch Clin Exp Ophthalmol. 2008;246(2):205-12. 16-19 tial for vision preservation. Those outcome between patients treated with 7. Cillino S, Casuccio A, Di Pace F, et al. A five-year ret- patients remaining unresponsive to the steroids or surgical decompression of rospective study of the epidemiological characteristics and visual outcomes of patients hospitalized for ocular therapy after several days, or those the optic canal. For patients presenting trauma in a Mediterranean area. BMC Ophthalmol. with poorer visual acuity (i.e., finger more than eight hours after the initial 2008;8(4):6. counting or worse) at initial presenta- injury, steroids are contraindicated as 8. McGwin G Jr, Owsley C. Incidence of emergency department-treated eye injury in the United States. Arch tion are considered candidates for tra- there are no proven data indicating Ophthalmol. 2005;123(5):662-6. ditional or endoscopic transnasal optic effectiveness in this time frame while 9. Parver LM, Dannenberg AL, Blacklow B, et al. 12,16,19 Characteristics and causes of penetrating eye injuries canal decompression surgery. the preparations remain capable of reported to the National Eye Trauma System Registry, The endoscopic transnasal approach is producing other collateral unwanted 1985-91. Public Health Rep. 1993;108(5):625-32. 17,18,22,23 10. May DR, Kuhn FP, Morris RE, The epidemiol- well suited for decompression of both side effects. Patients with trau- ogy of serious eye injuries from the United States Eye 19 the orbit and optic canal. A high- matic optic neuropathy should, there- Injury Registry. Graefes Arch Clin Exp Ophthalmol. resolution technique, requiring sub- fore, be managed via the above out- 2000;238(2):153-7. 11. Kuhn F, Morris R, Witherspoon CD, et stantial familiarity and skill, the nasal lined options on an individual basis, al. Epidemiology of blinding trauma in the United endoscope provides excellent visualiza- following proper assessment and con- States Eye Injury Registry. Ophthalmic Epidemiol. 17,18,22 2006;13(3):209-16. tion for bone removal along the orbital sultation. 12. Steinsapir KD, Goldberg RA. Traumatic optic neu- 19 apex and skull base. The technique is ropathy. Surv Ophthalmol 1994; 38(6):487-518. not without risk and may cause com- Clinical Pearls 13. Nishi T, Ueda T, Yukawa E, et al. Traumatic optic neuropathy caused by blunt injury to the inferior orbital plications, which include severe nasal • There is no classic presentation rim. J Neuroophthalmol. 2006;26(1):44-6. bleeding, cerebrospinal fluid rhinor- to traumatic optic neuropathy. The 14. Lieven CJ, Levin LA. Tools for studying early events in optic neuropathies. Eye. 2007;21 Suppl 1:S21-4. rhea, nasal polyps, chronic sinusitis and involved optic nerve may be edematous, 15. Gass A, Moseley IF. The contribution of mag- nasal synechia.20 hemorrhagic, or pale at the time of netic resonance imaging in the differential diagnosis Experimental paradigms to promote examination. Visual acuity and fields of optic nerve damage. J Neurol Sci. 2000;172 Suppl

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001_ro0410_hndbkv7.indd 51 4/5/10 8:47 AM 1:S17-22. 16. Bracken MB, Shepard MJ, Collins WF, et al. A severe presentations involve engorged Jacobson published their diagnostic 8 randomized, controlled trial of methylprednisolone or and tortuous retinal venules, peri- criteria, which includes the following: naloxone in the treatment of acute spinal-cord injury. papillary hemorrhages and/or cotton 1. If symptoms present, they may Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 1990; 322(20):1405-11. wool spots, and circumferential reti- only reflect those of generalized intra- 17. Levin LA, Beck RW, Joseph MP, et al. The treat- nal microfolds (Paton’s lines). Chronic cranial hypertension or papilledema. ment of traumatic optic neuropathy: The International Optic Nerve Trauma Study. Ophthalmology papilledema may result in atrophy of 2. If signs present, they may only 1999;106(7):1268-77. the nerve head, with associated pallor reflect those of generalized intracranial 18. Levin LA, Baker RS. Management of traumatic and gliosis. Most cases of true, acute hypertension or papilledema. optic neuropathy. J Neuroophthalmol 2003;23(1):72-5. 19. Pletcher SD, Sindwani R, Metson R. Endoscopic papilledema will not present with sig- 3. Documented elevated intracranial orbital and optic nerve decompression. Otolaryngol Clin nificant visual loss or a relative afferent pressure measured in the lateral decu- North Am. 2006;39(5):943-58. 20. Li HB, Shi JB, Cheng L, et al. Salvage optic nerve pupillary defect; however, visual field bitus position. decompression for traumatic blindness under nasal deficits may be present. The most 4. Normal cerebrospinal fluid (CSF) endoscopy: risk and benefit analysis. Clin Otolaryngol. 2007;32(6):447-51. common visual field defect associated composition. 21. Berry M, Ahmed Z, Lorber B et al. Regeneration with PTC is an enlarged blind spot, 5. No evidence of hydrocephalus, of axons in the . Restor Neurol Neurosci. followed a nasal visual field defect, typ- mass, structural, or vascular lesion on 2008;26(2-3):147-74. 22. Yu-Wai-Man P, Griffiths PG. Steroids for trau- matic optic neuropathy. Cochrane Database Syst Rev. 2007;17;(4):CD006032. 23. Wilhelm H. Traumatic optic neuropathy. Laryngorhinootologie. 2009;88(3):194-203.

PSEUDOTUMOR CEREBRI

Signs and Symptoms Pseudotumor cerebri (PTC), also known as idiopathic intracranial hyper- tension, is encountered most frequently in young, overweight women between the ages of twenty and forty-five years Papilledema in PTC; note the pronounced disc edema, splinter hemorrhages, and Paton’s folds. of age.1-3 Headache is the most com- mon presenting complaint, occurring ically affecting the inferior quadrants. magnetic resonance imaging (MRI) or in more than 90% of cases seen.4,5 Other field losses seen in PTC include contrast-enhanced computed tomogra- Dizziness, nausea and vomiting may arcuate defects, generalized constric- phy (CT) for typical patients, and MRI also be encountered, but typically there tion, and least commonly, cecocen- and MR venography for all others. are no alterations of consciousness or tral .7 Cranial nerve (CN) VI 6. No other cause of intracranial higher cognitive function. Tinnitus, palsy, secondary to compression of the hypertension identified. or a “rushing” sound in the ears, is nerve within the subarachnoid space as The precise mechanism of PTC is another frequent complaint. Visual it leaves the brainstem is possible; it is not fully understood. Cerebrospinal symptoms are present in up to 70% typically unilateral and intermittent.6 fluid is manufactured by the choroid of all patients with PTC, and include plexus and small blood vessels of the transient visual obscurations, general Pathophysiology brain. It is a necessary protective and blurriness, and intermittent horizontal Pseudotumor cerebri is a syndromic cushioning agent which protects neural diplopia.6 These symptoms tend to disorder that involves elevated intra- tissue. Many consider PTC to be a worsen in association with Valsalva cranial pressure in the absence of mass result of poor CSF absorption by the maneuvers and changes in posture. lesion, hydrocephalus, hemorrhage, or arachnoid villi of the meninges sur- Funduscopic evaluation demon- other identifiable intracranial pathol- rounding the brain and spinal cord.1 strates bilaterally swollen, edematous ogy. The modified Dandy Criteria Many conditions and factors have been optic nerves consistent with true pap- (originally penned by Walter E. Dandy proposed as causative or contributory illedema. Ophthalmoscopy may reveal in 1937) delineates the diagnostic para- agents, including exogenous drugs (e.g., striations within the nerve fiber layer, digm for PTC.8 Historically, J. Lawton naladixic acid, tetracycline, minocycline, blurring of the superior and inferior Smith and Michael Wall were among corticosteroids, vitamin A), anemias, margins of the neural rim, disc hyper- the first to modify the original Dandy blood dyscrasias, and chronic respira- emia, and capillary dilatation. More listing; most recently, Friedman and tory insufficiency, including obstructive

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sleep apnea.9 Also, it seems quite prob- cerebral ventricles with otherwise nor- ure rates and the risk of infection limits able that the metabolic and endocrine mal brain structure. Patients with unre- the utility and widespread use of such consequences of obesity play an impor- markable radiographic studies should surgical intervention. Bariatric surgery tant role in the pathogenesis of PTC.10 be subsequently referred for neurosurgi- (i.e., gastric bypass) has been used for Adipose tissue is now recognized as an cal consultation and lumbar puncture. some patients with PTC, and has shown active endocrine organ, and its prod- Additional medical testing may include anecdotal success, but is not considered ucts—leptin and gherlin—may contrib- serologic and hematological studies, a first-line treatment.18,19 ute to PTC development.11 Though depending upon the disposition of the Ophthalmic management of patients current theories are not without merit, attending physician. diagnosed with PTC should include there is still little consensus on the exact Weight loss is an important aspect careful and frequent evaluation with etiology. of treatment for all patients with PTC. threshold visual field assessment, acu- Whatever the cause, the subsequent Recent studies indicate that even small ity measurement, contrast sensitivity result is elevation of intracranial pres- changes in body mass index—on the testing, and indirect ophthalmoscopy. sure. However, because the process is order of 5% to 10%—can have a cru- Photodocumentation of the nerve heads typically slow and insidious, there is cial impact on symptom severity.13,14 should also be performed. Symptomatic ample time for the ventricular system Initial medical therapy usually involves relief of diplopia can be provided via to compensate. This is the reason that a carbonic anhydrase inhibitor, such as alternate eye patching. there is no dilation of the cerebral ven- oral acetazolamide (Diamox, Lederle tricles in PTC. Increased intracranial Laboratories), which serves to reduce Clinical Pearls pressure induces stress on the peripheral CSF production at the level of the • Past literature refers to PTC as aspects of the brain, including the cra- choroid plexus.1 For those who cannot benign idiopathic intracranial hyper- nial nerves. Stagnation of axoplasmic tolerate carbonic anhydrase inhibitors, tension; however, it should be stressed flow in the optic nerve (CN II) results in the diuretic furosemide (Lasix, Aventis that this condition is far from benign. papilledema and transient visual obscu- Pharmaceuticals) has been used suc- Patients may suffer intractable head- rations; when the abducens nerve (CN cessfully. Topiramate is yet another ache, severe nausea, intermittent diplo- VI) is involved, the result is intermit- option for patients with PTC. This pia and permanent vision loss via optic tent lateral rectus palsy with resultant drug, which is a partial carbonic anhy- atrophy if not properly managed. diplopia. drase inhibitor, has recently been shown • While PTC is most commonly to be as effective as acetazolamide in encountered in obese women of child- Management ameliorating headache symptoms, with bearing age, it may be encountered in All patients presenting with sus- the added advantageous side-effect of patients of both sexes and various ages. pected papilledema or other manifesta- concurrent weight loss.15 The use of Numerous cases involving men and chil- tions of intracranial hypertension war- systemic corticosteroids is not a viable dren have been documented.20,21 rant prompt medical evaluation and long-term option for PTC, and should • It is possible to encounter patients neuroimaging. PTC is a diagnosis of be avoided.15 with PTC that do not manifest papill- exclusion. Current protocol dictates that For patients in whom conventional edema. patients presumptively suspected of hav- medical therapy fails to alleviate the ing true papilledema undergo magnetic symptoms and prevent pathologic 1. Randhawa S, Van Stavern GP. Idiopathic intracra- nial hypertension (pseudotumor cerebri). Curr Opin resonance imaging within 24 hours. The decline, surgical intervention is the Ophthalmol. 2008;19(6):445-53. purpose of this test is to rule out any only definitive treatment. Optic nerve 2. Durcan FJ, Corbett JJ, Wall M. The incidence of pseudotumor cerebri. Population studies in Iowa and space occupying mass lesions, thus intra- sheath fenestration is recommended Louisiana. Arch Neurol. 1988;45(8):875-7. venous contrast media should be utilized for those patients with chronic disc 3. Radhakrishnan K, Ahlskog JE, Cross SA, et al. Idiopathic intracranial hypertension (pseudotumor cere- unless medically contraindicated. MRI edema and severe or progressive vision bri). Descriptive epidemiology in Rochester, Minn, is the preferred technique for visualizing loss. Although this technique fails to 1976-1990. Arch Neurol. 1993;50(1):78-80. soft tissue, with intravenous gadolinium directly address the issue of elevated 4. Kesler A, Hadayer A, Goldhammer Y, et al. Idiopathic intracranial hypertension: risk of recurrences. providing further image enhancement. intracranial pressure, it has been shown Neurology. 2004;63(9):1737-9. Plain CT is generally not adequate in to stabilize or improve visual function 5. Friedman DI. Pseudotumor cerebri presenting as headache. Expert Rev Neurother. 2008;8(3):397-407. these instances; however, if MRI is not in over 90% of patients, and may even 6. Giuseffi V, Wall M, Siegel PZ, Rojas PB. Symptoms 16,17 possible because of patient obesity or help alleviate headaches. Patients and disease associations in idiopathic intracranial claustrophobia, a CT scan with contrast with more severe complications or recal- hypertension (pseudotumor cerebri): a case-control study. Neurology. 1991;41(2 (Pt 1)):239-44. 12 is a better study than none at all. citrant PTC may be treated with a 7. Wall M, Hart WM Jr., Burde RM. Visual field defects In cases of PTC, neuroimaging typ- cerebrospinal fluid shunting procedure; in idiopathic intracranial hypertension (pseudotumor cerebri). Am J Ophthalmol. 1983;96(5):654-69. ically displays small to normal-sized unfortunately however, high overall fail- 8. Friedman DI, Jacobson DM. Diagnostic criteria

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001_ro0410_hndbkv7.indd 53 4/5/10 8:47 AM for idiopathic intracranial hypertension. Neurology. 2002;59(10):1492-5. posterior optic nerves. Clinically, this lobe (adenohypophysis) is derived from 9. Marcus DM, Lynn J, Miller JJ, et al. Sleep dis- may present in the form of blurred vision ectoderm, which ultimately forms the orders: A risk factor for pseudotumor cerebri? J in one or both eyes, color desaturation, roof of the mouth, while the posterior Neuroophthalmol. 2001;21(2):121-3. 10. Ooi LY, Walker BR, Bodkin PA, et al. Idiopathic diplopia and visual field loss. Classically, lobe (neurohypophysis) forms from the intracranial hypertension: can studies of obesity pro- patients with craniopharygioma expe- neuroectoderm of the diencephalon. vide the key to understanding pathogenesis? Br J Neurosurg. 2008;22(2):187-94. rience a bitemporal hemianopic field Rathke’s pouch is the name given to the 11. Lampl Y, Eshel Y, Kessler A, et al. Serum leptin level defect; however, in contradistinction evagination of tissue that grows upwards in women with idiopathic intracranial hypertension. J to , craniopharyn- to form the adenohypophysis; the down- Neurol Neurosurg Psychiatry. 2002;72(5):642-3. 12. Friedman DI. Pseudotumor cerebri. Neurol Clin. gioma tends to produce a defect that growth from the diencephalon is referred 2004;22(1):99-131, vi. progresses in density from inferior to to as the infundibulum. Both of these 13. Daniels AB, Liu GT, Volpe NJ, et al. Profiles of 3 obesity, weight gain, and quality of life in idiopathic superior. Less commonly, patients may diverticula migrate along a pathway intracranial hypertension (pseudotumor cerebri). Am J demonstrate a homonymous hemiano- known as the craniopharyngeal canal. Ophthalmol. 2007;143(4):635-41. pic defect or generalized constriction.3 As the pituitary gland develops, Rathke’s 14. Wong R, Madill SA, Pandey P, et al. Idiopathic intra- cranial hypertension: the association between weight loss and the requirement for systemic treatment. BMC Ophthalmol. 2007; 21(7):15. 15. Celebisoy N, Gökçay F, Sirin H, et al. Treatment of idiopathic intracranial hypertension: topiramate vs acet- azolamide, an open-label study. Acta Neurol Scand. 2007;116(5):322-7. 16. Banta JT, Farris BK. Pseudotumor cerebri and optic nerve sheath decompression. Ophthalmology 2000 107(10):1907-12. 17. Chandrasekaran S, McCluskey P, Minassian D, Assaad N. Visual outcomes for optic nerve sheath fenestration in pseudotumour cerebri and related con- ditions. Clin Experiment Ophthalmol. 2006;34(7):661-5. 18. Sugerman HJ, Felton WL III, Sismanis A, et al. Gastric surgery for pseudotumor cerebri associated with severe obesity. Ann Surg. 1999;229(5):634-4. 19. Nadkarni T, Rekate HL, Wallace D. Resolution of pseudotumor cerebri after bariatric surgery for related obesity. J Neurosurg. 2004;101(5):878-80. 20. Wolf A, Hutcheson KA. Advances in evaluation and management of pediatric idiopathic intracranial hyper- tension. Curr Opin Ophthalmol. 2008;19(5):391-7. Craniopharyngioma can present with a bitemporal hemianopia. 21. Kesler A, Goldhammer Y, Gadoth N. Do men with pseudomotor cerebri share the same characteristics as women? A retrospective review of 141 cases. J Funduscopic findings vary—patients pouch closes on itself, but the cells that Neuroophthalmol. 2001;21(1):15-7. with long-standing compression may line it migrate along the anterior aspect present with optic atrophy and associ- of the infundibulum forming the pars CRANIOPHARYNGIOMA ated disc pallor.4 Papilledema is possible, tuberallis. These cells are also retained though an uncommon manifestation between the lobes of the pituitary as the Signs and Symptoms associated with craniopharyngioma.5 pars intermedia.6 Craniopharyngioma represents an Non-ocular signs and symptoms represent defective development and uncommon intracranial tumor.1,2 The are quite varied. The most frequently proliferation of Rathke’s pouch and/or incidence of newly diagnosed cranio- described manifestations include head- remnants of the craniopharyngeal canal. pharyngiomas is between 0.13 and two aches, nausea/vomiting, growth failure The proposed pathogenic mechanisms cases per 100,000 persons per year in (in children) and hypogonadism (in include: 1. neoplastic transformation of the United States.1 Craniopharygiomas adults).6 Due to compressive forces and embryonic squamous cell nests of the demonstrate a bimodal age distribution, expansion of the lesion, pituitary func- involuted craniopharyngeal duct, and; 2. with peak incidence rates in children tion may also be compromised, leading metaplasia of adenohypophyseal cells in from five-14 years of age and in adults to potential hormonal dysfunctions, fur- the pituitary stalk or gland.7 between 50-74 years of age.2 There ther blurring the diagnostic line between Craniopharyngiomas extend hori- appear to be no significant differences in craniopharyngioma and pituitary ade- zontally in various directions as they gender or racial distribution.2 noma. grow. They can progress anteriorly into Craniopharygiomas are similar to the prechiasmatic cistern and subfron- pituitary adenomas in the way they pres- Pathophysiology tal spaces, or posteriorly into the pre- ent clinically; visual symptoms result Embryonically, the pituitary gland pontine and interpeduncular cisterns, from mass effects on the chiasm and develops from two sources. The anterior cerebellopontine angle, third ventricle,

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posterior fossa, and foramen magnum. raphy (MRA) is useful in delineating the patients require two or more anterior They can also extend laterally toward vascular supply to the craniopharyngio- pituitary hormone replacement ther- the subtemporal spaces. Rarely, they ma and also in helping to differentiate it apies. Permanent diabetes insipidus can extend extracranially into the naso- from possible vascular malformations.9 A occurs in up to 75% of adults and pharyngeal area or down the cervical medical referral is warranted to assess the 90% of children.16 Craniopharyngioma spine.7 Craniopharyngiomas that prog- hypothalamic-pituitary axis hormones patients require lifelong follow-up with ress anteriorly can impinge on the pos- and cortisol levels, as these may often be an endocrinologist. terior notch of the chiasm, subsequently disturbed. • In general, the 10-year survival damaging the superior nasal fibers which The decision to intervene therapeuti- rate for craniopharyngiomas is 90% decussate in that area. The resultant cally is typically based upon the overall and the 20-year survival rate for pedi- field defect is a bitemporal clinical picture and the radiologic find- atric craniopharyngiomas is approxi- with increased density inferiorly; because ings; confirmatory diagnosis is based mately 60%.17 tumor growth is not always symmetrical, upon histological examination. The pre- the field loss can likewise be asymmetri- ferred form of therapy in all cases of 1. Bunin GR, Surawicz TS, Witman PA, et al. The descriptive epidemiology of craniopharyngioma. J cal between the two eyes. craniopharyngioma is surgical, though Neurosurg. 1998;89(4):547-51. Craniopharyngiomas demonstrate approaches differ depending on the size 2. Karavitaki N, Wass JA. Craniopharyngiomas. Endocrinol Metab Clin North Am. 2008;37(1):173-93. benign histology, but paradoxically can of the tumor and the degree to which it 3. Garnett MR, Puget S, Grill J, et al. Craniopharyngioma. display malignant behaviors; they have has impacted adjacent structures, partic- Orphanet J Rare Dis. 2007;2:18. 4. Defoort-Dhellemmes S, Moritz F, Bouacha I, et a tendency to invade surrounding struc- ularly the hypothalamus. Radiotherapy is al. Craniopharyngioma: ophthalmological aspects at tures and recur after what was thought not considered a stand-alone treatment diagnosis. J Pediatr Endocrinol Metab. 2006;19 Suppl to be total resection. There are two for craniopharyngioma, but it is often 1:321-4. 5. Kennedy HB, Smith RJ. Eye signs in craniopharyn- main varieties of craniopharyngioma, used adjunctively with surgical interven- gioma. Br J Ophthalmol. 1975;59(12):689-95. based upon histologic analysis: the ada- tion, particularly when a planned, limited 6. Megdiche-Bazarbacha H, Ben Hammouda K, Aicha AB, et al. Intrasphenoidal rathke cleft cyst. AJNR Am J mantinomatous and papillary subtypes. technique is employed. External beam Neuroradiol. 2006;27(5):1098-100. Adamantinomatous tumors may be irradiation and stereotactic radiosurgery 7. Karavitaki N, Cudlip S, Adams CB, et al. diagnosed at any age, but predominantly (i.e., gamma knife) are also commonly Craniopharyngiomas. Endocr Rev 2006;27(4):371-97. 8. Weiner HL, Wisoff JH, Rosenberg ME, et al. affect young subjects during their first employed for any residual tumor fol- Craniopharyngiomas: a clinicopathological analysis of two decades of life.8 The major distin- lowing surgical excision, as revealed by factors predictive of recurrence and functional out- 10 come. Neurosurgery. 1994;35(6):1001-11. guishing characteristic is the presence of post-operative MRI. While systemic 9. Rossi A, Cama A, Consales A, et al. Neuroimaging calcification, most notably in the form of chemotherapy seems to be of little value of pediatric craniopharyngiomas: a pictorial essay. J bone or teeth within the mass. Papillary in craniopharyngioma, direct injections Pediatr Endocrinol Metab. 2006;19 Suppl 1:299-319. 10. Habrand JL, Saran F, Alapetite C, et al. Radiation craniopharyngiomas occur almost exclu- of bleomycin or interferon alpha into the therapy in the management of craniopharyngioma: sively in adults.8 Calcification is rarely tumor mass may be of benefit in purely Current concepts and future developments. J Pediatr 11,12 Endocrinol Metab. 2006;19 Suppl 1:389-94. seen in this type and infiltration of cystic lesions. 11. Hargrave DR. Does chemotherapy have a role in adjacent brain tissue is also less common the management of craniopharyngioma? J Pediatr Endocrinol Metab. 2006;19 Suppl 1:407-12. in the papillary variety as compared to Clinical Pearls 12. Cavalheiro S, Dastoli PA, Silva NS, et al. Use of 7,8 adamantinomatous type. • Based upon the tell-tale symp- interferon alpha in intratumoral chemotherapy for cys- toms and visual dysfunction, clinicians tic craniopharyngioma. Childs Nerv Syst. 2005;21(8- 9):719-24. Management must carefully inspect the optic discs 13. Wenzel D, Brandl U, Beck JD, et al. Visual evoked Patients who present with signs or to assess for papilledema or pallor, potentials in tumors from orbita to occipital lobe in childhood. Neurosurg Rev. 1988;11(3-4):279-86. symptoms indicative of chiasmal pathol- perform visual field testing and appro- 14. Stark KL, Kaufman B, Lee BC, et al. Visual recovery ogy, such as craniopharyngioma, warrant priately refer suspicious patients for after a year of craniopharyngioma-related amaurosis: prompt neuroimaging and medical con- medical evaluation. Electrodiagnostic report of a nine-year-old child and a review of patho- physiologic mechanisms. J AAPOS. 1999;3(6):366-71. sultation. Both computed tomography testing in the form of visually evoked 15. Cavazzuti V, Fischer EG, Welch K, et al. (CT) and magnetic resonance imaging potential may be helpful.13 Following Neurological and psychophysiological sequelae fol- lowing different treatments of craniopharyngioma in (MRI) may be used; each has its advan- cessation of therapy, visual function children. J Neurosurg. 1983;59(3):409-417. tages. CT is preferable for identifying and fields should be reassessed to mark 16. de Vile CJ, Grant DB, Hayward RD, et al. calcification associated with adamanino- improvements and track stability.14 Obesity in childhood craniopharyngioma: relation to postoperative hypothalamic damage shown by mag- matous tumors, but MRI with gado- • Despite the potential for visual netic resonance imaging. J Clin Endocrinol Metab. linium remains superior for delineating recovery, endocrine disturbances often 1996;81(7):2734-7. 17. Karavitaki N, Brufani C, Warner JT, et al. the extent of the mass and, in particular, persist and may even be exacerbated Craniopharyngiomas in children and adults: systematic its involvement with the hypothalamus.3 by surgery.15 Obesity is present in analysis of 121 cases with long-term follow-up. Clin In addition, magnetic resonance angiog- 50% of patients. Eighty percent of Endocrinol (Oxf). 2005;62(4):397-409.

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CAT SCRATCH DISEASE the ocular manifestation most associ- Management ated with CSD is neuroretinitis, a Proper diagnosis begins with clini- Signs and Symptoms combination of disc edema with a cal suspicion based upon ocular find- Patients with cat scratch disease stellate macular star of exudates.1,10-13 ings in association with an anteced- (CSD) are typically younger. Often, Anterior uveitis is also a common find- ent febrile illness. Testing for CSD there is a history of being scratched ing.1,14,15 Peripheral ulcerative keratitis involves obtaining ELISA Bartonella by a cat, though has also been henselae titres. Additionally, titres for this history is not reported.16 Bartonella quintana are appropriate as invariably pres- Other fun- well in order to avoid a false negative ent.1-5 However, dus findings result. An alternate diagnostic modal- there will usu- include cho- ity is a polymerase chain reaction anal- ally be a history of roiditis with ysis of lymphadenopathy aspirate. This exposure to cats, maculopathy, should be considered in the clinical though there have peripapil- situation where CSD is strongly sus- been reports where lary serous pected and ELISA titers are negative, patients could not macular borderline, or otherwise inconclusive.8 recall any feline detachment, In immunocompetent individuals, exposure.6 The discrete foci the course of CSD is self-limiting with incidence of case Florid disc edema and macular star in cat-scratch of a good prognosis.21 As such, medi- presentations neuroretinitis. manifested as cal treatment is generally unnecessary. tends to be higher white retinal However, cases with ocular involve- during breeding seasons of cats, which or choroidal lesions, vitritis, posterior ment are generally recommended for is in the fall and winter. uveitis, vascular occlusions, optic neu- treatment. The causative organism is The patient will manifest a regional ritis, and submacular exudates.17-20 susceptible to a number of antibiotics lymphadenitis with the appearance of including penicillins, cephalosporins, a small cutaneous lesion at the site of Pathophysiology aminoglycosides, tetracyclines, macro- the inoculation following an incuba- Cat scratch disease is caused by lides, fluoroquinolones and rifamicin. tion period ranging from several days the gram-negative bacillus, Bartonella Doxycycline 100mg p.o. b.i.d. for four to weeks after initial exposure.7,8 The henselae and, to a lesser extent, weeks is a recommended therapy. This patient will develop fever and flu-like Bartonella quintana.1-6 symptoms, which typically resolve over The organism is trans- three to six weeks. Vision varies wide- mitted through the ly, from normal to finger counting, bite or scratch of an depending upon the severity and types infected cat or kitten. of ocular manifestations. While patients Transmission through may be visually asymptomatic, as the flea bites is not report- disease affects ocular tissues, relative ed in humans, though afferent pupil defects, dyschromatopsia it likely occurs in cats. and field loss will be variably present Following inoculation, when the eye becomes involved.7,8 there is an incubation Systemic signs may include hepa- period followed by a tosplenic infection, encephalopathy, period of self-limiting osteomyelitis and endocarditis. One of febrile illness with the main ocular syndromes occurring lymphadenopathy. The Macula star and retinal edema with minimal disc swelling in cat- from CSD is Parinaud’s oculoglandular organism spreads to scratch neuroretinitis. syndrome, manifesting as conjuncti- numerous systems via vitis, retrotarsal conjunctival granula- blood and lymph.1-6,21 Curiously, it may be used alone or in combina- tions, regional preauricular and cervi- may be that there are unrecognized tion with Rifampin 300mg b.i.d.5,9-14 cal lymphadenitis and fever.9 Beyond healthy asymptomatic carriers of B. Azithromycin is an acceptable sub- Parinaud’s oculoglandular syndrome, henselae.15 stitute.17,21 In cases with vision loss,

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ease: a diagnostic conundrum. Int J STD AIDS. 2009 typically from neuroretinitis, oral pred- Aug;20(8):585-6. the ages of 46 and 75 years, though nisone is often employed with antimi- 7. Aupy B, Conessa C, Clement P, et al. Cat scratch some patients may begin manifesting 17 disease: a diagnosis to be aware of! Rev Laryngol Otol 1,3-5 crobial therapy. Any anterior uveitis Rhinol (Bord). 2008;129(1):53-6. the disorder much earlier. It is not can be treated in the traditional fash- 8. Eglantin F, Hamdad F, El Samad Y, et al. The diag- uncommon to encounter systemic dis- ion employing appropriate cycloplegia nosis of cat-scratch-disease-associated adenitis: diag- eases in association with Sjögren’s syn- nostic value of serology and polymerase chain reaction. and topical anti-inflammatory prepa- Pathol Biol (Paris). 2008 Nov-Dec;56(7-8):461-6. drome, particularly autoimmune and rations. 9. Chu BC, Tam VT. A serologically proven case of cat- collagen vascular disorders. Between scratch disease presenting with neuroretinitis. Hong Kong Med J. 2009 Oct;15(5):391-3. 25% and 50% of these patients suf- Clinical Pearls 10. Pinto Jr VL, Curi AL, Pinto Ada S, et al. Cat scratch fer from rheumatoid arthritis; other • CSD should be considered first disease complicated with aseptic meningitis and neu- disorders may include systemic lupus roretinitis. Braz J Infect Dis. 2008 Apr;12(2):158-60. when encountering neuroretinitis. 11. Hernandez-Da-Mota S, Escalante-Razo F. erythematosus (SLE), polymyositis, • When the diagnosis is correct Bartonellosis causing bilateral Leber neuroretini- thyroiditis, scleroderma, hypergam- tis: a case report. Eur J Ophthalmol. 2009 Mar- 1-3,6 and the cause of the neuroretinitis Apr;19(2):307-9. maglobulinemia, and anemia. is confirmed secondary to Bartonella 12. Reed JB, Scales DK, Wong MT, et al. Bartonella Fibromyalgia may also be associat- infection, the retinal condition, while henselae neuroretinitis in cat scratch disease. ed with Sjögren’s syndrome in some Diagnosis, management, and sequelae. Ophthalmology 3 appearing intimidating, almost always 1998 Mar;105(3):459-66. patients. resolves without inducing persistent 13. De Schryver I, Stevens AM, Vereecke G, et al. cat The most common symptoms scratch disease (CSD) in patients with stellate neuro- retinal edema, choroidal neovascular- retinitis: 3 cases. Bull Soc Belge Ophthalmol. 2002; encountered with Sjögren’s syndrome ization, chorioretinal scar formation or 286:41-6. involve dry eye and dry mouth com- 14. Martínez-Osorio H, Calonge M, Torres J, et al. other deleterious retinal consequences. Cat-scratch disease (ocular bartonellosis) presenting plaints. Severe dry eye in the form of • CSD is a benign, self-limiting as bilateral recurrent iridocyclitis. Clin Infect Dis. 2005 keratoconjunctivitis sicca (KCS) is typ- disease and the value of treatment in Mar 1;40(5):e43-5. ical and is often the first clinical mani- 15. Kamoi K, Yoshida T, Takase H, et al. Seroprevalence 5 immunocompetent individuals appears of Bartonella henselae in patients with uveitis and festation. Patients with KCS present to be in shortening the duration of the healthy individuals in Tokyo. Jpn J Ophthalmol. 2009 with mild to severe ocular burning and Sep;53(5):490-3. disease. 16. Prasher P, Di Pascuale M, Cavanagh HD. discomfort; a sandy or gritty feeling is • Always question for an ante- Bilateral chronic peripheral ulcerative keratitis second- often reported. Examination may reveal cedent history of febrile illness and ary to cat-scratch disease. Eye Contact Lens. 2008 a diminished tear meniscus, epithelial May;34(3):191-3. lymphadenopathy when encountering 17. Berguiga M, Abouzeid H, Bart PA, et al. corneal stippling, reduced fluorescein patients with painless vision loss with Severe occlusive vasculitis as a complication of cat tear break up time (FTBUT), and rose scratch disease. Klin Monatsbl Augenheilkd. 2008 disc edema, as well as retinochoroidal May;225(5):486-7. bengal or lissamine green staining in a exudates, vascular occlusions, serous 18. Asensio-Sánchez VM, Rodríguez-Delgado B, band-appearing region of the conjunc- detachments, occult maculopathy, and García-Herrero E, et al. Serous macular detachment as tiva and/or cornea. Tear volume assess- an atypical sign in cat scratch disease. Arch Soc Esp anterior uveitis. Oftalmol. 2006 Dec;81(12):717-9. ment via Schirmer test or Zone Quick • Neuroretinitis occurring from cat 19. Wimmersberger Y, Baglivo E. Bartonella henselae (phenol red thread test) will show infection presenting as a unilateral acute maculopathy. scratch disease tends to look much Klin Monatsbl Augenheilkd. 2007 Apr;224(4):311-3. significant reduction, as aqueous defi- worse than it really is in terms of visual 20. Biousse V. Optic neuritis in cat scratch disease. Rev ciency is a hallmark sign.5,7,8 Mucus Neurol (Paris). 2005 May;161(5):571-3. prognosis, which is typically good. 21. Windsor JJ. Cat-scratch disease: epidemiology, filaments are often present within the aetiology, and treatment. Br J Biomed Sci. 2001; tear film; when these become large 1. Ormerod LD, Dailey JP. Ocular manifestations of 58(2):101-10. and adhere to the corneal epithelium, cat-scratch disease. Curr Opin Ophthalmol. 1999 Jun 10(3):209-16. filamentary keratitis may result. Other 2. Dabrowska-Bień J, Pietniczka-Załeska M, Rowicki SJÖGREN’S SYNDROME associated ocular findings may include T. Cat scratch disease—a diagnostic problem, case report. Otolaryngol Pol. 2009 Mar-Apr;63(2):154-7. staphylococcal blepharitis, ropy mucus 3. Sala E, Lipiec A, Zygmunt A, et al. Cat scratch Signs and Symptoms strand accumulation, meibomian gland disease—course, diagnosis. Przegl Epidemiol. 2006;60(2):307-13. Sjögren’s syndrome has a distinct dysfunction, and corneal pannus in 7,8 4. Podsiadły E, Sapiejka E, Dabrowska-Bień J, et al. predilection for women, with most extreme cases. Diagnostics of cat scratch disease and present meth- sources citing a 9:1 female-to-male Dry mouth, or xerostomia, results ods of bartonellosis recognition—a case report. Pol 1-3 Merkur Lekarski. 2009 Feb;26(152):131-5. ratio. All racial and ethnic groups in complaints of dysphagia, loss of 5. Täger FM, Jahnsen KJ, Mediavilla RM, et al. Ocular may be affected. Sjögren’s also displays taste and painful lesions of the lips and bartonellosis: report of three clinical cases. Rev Chilena 1-3,5,6 Infectol. 2008 Feb;25(1):58-63. a greater incidence with increasing age; tongue. Patients may report diffi- 6. Scott C, Azwa A, Cohen C, et al. Cat scratch dis- the majority of patients fall between culty in chewing, swallowing, or speak-

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001_ro0410_hndbkv7.indd 57 4/5/10 8:47 AM ing. They may report the need to drink tion, though it may be as high as 3.4% other autoimmune conditions. Most copious amounts of fluid to simply fin- in older individuals.4,5,11 Although the of these individuals possess circulat- ish a meal. Signs of dry mouth include exact etiology of Sjögren’s syndrome ing antibodies specific to Sjögren’s fissures at the corners of the mouth, has not been identified, researchers syndrome, known as SS-A (or Ro) and generalized hyperemia of the oral tis- speculate that the condition results SS-B (or La).13 Secondary Sjögren’s sues, thick and/or diminished saliva, from a combination of genetic and syndrome is typically associated with and a smooth or grooved appearance environmental factors. Several differ- pre-existing systemic disorders such as of the tongue’s surface.9,10 Xerostomia ent genes may be implicated in dif- rheumatoid arthritis or SLE. Patients also enhances the likelihood of tooth ferent racial and ethnic groups, and with secondary Sjögren’s syndrome are decay, with many affected patients a “trigger” factor such as a viral or less likely to display antibodies, but reporting increased incidence of dental bacterial infection may serve to activate are more likely to display severe symp- misfortune. If the dry mouth extends the specific gene.12 Here, the immune toms and debilitation as a result of the to the oropharynx, hoarseness and disease.13 Actually, the distinction a dry cough result.3,9 In addi- between primary and secondary tion, parotid gland enlargement Sjögren’s syndrome can be far more may be seen to occur in as many as difficult than implied above. Often two-thirds of Sjögren’s syndrome there are confounding factors, such patients, leading to a “chipmunk” as non-rheumatoid arthropathies appearance of the face in later and arthralgias that prevent phy- stages.6 sicians from clearly defining the Sjögren’s syndrome may affect condition. organ systems beyond the eye and mouth. Impairment of the neuro- Management logic, pulmonary, rheumatologic, While there is no cure for dermatologic, renal and genitouri- Sjögren’s syndrome at the present nary systems is commonly encoun- time, early diagnosis is important tered.1-3,5-7,10 Symptoms that may for several reasons. First and fore- be described include dry skin or most, a number of therapies have skin rashes, pain or weakness in been introduced in recent years joints or muscles, numbness or that may significantly reduce the tingling in the extremities, labored potentially debilitating symptoms breathing, vaginal dryness, diffi- of Sjögren’s syndrome. Secondly, culties with memory and menta- studies have demonstrated that up tion, and fatigue. There is a wide Oral signs of Sjögren’s syndrome: advanced tooth decay, to 10% of patients with Sjögren’s range of severity seen with these cheilitis and dessication of the tongue. syndrome develop malignant lym- symptoms; they may be encoun- phoma as a late complication of tered as mild peripheral complaints or reaction that is initiated in response to the disease.14,15 While lymphoma is may be a source of debilitation. an infection is somehow altered and is very responsive to chemotherapy, it is redirected toward the exocrine glands. still a lethal disease in untreated cases. Pathophysiology The accumulation of lymphocytes Diagnosis begins with clinical sus- Sjögren’s syndrome is a chronic (white blood cells) and plasma cells in picion. Particular consideration should disorder characterized by lymphocytic these glands results in inflammation be given to older females with dry eye infiltration of the exocrine glands. It and disruption of normal glandular and any of the concurrent symptoms is classified as an autoimmune rheu- activity.3 Ultimately, the glands are delineated above. Patients should be matic disease, and is the second most rendered dysfunctional. directed to undergo a full rheumato- common disease in this category after Two forms of Sjögren’s syndrome are logic examination; a referral to a den- rheumatoid arthritis.1 The prevalence recognized clinically: primary Sjögren’s tist or oral surgeon skilled in managing of this condition varies based upon the syndrome and secondary Sjögren’s syn- Sjögren’s syndrome is also important. population, ranging in studies from drome. Primary Sjögren’s syndrome is Laboratory testing may be ordered by 0.6% to 1.5% in the general popula- generally diagnosed in the absence of any of the attending physicians. The

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major tests to consider include: Advanced ocular surface disease may often helpful to examine the hands • Antinuclear antibody (ANA)— necessitate the use of punctal occlusion of patients with suspected Sjögren’s high sensitivity, low specificity. therapy, moisture-retaining goggles, or syndrome. Simply inspecting the digits • Sjögren’s specific antibodies surgical intervention.18 may reveal enlargement of the knuckles (SS-A and SS-B)—medium sensitiv- Two medications that may offer and/or a “gnarled” appearance of the ity, high specificity. relief for both dry mouth and dry eye fingers, characteristic of arthritis. • Rheumatoid factor (RF)—high are oral pilocarpine (Salagen, MGI • To help with dry mouth, advise sensitivity, low specificity. patients to sip fluids (preferably • Erythrocyte sedimentation water) throughout the day. Also, rate (ESR)—high sensitivity, lozenges can help to stimulate saliva low specificity. production. Caution patients with In addition, serologic testing Sjögren’s syndrome to avoid sugared may reveal comorbidities such beverages and candy, as they are as hypergammaglobulinemia, prone to rapid tooth decay. cryoglobulinemia and thyroid • A small tabletop humidifier autoantibodies in a fair percent- may be a way of improving symp- age of patients.1 Biopsies of the toms in some Sjögren’s patients. lacrimal or salivary glands are Increasing environmental humid- very helpful in identifying lym- ity may help those with mild com- phocytic infiltration. The easiest Keratoconjunctivitis sicca associated with Sjögren’s syn- plaints of dry eye, dry skin, or even location to obtain a biopsy is drome. dry mouth. the mucosal surface of the lower • Sjögren’s syndrome is a mul- lip, which contains minor or accessory Pharma) and cevimeline (Evoxac, tisystem disorder that must be coman- salivary glands. This procedure may be SnowBrand Pharmaceuticals). These aged by a variety of medical special- performed by the patient’s rheumatolo- agents act on autonomic receptors ists. Always stress regular dental and gist, or an experienced oral surgeon. within the exocrine glands, such that rheumatological care to these patients. Treatment is aimed at reducing saliva and tear production is stimu- Be sure that the primary care physician symptoms such that the patient is able lated.1 While these agents are only is familiar with possible oculosystemic to carry on normal day-to-day activi- currently FDA approved for manag- associations. Correspond as a mem- ties. In the case of dry eye, tear replace- ing xerostomia, many rheumatologists ber of the health care team to review ment therapy is the initial management and ophthalmologists have reported systemic status and conduct systemic strategy. Non-preserved preparations a concurrent decrease in symptoms screening on a regular basis. should be used with frequency, on the of KCS for patients utilizing these order of four to six times daily depend- medications.18-20 Some rheumatolo- 1. Kassan SS, Moutsopoulos HM. Clinical manifesta- tions and early diagnosis of Sjögren syndrome. Arch ing on the severity of symptoms. gists also feel that hydroxychloroquine Intern Med. 2004 Jun;164(12):1275-84. Products with enhanced ocular sur- sulfate (Plaquenil, Sanofi Winthrop) 2. Carsons S. A review and update of Sjögren’s syn- drome: manifestations, diagnosis, and treatment. Am J face residence time (e.g., Systane Ultra may delay the progression of Sjögren’s Manag Care. 2001 Sep;7(14 Suppl):S433-43 Preservative-Free from Alcon, Blink syndrome and may lessen the severity 3. Fox RI. Sjögren’s syndrome. Lancet. 2005 Jul 21 23-29;366(9482):321-31. Tears from Abbott Medical Optics, of many associated symptoms. 4. Alamanos Y, Tsifetaki N, Voulgari PV, et al. and Refresh Liquigel or Celluvisc from Patients with rheumatoid arthritis Epidemiology of primary Sjögren’s syndrome in north- Allergan) may help provide relief with or other systemic complications typi- west Greece, 1982-2003. Rheumatology (Oxford). 2006 Feb;45(2):187-91. less frequent instillation. More symp- cally require anti-inflammatory thera- 5. Gabriel SE, Michaud K. Epidemiological studies in tomatic patients or those with evidence pies, including both NSAIDs and cor- incidence, prevalence, mortality, and comorbidity of the rheumatic diseases. Arthritis Res Ther. 2009;11(3):229. of ocular surface damage due to inflam- ticosteroids in some cases. This is best 6. Rehman HU. Sjögren’s syndrome. Yonsei Med J. mation may require a short course addressed by participating in comanage- 2003 Dec;44(6):947-54. of topical corticosteroids (e.g., 0.5% ment with the patient’s rheumatologist. 7. Fox RI, Liu AY. Sjögren’s syndrome in . Clin Dermatol. 2006 Sep-Oct;24(5):393-413. loteprednol etabonate q.i.d. for two to 8. Sullivan DA, Schaumberg DA, Suzuki T, et al Sex ste- four weeks), followed by twice-daily Clinical Pearls roids, meibomian gland dysfunction and evaporative dry eye in Sjögren’s syndrome. Lupus. 2002;11(10):667. administration of topical cyclosporin • Because of the high associa- 9. Margaix-Muñoz M, Bagán JV, Poveda R, et al. A (Restasis, Allergan) indefinitely.16,17 tion with rheumatoid arthritis, it is Sjögren’s syndrome of the oral cavity. Review and

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001_ro0410_hndbkv7.indd 59 4/5/10 8:47 AM update. Med Oral Patol Oral Cir Bucal. 2009 Jul 1;14(7):E325-30. 10. Sood S, Anthony R, Pease CT. Sjögren’s syn- drome. Clin Otolaryngol. 2000 Oct;25(5):350-7. 11. Haugen AJ, Peen E, Hultén B, et al. Estimation of the prevalence of primary Sjögren’s syndrome in two age-different community-based populations using two sets of classification criteria: the Hordaland Health Study. Scand J Rheumatol. 2008 Jan-Feb;37(1):30-4. 12. Nikolov NP, Illei GG. Pathogenesis of Sjögren’s syn- drome. Curr Opin Rheumatol. 2009 Sep;21(5):465-70. 13. Prabu A, Marshall T, Gordon C, et al. Use of patient age and anti-Ro/La antibody status to determine the probability of patients with systemic lupus erythemato- sus and sicca symptoms fulfilling criteria for secondary Sjögren’s syndrome. Rheumatology (Oxford). 2003 Jan;42(1):189-91. Typical retinal findings associated with hypertension: arteriolar attenuation, superficial hemorrhages 14. Pillemer SR. Lymphoma and other malignancies and cotton-wool spots. in primary Sjögren’s syndrome. Ann Rheum Dis. 2006 Jun;65(6):704-6. 15. Theander E, Henriksson G, Ljungberg O, et diovascular disease, diabetes, hypercho- and/or 80mm Hg to 89mm Hg dia- al. Lymphoma and other malignancies in primary 4,5 Sjögren’s syndrome: a cohort study on cancer inci- lesterolemia, obesity, sedentary lifestyle, stolic. Conversion to hypertension 4,5 dence and lymphoma predictors. Ann Rheum Dis. high sodium intake, high dietary fat is any reading above that threshold. 2006 Jun;65(6):796-803. intake, alcohol use, smoking, and a Longitudinal data obtained from the 16. Byun YJ, Kim TI, Kwon SM, et al. Efficacy of com- 1,2,9,10,11 bined 0.05% cyclosporine and 1% methylprednisolone stressful lifestyle. Framingham Heart Study have indicat- treatment for chronic dry eye. Cornea. 2009 Aug 31; The National Heart, Lung, and ed that BP values between 130-139mm [Epub ahead of print] 17. Jain AK, Sukhija J, Dwedi S, Sood A. Effect Blood Institute (NHLBI) is an orga- Hg/85-89mm Hg are associated with a of topical cyclosporine on tear functions in tear- nization under the guiding arm of The more than a two-fold increase in relative deficient dry eyes. Ann Ophthalmol (Skokie). 2007 United States Department of Health risk for cardiovascular disease (CVD) Spring;39(1):19-25. 4 18. Management and therapy of dry eye disease: report and Human Services. Its mission is to as compared with those with BP lev- of the Management and Therapy Subcommittee of the provide global leadership for research, els below 120mm Hg/80mmHg.6 In International Dry Eye WorkShop (2007).Ocul Surf. 2007 Apr;5(2):163-78. training and education for promoting multivariable analyses, age, sex, systolic 19. Papas AS, Sherrer YS, Charney M, et al. Successful the prevention and treatment of heart, and diastolic blood pressure, body mass treatment of dry mouth and dry eye symptoms in 3 Sjögren’s syndrome patients with oral pilocarpine: lung and blood diseases. The Joint index, parental hypertension, inactiv- a randomized, placebo-controlled, dose-adjustment National Committee (JNC) was cre- ity, and cigarette smoking were not study. J Clin Rheumatol. 2004 Aug;10(4):169-177. ated as an NHLBI working group and only risk factors but significant predic- 20. Ono M, Takamura E, Shinozaki K, et al. Therapeutic 6 effect of cevimeline on dry eye in patients with Sjögren’s assigned the ongoing task of devel- tors of hypertension. Additional risk syndrome: a randomized, double-blind clinical study. oping clinical practice guidelines for can be assessed via predictors such as Am J Ophthalmol. 2004 Jul;138(1):6-17. 21.Fox RI, Dixon R, Guarrasi V, Krubel S. Treatment of topic areas falling under its mission lipoprotein analysis, measurement of 4 primary Sjögren’s syndrome with hydroxychloroquine: statement. These published guidelines lipoprotein-associated phospholipase a retrospective, open-label study. Lupus. 1996 June;5 are systematically developed to assist A(2), C-reactive protein, assessment of Suppl 1:S31-6. both practitioners and patients through hyperglycemia, increased glomerular fil- the process of decision making regard- tration rate and liver function.4,7 While HYPERTENSION ing appropriate health care for specific the majority of cases may be attributed clinical circumstances.4 The guidelines “essential” etiology (renal dysfunction), Signs and Symptoms define the role of specific diagnostic and systemic hypertension may also result Hypertension is a world-wide dis- treatment modalities and offer manage- secondary to other disease processes, ease of predominately the middle-aged ment paradigms.4,5 The recommenda- such as Cushing’s syndrome, thyroid and older with a trend that demon- tions in the document are based on and parathyroid disease, medication or strates increasing prevalence with age.1- evidence from rigorous reviews of the substance related side effects, vitamin 9 Black adults have a higher incidence published medical literature.3,4 D deficiency or pheochromocytoma.4,12 of hypertension than Caucasian adults The JNC definition of “normal Hypertension is insidious, causing and typically a more severe form of the blood pressure (BP)” is <120mm Hg biomedical alterations to the heart, disease.10 Risk factors for the develop- systolic and <80mm Hg diastolic, blood vasculature, blood tissue and end ment of hypertension include a positive with “pre-hypertension” classified as organs, virtually asymptomatically.4,13 family history of hypertension or car- 120mm Hg to 139mm Hg systolic However, the process itself, by way of

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coronary-pressure-overload leads to left lates the kidneys to retain sodium such as stroke or myocardial infarc- ventricular hypertrophy (LVH), myo- and fluid.21 Angiotensin I is converted tion, coronary microvascular dysfunc- cardial fibrosis and impaired diastolic in the lungs, via the enzyme angio- tion and increased arterial stiffness.23 filling without systolic dysfunction.12 tensin converting enzyme (ACE) to As such, hypertension plays a sig- Systemic symptoms from this pro- angiotensin II.21 Angiotensin II is a nificant role in the development of cess include headache, fatigue, dyspnea potent vasoconstrictor, which increases arteriosclerosis and atherosclerosis.20 (shortness of breath), reduced exer- total peripheral vascular resistance and Hypertension reduces the elasticity of cise tolerance and peripheral extrem- hence elevates BP.21,22 As BP elevates, vessels allowing lipids to deposit in the ity edema.13 While chronic, recur- the looped system begins again with form of atheromas, which in turn leads rent headache is listed as a potential pressure diuresis. In healthy individu- to thrombus formation and possible symptom of hypertension and certainly als, this feedback loop maintains a con- emboli formation. This will impede mandates blood pressure measurement stant blood pressure with only minor blood flow and lead to ischemic dis- as one of the studies for uncovering fluctuations. In patients with essential ease. Coronary heart disease is the diagnosis, it is typically only present in hypertension, this feedback loop fails leading cause of death in hyperten- cases where blood pressure peaks from for any number of reasons. The result sive patients. Ventricular hypertrophy stress or is due to moderate or worse is a higher than normal level of pres- occurs as a result of increased cardiac untreated disease. sure within the renal artery, which output in the face of systemic vascu- Hypertension is manifested within causes the natural mechanisms of regu- lar resistance. Eventually, the heart the eye as both hypertensive retinopa- lation to become unstable and faulty.21 is unable to maintain this constant thy and hypertensive ocular complica- Endothelial dysfunction secondary output and the hypertrophied mus- tions.14-19 Hypertensive ocular compli- to the processes of systemic hyperten- cle outstrips its oxygen supply.4,13,14 cations include retinal vessel occlusion, sion reduces vascular availability of Hypertension induced arteriosclerosis , non-arterit- endothelium-derived nitric oxide.23 can worsen or hasten atrophy of the ic anterior ischemic optic neuropathy, This substance has the potential to renal glomeruli and tubules.22 Over glaucomatous alterations, increased mediate the adverse vascular effects time, this induces additional renal dis- risk of embolic events, internuclear ophthalmoplegia, cranial nerve palsy, and transient ischemic attack.14-19

Pathophysiology Essential hypertension develops from renal system dysfunction.20,21 The kidney is a filtering organ that retains vital blood components and excretes excess fluid. If too much fluid is retained, BP rises. If too little fluid is retained, BP decreases. Arterial pres- sure within the renal artery triggers a feedback loop.21,22 The kidneys excrete Stage IV retinopathy associated with severe hypertension. sodium, which osmotically draws fluid into the excretory system in a process of hypertension. Increased oxidant tress and other potentially mortal com- called pressure diuresis. This causes stress is thought to represent a major plications.22 Cerebrovascular disease is a decrease in both blood fluid vol- mechanism leading to reduced vascu- also a serious complication of hyper- ume and arterial pressure. As pressure lar availability of endothelium-derived tension.22 Hypertension is among the within the renal artery decreases, the nitric oxide.23 Complicated reactive leading causes of stroke.22 kidneys reflexively secrete an enzyme oxygen species are also players in the called renin.21 This enzyme causes the pathology.23 Endothelial dysfunction Management formation of a protein called angio- has been implicated in the macrovas- Reducing morbidity and mortality is tensin I.21 This protein directly stimu- cular complications of hypertension, the main goal in hypertension manage-

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001_ro0410_hndbkv7.indd 61 4/5/10 8:47 AM 8-10 Med J (KUMJ). 2003 Jan-Mar;1(1):27-31. ment. Any measurement fitting the weight loss form a solid base for blood 16. Rucker JC. Neuro-ophthalmology of systemic dis- definition of stage II disease (>160mm pressure protection but, in certain cases ease. Semin Neurol. 2009 Apr;29(2):111-23. HG systolic and/or >100mm Hg dia- of hypertension, they alone may not be 17. Costa VP, Arcieri ES, Harris A. Blood pressure and 2 glaucoma. Br J Ophthalmol. 2009 Oct;93(10):1276-82. stolic) requires either re-evaluation able to maintain healthy levels. 18. DellaCroce JT, Vitale AT. Hypertension and the eye. within one week to one month or Curr Opin Ophthalmol. 2008 Nov;19(6):493-8. 19. Dunlap AB, Kosmorsky GS, Kashyap VS. The fate immediate treatment, depending upon Clinical Pearls of patients with retinal artery occlusion and Hollenhorst the coexistence of other associated • Hypertensive complications are plaque. J Vasc Surg. 2007 Dec;46(6):1125-9. complications.4,5 mediated through arteriosclerosis and 20. Calò LA. Revisiting essential hypertension--a “mechanism-based” approach may argue for a bet- Antihypertensive therapy has been atherosclerosis. ter definition of hypertension. Clin Nephrol. 2009 associated with reductions in stroke • Weight reduction is the most Aug;72(2):83-6. 21. Siragy HM. Renin inhibition: a new modality for incidence and myocardial infarction. potent non-pharmacological method of hypertension management. Curr Hypertens Rep. 2007 It is estimated that in patients with hypertension management. Aug;9(4):291-4. stage 1 hypertension (SBP 140-159mm • Internists and family practitioners 22. Abassi Z, Armaly Z, Nakhoul F, et al. Oral inhibitors of renin and their potential use as therapeutic agents in Hg and/or DBP 90-99mm Hg) and are the most appropriate physicians to treating hypertension. Harefuah. 2008 Jun;147(6):536- additional cardiovascular risk factors, manage patients with hypertension. 42, 573. 23. Landmesser U, Drexler H. Endothelial function and achieving a sustained 12mm Hg reduc- hypertension. Curr Opin Cardiol. 2007 Jul;22(4):316- tion in SBP over 10 years will prevent 1. Langan RC, Bordelon PC, Ghetu MV. Eye on the 20. elderly. Hypertension care: striking the proper balance. 24. Chalmers J, Arima H. Management of hypertension: one death for every 11 patients treated. J Fam Pract. 2009 SEp;58(9):460-8. evidence from the Blood Pressure Lowering Treatment In the added presence of CVD or target 2. Aucott L, Rothnie H, McIntyre L, et al. Long-term Trialists’ Collaboration and from major clinical trials. Pol weight loss from lifestyle intervention benefits blood Arch Med Wewn. 2009 Jun;119(6):373-80. organ damage, only nine patients would pressure? A systematic review. Hypertension. 2009 require such BP reduction to prevent Oct;54(4):756-62. 3. NHLBI mission statement. Available at: www.nhlbi. one death. nih.gov/about/org/mission.htm (Accessed October 29, DIABETES MELLITUS Blood pressure reduction is done 2009). in a stepwise approach, often begin- 4. The Seventh Report of the Joint National Committee Signs and Symptoms on Prevention, Detection, Evaluation and Treatment of ning with non-pharmacologic meth- High Blood Pressure. Available at: www.nhlbi.nih.gov/ Diabetes mellitus (DM) is the most ods, such as weight loss and dietary and guidelines/hypertension/index.htm (Accessed October common endocrine disorder. It is char- 29, 2009). lifestyle modifications. This includes 5. Julius S. Should the results of TROPHY affect the acterized by a defective or deficient the regulation of fatty foods to decrease JNC 7 definition of prehypertension? Curr Hypertens insulin secretory process and or glucose fat and cholesterol ingestion, a modifi- Rep. 2007 Jun;9(3):202-5. underutilization creating hyperglyce- 6. Parikh NI, Pencina MJ, Wang TJ, et al. A risk score 1-23 cation for the intake of salt, restriction for predicting near-term incidence of hypertension: mia. Possible systemic signs and of over all caloric intake and an increase the Framingham Heart Study. Ann Intern Med. 2008 symptoms include polyuria (increased 4,5 Jan;148(2):102-10. in exercise and activity. 7. Borden WB, Davidson MH. Updating the assessment frequency of urination), polydipsia Should non-pharmacological meth- of cardiac risk: beyond Framingham. Rev Cardiovasc (increased thirst), polyphagia (increased ods prove unsuccessful, there are four Med. 2009 Spring;10(2):63-71. appetite), glycosuria, weakness, fatiga- 8. Mallick S, Kanthety R, Rahman M. Home blood pres- 1-18 families of drugs from which physicians sure monitoring in clinical practice: a review. Am J Med. bility, weight loss and nephropathy. traditionally choose: Diuretics (reduce 2009 Sep;122(9):803-10. Ophthalmic signs and symptoms may 9. Cushman WC. Are there benefits to specific anti- blood volume by inhibiting sodium and hypertensive drug therapy? Am J Hypertens. 2003 include chronic conjunctival injection, water retention), beta blockers (decrease Nov;16(11 Pt 2):31S-35S. changes in corneal curvature, large 10. Crook ED, Bryan NB, Hanks R, et al. A review of cardiac output), calcium antagonists interventions to reduce health disparities in cardiovas- fluctuations in refraction, premature (induce vasodilation), and ACE inhibi- cular disease in African Americans. Ethn Dis. 2009 cataractogenesis, nonproliferative and tors (decrease peripheral vascular resis- Spring;19(2):204-8. proliferative retinopathy and cranial 9,11,24 11. Moser M. Update on the management of hyper- 1-24 tance). Along with exercise and tension: recent clinical trials and the JNC 7. J Clin nerve III, IV or VI palsy. improved diet, medications from each Hypertens (Greenwich). 2004 Oct;6(10 Suppl 2):4-13. Type 1 diabetes, formerly known 12. Judd SE, Tangpricha V. Vitamin D deficiency and family can be combined to achieve the risk for cardiovascular disease. Am J Med Sci. 2009 as insulin-dependent diabetes melli- 9,11 desired pressure reduction. While Jul;338(1):40-4. tus (IDDM), juvenile-onset or ketose the product of one’s lifestyle is clearly 13. Gradman AH, Wilson JT. Hypertension and diastolic prone DM, usually begins by age 20 heart failure. Curr Cardiol Rep. 2009 Nov;11(6):422-9. a modifiable risk factor, recent work in 14. Cuspidi C, Negri F, Giudici V, et al. Retinal changes and is defined by an absolute lack this area suggests that diet and weight and cardiac remodeling in systemic hypertension. Ther of insulin caused by a reduction in Adv Cardiovasc Dis. 2009 Jun;3(3):205-14. 1-23 loss are only contributors to a complex 15. Karki KJ. Incidence of ophthalmoscopic fundus the beta-cell mass of the pancreas. problem.2 Proper diet, exercise and changes in hypertensive patients. Kathmandu Univ This may be the result of autoimmune

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processes and may involve genetic from noncarbohydrate precursors susceptibility.17,18 Type 2 diabe- such as glycogenic amino acids. tes, formerly known as non-insu- Elevated glucose levels (sus- lin-dependent diabetes mellitus tained hyperglycemia) result in the (NIDDM) or adult-onset DM, formation of excessive sorbitol (a usually begins after age 40 and is sugar alcohol) via the aldose reduc- a multifactorial disease that may tase/polyol pathway.2 Since sorbi- involve improper insulin secre- tol cannot readily diffuse through tion, malfunctioning insulin and/ cell membranes, tissue edema or insulin resistance in peripheral with resultant changes in function tissues.17,18 Approximately 10% ensue.2 Further, sorbitol poisons of diabetic cases are Type 1 and the supportive pericytes in capil- approximately 90% are Type 2.2,3 lary vessels. With respect to the Non-proliferative retinal changes associated with diabetes: dot & blot hemorrhages and hard exudates. This patient eye, this mechanism contributes to Pathophysiology also has macular edema. the evolution of premature catarac- The pancreas plays a primary togenesis (nuclear sclerotic, senile role in the metabolism of glucose by Glucagon is a hormone that opposes and snowflake, and posterior subcap- secreting the hormones insulin and the action of insulin. It is secreted when sular) and sight threatening diabetic glucagon.2 The Islets of Langerhans blood glucose levels fall. Glucagon retinopathy (via changes that com- secrete insulin and glucagon directly increases blood glucose concentration promise the supportive pericytes that into the blood. Insulin is a protein that partly by breaking down glycogen in line capillary walls in the neurosensory is essential for proper metabolism of the liver.1 Following a meal, glucose is retina).5,6,9,22,23 glucose and for maintenance of proper absorbed into the blood. In response to Another complication of hypergly- blood glucose levels. Inadequate secre- increased blood glucose levels, insulin cemia is non-enzymatic glycosylation. tion of insulin, or inadequate structure is secreted causing rapid uptake, stor- Non-enzymatic glycosylation is the or function of insulin or its recep- age or use of glucose by the tissues of binding of excess glucose to the amino tors results in impaired metabolism the body. Unused glucose is stored as group of proteins in the tissues.10 As of glucose, other carbohydrates, pro- glycogen in the liver. Between meals, a result, at the level of the capil- teins and fats.1-23 This is character- when blood glucose is at minimal lev- lary membranes, altered cell function ized by hyperglycemia and glycosuria.1 els, tissues continue to require an ener- eventually leads to the development of Hyperglycemia is the most frequently gy source to function properly. Stored microaneurysms, vascular loops, and observed sign of diabetes and is con- glycogen, via glucagon, is converted vessel dilation, creating the charac- sidered the etiologic source of diabetic into glucose by a pathway known as teristic blood, serum and lipid leak- complications both in the body and in glycogenolysis.1 Gluconeogenesis is age.2,7,8,10 Platelet aggregation second- the eye.2 the production of glucose in the liver ary to these changes initiates tissue hypoxia. These changes result in a system-wide accumulation of edema and release of other chemoattractants and cytokines (glyceraldehydes, endo- thelin, matrix metalloprotinases, his- tamines, renin, interleukin-6 and vas- cular endothelial growth factors), each with the potential to induce vascular constriction, hypoxia and resulting retinal sequelae.2,7,8,10,22,23 Evidence in a number of reports has suggested that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of DM and its Proliferative diabetic retinopathy is a sign of advanced, uncontrolled diabetes. associated cardiovascular risks.25,26 The

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001_ro0410_hndbkv7.indd 63 4/5/10 8:47 AM potential role of RAS blockers has also drates).17 When hyperglycemia persists the effects of the two treatments were recently been studied for their abil- despite dietary changes, oral hypogly- independent and additive.25 ity to delay or prevent the onset and cemic agents become necessary. These Other interventional trials have progression of diabetes mellitus and agents can be prescribed in small doses, shown that diabetic patients benefit cardiovascular disease.25,26 Data from adjusting the dosage to larger levels to greatly from aggressive blood pressure recently analyzed clinical trials suggest achieve tighter control, as necessary.17 control, especially when the drug regi- that RAS blockade not only reduces Insulin is always required for Type men includes an inhibitor of the renin- cardiovascular risk in patients with 1 DM and is an option for recal- angiotensin system.29 In a study that DM but also prevents or delays diabe- citrant cases of Type 2 diabetes.17 examined the effects of overall health tes in subjects-at-risk.26 The Diabetes Conventional therapy involves the improvement, Harder and coworkers Reduction Approaches With Ramipril administration of an intermediate- tested the effects of a low calorie diet And Rosiglitazone Medications acting insulin (NPH or lente), once (LCD) on body weight, lipid profile (DREAM) trial evaluated ramipril and or twice-a-day, with or without small and glycemic control, finding that it was its capacity to significantly increase the amounts of regular insulin.17 also an effective method for improving system’s regression toward normogly- Several studies have shown the glycemic control and blood lipids in cemia. The Nateglinide and Valsartan benefits of antihypertensive treat- overweight type 2 DM patients.30 in Impaired Glucose Tolerance ment and glucose-lowering therapy While early work focused on improv- Outcomes Research (NAVIGATOR) on the prevention of macrovascular ing glycemic control, new studies such trial evaluated whether creating a and microvascular disease.24-32 The as the European Diabetes Controlled reduced risk for DM could be associ- Action in Diabetes and Vascular dis- Trial of Lisinopril in Insulin-Dependent ated with a reduction in cardiovascular ease: PreterAx and DiamicroN modi- Diabetes (EUCLID) and new arms disease events.26 The outcomes from fied release Controlled Evaluation of older studies such as the United both trials have solidified the roles of (ADVANCE) study was designed to Kingdom Prospective Diabetes Study these suspected pathways.25,26 provide answers regarding blood-pres- (UKPDS) shifted the focus to observing sure-lowering therapy and intensive the control of blood pressure and spe- Management glucose control therapy in Type 2 cifically the RAS as a means of arresting Glycemic control over the course diabetics at high risk for cardiovascular diabetic sequelae.30-33 There is a body of of the disease has been shown to disease.25-29 Study data demonstrated evidence suggesting that a local RAS, reduce the risk of developing debil- that patients with Type 2 diabetes within the eye itself, may be activated itating organ disease and retinopa- mellitus exhibit a marked increase in upon conversion to clinically definite thy.11,13,14,21,27 Blood glucose levels are cardiovascular and renal risk.25,29 A diabetes.33 This appears to be directly of even greater importance in dia- sub-study of the ADVANCE report responsible, as well as indirectly respon- betic pregnant women, as hypergly- evaluated a comparison of blood sible through the production of other cemia during pregnancy may initiate pressure lowering with perindopril- mediators, for increasing the concen- swift and severe progression of diabetic indapamide vs placebo and an open tration of vascular endothelial growth retinopathy.4,15,27 Other concurrent comparison of standard vs intensive factor (VEGF), a selective angiogenic/ systemic variables that may potenti- glucose control (targeting an HbA1c vasopermeability factor already well ate the onset of diabetic retinopathy of less than or equal to 6.5%).25 The implicated in the pathogenesis of dia- include hypertension, nephropathy, study noted a trend of lower signifi- betic retinopathy.33 Inhibition of angio- cardiac disease, autonomic neuropathy cant risks for microaneurysms, hard tensin-converting enzyme appears to and ocular findings such as elevated exudates and macular edema in the reduce concentrations of VEGF, with intraocular pressure and myopia.11,13,14 group with the intensive glucose con- a concurrent anti-proliferative effect The easiest method of treating trol, with fewer patients on the blood independent of systemic VEGF levels Type 2 diabetes is with diet control.17 pressure-lowering treatment experi- or blood pressure.31,32 Dietary regulation is set by basing the encing significant progression of reti- Angiotensin II (Ang II) receptor caloric intake on the patient’s ideal nopathy compared to the patients on blockade has been shown to reduce body weight, selecting adequate sourc- the placebo.25 The study concluded retinal neovascularization independent es of protein and carbohydrate, while that, while the effects of the coman- of VEGF levels in animal models.30-32 maintaining a reasonable distribution agement were not clinically significant, This may be due to antagonism of of foods (proteins, fats, and carbohy- there was a trend demonstrating that activation of mitogen-activated protein

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kinase. This molecule is a potent cel- capsular) may form as well due to sor- 16. Benson WE, Tasman W, Duane TD. Diabetes Mellitus and the Eye. In: Tasman W, Jaeger EA, eds. lular proliferation stimulator set into bitol effects. The cataracts may mature Duane’s Clinical Ophthalmology: Philadelphia, Pa ; motion by Ang II. The ramifications quickly but have been documented to Lippincott-Raven, 1996;3 (30):1-29. 17. Wilson DJ. Diabetes Mellitus. In: Fauci A, Braunwald of this research may yield new medica- regress once the sugar levels are stabi- E, Isselbacher KJ, et al, eds. Harrison’s Principles of tions whose indirect mechanisms slow lized. Internal Medicine Companion Handbook. 14th ed. New or arrest the pathogenesis responsible • The test of choice for monitor- York, NY; McGraw-Hill, 1998:943-6. 18. Crawford JM. Liver Biliary System and Pancreas. for retinopathy and other pathologic ing diabetic control is the glycosylated In: Robbins SL, Cotran RS, Kumar V., eds. Pocket changes, not only in the eye but also hemoglobin test (HgbA1C), which is Companion to Robbins Pathologic Basis of Disease. 30-32 5th ed. Philadelphia, PA; WB Saunders Co, 1995:367- throughout the body. a readily available, in-office disposable 74. Currently, there are a number of test. 19. Kanski, JJ. Disorders of the Lens. In: Kansk, JJ. Clinical Ophthalmology: A Systemic Approach. Boston, large-scale trials evaluating the effects MA; Butterworth-Heinemannn, 1994:285–309. 1. Guyton AC. Insulin, Glucagon, and Diabetes Mellitus. of lipid-lowering therapies in patients 20. Burden G, Bryant SA. Retinal Vascular Disease: In: Guyton AC. Textbook of Medical Physiology: 30 Diabetes Mellitus. In: Burden, G, Bryant SA. Laboratory with diabetes. The Lipids in Diabetes Philadelphia, PA; WB Saunders Company. 1996:971- and Radiologic Tests for Primary Eye Care. Boston, 983. Study will hopefully provide insight MA; Butterworth-Heinemann, 1997:132-4. 2. Niffenegger JN, Fong D, Cavallerano J, et al. 21. Diabetes Control and Complications Trial Research for determining whether lipid lower- Diabetes Mellitus. In: Albert DM, Jakobiac FA. Principles Group. Progression of retinopathy with intensive versus and Practice of Ophthalmology. Philadelphia, PA; WB ing with a statin or fibrate medication conventional treatment in the DCCT. Ophthalmology. Saunders Company. 1994:2925-36. 1995;102(4):647-61. can substantially reduce cardiovascu- 3. Fore WW. Noninsulin-dependent diabetes mellitus, 22. Early Treatment of Diabetic Retinopathy Study lar morbidity and mortality in patients the prevention of complications. Med Clin North Am. Research Group. Photocoagulation for Diabetic Macular 1995 Mar;79(2):287-298. with Type 2 diabetes. The Atorvastatin Edema. Arch Ophthalmol. 1985 Dec;103(12):1796- 4. Aiello LP, Cavallerano J, Bursell S. Diabetic eye 1806. Study for the Prevention of Coronary disease. Endocrinol Metab Clin North Am. 1996 23. Bhagat N, Grigorian RA, Tutela A, et al. Diabetic Jun;25(2):271-291. Heart Disease Endpoints (ASPEN) macular edema: pathogenesis and treatment. Surv 5. Gurwood AS. Managing the diabetic patient. Br J Ophthalmol. 2009 Jan-Feb;54(1):1-32. is designed to compare double-blind Optom Dispens. 1995;3(3):115-122. 24. Gale J, Wells AP, Wilson G. Effects of exercise on treatment with atorvastatin against pla- 6. Ljubimov AV, Burgeson RE, Butkowski RJ, et al. ocular physiology and disease. Surv Ophthalmol. 2009 Basement membrane abnormalities in human eyes with cebo in over 2,500 U.S. diabetic patients May-Jun;54(3):349-55. diabetic retinopathy. J Histochem Cytochem. 1996 25. Beulens JW, Patel A, Vingerling JR, et al. Effects of without coronary heart disease. A sister Dec;44(12):1469-1479. blood pressure lowering and intensive glucose control 7. Alexander LJ. Retinal Vascular Disorders. In: trial in the U.K., the Collaborative on the incidence and progression of retinopathy in Alexander LJ. Primary Care of the Posterior Segment. patients with type 2 diabetes mellitus: a randomised Atorvastatin Diabetes Study (CARDS), Norwalk, CT; Appleton & Lange, 1994:232-250. controlled trial. Diabetologia. 2009 Oct;52(10):2027-36. 8. Kanski JJ. Retinal Vascular Disorders. In: Kanski is enrolling 1,820 diabetic patients for 26. Braga MF, Leiter LA. Role of renin-angiotensin 33 JJ. Clinical Ophthalmology: A Systemic Approach. completion of a British arm. The system blockade in patients with diabetes mellitus. Am Oxford, England; Reed Educational and Professional J Cardiol. 2009 Sep 15;104(6):835-9. results from these trials may provide Publishing, 1994:344-357. 27. Peterson GE. A checklist approach to selecting 9. Cullom RD, Chang B. Systemic Disorders: Diabetes information that will help determine the optimal treatment regimen for a patient with type Mellitus. In: Cullom RD, Chang B. The Wills Eye Manual: 2 diabetes. J Fam Pract. 2009 Sep 15;58(9 Suppl the future management of dyslipidemia Office and Emergency Room Diagnosis and Treatment Treating):S21-5. of Eye Disease. Philadelphia, PA, JB Lippincott in diabetics and indirectly affect all sys- 28. Grobbee DE. How to ADVANCE prevention of Company, 1990:402-408. cardiovascular complications in type 2 diabetes. temic disease in diabetics. 10. Spalton DJ, Shilling JS, Schulenberg WE. The Metabolism. 2003 Aug;52(8)(Suppl 1):24-8. Retina: Vascular Diseases II. In: Spalton DJ, Hitchings 29. Waeber B, de la Sierra A, Ruilope LM. The RA, Hunter PA. Atlas of Clinical Ophthalmology: Clinical Pearls ADVANCE Trial: Clarifying the Role of Perindopril/ London, England, Mosby-Year Book Europe Limited, Indapamide Fixed-Dose Combination in the Reduction • Large changes in refraction may 1994:15.02-15.20. of Cardiovascular and Renal Events in Patients 11. Elliot D, Pieramici D. Retina: Diabetic Retinopathy. be the first sign of diabetic disease. with Diabetes Mellitus. Am J Cardiovasc Drugs. In: Varma R. Essentials of Eye Care: The Johns Hopkins 2009;9(5):283-91. Often, myopic or hyperopic shifts are Wilmer Handbook. Philadelphia, PA ; Lippincott-Raven, 30. Harder H, Dinesen B, Astrup A. The effect of a created as the lens swells, secondary 1997:287-296. rapid weight loss on lipid profile and glycemic control in 12. Klein RK, Palta M, Allen C, et al. Incidence of reti- to sorbitol effects, resulting in large obese type 2 diabetic patients. Int J Obes Relat Metab nopathy and associated risk factors from time of diag- Disord. 2004 Jan;28(1):180-2. refractive changes, in what were other- nosis of insulin-dependent diabetes. Arch Ophthalmol. 31. The EUCLID Study Group. Randomised placebo- 1997;115(3):351-6. wise noted as “stable eyes.” Clinicians controlled trial of lisinopril in normotensive patients with 13. Krolewski AS, Warram JH, Freire MB. Epidemiology insulin-dependent diabetes and normoalbuminuria or should avoid prescribing refractive cor- of late diabetic complications. Endocrin Metab Clin microalbuminuria. The EUCLID Study Group. Lancet. North Am. 1996 Jun;25(2):217-41. rection during this time period, instead 1997 Jun 21;349(9068):1787-92. 14. Diabetes Control and Research Group. The effect educating patients as to why this may 32. Schjoedt KJ, Astrup AS, Persson F, et al. Optimal of intensive treatment of diabetes on the develop- dose of lisinopril for renoprotection in type 1 dia- have occurred and ordering appropriate ment and progression of long-term complications in betic patients with diabetic nephropathy: a randomised insulin-dependent diabetes mellitus. New Engl J Med. tests such as fasting blood glucose. crossover trial. Diabetologia. 2009 Jan;52(1):46-9. 1993;329(14):977-86. 33. Strain WD, Chaturvedi N. The renin-angiotensin- • Cataracts (senile posterior sub- 15. Best RM, Chakravarthy U. Diabetic retinopathy in aldosterone system and the eye in diabetes. Renin pregnancy. Br J Ophthalmol. 1997;81(3):249-51. capsular and snowflake posterior sub- Angiotensin Aldosterone Syst. 2002 Dec;3(4):243-6.

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