sign in sign up
<<
Home , Amaurosis fugax, Aniridia, Asteroid hyalosis, Bitemporal hemianopsia, Blepharochalasis, Cornea plana 2

SUPPLEMENT TO April 15, 2009

A JOBSON PUBLICATION www.revoptom.com

Eleventh Edition

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

Supported by an unrestricted grant from Alcon, Inc. 001_ro0409_handbook 4/2/09 9:42 AM Page 4

TABLE OF CONTENTS

Eyelids & Adnexa & & Viitreous & Retiina Neuro-Ophthalmic Oculosystemic Disease

EYELIDS & ADNEXA VITREOUS &

Blow-Out Fracture...... 6 Asteroid Hyalosis ...... 33

Acquired ...... 7 Retinal Arterial Macroaneurysm...... 34

Acquired ...... 9 Retinal Emboli...... 36

Verruca & Papilloma...... 11 Hypertensive ...... 37

Idiopathic Juxtafoveal Retinal Telangiectasia...... 39 CONJUNCTIVA & SCLERA ...... 40 Scleral Melt ...... 13 Retinal Artery Occlusion ...... 42 Giant Papillary ...... 14

Conjunctival Lymphoma ...... 15 NEURO-OPHTHALMIC DISEASE

Blue Sclera ...... 17 Dorsal Syndrome ...... 45

Pituitary Adenoma...... 46 CORNEA and Transient Ischemic Attack .....48 Corneal Laceration...... 19 Cranial III Palsy...... 50 Terrien’s Marginal Degeneration ...... 20 Cranial Nerve IV Palsy ...... 52 Chemical/Toxic ...... 22 Cranial Nerve VI Palsy ...... 53 Bacterial ...... 24 OCULOSYSTEMIC DISEASE UVEA & GLAUCOMA ...... 56 Axenfeld-Rieger Syndrome ...... 27 ...... 57 Malignant Glaucoma ...... 28 Thyroid Ophthalmopathy (Graves’ Disease) ...... 60 Crystalline Subluxation ...... 29 Albinism...... 63 ...... 31

A Peer-Reviewed Supplement The articles in this supplement were subjected to Review of ’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 .

©2009. Reproducing editorial content and photographs require permission from Review of Optometry. 001_ro0409_handbook 4/2/09 9:42 AM Page 5

FROM THE AUTHORS

To Our Colleagues,

This year sees the publication of the eleventh edition of The Handbook of Ocular Disease Management. The years that we have been compiling this compendium have been professionally very rewarding to us. We are forever grateful to the management and editorial staff at Review of Optometry. We especially thank Amy Hellem for her work and contribution. We also thank Alcon for its continued support.

When we first envisioned this supplement, we wanted to provide a quick reference on the most com- monly encountered ocular and offer readers our perspectives and experience in dealing with these conditions. However, as the compendium evolved, we quickly saw the need to rely more heavily on evidence- based medicine. Simply put, evidence-based medicine is the conscientious, explicit, and judicious use of current best research in making decisions about the care of individual patients. The practice of evidence- based medicine means integrating individual clinical expertise with the best avail- able external clinical evidence from systematic research. Good doctors combine individual clinical expertise with the best available external evidence. Without clinical expertise, practices risk becoming tyrannized by evidence, for even excellent external evidence may be inapplicable to or inappropriate for an individual patient. Without current best evidence, a practice risks becoming rapidly out of date, to the detriment of patients. We have gone back to the beginning. We want to ensure that every condition that we write about (or have written about) not only reflects our personal experience and perspective, but that our perspectives are backed through scrupulous research and reflect evidence based medicine.

Last year, we dedicated the Tenth Edition to our professors and mentors who helped shape our profes- sional development. This year, we dedicate the Eleventh Edition of the Handbook of Ocular Disease Management to our students and residents. With their interactions and questions, they challenge us to remain current and practical and to stay on top of our game.

To them we dedicate the eleventh edition of the Handbook of Ocular Disease Management.

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 and ocular urgencies and emergencies. He is a diplomate of the American Academy of Optometry’s Primary Care Section, a founding no financial inter- member of the Optometric Retina Society, a member of the Optometric Glaucoma Society and member of the Optometric Dry Eye Society. He serves on the American est in any product 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]. 001_ro0409_handbook 4/2/09 9:42 AM Page 6

EYELIDS AND ADNEXA

BLOWOUT FRACTURE eral wall is composed of the zygomatic eyeball, causing the to strike one of bone and the greater wing of the sphe- the orbital walls such that it fractures; or noid; the floor of the is composed 3) The force may be transmitted by the Blunt trauma to the orbital rim is the of the orbital plate of the maxilla, the globe via the principle of fluid incom- typical cause of orbital floor and medial zygomatic and orbital process of the pressibility, causing generalized orbital wall fractures.1-3 Although there pterygopalentine bone; the medial wall increased orbital content pressure or a is no epidemiologic predilection for “hydraulic” effect, resulting in bone frac- “blowout fracture,” there are some clini- tures.9-12 The point of breakage usually cal trends regarding those individuals occurs along the axis of least support in most likely to sustain these : an area where the tissue is weakest.9-12 male, between the ages of 18–30, Since the orbital floor is not parallel to engaged in activities of poor judgment, the horizontal plane, the vector of the with most incidents occurring in or near striking force seems to affect the result- the home.3,4 The specific term “blowout ant fracture patterns.9 Although all three fracture” is reserved to connote an iso- mechanisms are mentioned in the liter- lated orbital floor or medial wall fracture ature, the buckling mechanism and the in the setting of an intact orbital rim.1-3 hydraulic mechanism seem to have the Patients present with a history of blunt- most support.10-12 Fractures produced by force trauma, such as being struck with the buckling mechanism are often lim- a projectile, like a ball, bat or fist, or ited to the anterior part of the orbital being a participant in a collision , floor.11 In contrast, hydraulic fractures such as those caused by the impact of an are often larger, involving both the ante- airbag or the contact of an object fol- rior and posterior parts of the floor as lowing a fall.5 , and well as the medial wall of the orbit.11 lacrimation associated with post-trau- CT scan demonstrating a blowout fracture of The orbital floor has a lower thresh- matic uveal (iritis or iri- the right orbital floor. old for fracture than the medial wall docyclitis), variable facial swelling sec- and other orbital bones and occurs most ondary to fluid or air (orbital of the orbit is composed of maxilla, the frequently. When it gives way, the globe emphysema), crepitus (a crackling noise lacrimal, the ethmoid and body of the and its attached components become when tissue infiltrated with air is palpat- sphenoid.7 The other critical anatomi- unsupported, slipping down into the ed), gaze-evoked and pain cal players are the surrounding vacant sinus below, producing visible upon movement of the are all com- paranasal air sinuses.8 Several sinuses and gaze-evoked, symp- mon.6 Other associated collateral surrounding the orbit help to lessen the tomatic diplopia, along with degrees of injuries may include subconjunctival weight of the skull and aid in the reso- extraocular muscle dysfunction and hemorrhage, ruptured globe, corneal nance of the voice.8 Unfortunately, infraorbital nerve hypoesthesia.10,12 abrasion, conjunctival laceration, hyphe- these structures leave the superior, ma, iridodialysis, lenticular subluxation, medial and inferior walls of the orbit Management , vitreous hemor- unsupported and vulnerable to cata- For the optometrist, the treatment of rhage, choroidal rupture and strophic failure (blowout fracture, trap blowout fracture centers around ocular avulsion. If the eye settles inferiorly or door fracture) from blunt-force trauma. first aid. The most challenging aspect of medially into the exposed sinus, enoph- The sinuses surrounding the orbit beginning an examination on patients thalmos with restricted ocular motility include the ethmoidal air cells (anterior, who have experienced facial blunt-force will be present, with or without loss of middle and posterior), the sphenoidal injury is getting the eye open to look. facial sensation. sinuses, the maxillary sinuses and the Facial and orbital swelling or orbital frontal sinuses.7,8 emphysema can literally force the eye Pathophysiology There is some debate about the closed. In such cases, a Desmarre lid The seven bones of the orbit include mechanism of blowout fracture. When a retractor can be used as a speculum to lift the frontal, zygomatic, maxillary, eth- blunt force impacts the face, it may pro- the superior lid. The thin blade can be moid, sphenoid, lacrimal and ptery- duce a combination of effects: 1) The inserted between the lids and the superi- gopalentine.7 The orbital roof includes force may strike the bone, producing a or lid elevated by pulling upward. the orbital plate of the frontal bone and shock wave that causes “bone buckling”; Since blunt ocular trauma involving the lesser wing of the sphenoid; the lat- 2) The force may be transmitted to the the eye or face is the result of being

6A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 7 EYELIDS AND ADNEXA

struck by an object at velocity; upon con- Clinical Pearls floor fractures. Facial Plast Surg Clin North Am 2006;14(1):11-6. tact, a shock wave within the local area is • Patients presenting after orbital 16. Ozturk S, Sengezer M, Isik S, et al. Long-term out- generated. This produces what is known blunt trauma should be discouraged comes of ultra-thin porous polyethylene implants used as the coup injury, from the French/ from nose-blowing until orbital fractures for reconstruction of orbital floor defects. J Craniofac Surg 2005;16(6):973-7. Scottish meaning “to upset.” Injuries can be positively ruled out via imaging may also be seen directly opposite the (X-ray, CT or magnetic resonance imag- impact point, in line with the shock ing). This helps to avoid the unwanted ACQUIRED PTOSIS wave; these are known as the contrecoup of orbital emphysema. effects, from the French derivation • The only way to diagnose an orbital Signs and Symptoms meaning occurring at a site opposite the fracture is by neuro-imaging. Ptosis is a condition that may be area of impact. For these reasons, a dilat- • Air from the external environment either congenital or acquired; however, it ed fundus evaluation to rule out vitreous may enter the subcutaneous tissue sur- is typically those with acquired ptosis hemorrhage, retinal tearing and retinal rounding the orbit or globe via a com- who present with symptomology. Most detachment is required. munication created by a fracture. This is individuals with congenital ptosis have Computed tomography (CT) scan- often visible as soft or “puffy” swelling made adaptations, and they usually have ning remains the gold standard for and is known as orbital emphysema. only cosmetic concerns. Common assessing orbital fractures.13 The CT symptoms associated with acquired pto- 1. Lelli GJ Jr, Milite J, Maher E. Orbital floor fractures: technology (multislice CT) has improved Evaluation, indications, approach and pearls from an sis involve an inability to open the eye(s), the acquisition of coronal images of the ophthalmologist’s perspective. Facial Plast Surg decreased vision and superior loss of field orbit without the need for hyperexten- 2007;23(3):190-9. due to lid obstruction.1 Non-specific 2. Burm JS, Chung CH, Oh SJ. Pure orbital blowout 13 sion of the neck. Treatment of blowout fracture: New concepts and importance of medial symptomology may include , fracture may not be emergent. If there is orbital blowout fracture. Plast Reconstr Surg (from chronic compensatory a compressive threat to the optic nerve 1999;103(7):1839-49. contracture of the frontalis muscle), 3. Guly CM, Guly HR, Bouamra O, et al. Ocular injuries via swelling and retrobulbar hemorrhage, in patients with major trauma. Emerg Med J or even pain. it requires referral for an emergent lateral 2006;23(12):915-7. Examination of the patient with canthotomy and orbital decompression. 4. McGwin G Jr, Owsley C. Incidence of emergency acquired ptosis reveals a narrowed palpe- department-treated in the United States. Arch Typically, surgical intervention is post- Ophthalmol 2005;123(5):662-6. bral aperture and notable lid droop. The poned until orbital health is consistent 5. Lehto KS, Sulander PO, Tervo TM. Do motor vehicle condition may be unilateral or bilateral. with a good surgical environment, unless airbags increase risk of ocular injuries in adults? The laterality may be indicative of the Ophthalmol 2003;110(6):1082-8. a large amount of soft tissue is incarcer- 6. García-Medina JJ, García-Medina M, Pinazo-Durán underlying etiology. Unilateral ptosis ated in the bony rupture.14 MD. Severe orbitopalpebral emphysema after nose often stems from neurologic or mechan- Management of orbital floor frac- blowing requiring emergency decompression. Eur J ical disease, while bilateral ptosis is typi- Ophthalmol 2006;16(2):339-42. tures traditionally has been accom- 7. Snell RS, Lemp, MA. The orbital cavity. In: Snell RS, cally associated with generalized muscle plished through transconjunctival and Lemp, MA. Clinical Anatomy of the Eye (2nd ed).. disorders or aging. Associated signs may subciliary incisions.15 However, postop- Malden, MA: Blackwell Science, 1998, pp. 59-77. also help to identify the specific disorder. 8. Snell RS, Lemp, MA. The paranasal sinuses. In: erative lid malposition is a complica- Snell RS, Lemp, MA. Clinical Anatomy of the Eye (2nd For example, Horner’s syndrome involves tion.15 Some surgeons have begun to ed).. Malden, MA: Blackwell Science, 1998, pp. 78-89. a unilateral ptosis with a miotic . A evaluate an endoscopic approach to 9. Burnstine MA. Clinical recommendations for repair third nerve palsy demonstrates a ptosis of orbital facial fractures. Curr Opin Ophthalmol orbital floor fractures. This approach 2003;14(5):236-40. with restriction of both upgaze and offers a hidden incision and improved 10. Nagasao T, Miyamoto J, Nagasao M, et al. The adduction. Additionally, the pupil may be fracture visualization.15 When the effect of striking angle on the buckling mechanism in dilated and unresponsive to . Pain blowout fracture. Plast Reconstr Surg 2006; orbital floor requires replacement or 117(7):2373-80. and swelling of the lid may point to an reconstruction, ultra-thin porous poly- 11. Ahmad F, Kirkpatrick NA, Lyne J et al. Buckling and inflammatory or neoplastic disorder ethylene implants serve as durable sub- hydraulic mechanisms in orbital blowout fractures: Fact involving the lid, such as or or fiction? J Craniofac Surg 2006;17(3):438-41. stitutes that mimic the anatomy and 12. Rhee JS, Kilde J, Yoganadan N, et al. Orbital preseptal cellulitis. When ptosis is vari- avoid the morbidity of rejection.16 blowout fractures: Experimental evidence for the pure able and intermittent, myasthenia gravis In cases of orbital fracture in which hydraulic theory. Arch Facial Plast Surg 2002;4(2):98- is often the cause.2 101. is postponed or not considered, 13. Cruz AA, Eichenberger GC. Epidemiology and the patient can be prescribed a course of management of orbital fractures. Curr Opin Ophthalmol Pathophysiology broad-spectrum oral antibiotics, such as 2004;15(5):416-21. Acquired ptosis may present in a 14. Harris GJ. Orbital blow-out fractures: Surgical tim- cephalexin or amoxicillin, 500 mg b.i.d. ing and technique. Eye 2006;20(10):1207-12. number of clinical disorders, but all can p.o. while the osseous tissues heal. 15. Farwell DG, Strong EB. Endoscopic repair of orbital be ascribed to one of four categories:

APRIL 15, 2009 REVIEW OF OPTOMETRY 7A 001_ro0409_handbook 4/2/09 9:42 AM Page 8

aponeurogenic, myogenic, neurogenic genic ptosis implicates either the levator function and pupillary responses. or mechanical.1 via oculomotor palsy (i.e., cranial nerve Pseudoptosis—any condition that gives Aponeurogenic or involutional ptosis III palsy) or the muscle of Mueller via the appearance of a drooped lid but actu- is the most commonly encountered form oculosympathetic dysfunction (i.e., ally involves no lid dysfunction in the of acquired ptosis, particularly in older Horner’s syndrome). Occasionally, how- involved eye—must be ruled out. Some ever, neurogenic ptosis results examples of pseudoptosis include from a lesion to the supranuclear patients with small globes (e.g., pathway, a condition referred to microphthalmos, ), enoph- as apraxia of opening. This thalmos, blowout fracture, contralateral bilateral ptosis is characterized by lid retraction and ipsilateral hypotropia. inability to open closed lids vol- Mechanical etiologies are the simplest to untarily, and it may be seen in remedy, in principle: Removal of the patients with extrapyramidal dys- cause creating the resistance should ren- function, including progressive der improvement. In cases of extensive supranuclear palsy, Parkinson’s scarring from long-standing disease, a disease, Shy-Drager syndrome, surgical consultation may be advised.14 and Wilson’s disease.11 Aponeurogenic ptoses may be treated Involutional ptosis in an elderly patient. Mechanical ptosis can be by a variety of methods. The use of a caused by any condition that pro- prosthetic ptosis crutch attached to the adults.1 It involves local dehiscence, vides resistance to the action of the leva- spectacle frame can provide relief from stretching and disinsertion of the levator tor muscle.The most common etiologies some of the major symptoms encoun- aponeurosis from its attachments to the include trauma, lid tumors, dermatocha- tered by these patients. The principle tarsus and pretarsal orbicularis muscle.2 advantage of this modality is Histologic evaluation of the patient diminished cost without the risks demonstrates atrophy, fatty infiltration of surgical intervention.15 Of and fibrosis of the levator muscle, as well course, surgery offers a more con- as an attenuated levator aponeurosis.3 sistent and long-term solution for Although elderly patients are primarily patients with ptosis. Procedures affected, younger patients can develop such as levator resection and this condition as a result of trauma, aponeurosis tightening are prin- severe lid swelling, , ciple considerations. All surgical prior ocular surgery or long-term contact patients should be followed lens wear.4-6 closely for the development of Myogenic ptosis is less commonly secondary and encountered clinically than aponeuro- Mechanical ptosis resulting from trauma to the lid. exposure complications.14 genic ptosis. It results from one of a Ptosis that is neurogenic or number of muscular debilities involving lasis and conjunctival scarring (i.e., sec- myogenic in nature is best managed by a the levator palpebrae superioris. ondary to ocular cicatricial pemphigoid specialist with advanced training in Etiologies include acquired mitochondr- or Stevens-Johnson syndrome). Floppy neuro-ophthalmology. Such cases gener- ial dysfunction (chronic progressive eyelid syndrome also falls within this ally require imaging and other special- external ophthalmoplegia), muscle fibro- category. Excessive papillary responses, ized testing (e.g. Tensilon® in myasthe- sis and degeneration (myotonic dystro- such as vernal keratoconjunctivitis or nia gravis) for confirmatory diagnosis. phy and oculopharyngeal dystrophy) and giant papillary conjunctivitis, can also dysfunction of neuromuscular junction result in mechanical eyelid ptosis.1,12,13 Clinical Pearls signaling due to acetylcholine receptor • Consider the lid crease when differ- autoantibodies (myasthenia gravis).1,7-10 Management entiating congenital ptosis from acquired Neurogenic ptosis involves a disrup- Without question, the most impor- ptosis. Acquired ptosis will maintain a tion of innervation to the muscles of tant aspect of managing a patient with lid crease; congenital ptosis will not. A eyelid elevation. There are various eti- acquired ptosis is determining the high lid crease often heralds an aponeu- ologies, including vascular , underlying cause. A thorough history is rogenic ptosis. inflammation, infection, demyelination crucial. The clinician must consider lat- • Review of old photographs of the and neoplasia. Most commonly, neuro- erality and check associated motility patient may also often help to differenti-

8A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 9 EYELIDS AND ADNEXA

ate a congenital or long-standing ptosis 2001;124(Pt 3):522-6. tory should be elicited from all patients 9. Kuwabara T, Lessell S. Electron microscopic study from an acquired ptosis. of in . Am J presenting with entropion to assess for • The laterality of a ptosis can help Ophthalmol 1976;82(2):303-9. prior trauma, particularly in those who determine its etiology. In general, unilat- 10. Drachman DB. Therapy of myasthenia gravis. are younger than 60 years. Handb Clin Neurol 2008;91:253-72. eral ptosis may be due to Horner’s syn- 11. Esteban A, Traba A, Prieto J. Eyelid movements in drome, third nerve palsy, inflammation, health and disease. The supranuclear impairment of the Pathophysiology trauma or infiltrative disease. Bilateral palpebral motility. Neurophysiol Clin 2004;34(1):3-15. Etiologically, there are four com- 12. Griffin RY, Sarici A, Unal M. Acquired ptosis sec- ptosis suggests damage to the supranu- ondary to vernal conjunctivitis in young adults. Ophthal monly recognized forms of entropion: clear pathways of the or ocular Plast Reconstr Surg 2006;22(6):438-40. congenital, cicatricial, involutional and myopathies. Age-related (senile or invo- 13. Luxenberg MN. Blepharoptosis associated with spastic. giant papillary conjunctivitis. Arch Ophthalmol lutional) ptosis is typically bilateral but 1986;104(11):1706. Congenital entropion, by definition, may be unilateral or asymmetric. A pto- 14. Lyon DB, Dortzbach RK. Upper eyelid malposi- is present at birth or develops soon sis that is variable or “jumps” from one tions: Acquired ptosis. In: Albert DM, Jakobiec FA, eds. thereafter. It is relatively rare and typi- Principles and Practice of Ophthalmology (2nd ed). eye to the other is highly suggestive of Philadelphia: W.B. Saunders; 2000, pp. 3469–75. cally affects the upper eyelid, although myasthenia gravis. 15. Walsh G, Rafferty PR, Lapin J. A simple new the lower lid may be affected as well. • Ptosis is usually the initial and most method for the construction of a ptosis crutch. The pathophysiology may involve struc- common complaint in myasthenia Ophthalmic Physiol Opt 2006;26(4):404-7. tural defects in the tarsal plate, short- gravis.1 To confirm suspicions, clinicians ened posterior lamellae (tarsal plate and can test sustained upgaze and/or con- ACQUIRED ENTROPION conjunctiva) or eyelid retractor dysgene- duct the “sleep or ice-pack test.” sis.1,3 Congenital entropion must be dif- Tensilon® testing confirms a diagnosis Signs and Symptoms ferentiated from other developmental of systemic myasthenia. Entropion represents a condition of oddities such as epiblepharon (a fold of • Third nerve palsies are variable in eyelid malpositioning in which the lid skin that overlaps the eyelid margin, presentation and may or may not show margin rotates inward against the ocu- pushing the eyelid margin inward) and pupillary involvement. Associated ipsi- lar surface.1-5 This phenomenon may prominent epicanthus (a fold of skin lateral motility problems may be very occur unilaterally or bilaterally and may partially covering the inner , subtle and are often overlooked. involve the upper or lower eyelid, caruncle and plica semiluminaris), Remember that upgaze and adduction although the lower lids are affected which are similar in presentation but are affected most commonly. Third most frequently.1 Clinical features asso- different in etiology.1 nerve palsies are unilateral except in ciated with entropion may be observed Cicatricial entropion results from cases involving the third nerve nucleus. in and out of the slit lamp. The most scarring of the ocular tissues, resulting In the latter, patients present with bilat- obvious gross finding is a turning-in of in a vertical shortening of the tarsus. eral ptosis. the lid margin, with eyelid skin or eye- Most commonly, cicatricial injury is lashes contacting the cornea. Asso- associated with trauma (e.g., chemical, 1. Thakker MM, Rubin PA. Mechanisms of acquired ciated hyperemia of the conjunctiva thermal or blunt injury) but it can also blepharoptosis. Ophthalmol Clin North Am 2002;15(1):101-11. may also be noted. Biomicroscopy occur secondary to disorders such as 2. Sakol PJ, Mannor G, Massaro BM. Congenital and reveals variable corneal pathology, Stevens-Johnson syndrome, ocular acquired blepharoptosis. Curr Opin Ophthalmol including superficial punctate epithe- cicatricial pemphigoid, herpes zoster 1999;10(5):335-9. 3 3. Shore JW, McCord CD Jr. Anatomic changes in liopathy and, in severe or untreated and . involutional blepharoptosis. Am J Ophthalmol cases, corneal ulceration and pannus Involutional (formerly called senile) 1984;98(1):21-7. formation.1,2 Symptoms associated with entropion is by far the most common 4. Watanabe A, Araki B, Noso K, et al. Histopathology of blepharoptosis induced by prolonged hard contact entropion may involve ocular irritation form of entropion encountered clinically. lens wear. Am J Ophthalmol 2006;141(6):1092-6. and/or foreign body sensation, tear- It predominantly affects the lower eyelid 5. Tossounis CM, Saleh GM, McLean CJ. The long and ing/ and a persistent . and is associated with a variety of struc- winding road: -induced ptosis. Ophthal Plast Reconstr Surg 2007;23(4):324-5. Vision may be variably affected, tural features. These may include medial 6. Reddy AK, Foroozan R, Arat YO, et al. Ptosis in depending upon the extent and location and lateral canthal laxity or dehiscence, young soft contact lens wearers. Ophthalmol of corneal damage. disinsertion or stretching of the lower lid 2007;114(12):2370. 7. Aasly J, Lindal S, Torbergsen T, et al. Early mito- Most commonly, entropion occurs as retractor complex, override of the pre- chondrial changes in chronic progressive ocular an involutional change in older patients; septal orbicularis over the pretarsal com- myopathy. Eur Neurol 1990;30(6):314-8. however, it can also represent cicatricial ponent and extension of orbital fat ante- 8. Hill ME, Creed GA, McMullan TFW, et al. 3,6 Oculopharyngeal musculoar dystrophy: phenotypic and damage following blunt, chemical or rior to the orbital rim. genotypic studies in a UK population. Brain thermal injury to the lids. A careful his- Spastic entropion represents a very

APRIL 15, 2009 REVIEW OF OPTOMETRY 9A 001_ro0409_handbook 4/2/09 9:42 AM Page 10

different type of disease state compared transient of the eyelid protrac- anatomical position within 1 or 2 sec- with the other three categories. It tor muscles, may help onds before blinking, it is indicative of occurs when the preseptal orbicularis to alleviate the inward turning of the lid pathological laxity.1 Another diagnostic muscle becomes overactive and hyper- margin for several weeks, until surgical technique is the dislocation or distrac- trophic secondarily to blepharospasm, intervention can be undertaken. In tion test. This is performed by grasping inflammation, irritation or surgery.1 In cases of spastic entropion, the injection the lower eyelid and pulling it anterior- addition, some degree of eyelid is of botulinum toxin into the orbicularis ly away from the globe. If the lid can be also present; this adds to the abnormal muscle may break the cycle of spasm pulled more than 7mm from the globe, mechanical forces turning the margin and irritation.10 then increased horizontal lid laxity is the inward. Unlike the other forms of entro- Surgery provides the longest-lasting source of the entropion.1 pion, spastic entropion typically resolves solution and is ultimately the best • The easiest way to resolve spastic when the underlying inflammatory or therapeutic option in most cases of entropion is to remove the offending irritative factors are eliminated.5 entropion. In cicatricial cases, surgical irritant. In cases that involve the seventh repair may include excision of the cranial nerve (essential blepharospasm, Management with a tarsal plate graft from preserved orofacial dyskinesia, hemifacial spasm, While the treatment of choice sclera, ear cartilage or hard palate (in facial myokymia) a neuro-ophthalmic should be guided by the underlying most severe circumstances), along with consult is indicated. In some instances, cause, the fundamental philosophies of conjunctival and mucous membrane these conditions can be managed phar- entropion management include: 1) grafting using fetal amniotic mem- macologically using anti-seizure med- moving the lid margins and lashes brane tissue.2 For involutional entropi- ications. away from the cornea, and 2) providing on, common surgical options include • Thermal cautery of the lid was lubrication for the compromised ocular the Quickert suturing technique or a once a popular corrective procedure for surface. A simple method for alleviat- base-down triangular tarsal resection. the treatment of involutional entropion; ing contact between the eyelid and If significant horizontal lid laxity is however, this technique appears to have ocular surface is to apply surgical tape present, then a combination technique fallen out of favor over the last 10 to 20 to the lid to rotate it out and away from involving horizontal shortening of the years, particularly among oculoplastic the globe. Unfortunately, this tech- eyelid and resuspension of the lower surgeons.2 nique is neither precise nor permanent, eyelid retractors may be performed.1,2,11 and it requires cooperation and partic- 1. Skorin L Jr. A review of entropion and its manage- ment. Cont Lens Anterior Eye 2003;26(2):95-100. ipation by the patient. It is typically Clinical Pearls 2. Eliasoph I. Current techniques of entropion and employed as a stopgap measure for • A thorough history should be com- correction. Otolaryngol Clin North Am individuals who are not amenable to pleted for all patients with entropion. 2005;38(5):903-19. 3. Vallabhanath P, Carter SR. Ectropion and entropion. prompt surgical intervention. The lib- Attention to previous , trau- Curr Opin Ophthalmol 2000;11(5):345-51. eral use of artificial tear products is rec- ma, chemical injury, chronic infection 4. Piskiniene R. Eyelid malposition: Lower lid entropion ommended for all entropion patients, and changes in eyelid tonus should be and ectropion. Medicina (Kaunas) 2006;42(11):881-4. 5. Choo PH. Distichiasis, , and entropion: regardless of the etiology; gel-forming provided. Advances in management. Int Ophthalmol Clin solutions, gels and ointments may pro- • The differential diagnosis of 2002;42(2):75-87. vide greater and more sustained relief entropion includes anomalies 6. Carter SR, Chang J, Aguilar GL, et al. Involutional entropion and ectropion of the Asian lower eyelid. of symptoms than drops. Bandage con- such as trichiasis (inward turning of the Ophthalmic Plast Reconstr Surg 2000;16(1):45-9. tact lenses may also prove helpful in cilia) and distichiasis (multiple rows of 7. Montero J, Sparholt J, Mély R, et al. Retrospective providing a barrier between the ocular ), neuro-ophthalmic blepharo- case series of therapeutic applications of lotrafilcon a silicone hydrogel soft contact lenses. Eye Contact Lens 7 surface and entropic lid margin. spasm, traumatic etiologies, scarring 2003;29(2):72-5. Prophylactic antibiotic coverage may from chemical injuries and lid mal- 8. Christiansen G, Mohney BG, Baratz KH, et al. be beneficial in cases of more severe position secondary to previous ocular Botulinum toxin for the treatment of congenital entropi- on. Am J Ophthalmol 2004;138(1):153-5. keratitis. In lieu of bacitracin or ery- . 9. Steel DH, Hoh HB, Harrad RA, et al. Botulinum toxin thromicin ointment q.i.d., AzaSite® • Focused physical testing can aid in for the temporary treatment of involutional lower lid (azithromycin 1% in DuraSite®) offers the diagnosis of entropion. One such entropion: A clinical and morphological study. Eye 1997;11(Pt 4):472-5. a similar antimicrobial spectrum and examination technique is the “snap-back 10. Wabbels B, Förl M. [Botulinum toxin treatment for efficacy at just once-daily dosing. test,” in which the patient is asked to crocodile tears, spastic entropion and for dysthyroid Botulinum toxin has been shown in look upward slightly while the examiner upper eyelid retraction]. Ophthalmologe 2007;104(9):771-6. several series to provide temporary pulls the lower eyelid inferiorly; if the 11. Quickert MH, Rathbun E. Suture repair of entropi- relief of entropion.8-10 By affecting a eyelid fails to return to its normal on. Arch Ophthalmol 1971;85(3):304-5.

10A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 11 EYELIDS AND ADNEXA

VERRUCA & PAPILLOMA erally round, flat-topped, slightly ele- those aged 30 and older, and the fre- vated lesions. Compared with other quency increases steadily with age. Signs and Symptoms papillomas, their surface is remarkably There is no known race or gender The term papilloma refers to a smooth. Verruca filiformis,as benign epithelial lesion of the skin or the name implies, present with mucosa.1 Papillomas affecting the eye numerous “finger-like” projec- primarily appear on the skin of the eye- tions from a larger base. Close lid, but they are occasionally seen on the inspection of all verrucae palpebral and bulbar conjunctivae. All reveals that they are comprised papillomas have a similar characteristic of multiple stalks of fibrovascu- configuration, consisting of lobular pro- lar tissue.3 Often, tiny red or jections that can resemble mulberries or black dots are evident near the cauliflower. They may be flat or planar surface of these projections, or they may be pedunculated (i.e., on a representing thrombosed, dilat- stalk). They may be solitary or multiple ed capillaries.4 Verrucae of the in presentation. lids may become quite large Verrucae are papillomas of viral ori- and often become keratinized A large squamous papilloma on the lower lid. gin. They are sometimes referred to in over time; associated cutaneous the literature as viral papillomas, verru- horns are not uncommon. Verrucae of predilection for either of these types of ca vulgaris or viral warts.2 They may the conjunctiva are less common and lesions, although acrochordons are tend to maintain a more “fleshy” encountered more commonly in obese appearance.5 and pregnant individuals.6 Patients Squamous papilloma is a with papillomas rarely present with generic term describing any symptoms beyond cosmetic concern, papilloma of non-viral origin. although in rare instances large lesions Most often these lesions repre- may induce mild lid dysfunction or dis- sent a benign dermatologic comfort.8 Patients who attempt to entity known as acrochordon,or remove these lesions by “picking” at “skin tag.”6 Clinically, squamous them may develop secondary, localized papillomas present as round or bacterial infections. oval multilobular lesions. They Verruca plana. may be sessile or pedunculated. Pathophysiology Like verrucae, they may vary in Papillomas represent benign over- pigmentation. Most common- growths of normal epithelium, with ly, the coloration approximates varying levels of keratinization and that of the patient’s skin; i.e., pigmentation. Histopathologically, the dark-skinned patients present lesions consist of multiple epithelial with more densely pigmented projections, the cores of which are vas- papillomas. Upon close inspec- cularized, fibrous connective tissue. tion, one may note a central These are covered by acanthotic (i.e., vascular core within each thickened, prickle-cell layer of the lesion, which provides blood to skin) and hyperkeratotic epithelium.1,9 the proliferating epithelium. Verrucae arise from viral infection; The surface is typically rough- their cores represent inflammatory ened or granulated, reflecting hypertrophy of tissue with viral inclu- the redundant epithelial cell sions.10 The causative agent in these Verruca filiformis. growth.6 lesions is the human papilloma virus Patients with verrucae tend (HPV), a double-stranded, non- vary in pigmentation from yellow to to be younger, typically between ages 5 enveloped DNA virus that is spread by pink to dark brown or even black. At and 20; less than 15% of patients are direct contact.2-5,8,11 There are more least two types of verrucae may be iden- older than 35.7 Squamous papilloma, than 60 strains of HPV, although most tified clinically. Verruca plana are gen- on the other hand, is more common in lesions are attributable to only a few of

APRIL 15, 2009 REVIEW OF OPTOMETRY 11A 001_ro0409_handbook 4/2/09 9:42 AM Page 12

the known serotypes.11 As with many lar papillomas and other benign skin spread to form satellite lesions around viral diseases, patients who are lesions. Application of these agents is the eye, affect skin in different regions of immunocompromised by chronic dis- simple and safe, provided the sur- the body or be transferred to other indi- ease (, HIV infection, and so rounding skin is coated with petrole- viduals. HPV is often spread by sexual on) are more susceptible to infection. um ointment and the chemicals are contact; patients should be asked Squamous papillomas may have not applied on the lid margin or con- whether similar lesions exist elsewhere numerous etiologies, but most often junctival surface. Cryotherapy with on the body; if so, appropriate referrals they arise de novo as a normal senescent liquid nitrogen is another common should be made. skin change.The onset tends to be grad- treatment modality for papillomas, • Some states permit optometrists to ual rather than sudden. Lesions tend not although this is typically not used out- remove benign skin lesions via chemical to resolve spontaneously, nor is acute side of a dermatologist’s office. cautery.The Derma-Cauter-All® Chem- enlargement common. However, squa- Recently, however, over-the-counter ical Cauterization Kit is available to eye- mous papillomas may in rare instances cryogens such as Verruca-Freeze® care practitioners and includes all of the represent precancerous lesions, so (CryoSurgery, Inc., Nashville, TN) necessary items to perform in-office malignant conversion must remain a have made it possible for other health chemical cautery (dichloracetic acid, consideration.12 professionals to employ this technique. petrolatum, cleaning pads, acid recepta- Again, exercise caution when using cle, applicators, dropper and an instruc- Management cryotherapy on periocular lesions; tion packet with a DVD).14 The kit may Because of their benign nature, ver- adverse effects can include hypo- or be ordered online from Sigma Pharma- ruca and squamous papillomas typically hyperpigmentation (especially in dark ceuticals, LLC (www.sigmapharmaceuti- warrant intervention only in cases of skin) as well as nerve damage when cals.com) or from North Pine Enterprises cosmetic concern, impairment of lid therapy is too aggressive.12 Inadvertent (www.northpineenterprises.com). function or discomfort. Obviously, application of cryogens to the ocular 1. Dutton JJ, Gayre GS, Proia AD. Papilloma. In: should any signs suggestive of of malig- surface can result in corneal scarring, Dutton JJ, Gayre GS, Proia AD, eds. Diagnostic Atlas of nancy develop, biopsy and removal are , and a host of other Common Eyelid Diseases. New York: CRC Press, essential. Typical management involves complications. 2007, pp. 225-6. 2. Dutton JJ, Gayre GS, Proia AD. Verruca vulgaris. In: patient reassurance, photodocumenta- Other treatment options for periocu- Dutton JJ, Gayre GS, Proia AD, eds. Diagnostic Atlas of tion and periodic observation. lar papillomas include laser ablation Common Eyelid Diseases. New York: CRC Press, When warranted, papillomas may using the CO laser, Nd:YAG laser or 2007, pp. 258-60. 2 3. Welch JL, Edison KE. Treatment options for the 13 be removed via several methods. pulsed dye laser. Verrucae may also common wart. Mo Med 2007;104(6):502-5. Electrocautery and surgical curettage respond to a number of topical therapies, 4. Lio P. Warts, molluscum and things that go bump on are some of the oldest and still most including cantharadin, podophyllin, the skin: A practical guide. Arch Dis Child Educ Pract Ed 2007;92(4):ep119-24. widely practiced therapeutic options bleomycin and imiquimod. 5. Miller DM, Brodell RT, Levine MR. The conjunctival for both ocular and non-ocular wart: Report of a case and review of treatment options. lesions.13 The application of electric Clinical Pearls Ophthalmic Surg 1994;25(8):545-8. 6. Pariser RJ. Benign of the skin. Med Clin current results in iatrogenic necrosis • Although the nomenclature regard- North Am 1998;82(6):1285-307,v-vi. and subsequent regression, usually ing papillomas is sometimes confusing 7. Bellew SG, Quartarolo N, Janniger CK. Childhood within a week to 10 days. Unfor- and contradictory, the terms all refer to warts: an update. Cutis 2004;73(6):379-84. 8. Ciconte A, Campbell J, Tabrizi S, et al. Warts are not tunately, both electrocautery and benign epithelial lesions. merely blemishes on the skin: a study on the morbidity curettage can be painful unless local • Whether the origin is hyperplasia associated with having viral cutaneous warts. Australas anesthesia is used, and they can result or viral infection, recognition and differ- J Dermatol 2003;44(3):169-73. 9. D’hermies F, Morel X, Bourgade JM, et al. in cosmetically displeasing scarring. entiation from malignant skin lesions is Hyperkeratosis papilloma of the eyelid. An anatomic Additionally, physicians must take care the first concern. Red flags for malig- clinical case. J Fr Ophtalmol 2001;24(5):558-61. when surgically removing verrucae to nancy include the following: asymmetry 10. Steigleder GK. Histology of benign virus induced tumors of the skin. J Cutan Pathol 1978;5(2):45-52. prevent spread of the virus by cutting of shape, irregular borders, abrupt 11. Jablonska S. Wart viruses: human papilloma virus- across the stalk of pedunculated changes in coloration or size, crusting or es. Semin Dermatol 1984;3(2):120-9. lesions. The virus may also spread if with minimal manipulation. 12. Schwartz RA, Tarlow MM, Lambert WC. Keratoacanthoma-like squamous cell carcinoma within not enough of the adjacent tissue is Rarely, malignant lesions may arise from the fibroepithelial polyp. Dermatol Surg 2004;30(2 Pt removed. or adjacent to benign papillomas.12 2):349-50. Chemical cautery with trichlo- • Patients should be advised of the 13. Lipke MM. An armamentarium of wart treatments. Clin Med Res 2006;4(4):273-93. racetic or dichloracetic acid is a popu- infectious nature of verrucae. They 14. Napper G, Douglas I, Albietz J. Ocular therapeu- lar therapeutic alternative for periocu- should be educated that these may tics. Clin Exp Optom 2007;90(3):212-3.

12A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 13

CONJUNCTIVA & SCLERA CONJUNCTIVA & SCLERA

SCLERAL MELT Pathophysiology Management The most common predisposing fac- Therapeutic intervention in cases of Signs and Symptoms tor in cases of scleral melting is prior ocu- scleral melt depends on a number of Scleral melt, also known as scleral lar surgery. There is a particularly high factors, most notably the disposition of necrosis, is an uncommon condition association with bare sclera the patient and the risk of globe perfo- that typically presents in older adults. excision, particularly cases in which ration. For cases that are relatively In most cases, scleral melt represents a adjunctive radiation or chemotherapy asymptomatic and not in danger of late complication of ocular surgery or was used.4,5 Scleral melt has also been perforation, simple periodic observa- trauma. Clinically, the condition may described as occurring after Image courtesy of Wayne Bizer, D.O. be seen as a focal area of scleral thin- extraction, , strabis- ning between the and mus surgery, retinal detachment the insertion of the extraocular mus- repair and orbital/ocular radia- cles, with the dark blue/black col- tion.1,2 Alternatively, the patient oration of the underlying uvea visible may report a prior incident involv- beneath the lesion. A variable degree of ing a severe chemical or thermal adjacent conjunctival inflammation burn to the ocular surface.The con- accompanies scleral melting, depend- dition may occur as soon as one day ing upon the etiology and associated or as late as 40 years after the pathology. antecedent trauma.4,6 Less com- Individuals presenting with scleral monly, scleral melt is encountered melting generally report symptoms of as a sequela of severe ocular surface Scleral necrosis. mild-to-moderate discomfort. Foreign disease (e.g., keratoconjunctivitis body sensation or stinging is common, sicca), ocular infection, systemic tion (e.g., every 4–6 months) along as is excessive lacrimation and possibly or connective tissue disorders.7,8 with liberal use of ophthalmic lubri- photophobia. Blurred vision is another Scleral melting is presumed to repre- cants may be all that is required.2 More frequent symptom. Rarely do patients sent a delayed-onset hypersensitivity severe cases may require the applica- complain of intense ocular pain. No race response to localized ischemia involving tion of surgical patch grafts to maintain predilection has been identified, but the episcleral blood vessels.9 Such tectonic support of the globe.2 women do appear to be affected more ischemia can be precipitated by surgical Tenonplasty—a surgical procedure often than men.1 A history of systemic trauma (especially when accompanied by involving excision of necrotic superfi- autoimmune disease is another common beta irradiation or mitomycin C thera- cial tissue along with dissection and finding; some of the associated condi- py), chemical or thermal injury or, less advancement of viable underlying tions may include rheumatoid arthritis, commonly, by severe autoimmune dis- Tenon’s capsule—is performed initially ease or vasculitis.2 The exact to reestablish the blood supply to the Image courtesy of Wayne Bizer, D.O. mechanism of damage is poorly ischemic sclera. Then, donor sclera tis- understood, but enzymes pro- sue or a lamellar corneal graft is typi- duced by polymorphonuclear cells cally transplanted to the wound and are likely implicated, leading to covered with either amniotic mem- destruction of collagen and pro- brane or a conjunctival flap.2,13,14 teoglycans that comprise the scle- Postoperatively, treatment with topi- ral stroma.10 Evidence to support cal corticosteroids (e.g., 1% pred- these hypotheses include the suc- nisolone acetate, q.i.d.) and prophylac- cess of systemic immunosupres- tic antibiotics (e.g., 0.5% moxifloxacin, sion in the treatment of scleral t.i.d.) helps control subsequent inflam- melts, as well as the presence of mation and infection.2 A variety of Scleral melt. immune complexes in the episcle- other surgical techniques have been ral vessel walls among such piloted, with varying success.14,15 The systemic erythematosus, pol- patients.11 Research has identified ele- concurrent use of immunosuppressive yarteritis nodosa, inflammatory bowel vated levels of both tumor necrosis factor agents, such as oral cyclophosphamide, disease, Wegener’s granulomatosis, alpha (TNF-Ȋ) and matrix metallopro- azithioprine, cyclosporin A and tacroli- relapsing polychondritis, diabetes melli- teinase-9 (MMP-9) in patients with mus, may be helpful to prevent graft tus and thyroid disorders.1-3 surgically induced scleral necrosis.12 rejection in difficult cases.16

APRIL 15, 2009 REVIEW OF OPTOMETRY 13A 001_ro0409_handbook 4/2/09 9:42 AM Page 14

Ocul Immunol Inflamm 2006; 14(5):317-9. Clinical Pearls 8. Shome D, Jain V, Jayadev C, et al. Scleral necrosis between 0.3–1.0mm and are typically 6 • Scleral melt is a serious and chal- in a patient with aplastic anaemia. Eye 2007;21(7): uniformly shaped. Additionally, tarsal lenging clinical problem, because it 1017. conjunctival hyperemia and thickening 9. Jain V, Shome D, Natarajan S, et al. Surgically threatens the integrity of the eye. Even induced necrotizing scleritis after pterygium surgery may be observed. Vision can be affected asymptomatic cases likely warrant a sur- with conjunctival autograft. Cornea 2008;27(6):720-1. due to deposits on the lens, as the result gical consultation to assess the potential 10. Schotveld JH, Beerthuizen JJ, Zaal MJ. Scleral of contact lens displacement secondary melting in a patient with carotid artery obstruction. for perforation. Cornea 2006; 25(1):101-3. to superior lid papillary hypertrophy or • Numerous conditions can masquer- 11. Diaz-Valle D, Benitez del Castillo JM, Castillo A, et from repetitive mechanical corneal abra- ade as scleral melting. These include al. Immunologic and clinical evaluation of postsurgical sion (shield ulceration). necrotizing sclerocorneal ulceration. Cornea benign entities such as senile scleral 1998;17:371–5. plaques and dellen, as well as more seri- 12. Seo KY, Lee HK, Kim EK, et al. Expression of tumor Pathophysiology ous conditions including necrosis factor alpha and matrix metalloproteinase-9 in GPC is loosely classified as a form of surgically induced necrotizing scleritis. Ophthalmic Res melanoma and scleromalacia perforans. 2006;38(2):66-70. ocular allergy, mostly because it is known 1,2 Scleromalacia perforans can be differen- 13. Kuckelkorn R, Redbrake C, Reim M. Tenonplasty: to involve mast-cell degranulation. tiated from scleral melt in that patients A new surgical approach for the treatment of severe eye Patients with GPC are also likely to have burns. Ophthalmic Surg Lasers 1997; 28(2):105-10. with the former are generally asympto- 14. Esquenazi S. Autogenous lamellar scleral graft in the a history of atopy (e.g., asthma, allergic 2,3 matic and present with bilateral involve- treatment of scleral melt after pterygium surgery. Graefes rhinitis, hayfever). However, this con- ment. In addition, the eyes are usually Arch Clin Exp Ophthalmol 2007;245(12):1869-71. dition differs from the more common 15. Davidson RS, Erlanger M, Taravella M, et al. otherwise quiet in the setting of the Tarsoconjunctival pedicle flap for the management of a clinical presentations such as seasonal patient having a longstanding, chronic severe scleral melt. Cornea 2007; 26(2):235-7. and perennial in history of rheumatoid arthritis. 16. Young AL, Wong SM, Leung AT, et al. Successful that GPC has a greater eosinophil and treatment of surgically induced necrotizing scleritis with • When scleral melting occurs as a tacrolimus. Clin Exp Ophthalmol 2005;33(1):98-9. basophil response than other acute forms complication of ocular surgery, the term of allergic conjunctivitis. Additionally, “surgically-induced necrotizing scleritis” GPC shows comparatively low tear his- (SINS) is often used. GIANT PAPILLARY tamine levels.1,4 • In cases of scleral melt that do not CONJUNCTIVITIS From a pathophysiological perspec- have an obvious traumatic or iatrogenic tive, GPC does not appear to be trig- etiology, and especially in those cases Signs and Symptoms gered by a foreign antigen-like typical that involve the limbal and peripheral Patients with giant papillary conjunc- allergic reactions; rather, it is believed to corneal regions, a medical workup to tivitis (GPC) present clinically with ocu- result from a combination of traumatic examine for collagen is lar irritation and itching, increased and autoimmune elements. The chronic highly advised. Contributory systemic mucus accumulation and variable palpe- mechanical “hammering” of the tarsal disorders are present in as many as 40% bral conjunctival redness. By definition, surface by a contact lens or other object, of scleral melt cases, and 62% of subjects the condition is always associated with combined with proteinaceous surface carry serologic markers for connective an object interacting with the ocular sur- deposits on these substrates has been tissue disease.4,6 face, such as an exposed suture, extruded hypothesized to induce a cell-mediated scleral buckle, cyanoacrylate glue, a con- response, which results in papillary 1. Tamhankar MA, Volpe NJ. Atypical necrotizing scleri- tact lens or ocular prosthesis.1-6 Since the hypertrophy and other elements of sur- tis after surgery. J AAPOS 2008;12(2):190-2. 5 2. Casas VE, Kheirkhah A, Blanco G, et al. Surgical condition is most commonly associated face inflammation. GPC seems to approach for scleral ischemia and melt. Cornea with contact lens wear, some distinguish involve both a Type I (immediate) and a 2008;27(2):196-201. the etiology of that specific cause and Type IV (delayed) hypersensitivity reac- 3. Ozcan AA, Bilgic E, Yagmur M, et al. Surgical man- agement of scleral defects. Cornea 2005;24(3):308-11. effect as contact lens papillary conjunc- tion, implicating a response by both mast 4. Alzagoff Z, Tan TD, Chee SP. Necrotising scleritis tivitis (CLPC).2 Patients with CLPC cells and inflammatory T-cells.2 after bare sclera excision of pterygium. Br J Ophthalmol generally report symptoms of lens dis- 2000;84(9):1050-2. 5. Tsai YY, Lin JM, Shy JD. Acute scleral thinning after comfort and intolerance, increased lens Management pterygium excision with intraoperative mitomycin C: A movement and surface coating and ocu- The initial treatment of GPC involves case report of scleral dellen after bare sclera technique lar itching after lens removal. The initial removing the allergic/inflammatory stim- and review of the literature. Cornea 2002; 21(2):227-9. 6. O’Donoughue E, Lightman S, Tuft S, et al. Surgically presentation may occur months or even ulus whenever possible. In cases of CLPC, induced necrotising sclerokeratitis (SINS)—precipitating years after lens wear has been initiated. this means suspending contact lens wear factors and response to treatment. Br J Ophthalmol Biomicroscopic examination reveals for an indeterminate length of time. 1992 ;76(1):17-21. 7. Gungor IU, Ariturk N, Beden U, Darka O. Necrotizing large papillae along the upper tarsal con- Numerous topical have been scleritis due to varicella zoster infection: a case report. junctiva; these papillae are generally advocated for adjunctive therapeutic relief.

14A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 15 CONJUNCTIVA & SCLERA

Perhaps the oldest and most well-known plete elimination is not a realistic goal. recently been proved effective in refrac- therapeutic agents to be used in this Upon reinitiating lens wear, a decreased tory GPC.18 capacity are the mast-cell stabilizers. wearing schedule, increased frequency of 1. Donshik PC, Ehlers WH, Ballow M. Giant papillary conjunctivitis. Immunol Allergy Clin North Am Historically, cromolyn sodium 4% was contact lens cleaning, enzymatic removal 2008;28(1):83-103. widely accepted as the gold standard in of proteins and/or frequent replacement 2. Stapleton F, Stretton S, Sankaridurg PR, et al. becomes paramount. Hypersensitivity responses and contact lens wear. Cont Lens Anter Eye 2003;26(2):57-69. 3. Begley CG, Riggle A, Tuel JA. Association of giant Clinical Pearls papillary conjunctivitis with seasonal allergies. Optom • CLPC has been noted to Vis Sci 1990;67(3):192-5. 4. Allansmith MR, Baird RS. Percentage of degranulat- occur with all types of contact ed mast cells in vernal conjunctivitis and giant papillary lenses, although it is most com- conjunctivitis associated with contact-lens wear. Am J mon with HEMA-based soft Ophthalmol 1981;91(1):71-5. 5. Korb DR, Greiner JV, Finnemore VM, Allansmith MR. 1,6,12 lenses. Silicone hydrogels Biomicroscopy of papillae associated with wearing of have also been implicated in the soft contact lenses. Br J Ophthalmol 1983;67(11):733-6. development of CLPC; howev- 6. Suchecki JK, Donshik P, Ehlers WH. Contact lens complications. Ophthalmol Clin North Am er, the presentation in these 2003;16(3):471-84. Giant papillary conjunctivitis in a contact lens wearer. patients may be somewhat atyp- 7. Meisler DM, Berzins UJ, Krachmer JH, Stock EL. ical, inducing a localized presen- Cromolyn treatment of giant papillary conjunctivitis. Arch Ophthalmol 1982;100(10):1608-10. tation in which the papillae are 8. Allansmith MR, Ross RN. Ocular allergy and mast confined to just one or two areas cell stabilizers. Surv Ophthalmol 1986;30(4):229-44. of the tarsal conjunctiva near the 9. Lustine T, Bouchard CS, Cavanagh HD. Continued contact lens wear in patients with giant papillary con- 13,14 lid margin. junctivitis. CLAO J 1991;17(2):104-7. • The use of topical steroids 10. Bielory L. Ocular allergy guidelines: A practical as first-line agents in GPC treatment algorithm. Drugs 2002;62(11):1611-34. 11. Ilyas H, Slonim CB, Braswell GR, et al. Long-term remains controversial, primari- safety of loteprednol etabonate 0.2% in the treatment of ly due to the potential side seasonal and perennial allergic conjunctivitis. Eye effects of long-term steroid Contact Lens 2004;30(1):10-13. 12. Donshik PC. Giant papillary conjunctivitis. Trans use. These include elevated Am Ophthalmol Soc 1994;92:687-744. managing GPC throughout the 1980s , cataractogenesis 13. Skotnitsky CC, Naduvilath TJ, Sweeney DF, San- and early 90’s.7-9 Today, however, many and increased susceptibility to ocular karidurg PR. Two presentations of contact lens-induced papillary conjunctivitis (CLPC) in hydrogel lens wear: prefer the antihistamine/mast-cell stabi- infection. For this reason, most sources local and general. Optom Vis Sci 2006;83(1):27-36. lizer combinations, such as olopatadine stress that corticosteroids should be 14. Skotnitsky C, Sankaridurg PR, Sweeney DF, and epinastine, because these agents pro- used only for short-term management Holden BA. General and local contact lens induced papillary conjunctivitis (CLPC). Clin Exp Optom vide more rapid and complete sympto- of GPC, if at all. 2002;85(3):193-7. matic relief, less frequent dosing (once or • Ester-based steroids such as 15. Friedlaender MH, Howes J. The Loteprednol twice daily) and greater comfort upon loteprednol have also been widely Etabonate Giant Papillary Conjunctivitis Study Group I. A double-masked, placebo-controlled evaluation of the 2,10 instillation than the older treatment. In advocated over ketone-based steroids efficacy and safety of loteprednol etabonate in the treat- lieu of anti-allergy therapies, topical corti- (e.g., prednisolone acetate or fluoro- ment of giant papillary conjunctivitis. Am J Ophthalmol costeroids likely represent the most com- metholone) in GPC because they enjoy 1997;123(4):455-64. 16. Asbell P, Howes J. A double-masked, placebo- prehensive option in GPC management. the reputation of having a greater safe- controlled evaluation of the efficacy and safety of Steroids completely inhibit the arachi- ty profile than the latter.11,15,16 loteprednol etabonate in the treatment of giant papillary donic acid pathway, preventing both • Topical cyclosporine A offers a conjunctivitis. CLAO J 1997;23(1):31-6. 17. Daniell M, Constantinou M, Vu HT, Taylor HR. prostaglandin and leukotriene synthesis. long-term immunomodulatory option Randomised controlled trial of topical ciclosporin A in In addition, these drugs have the capacity without the potential side effects of steroid dependent allergic conjunctivitis. Br J to stabilize cell membranes and hence may corticosteroids. Although no peer- Ophthalmol 2006;90(4):461-4. 18. Kymionis GD, Goldman D, Ide T, Yoo SH. 11 diminish mast-cell degranulation. reviewed data currently exists in the lit- Tacrolimus ointment 0.03% in the eye for treatment of Resolving GPC may be a long and erature supporting cyclosporine for giant papillary conjunctivitis. Cornea 2008;27(2):228-9. arduous process. For those with CLPC, GPC management, its utility in the lens wear may resume when symptoms treatment of other forms of allergic CONJUNCTIVAL LYMPHOMA are diminished and the hyperemic conjunctivitis is well established.17 response lessened. The papillary Similarly, another immunomodulatory Signs and Symptoms response may never fully abate, so com- agent, topical tacrolimus ointment, has Conjunctival lymphomas present as

APRIL 15, 2009 REVIEW OF OPTOMETRY 15A 001_ro0409_handbook 4/2/09 9:42 AM Page 16

rapidly growing mass lesions of the Organization (WHO) classification, proven lymphoma deserve a complete superficial ocular surface. They can be established in 2001.6,7 This system rec- medical evaluation to determine seen as isolated entities or they may ognizes three broad categories: precur- whether systemic lymphoma is present. occur as a localized manifestation of sor cell lymphomas, peripheral B-cell This includes basic hematology (CBC systemic lymphoma.1,2 The typical neoplasms and peripheral T and NK with differential) as well as evaluation appearance is that of a pink, “fleshy” cell neoplasms. It further subdivides by an oncologist. Radiographic imag- mass that arises from within the fornix these into numerous specific entities ing of the head, chest and abdomen and extends toward the cornea; classi- based upon morphologic, immunologic should also be obtained if systemic cally, they are described as “salmon-col- and genetic characteristics.6,7 involvement is suspected.9 ored patches.” They may present bilat- Therapy for conjuncti- erally in 20% to 38% of patients.2-4 val lymphoma depends Individuals with conjunctival lym- on the disposition of the phoma are usually between 60 to 68 tumor and whether there years; the condition predominantly is disseminated lym- affects female patients.2-5 These phoma elsewhere in the patients may have cosmetic concerns body. Isolated conjuncti- regarding chronic redness, and they val lymphoma (i.e., occasionally report dryness and irrita- involving the conjunctiva tion, but they rarely experience sub- but not other ocular or sys- stantial ocular discomfort. Vision may temic structures) is often be variably impacted, depending upon treated with external beam the location and extent of the lesion. irradiation, on the order of 2,000–4,000cGy.2,10 Dos- Pathophysiology MALT lymphoma. age and exposure tends Lymphoid tissue is present in most to be higher for more organs throughout the body. It is con- Most conjunctival lymphomas fall aggressive non-MALT lymphomas, nected by channels and conduits to into the category of B-cell neoplasms although care must be taken to mini- lymph nodes, located primarily in the of the non-Hodgkin’s variety.6,8 These mize long-term complications of ocu- neck, axillae, groin and abdomen. are frequently broken down further lar radiation such as or Lymphoma is an abnormal, malignant into mucosa-associated lymphoid tis- cataract formation.11 Other therapeutic growth of lymphoid tissue; a cancer of sue (MALT) lymphomas and non- options for these patients may include the various elements of the lymphatic MALT lymphomas. MALT lym- brachytherapy, cryotherapy, intrale- system. In the eye, lymphoma typical- phomas generally follow a more sional interferon-A, rituximab or sim- ly manifests as a conjunctival or orbital indolent course; non-MALT lesions ple observation.10,12,13 Those with inva- mass; less common presentations are considered highly malignant and sive or disseminated lymphoma may include choroidal infiltration with sec- invasive.9 require systemic chemotherapy in ondary uveitis and infiltrative optic addition to local treatment. The stan- neuropathy.3 Management dard regimen for non-Hodgkin’s lym- Over the years, a number of classifi- Although conjunctival lymphomas phoma is a combination of cyclophos- cation systems have been developed to often have a characteristic appearance, phamide, doxorubicin, vincristine and describe lymphoid tumors. These it is important to differentiate them prednisone, referred to in oncologic include the Rappaport, Kiel, Lukes- from other benign tumors of the ocular circles as CHOP.14,15 Collins, Working Formulation, British surface, such as squamous papilloma, National Lymphoma Investigation, pyogenic granuloma and lymphangiec- Clinical Pearls and Revised European-American tasis. Furthermore, it is not possible to • Conjunctival lymphoma should be Lymphoma (REAL) classifications.6 differentiate between benign and part of the differential in all cases of These systems were based on the histo- malignant lymphoid tumors (or sudden-onset rapidly growing lesions logical appearance of tumor growth MALT vs. non-MALT lymphomas) of the fornix, particularly those that are (nodular or diffuse), size of cells (small, simply on the basis of clinical presenta- highly vascularized and fleshy. Never medium or large) and cell immunophe- tion. Hence, excisional biopsy is crucial assume that these lesions are benign; notype (B, T, NK or null).6 Today, the to establish a definitive diagnosis. In the most prudent course of action is to accepted standard is the World Health addition, any patients with biopsy- obtain a prompt biopsy.

16A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 17 CONJUNCTIVA & SCLERA

• Though conjunctival lymphoma 15. Thieblemont C, de la Fouchardière A, Coiffier B. glaucoma and malignant melanoma Nongastric mucosa-associated lymphoid tissue lym- 4 may be associated with systemic lym- phomas. Clin Lymphoma 2003;3(4):212-24. are two known ocular complications. phoma, the ocular lesions have not Ehlers-Danlos syndrome is a het- been shown to metastasize to any sig- erogeneous group of connective tissue nificant degree. The five-year sur- BLUE SCLERA disorders characterized by joint hyper- vival rate for MALT lymphomas is mobility, skin hyperelasticity, tissue excellent.15 Signs and Symptoms fragility, easy bruising and poor • Localized therapy for conjunctival Blue sclera is not a diagnosis but a .5 Abnormal bruising lymphoma may not be required in indi- sign of imperfect connective tissue, and bleeding with skin extensibility viduals with disseminated lymphoma collagen and collagen-vascular con- are cardinal features.6 The vascular who are already undergoing systemic struction and assemblence.1-4 The eti- complications seen in Type IV disease chemotherapy. ology of the blue hue comes from the may affect all anatomical areas, with a pigmentation of the uveal tunic 1. Coupland SE, Hummel M, Stein H. Ocular adnexal showing through beneath an lymphomas: Five case presentations and a review of 1-4 the literature. Surv Ophthalmol 2002;47(5):470-90. abnormally thin scleral coat. 2. Shields CL, Shields JA, Carvalho C, et al. This is in contradistinction to Conjunctival lymphoid tumors: clinical analysis of 117 ocular melanosis, which pro- cases and relationship to systemic lymphoma. Ophthalmol 2001;108(5):979-84. duces a brown scleral hue. 3. Knowles DM, Jakobiec FA, McNally L, et al. Although the blue coloration Lymphoid hyperplasia and malignant lymphoma occur- may be apparent to examiners, ring in the ocular adnexa (orbit, conjunctiva, and eye- lids): a prospective multiparametric analysis of 108 in most instances, unless there cases during 1977 to 1987. Hum Pathol is accompanying ocular inflam- 1990;21(9):959-73. mation or vision loss secondary 4. Johnson TE, Tse DT, Byrne GE, Jr., et al. Ocular- adnexal lymphoid tumors: a clinicopathologic and to an associated vascular occlu- molecular genetic study of 77 patients. Ophthal Plast sion or choroidal neovascular- Reconstr Surg 1999;15(3):171-9. ization (CNV), there are no 5. Uno T, Isobe K, Shikama N, et al. Radiotherapy for extranodal, marginal zone, B-cell lymphoma of symptoms. The ocular signs and mucosa-associated lymphoid tissue originating in the symptoms that accompany the Two examples of blue sclera. ocular adnexa: a multiinstitutional, retrospective review findings of blue sclera will be of 50 patients. Cancer 2003;98(4):865-71. 6. Jakiç-Razumoviç J, Aurer I. The World Health consistent with the underlying Organization classification of lymphomas. Croat Med J syndrome producing it. The 2002;43(5):527-34. systemic diseases frequently 7. Harris NL, Jaffe ES, Diebold J, et al. The World Health Organization classification of neoplastic dis- associated with blue sclera eases of the haematopoietic and lymphoid tissues: include Nevus of Ota, Ehlers- Report of the Clinical Advisory Committee Meeting, Danlos syndrome (EDS), Airlie House, Virginia, November 1997. Histopathol 2000;36(1):69-86. Marfan’s syndrome, osteogene- 8. Bardenstein DS. Ocular adnexal lymphoma: classifi- sis imperfecta and rheumatoid cation, clinical disease, and molecular biology. arthritis.1-4 Ophthalmol Clin North Am 2005;18(1):187-97. 9. Lauer SA. Ocular adnexal lymphoid tumors. Curr Opin Ophthalmol 2000;11(5):361-6. Pathophysiology 10. Tsai PS, Colby KA. Treatment of conjunctival lym- Nevus of Ota is a benign dermal tendency toward large and medium phomas. Semin Ophthalmol 2005;20(4):239-46. 4 7 11. Bessell EM, Henk JM, Whitelocke RA, et al. Ocular melanocytosis. It involves the facial diameter arteries. In addition to a morbidity after radiotherapy of orbital and conjunctival skin as a macular discoloration and blue sclera via scleral thinning, dissec- lymphoma. Eye 1987;1(Pt 1):90-6. can involve the ocular structures such tions of the vertebral arteries and the 12. Blasi MA, Gherlinzoni F, Calvisi G, et al. Local 7 chemotherapy with interferon-alpha for conjunctival as the episclera, sclera, conjunctiva, carotid arteries are typical. Patients mucosa-associated lymphoid tissue lymphoma: A pre- cornea, retina and uveal tract. with EDS may present with blue scle- liminary report. Ophthalmol 2001;108(3):559-62. Melanocytes are derived from neural ra and dilated and tortuous conjuncti- 13. Nückel H, Meller D, Steuhl KP, et al. Anti-CD20 8 monoclonal antibody therapy in relapsed MALT lym- crest cells that migrate to the conjunc- val vessels with pulsatile proptosis. phoma of the conjunctiva. Eur J Haematol tiva and uvea. When these cells invade Patients experiencing vascular dissec- 2004;73(4):258-62. the episclera and sclera they can pro- tion (a stretching and tearing of the 14. Coiffier B. Effective immunochemotherapy for aggressive non-Hodgkin’s lymphoma. Semin Oncol duce patchy areas of bluish subcon- affected vessels) may present with 2004;31(1 Suppl 2):7-11. junctival discoloration. Open-angle variable headache along with fleeting

APRIL 15, 2009 REVIEW OF OPTOMETRY 17A 001_ro0409_handbook 4/2/09 9:42 AM Page 18

visual symptoms such as transient Management syndrome. Arthritis Rheum 2006;54(2):515-23. 2. Hackley L, Merritt L. Osteogenesis imperfecta in the 9 vision loss and transient visual blur. There is no management for blue neonate. Adv Neonatal Care 2008;8(1):21-30. Ehlers-Danlos syndrome may produce sclera. The key is recognizing its 3. Takaesu-Miyagi S, Sakai H, Shiroma T, et al. Ocular radiating angioid streaks, which are appearance and referring for the proper findings of Beals syndrome. Jpn J Ophthalmol 2004; 48(5):470-4. known to induce choroidal neovascu- medical workup. Because the manage- 4. Kannan SK. Oculodermal melanocytosis—Nevus of larization (CNV).10 ment of a discovered systemic disease Ota (with palatal pigmentation). Indian J Dent Res Marfan’s syndrome is an autosomal- and its potential complications will rest 2003;14(4):230-3. 5. Volkov N, Nisenblat V, Ohel G, et al. Ehlers-Danlos dominant multisystem connective tis- within the domain of the internist or syndrome: insights on obstetric aspects. Obstet sue disorder resulting from specialist, the role of the primary eye- Gynecol Surv 2007;62(1):51-7. in the gene for fibrillin, FBN1.11-13 The care provider is to discover undiagnosed 6. Parapia LA, Jackson C. Ehlers-Danlos syndrome— a historical review. Br J Haematol 2008;141(1):32-5. clinical diagnosis is based on a set of cases and monitor ocular health for the 7. Germain DP. Ehlers-Danlos syndrome type IV. well-defined clinical criteria (long abovementioned conditions. Orphanet J Rare Dis 2007;19(2):32. face, cardiac issues, dental issues, ocu- Medical testing may be required to 8. Miller NR. Diagnosis and management of dural carotid- fistulas. Neurosurg Focus lar issues and lumbosacral dural ecta- determine potential causes for blue 2007;23(5):E13. sia).11,12 Ocular complications include sclera. The laboratory testing potential- 9. Caplan LR. Dissections of brain-supplying arteries. blue sclera, lens subluxation (typically ly includes complete blood count with Nat Clin Pract Neurol 2008;4(1):34-42. 10. Chang LK, Spaide RF, Brue C, et al. Bevacizumab superiorly, a common diagnostic fea- differential and platelets (CBC, c Diff treatment for subfoveal choroidal neovascularization ture), vitreous degeneration and and PL), X-rays of the chest and hands, from causes other than age-related macular degenera- angioid streaks which also predispose sacrolumbar/iliac X-ray, erythrocyte tion. Arch Ophthalmol 2008;126(7):941-5. 11. Dean JC. : clinical diagnosis and 14,15 the potential for CNV. sedimentation rate, rheumatoid factor management. Eur J Hum Genet 2007;15(7):724-33. Osteogenesis imperfecta (OI) is a (RF), human leukocyte antigen (HLA- 12. Coucke P, Van Acker P, De Paepe A. rare heritable condition characterized B27), rapid plasma reagin (RPR), vene- analysis of the FBN1 gene in patients with Marfan syn- drome. Methods Mol Med 2006;126:81-95. by bone fragility and reduced bone real disease research lab test (VDRL), 13. Ammash NM, Sundt TM, Connolly HM. Marfan mass.16,17 OI produces systemic com- fluorescent treponemal antibody syndrome—diagnosis and management. Curr Probl plications that include dentinogenesis absorption test (FTA-Abs), blood urea Cardiol 2008; 33(1):7-39. 14. Zangwill SD, Brown MD, Bryke CR et al. Marfan imperfecta, hearing loss, joint laxity, nitrogen (BUN), total serum protein, syndrome type II: there is more to Marfan syndrome restrictive pulmonary disease and short homocysteine, skin biopsy and genetic than fibrillin 1. Congenit Heart Dis 2006;1(5):229-32. stature. Its ocular complications analysis.24 15. Hamod A, Moodie D, Clark B, et al. Presenting signs and clinical diagnosis in individuals referred to rule include blue sclera, fragile cornea, out Marfan syndrome. Ophthalmic Genet decreased ocular rigidity, , glau- Clinical Pearls 2003;24(1):35-9. coma, , , • Blue sclera may be associated with 16. Cheung MS, Glorieux FH. Osteogenesis Imperfecta: update on presentation and management. small corneal diameter and congenital Ehlers-Danlos syndrome and these Rev Endocr Metab Disord 2008;9(2):153-60. Bowman’s layer agenesis.18-20 patients’ angioid streaks may also be 17. Forin V. Osteogenesis imperfecta. Presse Med Rheumatoid arthritis (RA) is a sys- produced by sickle cell anemia, pseu- 2007;36(12 Pt 2):1787-93. 18. Martin E, Shapiro JR. Osteogenesis imperfecta: temic disease with manifestations in doxanthoma elasticum, high myopia, Epidemiology and pathophysiology. Curr Osteoporos many organ systems.21 While the artic- age-related causes and Paget’s disease Rep 2007;5(3):91-7. ulating surfaces are a focus, extra- of the bone. Any patient with blue scle- 19. Natarajan R, Shah GY, Rao SK, et al. Penetrating keratoplasty as a globe-saving procedure in fragile articular manifestations occur in ra should be monitored for angioid cornea. Cornea 2003;22(2):164-5. almost every organ system with varied streak formation and subsequent CNV. 20. Evereklioglu C, Madenci E, Bayazit YA, et al. Central incidence.21-23 Pathogenic mechanisms • Corneal thickness has been corneal thickness is lower in osteogenesis imperfecta and negatively correlates with the presence of blue scle- include pro-oxidative dyslipidemia, reported to be reduced in patients with ra. Ophthalmic Physiol Opt 2002;22(6):511-5. insulin resistance, prothrombotic state, OI and blueness of the sclera. This may 21. Dhawan SS, Quyyumi AA. Rheumatoid arthritis and immune be of importance because these and cardiovascular disease. Curr Atheroscler Rep 2008;10(2):128-33. mechanisms such as T-cell activation. patients may exhibit artificially low 22. Mathews SA, Kurien BT, Scofield RH. Oral mani- Ophthalmic presentations may include intraocular pressure measurements. festations of Sjögren’s syndrome. J Dent Res blue sclera, Sjögren’s syndrome • Scleritis occurring in RA has the 2008;87(4):308-18. 23. Sainz de la Maza M, Jabbur NS, Foster CS. (autoimmune rheumatic variant char- potential to produce blinding conse- Severity of scleritis and . Ophthalmol acterized by fatigue, dry eyes and dry quences. Systemic and ocular treat- 1994;101(2):389-96. mouth), episcleritis, scleritis, sclero- ment is required. 24. Burden, G, Bryant, SA. The sclera. In: Burden, G, Bryant, SA. Laboratory and Radiologic Tests for Primary malacia perforans (inflammation and Eye Care. Boston: Butterworth-Heinemann, 1997, pp. 1. Bravo JF, Wolff C. Clinical study of hereditary disor- 153-7. thinning of the wall of the eyeball), ders of connective tissues in a Chilean population: joint artery and vein occlusion.21-23 hypermobility syndrome and vascular Ehlers-Danlos

18A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 19

CORNEA

CORNEAL LACERATION nostic of a perforating corneal injury is thickness laceration. the presence of air bubbles within the The obvious danger in a full-thick-

Signs and Symptoms anterior chamber. Other key signs ness corneal laceration is the subse- CORNEA Corneal lacerations are invariably include corectopia (i.e., irregularity of quent extrusion of intraocular contents accompanied by a recent history of ocu- the pupil) and prolapse into or through the wound or introduction of lar trauma. Typically, this involves a through the wound. Accompanying harmful debris. As the pressure in the sharp object such as a pathology related to the anterior chamber drops, the pressure knife, hand tool or glass inciting trauma is also from the forces the lens shard, although cases common; subconjuncti- and iris forward. Excessive manipula- have been documented val hemorrhage, hyphe- tion or further trauma may induce a involving some very ma, iridodialysis, lens prolapse of these tissues through the obscure etiologies, dislocation, cataract, vit- laceration. An additional risk is the including such odd reous hemorrhage and transmission of potential pathogens items as fish hooks, plas- Repaired corneal laceration with vitreous incarceration into the eye, resulting in infection. tic toys, ninja stars and interrupted sutures. are all possible findings.4 Numerous cases of the talons from a bird of have been documented, in some cases prey.1-4 Lacerations may also result from Pathophysiology involving highly unusual organisms.7-9 penetration by a high-velocity projectile The cornea possesses great tensile or may occur secondary to severe blunt strength and is generally resistant to Management injury.5 Patients with corneal laceration penetration by blunt perpendicular From a primary care point of view, typically report intense pain at the forces; however, tangential injuries of the management of corneal laceration onset, although this may diminish over sufficient force—particularly those involves first aid. The clinician must time due to severing of the corneal induced by sharp objects—have the make a definitive diagnosis as quickly as . Additional symptoms may potential to cause the lamellar sheets of possible using the least amount of include photophobia, excessive lacrima- the corneal stroma to separate, allowing manipulation or intervention. It is most tion and variably reduced vision. for entry into the tissue. By definition, a important to differentiate corneal abra- Inspection of the eye reveals pro- laceration refers to a wound produced sions and partial-thickness lacerations nounced ocular injection, secondary by the tearing of a bodily tissue; it is from full-thickness lacerations. This is blepharospasm and pseudoptosis sec- usually traumatic, irregularly shaped facilitated by using the Seidel’s test. ondary to pain and photophobia. The and induced unintentionally by a for- Here sodium fluorescein is applied corneal laceration may be obvious if it is eign object.6 Lacerations may vary in directly to the wound, and then careful- large or irregularly shaped. One may thickness. When the cornea is penetrat- ly inspected under cobalt blue illumina- observe a jagged defect that extends tion. In cases of corneal from the corneal epithelium into and perforation, aqueous through the underlying stroma. Small, will slowly percolate linear breaks may be more difficult to from the lesion, creating visualize, because the opposing surfaces a dark-appearing area of the wound may close like a “flap- with a steady flow of valve” under the sustained intraocular fluid to the inferior flu- pressure of the eye. If the laceration is orescent tear lake. full thickness, the anterior chamber Tonometry, may be shallow or even flat, again and other procedures depending upon the extent of the requiring pressure on injury. Aqueous can be visualized per- the globe should be colating from the edge of the wound deferred if there is any when fluorescein is applied (Seidel’s suspicion of potential sign). The intraocular pressure will be Acute corneal laceration due to screwdriver injury. ocular perforation. substantially reduced in cases of full- To facilitate exami- thickness laceration, sometimes reach- ed through all layers into the anterior nation in cases of corneal trauma, it is ing as low as 0-2mm Hg depending chamber, it is referred to as a full-thick- often advantageous to instill a topical upon the timing of the evaluation com- ness laceration. A cleft that does not anesthetic. This helps to alleviate pared to the time of injury. completely traverse the stroma and patient discomfort and permits the cli- One finding that is particularly diag- endothelium is considered a partial- nician to perform a more thorough

APRIL 15, 2009 REVIEW OF OPTOMETRY 19A 001_ro0409_handbook 4/2/09 9:42 AM Page 20

evaluation of the eye, including visual more likely in males than females, and dispersed lens fragments. J Cataract Refract Surg 2007;33(4):739-40. acuity assessment, pupillary evaluation are also more common in younger age 10. Hamill MB. Cornea. In: Kuhn F, Pieramici DJ, eds. 11 and biomicroscopy. The downside of groups. Ocular Trauma: Principles and Practice. New York: using a topical anesthetic—or any topi- • Although fingernail scratches typi- Thieme, 2002, pp. 95-109. 11. Hamill MB. Corneal and scleral trauma. cal agent—in cases of corneal laceration cally do not generate enough force to Ophthalmol Clin North Am 2002;15(2):185-94. is the potential for deep tissue toxicity lacerate the cornea, at least one case of 12. Taneja S, Arora R, Yadava U. Fingernail trauma or introduced infection. With a com- this has been documented in the litera- causing corneal laceration and intraocular cilia. Arch promised cornea, topically applied ture; hence, it is important to rule out Ophthalmol 1998;116(4):530-1. drugs achieve intraocular concentra- laceration in all cases of corneal trauma.12 tions much greater than normally • With a corneal laceration, the TERRIEN’S MARGINAL intended. This can lead to unwanted patient may be lacrimating so heavily as DEGENERATION sequelae. Hence, any topical agents to render the Seidel test inaccurate. In should be used sparingly if at all, and these cases, a shallow or flat anterior Signs and Symptoms preservative-free options, where avail- chamber or the presence of bubbles Terrien’s marginal degeneration able, are preferred.10 within the anterior chamber indicates a (TMD) is a rare, slowly progressive Once the diagnosis is established, breach in the corneal integrity. thinning disorder of the cornea. The the primary goal is to stabilize the eye • For full-thickness corneal lacera- condition is typically bilateral and pre- and ensure that no further damage tions, the less done in the office the bet- dominantly affects men aged 40 years occurs. An eye shield should be gently ter. Assess the injury, arrange for the and older, although women and placed to protect the globe; however, appropriate referral and shield the eye younger patients may also present with the use of a pressure patch or bandage gently for protection while the patient a variant of this condition.1-3 Individuals contact lens is ill-advised, primarily is in transit to the surgeon. with TMD generally do not exhibit due to the manipulation required to • The patient should be educated pain, photophobia, lacrimation or con- apply these measures. In the event that that the initial entering acuity may rep- junctival redness upon presentation. In material is lodged in the wound, it resent the best vision that can be fact, aside from possible visual changes should not be removed. Immediately expected after surgical repair. Of course, (resulting from increased regular and refer to a corneal specialist to initiate may improve following irregular ), these patients surgical repair of the laceration. surgery; however, it is best not to ele- are often asymptomatic. Patients must be instructed not to eat vate a patient’s expectations. In its earliest stages, TMD presents or drink before the surgical consulta- • A fresh, previously unopened bot- as a fine, white punctate opacification of tion, because this may delay the proce- tle of topical anesthetic is preferred the peripheral cornea. As in arcus dure. If the patient is nauseous or over- when a full thickness corneal laceration senilis, a clear zone is preserved between ly anxious, consider prescribing an or is suspected. the limbus and the affected region of the antiemetic agent such as meclizine 25 cornea, although this area may be mg p.o. to prevent vomiting. 1. Muller L, Kohnen T. Scleral and corneal laceration bridged by fine vascularization resem- Repair of corneal lacerations involves with iris prolapse caused by an eagle claw. Graefes bling pannus. The proximal edge of the Arch Clin Exp Ophthalmol 2005;243(4):377-9. a variety of measures. Partial-thickness 2. Alfaro DV 3rd, Jablon EP, Rodriguez Fontal M, et al. degeneration is demarcated by a circum- and self-sealing lacerations may be Fishing-related ocular trauma. Am J Ophthalmol ferential yellow line, representing lipid treated with nothing more than topical 2005;139(3):488-92. infiltration.4 Although these changes 3. Jeng BH, Steinemann TL, Henry P, et al. Severe antibiotics, cycloplegics and a bandage penetrating ocular injury from ninja stars in two children. can be noted anywhere along the contact lens. Larger wounds or those Ophthalmic Surg Lasers 2001;32(4):336-7. corneal periphery, the superior and that are prone to leakage may some- 4. Segev F, Assia EI, Harizman N, et al. Corneal lacer- superonasal aspects of the cornea are ation by sharp objects in children seven years of age times be managed with cyanoacrylate and younger. Cornea 2007;26(3):319-23. characteristically involved. Over time, tissue adhesive in lieu of surgical 5. Baker RS, Flowers CW Jr, Singh P, et al. the region undergoes stromal thinning repair.11 However, most corneal lacera- Corneoscleral laceration caused by air-bag trauma. Am such that the area resembles a sloping J Ophthalmol 1996;121(6):709-11. tions—certainly most full-thickness 6. Dorland WA. Dorland’s Illustrated Medical Dictionary “gutter” with a peripheral lip defined by lacerations—require suturing to restore (31st ed.). Philadelphia: Saunders, 2007. the corneal limbus.2,5 Despite the loss of corneal integrity. 7. Ryan EH Jr, Cameron JD, Carpel E. Intraocular mol- corneal tissue, the overlying epithelium luscum contagiosum after a corneoscleral laceration. 5 Am J Ophthalmol 1997;124(4):560-1. remains intact. Late changes may Clinical Pearls 8. Sharma S, Saffra NA, Chapnick EK. Post traumatic include localized corneal ectasia, • According to the database of the polymicrobial endophthalmitis, including Neisseria sub- hydrops and opacification. Perforation is flava. Am J Ophthalmol 2003;136(3):554-5. United States Eye Injury Registry 9. Moinfar N, Smiddy WE, Miller D, et al. Posttraumatic a rare sequela, encountered in only (USEIR), corneal injuries are five times Aspergillus terreus endophthalmitis masquerading as about 15% of cases; although the major-

20A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 21

ity of these complications are due to corneal steepening 90° away from the )—bilateral, typical- coincident trauma, spontaneous perfo- area of flattening, with a relatively ly painful and progressive to perforation

ration has been encountered in TMD.1,3 spherical and regular central area.11 • Mooren’s ulcer—unilateral or CORNEA Therapeutic management of bilateral, painful corneal thinning with Pathophysiology Terrien’s marginal degeneration is neovascularization. The precise etiology of TMD has largely supportive, as the majority of • Pellucid marginal degeneration— never been fully elucidated; however, patients remain asymptomatic. TMD painless, inferior, peripheral corneal the disorder has been loosely associated patients are known to suffer from peri- thinning, a variant of keratoconus. with vernal keratoconjunctivitis, poste- odic episodes of red, irritated eyes sec- • Furrow degeneration—painless, rior polymorphous dystrophy and ery- ondary to mild adjacent conjunctival peripheral corneal thinning adjacent to inflammation. In addition to corneal arcus, without vascularization. lubrication with artificial tears, • Dellen—reversible, painless oval these cases often respond effec- thinning secondary to corneal dehydra- tively to topical corticosteroid tion. therapy (e.g., prednisolone • Marginal keratitis secondary to acetate 0.12 % or 1%, lotepred- staphylococcal hypersensitivity—pain- nol 0.5% q.i.d.). Refractive cor- ful, infiltrate present, inset from limbus. rection is paramount to com- • Fuch’s Marginal Keratitis— pensate for the acquired peripheral corneal inflammation astigmatism, although this can marked by pannus and thinning. be difficult because of the irreg- 1. Srinivasan S, Murphy CC, Fisher AC, et al. Terrien ularity and severity of the dis- marginal degeneration presenting with spontaneous turbance. Contact lenses may corneal perforation. Cornea 2006;25(8):977-80. Terrien’s marginal degeneration. offer a better option for visual 2. Austin P, Brown SI. Inflammatory Terrien’s marginal corneal disease. Am J Ophthalmol 1981;92(2):189-92. success, but they often require 3. Beauchamp GR. Terrien’s marginal corneal degen- thema elevatum diutinum (a rare complex fitting techniques (e.g., piggy- eration. J Pediatr Ophthalmol Strabis 1982;19(2):97-9. chronic skin disease with cutaneous back lens systems) by trained special- 4. Guyer DR, Barraquer J, McDonnell PJ, et al. Terrien’s marginal degeneration: Clinicopathologic case vasculitis), suggesting a possible autoim- ists. Because patients with severe TMD reports. Graefes Arch Clin Exp Ophthalmol mune mechanism.6-8 Studies have are at risk for corneal perforation, poly- 1987;225(1):19-27. demonstrated evidence of increased carbonate spectacles are highly recom- 5. Pesudovs K. Terrien’s marginal degeneration: Case reports and literature review. Clin Exp Optom 9,10 lysosomal activity. Histopathologi- mended, even in cases where contact 1994;77(3):97-104. cally, the principle findings include lenses are the primary refractive correc- 6. Kremer I. Terrien’s marginal degeneration associated fibrosis, vascularization and phagocyto- tion. When vision cannot be corrected with vernal conjunctivitis. Am J Ophthalmol 1991;15; 111(4):517-8. sis of corneal stromal collagen by histi- or the risk of perforation is high, surgi- 7. Wagoner MD, Teichmann KD. Terrien’s marginal ocytes.9 The epithelium remains intact, cal intervention may need to be consid- degeneration associated with posterior polymorphous but there is degeneration of basal ered. A variety of procedures have been dystrophy. Cornea 1999;18(5):612-5. 8. Shimazaki J, Yang HY, Shimmura S, et al. Terrien’s epithelial cells and an abnormal base- employed with modest success, includ- marginal degeneration associated with erythema eleva- ment membrane-like layer. Bowman’s ing thermokeratoplasty, annular full tum diutinum. Cornea 1998;17(3):342-4. membrane is typically lost; Descemet’s thickness penetrating keratoplasty, 9. Süveges J, Léval G, Alberth B. Pathology of Terrien’s disease. Histochemical and electron microscopic study. membrane may be intact, thickened or lamellar penetrating keratoplasty, and Am J Ophthalmol 1972;74(6):1191-200. thinned, and sometimes appears wavy. large eccentric corneal grafts.12-14 10. Hayasaka S, Tsuchiya M, Sekimoto M, et al. The endothelium may be normal or Lysosomal enzymes in tear fluids from patients with Terrien’s marginal corneal degeneration. Graefes Arch 9 attenuated. Clinical Pearls Clin Exp Ophthalmol 1987;225(5):335-7. • Suspect Terrien’s marginal degen- 11. Wilson SE, Lin DT, Klyce SD, et al. Terrien’s mar- Management eration in cases of bilateral or asym- ginal degeneration: . Refract Corneal Surg 1990;6(1):15-20. The most important aspect of man- metrical peripheral corneal thinning in 12. Cheng CL, Theng JT, Tan DT. Compressive C- aging patients with TMD is recogniz- a non-inflamed, otherwise asympto- shaped lamellar keratoplasty: A surgical alternative for ing the condition and differentiating it matic eye. the management of severe astigmatism from peripheral corneal degeneration. Ophthalmol 2005;112(3):425-30. from other peripheral corneal degener- • Key differential diagnoses of TMD 13. Hahn TW, Kim JH. Two-step annular tectonic lam- ations. In questionable cases, corneal include the following: ellar keratoplasty in severe Terrien’s marginal degenera- topography can be a helpful diagnostic • Peripheral corneal melting (kera- tion. Ophthalmic Surg 1993;24(12):831-4. 14. Chen L, Chen J, Yang B, et al. A preliminary report technique, demonstrating corneal flat- tolysis) secondary to collagen vascular of epikeratophakia for the treatment of Terrien’s degen- tening at the juncture of the furrow and disease (e.g., rheumatoid arthritis or eration. Yan Ke Xue Bao 1997;13(2):79-81.

APRIL 15, 2009 REVIEW OF OPTOMETRY 21A 001_ro0409_handbook 4/2/09 9:42 AM Page 22

CHEMICAL/TOXIC KERATO- termed punctate epitheliopathy and fibrosis in 66% of cases, severe inflam- CONJUNCTIVITIS exactly resembles its description (dif- mation in 21% of cases, giant cell reac- fuse, dot-like compromise either con- tion in 28% of cases and stromal calci- Signs and Symptoms fined to the area of contact or distrib- fication in 14% of cases.7 Further, Toxic keratoconjunctivitis, some- uted equally throughout the entire goblet cell absence was associated with times referred to as chemical keratitis or tissue). The conjunctivae, while inject- squamous metaplasia of the conjunctiva toxic follicular conjunctivitis, results ed, will appear elevated, boggy and and associated with long duration of when the cornea, palpebral and bulbar insult, indicating that chemical conjunctiva and surrounding tissue are injuries may produce lasting exposed to any number or combinations effects, even after the event has of foreign substances.1-4 The process passed.7 may occur unilaterally or bilaterally. The immune system has two Symptoms occurring from chronic divisions, each containing several exposure include ocular itching, burn- components. The cellular immune ing and tearing, corneal punctate system has a cellular component epitheliopathy, injection of the bulbar (leukocytes and other supportive and palpebral conjunctivae, of cells) and a humoral component the conjunctiva and adnexa and inferior (antibodies).13 The system relies and/or superior conjunctival follicles Chemical keratitis: note the “ground glass” appearance primarily on the cellular system to and papillae in the absence of lym- of the cornea. recognize foreign substances and phadenopathy.1-4 If the reaction is sub- initiate the first attack.13,14 The stantial, involves a large area or the chemotic without being firm, warm or components of the cellular system exposure is diffuse, an anterior chamber painful to the touch. In some instances, include granulocytes (neutrophils, reaction is possible. The severity of the the term “watch glass” is employed basophils, eosinophils) and macro- external damage and internal inflam- because the domed appearance of the phages (which phagocytize antigen and mation depends upon the nature of the conjunctiva, as it is juxtaposed against present it to T-cells). It also includes T- offending substance (caustic, bland, the cornea, resembles the way a watch’s helper lymphocytes, which recognize acid, base, solid, liquid, gas or light) crystal interfaces with its casing. foreign proteins presented by macro- along with the duration (long time vs. Likewise, the skin and adnexa may be phages and bind to them, causing the short time) and type of contact (direct involved, with a response ranging from release of lymphokines and alerting or indirect).5 It is important to recall itching to full-blown urticaria or boggy other lymphocytes to the presence of that phototoxicity (exposure to ultravi- edema. foreign antigens and cytotoxic T-cells olet light, typically from a welder’s arc that destroy abnormal host cells. or sunlight reflected by snow) is a ker- Pathophysiology Suppressor T-cells also play a role by atitis-producing source.4,6 When expo- The toxic/allergic response is classi- suppressing the immune response. B sure to an agent or combination of sub- cally considered an overreaction of the cells differentiate into plasma cells, stances or irritants (mechanical body’s immune system to immunogens producing antibodies against foreign included) continues without treatment or allergens.7-13 The reaction can be invaders. An antibody is a complex gly- or antidote, a fibrovascular adaptation innate or acquired. This overaction is coprotein produced by plasma cells that of the conjunctival tissue may ensue.7 manifested when the body responds are highly specific for the antigen that This finding is known as pannus.7 hyperactively to any exogenous materi- stimulated their production. Mast cells Typically, patients present in one of al. The chemical may be overtly are also included as members of the two ways: either they report with an destructive (such as gasoline, ammonia cellular immune team.13,14 unexplained red eye, oblivious to a or chlorine) or may be a topical medi- Notwithstanding the other elements causative vector, or they report that cine, a contact lens, contact lens solu- of the response, the key component to their eye was accidentally exposed to tion, dust or dander.1-13 The resultant the ocular allergic response is the mast something noxious. In the case of the tissue response is generated by the cell. When mast cells interact with spe- phenomenon known as medicamen- release of cytokines and chemoattrac- cific allergens, it is like a lock being tosa, there will be a history of starting a tants. When researchers analyzed the opened by a key. They open (degranu- new ocular , preparation tissue response that produces pannus late), discharging chemical substances (i.e., contact lens solution, rewetting following chemical injury, they found called mediators into the surrounding drop) or contact lens.8 Diagnosis is typ- that the tissue contained epithelial tissues.11 The primary chemical media- ically straightforward. The keratitis is hyperplasia in 62% of cases, active tors include histamine (responsible for

22A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 23

increased vascular permeability, vasodi- bral conjunctival epithelium infiltrated dote for the exposure is irrigation. This latation, bronchial constriction and by lymphocytes and plasma cells.13,15 information should be on the product

increased secretion of mucous), neutral The keratitis that occurs may be sec- label or material safety data sheet CORNEA proteases (which generate other inflam- ondary to the agent itself or may be (MSDS). The procedure for self-lavage matory mediators) and arachidonic acid cytokine expression. Absorption of is to run water from a tap or nozzle into (a crucial component of the cyclooxyge- excessive amounts of ultraviolet light cupped hands, placing the eye into the nase pathway leading to production of (UVA,UVB) can overwhelm the corneal formed receptacle. Copious blinking prostaglandins and leukotrienes).15 endothelial pump, inducing corneal enables the rinse.5,16 In the office, irriga- Pathophysiologically, there are four edema with all its concomitant signs and tion can be augmented manually by types of hypersensitivity reactions.13 symptoms.4 using a sterile ophthalmic saline applied Type I reactions are immediate hyper- Another type of corneal toxic/allergic forcefully and directly to all surfaces or sensitivity or anaphylactic reactions. reaction has recently been reported.8 by flushing the eye with a sterile intra- They produce sudden mass degranula- Researchers have discovered a potential venous saline solution run through a tion of mast cells mediated by the anti- long-term inflammatory upregulation Morgan lens apparatus.5,16 body IgE.13 Type II reactions are classi- within the cornea and conjunctiva sec- Following any necessary first aid, fied as autoimmune and involve a ondary to the preservative benzalkonium cold compresses, artificial tears and body’s impaired ability to distinguish chloride.8 It has been postulated that ointments can soothe and lubricate the self from non-self.13 Abnormalities in other preservatives may also produce this conjunctiva, skin and cornea as needed. this element of the system give rise to response. In a report outlining two com- Topical decongestants (naphazoline, diseases in which auto-antibodies are bined studies, histopathological effects , and so on, b.i.d.–q.i.d.) produced and directed against the of antiglaucoma drugs on the conjuncti- produce vasconstriction, which reduces host.13 Type III reactions involve com- va and trabecular meshwork demon- hyperemia, chemosis and other symp- bined formations of antigen and anti- strated toxic/immunoinflammatory toms by retarding the release of the body known as immune complexes.13 effects on both tissues.8 This data sup- chemical mediators into the tissues Offending triggers may be intrinsic ports other findings, and together they from the bloodstream. Topical antihist- (e.g., a protein molecule) or extrinsic (a illuminate a mechanism by which surgi- amines along with antihistamine/mast- penicillin molecule) producing a signif- cal glaucoma treatment (trabeculectomy) cell stabilizing combinations (Pataday, icant tissue response.13 Type IV reac- may fail in young patients. Evidence has Patanol, Zaditor, Optivar) and oral tions, sometimes referred to as cell- been gathered citing the upregulated antihistamines (Benadryl, 25–50 mg, mediated hypersensitivity reactions, inflammatory processes, created by plac- p.o., t.i.d.) are also excellent therapies involve the T lymphocytes and lym- ing some individuals on these prepara- for acute signs and symptoms.15 The phokines.13 The reaction is classically tions for a long period, as inducing nonsteroidal anti-inflammatory drugs delayed until a sufficient volume of increased, aggressive healing that renders (NSAIDS; Acular, Voltaren, Xibrom, antigens stimulate the chemical cas- some of the surgical corrective proce- Nevanac b.i.d.–q.i.d.) may offer signifi- cade.13 Here, the individual has the dures ineffective.8 cant pain relief in moderate cases, with potential to respond when the appro- topical steroidal preparations (Alrex, priate levels of antigen become present. Management Lotemax, Pred Mild and Forte, This may take one exposure or 100 Since there are many strata of ocular Inflammase Mild and Forte, FML and exposures. Classically, following the allergic reactions, management is pri- FML Forte suspensions b.id.–q.i.d.) response, which is rarely life-threaten- marily aimed at eliminating the reserved for the most severe presenta- ing, the patient is bewildered, recogniz- causative substance and reducing symp- tions.1-15 In instances in which the ing that he or she had been engaged tomatology.1-17 In the event of an acute cornea is sufficiently tattered, topical with that substance a number of times injury, lavage should be completed with antibiotic coverage may be prudent. without any complication whatsoever. single and double lid eversion. If Bandage contact lenses and The Type I and IV reactions govern patients call to report that they have can also be included as needed.17 toxic/allergic keratoconjunctival disease. been involved in an accidental chemical Finally, oral analgesics such as or In the ocular tissues, the result of exposure, they should be advised to ibuprofen can be used to settle excessive these chemical exchanges appear as copiously lavage immediately before discomfort and referred pain.17 If conjunctival and adnexal vasodilation, coming to the office. Patients who corneal edema is significant, topical producing chemosis and edema.12,14 require over-the-phone first aid should hypertonic drops and ointments can be Conjunctival follicles are hyperplasia of be advised to brush off all powdered used q.d.–q.i.d. to restore normal levels lymphoid tissue within the eyelid stro- chemicals before attempting lavage and of hydration. ma and papillae are hyperplastic palpe- to make sure the recommended anti-

APRIL 15, 2009 REVIEW OF OPTOMETRY 23A 001_ro0409_handbook 4/2/09 9:42 AM Page 24

suppl):S91-S104. Clinical Pearls 11. Butrus S, Portela R. Ocular allergy: Diagnosis and cornea is prone to colonization by path- • The diagnosis of toxic/allergic treatment. Ophthalmol Clin North Am 2005;18(4):485-92. ogenic bacteria. Factors known to com- conjunctivitis can be made based upon 12. Jennings B. Mechanisms, diagnosis and manage- promise corneal defenses include direct ment of common ocular allergies. J Am Opt Assoc history and course. Patients who 1990;61(6 suppl):S33-S41. corneal trauma, chronic eyelid disease, receive a chemical splash should be 13. Onofrey BE. Principles of immunology and the systemic immune disease, tear film asked to bring the material safety data immune response. In: Onofrey, BE, ed. Clinical abnormalities affecting the ocular sur- Optometric Pharmacology and Therapeutics. Phila- sheet (MSDS) or the product itself so delphia: J.B. Lippincott, 1994. pp. 1-13. face and hypoxia induction from con- 1-4 that the chemical can be identified and 14. Leonardi A. Emerging drugs for ocular allergy. tact lens wear. referenced with poison control. Expert Opin Emerg Drugs 2005;10(3):505-20. Pathogenic bacteria colonize the cor- 15. Schultz BL. Pharmacology of ocular allergy. Curr • Some clinicians prefer the con- Opin Allergy Clin Immunol 2006;6(5):383-9. neal stroma and immediately become venience of prescribing combination 16. Ikeda N, Hayasaka S, Hayasaka Y, et al. Alkali antigenic, both directly and indirectly, antibiotic/steroid preparations to pre- burns of the eye: Effect of immediate copious irrigation by releasing enzymes and toxins. This with tap water on their severity. Ophthalmologica scribing two separate agents. However, 2006;220(4):225-8. sets up an antigen-antibody immune if therapy is required over a longer peri- 17. Wilson SA, Last A. Management of corneal abra- reaction with chemotactic factors od, titration and tapering can become sions. Am Fam Physician 2004;70(1):123-8. inducing an inflammatory reaction. an issue, because the antibiotic and The body mobilizes polymorphonu- steroid in a combination drop cannot BACTERIAL KERATITIS clear leukocytes (PMN), which aggre- be tapered independently. gate at the area of infection, creating an • Even if left untreated, uncompli- Signs and Symptoms infiltrate. The PMNs phagocytize and cated injuries resolve within eight days. A patient with bacterial keratitis will digest the bacteria and also damage • In true toxic keratoconjunctivitis, generally present with a unilateral, stromal tissue by releasing numerous there will not be a palpable preauricu- acutely painful, photophobic, intensely collagenolytic enzymes that directly lar lymph node. Toxic substances relat- injected eye. Visual acuity is often impact stromal tissue.1,4 ed to acts of terrorism, such as mustard reduced and profuse tearing is common. The collagen of the corneal stroma gas, may necessitate the use of the There will be a focal stromal infiltrate is poorly tolerant of the bacterial and American Association of Poison Con- with an overlying area of epithelial exca- leukocytic enzymes and undergoes trol Centers. If the circumstances sur- vation. Often, the patient will have a degradation, necrosis and thinning. rounding the exposure are suspicious, history of contact lens wear, which is the This leads to scarring of the cornea. As the patient should be quarantined and most common precipitating condition thinning advances, the cornea may per- the authorities called immediately after in developed nations.1-3 Corneal trauma forate, thus introducing bacteria into first aid has been administered. or pre-existing keratopathy are also the eye with ensuing endophthalmitis. common precipitating conditions.1-3 The most commonly occurring 1. Balali-Mood M, Hefazi M. Comparison of early and Mucopurulent discharge may organisms in bacterial keratitis vary late toxic effects of sulfur mustard in Iranian veterans. Basic Clin Pharmacol Toxicol 2006;99(4):273-82. emanate from the lesion. The cornea is depending on the precipitating factors 2. Wirbelauer C. Management of the red eye for the often edematous. The conjunctival and of the ulcer and the geographic loca- primary care physician. Am J Med 2006;119(4):302-6. episcleral vessels will be deeply tion of the patient. In cases involving 3. Lubeck D, Greene JS. Corneal injuries. Emerg Med Clin North Am 1988;6(1):73-94. engorged and inflamed, often greatly contact lens wear and cosmetic mas- 4. Records RE. Primary care of ocular emergencies. 2. out of proportion to the size of the cara, the most common infective Thermal, chemical, and nontraumatic eye injuries. corneal defect. In bacterial keratitis, organism is Pseudomonas aeruginosa.1,5 Postgrad Med 1979;65(5):157-60, 163. 5. Burns FR, Paterson CA. Prompt irrigation of chemi- injection is typically 360° rather than Throughout North America, the most cal eye injuries may avert severe damage. Occup sectoral as seen in non-infectious ker- common infective organism in bacteri- Health Saf 1989;58(4):33-6. atitis. A pronounced anterior chamber al keratitis is Staphylococcus aureus, and 6. Peate WF. Work-related eye injuries and illnesses. Am Fam Physician 2007;75(7):1017-22. reaction, often with , is pres- it appears that there is an increased 7. Fatima A, Iftekhar G, Sangwan VS, et al. Ocular sur- ent in severe cases. Intraocular pressure incidence of Gram-positive recovery in face changes in limbal stem cell deficiency caused by may be either reduced due to secretory infectious keratitis.1,5 chemical injury: A histologic study of excised pannus from recipients of cultured corneal epithelium. Eye hypotony of the ciliary body or elevat- 2007;21(6):[Epub ahead of print]. ed due to inflammatory cell blockage Management 8. Baudouin C, Pisella PJ, Fillacier K et al. Ocular sur- or direct inflammation of the trabecu- Proper diagnosis and prompt thera- face inflammatory changes induced by topical antiglau- coma drugs: Human and animal studies. Ophthalmol lar meshworks. Often, the eyelids will py are essential to preserve vision in 1999;106(3):556-63. also be edematous and ptotic.1,4 bacterial keratitis. Microbial identifi- 9. Baudouin C. Allergic reaction to topical eyedrops. cation and antibiotic sensitivity studies Curr Opin Allergy Clin Immunol 2005;5(5):459-63. 10. Jackson WB. Differentiating conjunctivitis of Pathophysiology will aid in management. The first step diverse origins. Surv of Ophthalmol 1993;37(4 Once defenses are breached, the in management should be to obtain

24A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 25

corneal scrapings for microbiologic resistance were encountered more com- and every two hours at night. For days studies. The standard of care supports monly in the fluoroquinolone group, 4 and 5, one drop every two hours by

culturing most, if not all, suspected caution should be exercised in using flu- day and every four hours at night, and CORNEA infectious ulcers using a platinum oroquinolones in large, deep ulcers in for days 6 and 7, one drop every four spatula with plating directly onto elderly patients.7,8 hours. After day 7, the antibiotic was blood and chocolate agar medium. Despite clear efficacy of fluoro- tapered to every six hours and stopped quinolones in managing bacterial when appropriate.21 keratitis, consideration must be Although fourth-generation fluoro- given to the increasing resistance to quinolones have assisted greatly in these drugs.4,9-11 Since their incep- managing bacterial keratitis, it must be tion, there has been a rise in the inci- noted that they are not without fail. dence of bacterial isolates in keratitis There are now reports of patients Bacterial keratitis with mucopurulent discharge. that exhibit resistance to the early- developing resistance to these medica- generation fluoroquinolones, espe- tions.24,25 Recently approved by the Certainly, culturing is mandated when cially among the Gram-positive organ- FDA is a higher-dose formulation of the infiltrate is in the visual axis, if the isms.4,5,12-15 Even cephazolin, commonly levofloxacin, 1.5% (Iquix), for treating depth of the infiltrate approaches 25% employed in fortified form, has seen bacterial keratitis. This formulation is or 50% of the corneal thickness, if increasing bacterial resistance.14 the highest concentration available for there is scleral extention, if the infil- One method of combating the any ocular antibiotic.26 trate is not responding in a seemingly increasing problem of fluoroquinolone Strong cycloplegia is also recom- appropriate fashion to therapy, or if resistance and rising level of Gram-pos- mended, in the form of the infiltrate occurs in an immuno- itive infections are the fourth-generation 5% or 0.25% b.i.d.. If this compromised or hospitalized patient. topical fluoroquinolones. Two fourth- is insufficient, then 1% b.i.d. Additionally if a rare infection is sus- generation fluoroquinolones—moxi- is indicated. Adjunctive use of cold pected or atypical infiltrate is seen, floxacin (Vigamox, Alcon) and gati- compresses will also help to reduce cultures are also mandated. An alter- floxacin (Zymar, Allergan)—have a inflammation. native for culturing of less-threatening greatly lowered resistance rate, while The patient should be followed keratitis involves a mini-tip calcium providing much greater Gram-positive daily until the infection is well under alginate culturette and transport- activity than previous-generation fluoro- control. If the results of cultures and media–containing carrier. However, quinolones.15-21 Gatifloxacin was shown sensitivities show that the initially pre- the effectiveness of the fluoro- to have a significantly better action scribed quinolone antibiotics has led many against Gram-positive cocci both in antibiotic is practitioners away from this standard. vitro and in vivo compared with appropriate Microbiologic identification is most ciprofloxacin.22 for the infec- crucial for central lesions that threaten Another study examining the efficacy tive organ- vision, cases in which perforation is a of moxifloxacin compared with standard ism, or if the risk, and in institutionalized patients therapies in patients with bacterial ker- Bacterial keratitis. patient in nursing homes and hospitals where atitis reported no difference in healing shows signs methicillin-resistant S. aureus (MRSA) rate, cure rate or complications between of clinical improvement (the ulcer does infections are possible.6 fortified cep- not worsen and pain and photophobia Empirical broad-spectrum antibiotic hazolin and are reduced) at the 24–48 hour follow- therapy must be initiated prior to tobramycin, up visit, a topical corticosteroid, such as obtaining culture results. Monotherapy ofloxacin or prednisolone acetate 1% or loteprednol with fluoroquinolone eye drops was moxifloxacin, etabonate 0.5% q.i.d.-q2h can be shown in one report to result in shorter although it added with caution to speed resolution duration of intensive therapy and short- Bacterial keratitis with must be noted and decrease corneal scarring. er hospital stay compared to that of hypopyon. that the con- Although steroids have historically combined fortified therapy (tobramycin- centration of been avoided in managing infectious cefazolin). This finding may have result- moxifloxacin used in this study was keratitis, judicious use can be benefi- ed from quicker clinical response of double that available commercially.23 In cial. Antibiotics can suppress the infec- healing as a result of less toxicity in the this study, moxifloxacin was instilled tive organism, and corticosteroids can patients treated with fluoroquinolones. every hour, day and night, for 48 hours, inhibit the corneotoxic inflammatory However, as some poor outcomes due to and on the third day, every hour by day response. It has been feared that the

APRIL 15, 2009 REVIEW OF OPTOMETRY 25A 001_ro0409_handbook 4/2/09 9:42 AM Page 26

immunosuppressive effects of steroids reduces beneficial effects. A cautionary activity of fluoroquinolones against ocular bacterial iso- lates in São Paulo, Brazil. Cornea 2007;26(2):194-8 could enhance bacterial replication note: Be comfortable that the antibiot- 18. Duggirala A, Joseph J, Sharma S, et al. Activity of and worsen infection. However, if the ic has sterilized the ulcer before insti- newer fluoroquinolones against Gram-positive and chosen antibiotic is effective against tuting the steroid. Gram-negative bacteria isolated from ocular infections: an in vitro comparison. Indian J Ophthalmol the organism, the concurrent use of • Oral doxycycline and high-dose 2007;55(1):15-9. steroids will not inhibit the bacterici- vitamin C may reduce stromal damage 19. Caballero AR, Marquart ME, O’Callaghan RJ, et al. dal effect of the antibiotic.27-33 in conditions such as bacterial keratitis. Effectiveness of fluoroquinolones against Mycobacterium Steroids should not be employed abscessus in vivo. Curr Eye Res 2006;31(1):23-9. 1. Green M, Apel A, Stapleton F. Risk factors and 20. Lee SB, Oliver KM, Strube YN, et al. Fourth-gener- until the antibiotic has been given causative organisms in microbial keratitis. Cornea ation fluoroquinolones in the treatment of mycobacteri- enough time to sterilize the ulcer. A 2008;27(1):22-7. al infectious keratitis after laser-assisted in situ ker- minimum 24-hour loading period is 2. Keay L, Edwards K, Naduvilath T, et al. Microbial atomileusis surgery. Can J Ophthalmol 2005;40(6): keratitis predisposing factors and morbidity. 750-3. recommended. One must also be cer- Ophthalmol 2006;113(1):109-16. 21. Callegan MC, Ramirez R, Kane ST, et al. tain that the infection observed is not 3. Bourcier T, Thomas F, Borderie V, et al.. Bacterial Antibacterial activity of the fourth-generation fluoro- of herpetic viral, fungal or protozoan keratitis: predisposing factors, clinical and microbiolog- quinolones gatifloxacin and moxifloxacin against ocular ical review of 300 cases. Br J Ophthalmol pathogens. Adv Ther 2003;20(5):246-52. origin before initiating topical steroids. 2003;87(7):834-8. 22. Parmar P, Salman A, Kalavathy CM, et al. Steroids should be used only in con- 4. Schaefer F, Bruttin O, Zografos L, et al. Bacterial Comparison of topical gatifloxacin 0.3% and cipro- junction with true bactericidal antibi- keratitis: A prospective clinical and microbiological floxacin 0.3% for the treatment of bacterial keratitis. Am study. Br J Ophthalmol 2001;85(7):842-7. J Ophthalmol 2006;141(2):282-286. otics, such as fluoroquinolones or forti- 5. Alexandrakis G, Alfonso EC, Miller D. Shifting trends 23. Constantinou M, Daniell M, Snibson GR, et al. fied antibiotics. A recent report noted in bacterial keratitis in south Florida and emerging Clinical efficacy of moxifloxacin in the treatment of bac- improved visual outcomes for eyes with resistance to fluoroquinolones. Ophthalmol terial keratitis: A randomized clinical trial. Ophthalmol 2000;107(8):1497-502. 2007;114(9):1622-9. bacterial keratitis from 1995–2005, 6. Sotozono C, Inagaki K, Fujita A, et al. Methicillin- 24. Moshirfar M, Meyer JJ, Espandar L. Fourth-gener- commensurate with increased use of resistant Staphylococcus aureus and methicillin-resist- ation fluoroquinolone-resistant mycobacterial keratitis topical corticosteroids in conjunction ant Staphylococcus epidermidis infections in the after laser in situ . J Cataract Refract cornea. Cornea 2002;21(7 Suppl):S94-S101. Surg 2007;33(11):1978-81. with topical antibiotics. The authors 7. Gangopadhyay N, Daniell M, Weih L, et al. 25. Jhanji V, Sharma N, Satpathy G, et al. Fourth-gen- speculated that increased emphasis on Fluoroquinolone and fortified antibiotics for treating eration fluoroquinolone-resistant bacterial keratitis. J management of inflammation in con- bacterial corneal ulcers. Br J Ophthalmol Cataract Refract Surg 2007;33(8):1488-9. 2000;84(4):378-84. 26. McDonald MB. Research review and update: junction with the infectious process 8. Prajna NV, George C, Selvaraj S, et al. Bacteriologic IQUIX (levofloxacin 1.5%). Int Ophthalmol Clin 2006; may have contributed to the improved and clinical efficacy of ofloxacin 0.3% versus 46(4):47-60. outcomes.34 ciprofloxacin 0.3% ophthalmic solutions in the treat- 27. Engel LS, Callegan MC, Hobden JA, et al. ment of patients with culture-positive bacterial keratitis. Effectiveness of specific antibiotic/steroid combinations Cornea 2001;20(2):175-8. for therapy of experimental Pseudomonas aeruginosa Clinical Pearls 9. Wilhelmus KR, Abshire RL, Schlech BA. Influence of keratitis. Curr Eye Res 1995;14(3):229-34. • If a patient presents with a corneal fluoroquinolone susceptibility on the therapeutic 28. Hobden JA, Hill JM, Engel LS, et al. Age and ther- response of fluoroquinolone-treated bacterial keratitis. apeutic outcome of experimental Pseudomonas aerug- infiltrate without overlying epithelial Arch Ophthalmol 2003;121(9):1229-33. inosa keratitis treated with ciprofloxacin, prednisolone, staining, then the condition is likely 10. Parmar P, Salman A, Kalavathy CM, et al. and flurbiprofen. Antimicrob Agents Chemother not infectious bacterial keratitis. Pneumococcal keratitis: a clinical profile. Clin Exper 1993;37(9):1856-9. Ophthalmol 2003;31(1):44-7. 29. Hobden JA, Engel LS, Hill JM, et al. Prednisolone • Using strong bactericidal antibi- 11. Goldstein MH, Kowalski RP, Gordon YJ. Emerging acetate or prednisolone phosphate concurrently admin- otics will eliminate the infective organ- fluoroquinolone resistance in bacterial keratitis: A 5-year istered with ciprofloxacin for the therapy of experimen- isms and sterilize the ulcer, but it will review. Ophthalmol 1999;106(7):1313-8. tal Pseudomonas aeruginosa keratitis. Curr Eye Res 12. Afshari NA, Ma JJ, Duncan SM, et al. Trends in 1993;12(5):469-73. do nothing to quell the inflammatory resistance to ciprofloxacin, cefazolin, and gentamicin in 30. Hobden JA, O’Callaghan RJ, Hill JM, et al. reaction. In such instances, the inflam- the treatment of bacterial keratitis. J Ocul Pharmacol Ciprofloxacin and prednisolone therapy for experimen- matory reaction is as damaging to the Ther 2008;24(2):217-23. tal Pseudomonas keratitis. Curr Eye Res 13. Sharma V, Sharma S, Garg P, et al Clinical resist- 1992;11(3):259-65. cornea as is the infective organism. If ance of Staphylococcus keratitis to ciprofloxacin 31. Carmichael TR, Gelfand Y, Welsh NH. Topical evidence exists that the antibiotic is monotherapy. Indian J Ophthalmol 2004;52(4):287-92. steroids in the treatment of central and paracentral suppressing the infective organism, 14. Leibovitch I, Lai TF, Senarath L, et al. Infectious corneal ulcers. Br J Ophthalmol 1990;74(9):528-31. keratitis in South Australia: Emerging resistance to cep- 32. Wilhelmus KR. Indecision about corticosteroids for then corticosteroid use will inhibit the hazolin. Eur J Ophthalmol 2005;15(1):23-6. bacterial keratitis: An evidence-based update. inflammatory reaction and speed heal- 15. Kowalski RP, Dhaliwal DK, Karenchak LM, et al. Ophthalmol 2002;109(5):835-42. ing and reduce corneal scarring. Gatifloxacin and moxifloxacin: An in vitro susceptibility 33. Stern GA, Buttross M. Use of corticosteroids in comparison to levofloxacin, ciprofloxacin, and ofloxacin combination with antimicrobial drugs in the treatment of • For steroids to be most beneficial, using bacterial keratitis isolates. Am J Ophthalmol infectious corneal disease. Ophthalmol. 1991;98(6): prescribe them while the ulcer bed is 2003;136(3):500-5. 847-53. still open, usually within the first 16. Mather R, Karenchak LM, Romanowski EG, et al. 34. Al-Shehri A, Jastaneiah S, Wagoner MD. Changing Fourth generation fluoroquinolones: New weapons in trends in the clinical course and outcome of bacterial 24–48 hours after you initiate antibiot- the arsenal of ophthalmic antibiotics. Am J Ophthalmol keratitis at King Khaled Eye Specialist Hospital. Int ic therapy. Waiting until the ulcer re- 2002;133(4):463-6. Ophthalmol 2008;Apr 3 [Epub ahead of print]. epithelializes before adding a steroid 17. Oliveira AD, D’Azevedo PA, Francisco W. In vitro

26A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 27

UVEA AND GLAUCOMA UVEA AND GLAUCOMA AXENFELD-RIEGER and a characteristic facial appearance.10 Management SYNDROME ARS is typically diagnosed in early Pathophysiology childhood. If it has not yet been discov- Signs and Symptoms ARS is the result of developmental ered by that time, a primary eyecare Axenfeld-Rieger syndrome (ARS) is a arrest in the third trimester of gestation.11 physician may play a role in identifying rare inherited disorder affecting the At this point, tissues derived from the its unique characteristics, resulting in development of the eyes, teeth and neural crest cells falter, accounting for the abdomen.1 The ocular component of ocular and most non-ocular abnormali- ARS often garners the most clinical ties.11 The mesodermal dysgenesis and attention.1 The spectrum of developmen- anterior chamber cleavage syndromes tal eye disorders affecting the iris and have not been found to be consistent with angle include Rieger’s anomaly (periph- recent observations, resulting in the sug- eral iris strands, prominent Schwalbe’s gestion for the alternative nomenclature, line, stromal atrophy of the iris), Peter’s Axenfeld-Rieger syndrome.11 The autoso- anomaly (corneal leukoma with adhe- mal dominant inheritance is characterized sions and anterior segment anomalies but by complete penetrance with variable Axenfeld-Rieger Syndrome, showing iris no cataract), and Axenfeld’s anomaly expressivity, producing ocular and extra- strands and posterior embryotoxon. ocular malformations.1-11 Mutations in several chromosomal loci have been impli- diagnosis. Managing the systemic effects cated including PITX2, FOXC1 (fork- of ARS requires a team approach. head transcription factor gene-alterations Dental, auditory and cardiovascular spe- in this gene are known to induce anterior cialists are all required.1-14 The ocular segment abnormalities) and PAX6.8-12 effects of ARS may also require special- Full-spectrum ARS is caused primarily by ists. The cosmetic and functional correc- mutations in the PITX2 gene.8,12 A 6p25 tion of iris atrophy and correctopia can be microdeletion has the capability of induc- accomplished using specialty opaque/ ing the additional non-ocular findings of painted contact lenses. The open-angle Gonioscopic view of patient with Axenfeld- Rieger Syndrome. hearing loss, developmental delay and car- glaucoma induced by ARS can be man- diac complications.9,13,14 aged initially as with its primary open- (prominent Schwalbe’s line and peripher- Since the principle ocular abnormality angle counterpart. Topical prostaglandin al iris strands). If glaucoma occurs with includes an interruption of the iris-angle medications and aqueous suppressants these anomalies, then they are termed relationship, faulty aqueous outflow pro- are reasonable choices. In advanced cases Rieger’s syndrome, Peter’s syndrome, or duces a secondary open-angle glauco- or those exhibiting a rapid progression, Axenfeld’s syndrome, respectively. The ma.15 Additional data has uncovered a surgical intervention may be required.20 glaucoma that occurs is an aggressive form relationship between the genetic markers with an early onset that poses a challenge that produce ARS (PITX2, FOXC1) Clinical Pearls for diagnosis and management.1-6 and decreased central corneal thickness, a • Truncus arteriosus is a cardiac anom- Patients with ARS possess mal- highly speculated independent marker aly associated with ARS, characterized by formed irido-angular structures that are for the risk of glaucoma.16,17 Other inves- a large defect in the ventricular septum readily visible upon biomicroscopic and tigations have shown direct common (separating the ventricles), where one large gonioscopic examination. Prominent linkage between the genetic mutations single vessel (truncus) arises to carry blood bilateral forward-positioned Schwalbe’s implicated in both ARS and glaucoma both to the body and the lungs. Appropri- rings (posterior embryotoxon), peripher- (PITX2 and CYP1B1 genes).18,19 ate cardiovascular history should be gath- al contractile iridocorneal strands, iris ered from patients with ARS. hypoplasia and corectopia (decentered • Genetic counseling is recommend- pupil) are all observable anatomic varia- ed, given the disease’s known heritability. tions.6-8 Dental abnormalities are consid- • Posterior embryotoxon has been ered a definitive differentiating feature documented to exist in as many as 15% of for the diagnosis of the Rieger type.9 normal eyes having no connection with Genetic variations have the ability to ARS. Conversely, patients may have ARS alter the clinical phenotype, producing without having posterior embryotoxon. individuals with variable amounts of • The irido-corneal-endothelial syn- hearing loss, congenital heart disease, Axenfeld-Rieger Syndrome, showing dromes known as Chandler syndrome, dental anomalies, developmental delay correctopia and posterior embryotoxon. iris nevus syndrome and Cogan-Reese

APRIL 15, 2009 REVIEW OF OPTOMETRY 27A 001_ro0409_handbook 4/2/09 9:42 AM Page 28

syndrome are among the differential MALIGNANT GLAUCOMA Pathophysiology diagnoses. In these cases, there are no Malignant glaucoma is actually an systemic complications. Signs and Symptoms inappropriate term, since no malignancy Malignant glaucoma, sometimes is associated with the condition. The

1. Hjalt TA, Semina EV. Current molecular understand- referred to as aqueous misdirection syn- term arose because the condition was his- ing of Axenfeld-Rieger syndrome. Expert Rev Mol Med drome or ciliary block glaucoma, has no torically difficult to treat and typically 2005; 7(25):1-17. race or gender predilection. Patients typ- resulted in significant visual morbidity. 2. Dietlein TS, Jacobi PC, Krieglstein GK. Outcome of anterior-segment surgery in Rieger’s anomaly. Ger J ically have hyperopic and small or Likewise, aqueous misdirection syn- Ophthalmol 1996;5(6):439-42. nanophthalmic eyes. Most significantly, drome is also somewhat of a misnomer in 3. Thurschwell LM, Michelson MA. Axenfeld’s anomaly there is a history of antecedent ocular that it is not universally accepted that the and related disorders. J Am Optom Assoc 1986;57(5):360-5. surgery (typically ) aqueous is actually misdirected in every 4. Zaidman GW, Rabinowitz Y, Forstot SL. Optical iri- shortly after complications begin. It is case.There is evidence, however, that this dectomy for corneal opacities in Peter’s anomaly. J most commonly encountered after tra- does happen in many instances.9,12-14 Cataract Refract Surg 1998;24(5):719-22. 5. Haddad AM, Greenfield DS, Stegman Z, et al. beculectomy, glaucoma drainage device Malignant glaucoma often occurs fol- Peter’s anomaly: Diagnosis by ultrasound biomi- implant surgery, peripheral or lowing ocular surgery (typically for angle- croscopy. Ophthalmic Surg Lasers 1997;28(4):311-2. iridotomy or .1-6 Fre- closure glaucoma) in an eye with a pre- 6. Fuse N, Takahashi K, Yokokura S, et al. Novel muta- tions in the FOXC1 gene in Japanese patients with quently, a period of hypotony may have existing narrow angle and shallow Axenfeld-Rieger syndrome. Mol Vis 2007;13:1005-9. occurred as a result of overfiltration fol- chamber. Certainly, eyes with shallow 7. Espana EM, Mora R, Liebmann J, et al. Bilateral lowing glaucoma surgery, and initially anterior chambers undergoing surgery are prominent Schwalbe ring in the anterior chamber in a patient with Axenfeld-Rieger syndrome and megalo- malignant glaucoma may present with at risk for the condition. cornea. Cornea 2007;26(3):379-81. statistically normal, though rising, The widely accepted theory holds that 8. Sim KT, Karri B, Kaye SB. Posterior embryotoxon intraocular pressure (IOP) with concur- following surgery or through a natural may not be a forme fruste of Axenfeld-Rieger’s 1,7 Syndrome. J AAPOS 2004;8(5):504-6. rent anterior chamber shallowing. predisposition, the ciliary body and ciliary 9. Jena AK, Kharbanda OP. Axenfeld-Rieger syn- Biomicroscopically, a shallow or non- processes form a tight apposition to the drome: Report on dental and craniofacial findings. J existent anterior chamber will be evi- peripheral lens and the anterior vitreous. Clin Pediatr Dent 2005;30(1):83-8. 10. Maclean K, Smith J, St Heaps L, et al. Axenfeld- dent in the presence of an intact iridec- This prevents the aqueous from flowing Rieger malformation and distinctive facial features: tomy or iridotomy.8-10 Frequently there into the anterior chamber and diverts it Clues to a recognizable 6p25 microdeletion syndrome. is a preoperative history of anatomically instead into the vitreous cavity, increasing Am J Med Genet A 2005;132(4):381-5. 11. Shields MB, Buckley E, Klintworth GK et al. narrow angles along with miotic thera- the volume inside the cavity. An abnor- Axenfeld-Rieger syndrome. A spectrum of develop- py.9 Patients who develop significant mally impermeable anterior hyaloid face mental disorders. Surv Ophthalmol. 1985; 29(6):387- inflammation, such as that seen with may play a role by preventing aqueous 409. 12. Honkanen RA, Nishimura DY, Swiderski RE, et al. scleritis, may also develop malignant from diffusing through the vitreous into A family with Axenfeld-Rieger syndrome and Peters glaucoma. In rare cases, trauma can pre- the anterior chamber, and thus causes an Anomaly caused by a point mutation (Phe112Ser) in the cipitate malignant glaucoma. Retinal increase in the volume of the vitreous. FOXC1 gene. Am J Ophthalmol 2003;135(3):368-75. 13. Gürbüz-Köz O, Atalay T, Köz C, et al. Axenfeld- detachment surgery, panretinal photo- This expansion of the vitreous secondari- Rieger syndrome associated with truncus arteriosus: A coagulation and central retinal vein ly pushes the lens and iris towards the case report. Turk J Pediatr 2007;49(4):444-7. occlusion have also been reported in cornea, with subsequent shallowing of the 14. Dorfman AL, Geva T. Magnetic resonance imaging evaluation of congenital heart disease: Conotruncal association with the development of anterior chamber and closure of the anomalies. J Cardiovasc Magn Reson 2006;8(4):645- malignant glaucoma.11 angles. The classic appearance that occurs 59. Predisposing factors such as hyper- is that of a shallow anterior chamber axial 15. Pearce WG, Mielke BC, Kulak SC, et al. Histopathology and molecular basis of iridogoniodysge- opia, a narrow iridocorneal angle, plateau depth (lens-corneal distance) along with nesis syndrome. Ophthalmic Genet 1999;20(2):83-8. iris configuration and a history of miotic an accompanying shallow peripheral 16. Asai-Coakwell M, Backhouse C, Casey RJ, et al. use are risks for malignant glaucoma anterior chamber depth (iris-corneal dis- Reduced human and murine corneal thickness in an 1,14,15 Axenfeld-Rieger syndrome subtype. Invest Ophthalmol development, especially after the patient tance). In contradistinction, a patient Vis Sci 2006;47(11):4905-9. has corrective ocular surgery.9 Pro- with acute pupil block primary-angle clo- 17. Brandt JD. Central corneal thickness, tonometry, gressive flattening of the anterior cham- sure will have a normal axial depth and a and glaucoma risk—a guide for the perplexed. Can J Ophthalmol 2007;42(4):562-6. ber following surgery with progressive shallow peripheral depth. In pupil block 18. Craig JE, Mackey DA. Glaucoma genetics: Where IOP rise is the hallmark of malignant glaucoma, a peripheral iridotomy will lead are we? Where will we go? Curr Opin Ophthalmol glaucoma.9 Further, there will be no iris to deepening of the chamber. In malig- 1999;10(2):126-34. 19. Vasiliou V, Gonzalez FJ. Role of CYP1B1 in glauco- bombé or evidence of supraciliary effu- nant glaucoma, there will be no effect by ma. Annu Rev Pharmacol Toxicol 2008;48:333-58. sion.1,9,12,13 Should IOP elevate abruptly, iridotomy, and indeed, the hallmark is a 20. Mandal AK, Prasad K, Naduvilath TJ. Surgical classic signs and symptoms similar to closed angle with a shallow chamber and results and complications of mitomycin C–augmented trabeculectomy in refractory developmental glaucoma. those of acute angle-closure glaucoma narrow axial depth that remains despite Ophthalmic Surg Lasers 1999;30(6):473-80. may occur. patent iridotomy or iridectomy.

28A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 29 UVEA AND GLAUCOMA Management chamber.18,19 Diode laser cyclodestruction 5. Przybylska-Rybczyfska I, Kosowska-Zawadka A, Pecold-Stepniewska H. Malignant glaucoma following Management of malignant glaucoma has been used as a complementary treat- trabeculectomy—case report. Klin Oczna 2004;106(1-2 begins medically with the goal of break- ment in managing the IOP in cases of Suppl):S261-S262. ing the apposition of the ciliary body and refractory malignant glaucoma.2,20 6. Arya SK, Sonika, Kochhar S, et al. Malignant glauco- ma as a complication of Nd:YAG laser posterior capsulo- ciliary processes to the lens and anterior Unfortunately, after successful treat- tomy. Ophthal Surg Lasers Imag 2004;35(3):248-50. vitreous.This is accomplished by relaxing ment of malignant glaucoma, the angle 7. Burgansky-Eliash Z, Ishikawa H, Schuman JS. the ciliary body and lens zonules to allow may remain closed from extensive Hypotonous malignant glaucoma: Aqueous misdirection with low intraocular pressure. Ophthal Surg Lasers Imag. the lens to release posteriorly.This can be peripheral anterior synechiae. If more 2008;39(2):155-9. achieved with a potent cycloplegic such than one-half of the angle remains 8. Valtot F. What should be done when laser iridotomy as atropine.1,7 Aqueous suppressants can closed, IOP will remain permanently ele- does not physically eliminate angle closure? J Fr Ophtalmol 2006;29(Spec No. 2):61-6. be used to temporize the IOP, and topi- vated, despite successful treatment of the 9. Schroeder W, Fischer K, Erdmann I, et al. Ultrasound cal steroids will ameliorate any inflam- underlying cause. In such cases, the sur- biomicroscopy and therapy of malignant glaucoma. Klin mation. Miotics are contraindicated geon may try to break the peripheral Monatsbl Augenheilkd 1999;215(1):19-27. because they can precipitate or worsen anterior synechiae with a goniosynechial- the condition. Oral carbonic anhydrase ysis, or the patient may require a form of CRYSTALLINE LENS inhibitors and hyperosmotic agents can permanent medical therapy. SUBLUXATION be used to dehydrate and shrink the vit- reous, adding additional room for the Clinical Pearls Signs and Symptoms lens to settle. Medical control can be • Pupillary block is the most common While subluxation of the crystalline effective in a moderate number of cases, condition mimicking malignant glauco- lens can occur in any patient, it is com- and represents the safest first option.1,14 ma. Laser iridotomy will relieve pupil mon in three distinct situations.The first Should medical control be ineffective, block angle closure, but it will have no is a patient who has received significant there are surgical options. Treating malig- effect on malignant glaucoma. However, blunt trauma to the eye, or in some cases nant glaucoma and aqueous misdirection laser iridotomy must be performed to to the head.1-4 The second is in patients caused by increased resistance to aqueous differentiate the two conditions. who have a systemic condition known to flow anteriorly through the ciliary body- • Choroidal effusion with a shallow be associated with lens subluxation, such zonule-lens capsule complex requires the anterior chamber, particularly after glau- as Marfan’s syndrome, , establishment of a conduit to allow fluid coma filtration surgery, is the second , familial , passage.16 The first of the surgical options most-common differential diagnosis for sulfite oxidase deficiency, Weill- is hyaloidotomy with disruption of the malignant glaucoma. Large effusions Marchesani syndrome, and anterior hyaloid face to allow aqueous to will be seen ophthalmoscopically. Small Ehlers-Danlos syndrome.5-13 The third escape from the ballooning vitreous cavi- suprachoroidal effusion can cause an situation is a patient with a hypermature ty.This option attempts to facilitate aque- anterior rotation of the ciliary body and cataract in which zonular support has ous redirection into the anterior chamber precipitate this condition. Small effu- been lost.13 Additionally, crystalline lens rather than the posterior chamber. The sions are typically detected only with subluxation can occur idiopathically and most common method involves Nd:YAG ultrasound biomicroscopy. spontaneously.14,15 Other potential causes laser photodisruption of the anterior vit- • After glaucoma surgery such as tra- include ocular surgery, exfoliation syn- reous face through an iridectomy or irido- beculectomy, a flat anterior chamber and drome and vigorous eye rubbing.16-17 tomy hole or through the pupil. This may low IOP are suggestive either of overfil- Symptoms of lens subluxation include create an opening for aqueous to reach tration or bleb leakage. If the anterior visual disturbance from extreme hyper- the anterior chamber.1,9 chamber is flattening and shallowing opic or myopic shift, astigmatism or A more invasive method of surgically and the IOP is rising, malignant glauco- acquired . Occasionally, the correcting malignant glaucoma is through ma should be considered the cause. vision fluctuates dramatically as the .16-19 Here, the anterior vitreous patient may alternate between phakic is “debulked,” the iris is given a chance to 1. Greenfield DS, Tello C, Budenz DL, et al. Aqueous and aphakic vision.18 There may also be relax and the anterior chamber to deepen. misdirection after glaucoma drainage device implantation. monocular diplopia. In most cases, there Ophthalmol 1999;106(5):1035-40. Further, pockets of aqueous within the 2. Muqit MM, Menage MJ. Malignant glaucoma after are no physical sensations unless the lens vitreous are removed and the anterior vit- : treatment with diode laser cyclopho- blocks the pupil leading to pupil block reous face is disrupted, potentially rectify- tocoagulation. J Cataract Refract Surg 2007;33(1):130-2. and secondary angle closure. In this sce- 3. Stan C. Bilateral malignant glaucoma—case report. ing the blockage that prevented the mis- Oftalmologia 2005;49(4):33-4. nario the patient may manifest the directed aqueous from ultimately getting 4. Martínez-de-la-Casa JM, García-Feijoó J, Castillo A, et symptoms of acute angle-closure glauco- through the pupil. All surgical options are al. Malignant glaucoma following combined Ahmed valve ma including a steamy cornea, blurred implant and phacoemulsification surgery for chronic designed to establish a communication angle-closure glaucoma. Arch Soc Esp Oftalmol vision, headache, pain, photophobia, between the vitreous cavity and anterior 2005;80(11):667-70. lacrimation, nausea and vomiting.19-21

APRIL 15, 2009 REVIEW OF OPTOMETRY 29A 001_ro0409_handbook 4/2/09 9:42 AM Page 30

Although secondary glaucoma is com- placement in each case is characteristic the lens into the anterior chamber can monly associated with crystalline lens but by no means completely diagnostic. also result in a reverse pupil block angle- subluxation, the cause is not always pupil Marfan’s syndrome is the most common- closure glaucoma.27 block; open-angle glaucoma can occur as ly encountered underlying condition in well, presumably from lens-induced patients with crystalline lens subluxation. Management inflammation.10 More than 70% of patients with Marfan’s Extraction of a dislocated lens can Biomicroscopically, there will be a syndrome have displacement of the crys- prove to be difficult. For that reason, lens displaced crystalline lens.This appears as talline lens.23 In Marfan’s syndrome, the subluxation alone is not sufficient to a black crescent at the edge of the lens lens tends to be displaced superior tem- mandate surgery.9 It is recommended against a red reflex from the fundus. The porally.This results from a predominance that, in the absence of pupil block glau- lens can be dislocated up and out, down of abnormally constructed collagen vas- coma, corneal decompensation, inflam- and in, down and out, nasally or tempo- cular tissue and faulty lens zonules and is mation or intractable visual disability, a rally, or completely displaced into the typically non-progressive. Further, as the subluxed lens should be left alone in posterior or anterior chamber. There zonules are still attached to the lens, favor of less invasive options.9 For may also be phacodonesis (tremulous- some degree of exists. induced refractive errors that are stable, ness of the lens due to loss of zonular Homocystinuria, a defect in amino visual correction with glasses or contact support) and iridodonesis (tremulous- acid metabolism, results in brittle zonules lenses should be investigated. ness of the iris).13 that rupture.5,13 This allows the lens to If the lens dislocates into the posterior displace inferior nasally or even into the chamber but the posterior capsule remains Pathophysiology anterior chamber. There is no accommo- intact and no inflammation is induced, it Subluxation implies displacement of dation in this case and the condition may can be monitored.9 However, if inflamma- the crystalline lens. Luxation refers to a be progressive.5,13 Two other conditions tion that cannot be managed topically is lens that is totally dislocated. The term that should be mentioned are simple induced or retinal damage is threatened, ectopia lentis has been used interchange- ectopia lentis and ectopia lentis et pupillae. then vitrectomy and lens extraction are ably with subluxation. Simple ectopia lentis is an necessary. Late onset inflammation is However, this should be a autosomal dominant con- always possible. Patients require life-long, term reserved for bilateral dition in which the lenses timely and periodic observation.9 cases. Subluxation of the are dislocated superotem- In cases where there is suspected loss crystalline lens has been porally, but there are no of zonular adherence (often with hyper- described as being either other associated systemic mature ) with subsequent risk of acquired or congenital. abnormalities. Ectopia dislocation into the anterior chamber, Better terminology would Crystalline lens subluxation. lentis et pupillae is likewise pharmacological dilation should be be that subluxation of the an isolated inherited condi- avoided until surgical consultation can lens can be either acquired (such as from tion, albeit autosomal recessive, in which be obtained. In cases where the lens has trauma) or due to congenital systemic the lenses are displaced temporally in already dislocated into the anterior causes. Rarely are infants born with dis- opposing directions.24-26 chamber, the patient can be reclined and placed lenses; instead the phenomenon The main concern with dilated, to attempt reposi- develops during life due to a predispos- lens subluxation is the tioning by carefully manip- ing systemic condition.22 development of secondary ulating the head until the Traumatic subluxation is slightly angle-closure glaucoma. lens falls back into place. more common than lens displacement Any time the crystalline Following this, pilocarpine associated with underlying systemic dis- lens displaces, the possibili- solution can be instilled to orders.12 Traumatic mechanical stretch- ty exists that the lens can stabilize the structure, and ing of the zonules is the cause of the sub- come into firm apposition Crystalline lens subluxation a surgical consultation can as seen on funduscopy. luxation. This occurs as the eye is with the back surface of the be obtained. compressed in an anterior-posterior iris. When the pupil is In cases in which pupil direction (such as with impact by a fist or obstructed, there is pupil block, iris block angle-closure glaucoma develops, other projectile) and the subsequent dis- bombé and secondary angle closure.19-21 laser peripheral iridotomy should be per- tention of the globe in the medial-later- Should a lens completely dislocate into formed as soon as possible. However, this al plane ruptures the zonular fibers. the anterior chamber, concern must be rarely manages the condition successful- Spontaneous lens subluxation associ- for the lens touching the cornea, irre- ly. Patients frequently require lens extrac- ated with congenital conditions varies in versibly damaging the endothelial cells tion with intraocular lens implantation. pathophysiologic mechanism depending with subsequent chronic corneal edema Phacoemulsification with posterior upon the condition. The direction of dis- and decompensation.13 Displacement of chamber intraocular lens and capsular

30A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 31 UVEA AND GLAUCOMA tension ring implantation has been a very 2007;26(4):487-9. automobile airbag or the contact with an 14. Choi DY, Kim JG, Song BJ. Surgical management of 2 successful surgical management of crys- crystalline lens dislocation into the anterior chamber with object during a fall. Pain, photophobia 28-30 talline lens subluxation. More recent- corneal touch and secondary glaucoma. J Cataract and lacrimation associated with post- ly, a modified capsular tension ring and Refract Surg 2004;30(3):718-21. traumatic uveal inflammation (iritis or 15. Melamed S, Barraquer E, Epstein DL. Neodym- capsular tension segment has improved ium:YAG laser iridotomy as a possible contribution to lens iridocyclitis), variable facial swelling sec- capsular stability and intraocular lens dislocation. Ann Ophthalmol 1986;18(10):281-2. ondary to fluid accumulation, pain upon centration via scleral-suture fixation.30 16. Freissler K, Küchle M, Naumann GO. Spontaneous movement of the eyes and diplopia sec- dislocation of the lens in pseudoexfoliation syndrome. Arch Ophthalmol 1995;113(9):1095-6. ondary to incidental corectopia are all 3 Clinical Pearls 17. Peter NM, Nath R, Tranos PG, et al. Bilateral lens common. The prominent sign is the • In any case of lens dislocation, there subluxation associated with atopic eczema. Eur J classic D-shaped pupil, with the flat Ophthalmol 2005;15(3):409-11. exists a strong possibility of pupil block 18. Loo AV, Lai JS, Tham CC, et al. Traumatic subluxa- pupillary margin observed at the pupil- and secondary angle-closure glaucoma. tion causing variable position of the crystalline lens. J lary margin opposite the point of iris • More than 70% of patients with Mar- Cataract Refract Surg 2002;28(6):1077-9. release. Other associated collateral 19. Synder A, Latecka-Krajewska B, Omulecki W. fan’s syndrome develop lens subluxation. Secondary glaucoma in patients with lens subluxation or injuries may include subconjunctival • The mere fact that a lens is subluxed is luxation. Klin Oczna 2000;102(6):409-12. hemorrhage, ruptured globe, corneal not sufficient reason for surgical extraction. 20. Dagi LR, Walton DS. Anterior axial lens subluxation, abrasion, conjunctival laceration, hyphe- progressive myopia, and angle-closure glaucoma: recog- • Symptomatic subluxation can be nition and treatment of atypical presentation of ectopia ma, angle recession (with glaucoma), managed effectively with opaque contact lentis. J AAPOS 2006;10(4):345-50. raised intraocular pressure (IOP), lens lenses or long-term pilocarpine therapy. 21. Inatani M, Tanihara H, Honjo M, et al. Secondary subluxation, orbital bone fracture, glaucoma associated with crystalline lens subluxation. J • Patients with crystalline lenses that Cataract Refract Surg 2000;26(10):1533-6. blowout fracture, retinal detachment, dislocate into the vitreous are at risk of 22. Anteby I, Isaac M, BenEzra D. Hereditary subluxated vitreous hemorrhage, choroidal rupture chronic and severe inflammation, some- lenses: Visual performances and long-term follow-up after and optic nerve avulsion.4-6 surgery. Ophthalmol 2003;110(7):1344-8. times occurring years later. 23. Wakita M, Ryu E, Nakayasu K, et al. Statistical analy- sis of Marfan’s syndrome. Nippon Ganka Gakkai Zasshi. Pathophysiology 1. Blackmon SM, Fekrat S, Setlik DE, et al. Posterior dis- 1989;93(6):682-90. The anterior chamber is defined by location of a crystalline lens associated with airbag deploy- 24. Goldberg MF. Clinical manifestations of ectopia lentis ment. J Cataract Refract Surg 2005;31(12):2431-2. et pupillae in 16 patients. Trans Am Ophthalmol Soc the boundaries of the iris, lens cornea 2. Izadi S, Stewart RM, Jain S. Bilateral posterior dislo- 1988;86:158-77. and limbal-scleral junction where the cation of the crystalline lens after a head injury sustained 25. Ekonomidis P, Androudi S, Brazitikos P, et al. Ectopia thin iris root forms an “angle” just below during a seizure. Emerg Med J 2007;24(1):e6. lentis et pupillae: report of a unilateral case and surgical 3. Yurdakul NS, Ugurlu S, Yilmaz A, et al. Traumatic sub- management. Graefes Arch Clin Exp Ophthalmol the trabecular meshwork as it inserts 1,7 conjunctival crystalline lens dislocation. J Cataract Refract 2006;244(7):878-9. into the ciliary body. Upon direct con- Surg 2003;29(12):2407-10. 26. Wu-Chen WY, Letson RD, Summers CG. Functional tact with an object or secondary to a sud- 4. Jones LD, Sampat V, Hero M. Indirect trauma causing and structural outcomes following lensectomy for ectopia dislocation of the crystalline lens—a case report. Eur J lentis. J AAPOS 2005;9(4):353-7. den acceleration or deceleration, energy Ophthalmol 2003;13(1):91-2. 27. Schäfer S, Spraul CW, Lang GK. Spontaneous dislo- is perpetuated inside the eye by a 5. Hagee MJ. Homocystinuria and ectopia lentis. J Am cation to the anterior chamber of a lens luxated in the vit- hydraulic shock wave.8 This wave travels Optom Assoc 1984;55(4):269-76. reous body: Two cases. Klin Monatsbl Augenheilkd 6. Aspiotis M, Asproudis I, Stefaniotou M, et al. Artisan 2003;220(6):411-3. through the ocular media transferring aphakic intraocular lens implantation in cases of subluxat- 28. Dorecka M, Rokicki W, Nita M, et al. Phacoemul- sufficient forces to the contrecoup region ed crystalline lenses due to Marfan syndrome. J Refract sification of subluxated lens with capsular tension ring (area 180° from or directly opposite the Surg 2006;22(1):99-101. implantation. Klin Oczna 2007;109(7-9):280-2. 7. Sachdev N, Wakefield D, Coroneo MT. Lens disloca- 29. Marques DM, Marques FF, Cionni RJ, et al. site of impact) to detach the iris at its tion in Marfan syndrome and UV-B light exposure. Arch Evaluation of the modified capsular tension ring in cases thinnest and most vulnerable location. Ophthalmol 2003;121(4):585. of traumatic lens subluxation. Arq Bras Oftalmol This peripheral anchor, which connects 8. Kumar A, Garg SP, Verma L, et al. Bilateral posterior 2007;70(5):746-51. lens dislocation in Marfan’s syndrome. Indian J 30. Blecher MH, Kirk MR. Surgical strategies for the the iris to the ciliary body/muscle, is 8 Ophthalmol 1989;37(4):202-4. management of zonular compromise. Curr Opin known as the iris root. As the tissue 9. Pelit A, Akova YA. Spontaneous posterior dislocation Ophthalmol 2008;19(1):31-5. becomes freed, it creates an alternate, of both lenses in a patient with Marfan’s syndrome: 17 years without complications. Int Ophthalmol 2005;26(1- oval pupil confined by its points of 2):49-51. IRIDODIALYSIS attachment, and causes the iris body 10. Croxatto JO, Lombardi A, Malbran ES. Inflamed eye adjacent to the separation to become in Marfan’s syndrome with posteriorly luxated lens. Ophthalmologica 1986;193(1-2):23-6. Signs and Symptoms slack, creating a flat iris border. This 11. Chu BS. Weill-Marchesani syndrome and secondary Iridodialysis is defined as a rupture of results in the D-shaped pupil. Since the glaucoma associated with ectopia lentis. Clin Exp Optom the iris at its thinnest area, the iris root.1 trabecular meshwork is also susceptible 2006;89(2):95-9. 12. González-Castaño C, Castro J, Alvarez-Sánchez M. Patients with iridodialysis present with a to the hydraulic effects of the shock Subluxation of the lens: Etiology and results of treatment. history of jarring blunt-force trauma, wave, it too may incur damage, altering Arch Soc Esp Oftalmol 2006;81(8):471-8. such as being struck with a projectile or aqueous egress either acutely or on a 13. Kawashima M, Kawakita T, Shimazaki J. Complete 9,10 spontaneous crystalline lens dislocation into the anterior being a participant in a collision injury delayed time line. Cases of iridodialy- chamber with severe corneal endothelial cell loss. Cornea such as those caused by the impact of an sis involving more than 180° have a

APRIL 15, 2009 REVIEW OF OPTOMETRY 31A 001_ro0409_handbook 4/2/09 9:42 AM Page 32

greater statistical risk for the develop- has several options. Microsurgical repair prostaglandins (a mediator of the ment of late glaucoma.11 using a 22.0-mm plastic-handled 27- immune response), so they may worsen gauge straight needle through a 1.0-mm inflammation. Also, they take too long Management distal hole can serve as a passage for 9–0 to reach a therapeutic effect. Because iridodialysis involves the or 10–0 mm polypropylene or nylon • The D-shaped pupil caused by iri- traumatic (injurious or surgical) dissec- sutures.13 Alternately, a sutureless tech- dodialysis should not be confused with tion of well-vascularized and innervated nique (for the repair itself ) involves a the “peaked” or “pointed” pupil found in iris tissue, an accompanying secondary limbal peritomy, multiple sclerostomies penetrating injuries. iridocyclitis and should be to gain access to the iris base at multiple • Following a severe injury with sub- anticipated during the acute phase of clock hours of the iridodialysis (using a stantial peripheral iris release, the structure the trauma.12 In such cases, microvitreoretinal blade) may appear floppy or tremulous as the eye topical cycloplegics such as and placement with incar- moves. This is known as iridodonesis. If atropine 1% q.d.–t.i.d. can ceration of the peripheral the zonules are involved and the lens provide pain relief by miti- iris through these ports appears unstable as the eye moves, the gating the spasmodic using a vitreoretinal for- phenomenon is known as phacodonesis. response both of the iris ceps with conjunctival clo- • Iris is the result of an and ciliary body, while the sure using absorbable arrested developmental syndrome asso- aggressive use of topical Partial iridodialysis. sutures can be performed.13 ciated with the PAX6 gene. Here, por- steroidal and nonsteroidal The latter technique is tions or entire sectors of the iris may be anti-inflammatory preparations can be suitable for use in simple iridodialysis missing, with or without affecting employed to reduce the incited immune repair in conjunction with other intraoc- pupil shape. However, the patient will response. In the event that IOP ular procedures.14 Surgical repair of this provide a history of having had that becomes acutely raised secondary to defect since birth. obstruction of the trabecular meshwork 1. Oyster CW. The iris and pupil. In: Oyster CW. The by blood or inflammatory debris, topical : Structure and Function. Sunderland, MA: brimonidine, beta-blocker or carbonic Sinauer Assoc., Inc., 1999, pp. 411-46. anhydrase therapy can be used until the 2. Lehto KS, Sulander PO, Tervo TM. Do motor vehicle airbags increase risk of ocular injuries in adults? injury is healed. Ophthalmol 2003;110(6):1082-8. Because the consequence of angle 3. García-Medina JJ, García-Medina M, Pinazo-Durán MD. Severe orbitopalpebral emphysema after nose blow- recession and of late or post-traumatic ing requiring emergency decompression. Eur J glaucoma exists in all patients sustaining Ophthalmol 2006;16(2):339-42. ocular blunt trauma—whether or not Complete iridodialysis. 4. Morris DS. Ocular blunt trauma: Loss of sight from an ice hockey injury. Br J Sports Med 2006;40(3):e5. visible damage is evident—following the 5. Vize CJ, Gauba V, Atkinson PL Eye injury as a result of repair and recovery from all acute seque- injury is not emergent and often accom- coat toggle trauma. Eye 2007;21(1):94-5. 6. Wong MH, Yang M, Yeo KT. Elastic cord-related ocu- lae, the entire angle in both eyes (for plished following the resolution of all lar injury. Singapore Med J 2008;49(4):e90-2. comparison) should be inspected with resultant acute traumatic complications. 7. Oyster CW. The limbus and the anterior chamber. In: gonioscopy.12 Patients with an ocular Oyster CW. The Human Eye: Structure and Function. Sunderland, MA: Sinauer Assoc., Inc., 1999, pp. 379-410. blunt-force history should be periodical- Clinical Pearls 8. Ahmad F, Kirkpatrick NA, Lyne J, et al. Buckling and ly assessed for rising IOP to exclude a • Any trauma capable of producing hydraulic mechanisms in orbital blowout fractures: Fact or fiction? J Craniofac Surg 2006;17(3):438-41. delayed traumatic effect on aqueous iridodialysis is capable of producing con- 9. Ellong A, Ebana Mvogo C, Nyouma Moune E, et al. 9-12 drainage. In the event that late or trecoup posterior segment complica- Post-traumatic glaucoma with irido-corneal angle injuries post-traumatic glaucoma develops, it can tions. In all instances, the posterior seg- in Cameroon. Bull Soc Belge Ophtalmol 2005;(298):21-8. 10. Manners T, Salmon JF, Barron A, et al. be treated using the same algorithm as ment of both eyes should be evaluated. Trabeculectomy with mitomycin C in the treatment of with primary open-angle glaucoma. • Since a frequent complication of post-traumatic angle recession glaucoma. Br J Ophthalmol 2001;85(2):159-63. Iridodialyses not requiring surgical iridodialysis is hyphema, gonioscopy at 11. Sihota R, Kumar S, Gupta V, et al. Early predictors of repair and not producing ill cosmetic the time of acute presentation may not traumatic glaucoma after closed globe injury: Trabecular effects require no additional ophthalmic be desirable. The procedure will not pro- pigmentation, widened angle recess, and higher baseline intraocular pressure. Arch Ophthalmol 2008;126(7):921-6. management. Those patients upset by vide information that improves treat- 12. Walker NJ, Foster A, Apel AJ. Traumatic expulsive iri- the shape of their pupil or the appear- ment and may move a well-formed clot, dodialysis after small-incision sutureless cataract surgery. ance of the iris or suffering from any sec- promoting bleeding. J Cataract Refract Surg 2004;30(10):2223-4. 13. Bardak Y, Ozerturk Y, Durmus M, et al. Closed cham- ondary effects of having an additional • The topical prostaglandins are not ber iridodialysis repair using a needle with a distal hole. J iris opening may be fit with large diam- an effective choice for reducing IOP in Cataract Refract Surg 2000;26(2):173-6. 14. Richards JC, Kennedy CJ. Sutureless technique for eter painted/opaque contact lens. In the wake of any acute injury. They are repair of traumatic iridodialysis. Ophthalmic Surg Lasers cases requiring surgical remediation, one chemically similar to our own Imag 2006;37(6):508-10.

32A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 33

VITREOUS AND RETINA VITREOUS AND RETINA ASTEROID HYALOSIS phospholipids.11-15 Proteoglycans and dense asteroid hyalosis obscures oph- their glycosaminoglycan side chains are thalmoscopic views. Fluorescein angiog- Signs and Symptoms implicated in regulating the biomineral- raphy optically “removes” the asteroid Asteroid hyalosis is primarily a unilat- ization process.15 bodies from the vitreous, allowing eral disorder that occurs in patients aged Determining the exact composition detailed angiographic evaluation.22,23 60 years or older.1 Although there is no has been difficult as research scientists Additionally, optical coherence tomog- known race predilection, men appear to have yet to reproduce this condition raphy allows for anatomic visualization be more frequently affected.1 This condi- experimentally in laboratory subjects. and detection of , in spite tion is typically asymptomatic, with only Although we understand the compo- of dense asteroid hyalosis.24,25 the most severe cases causing a mild sition of the asteroid bodies, the exact decrease in visual acuity. Some patients genesis remains unclear. The large Clinical Pearls report glare; curiously, are rarely quantity of complex lipids and calci- • Asteroid hyalosis presents a classic reported.2,3 In two large population stud- um in asteroid bodies suggests a deri- picture akin to “stars in the night sky.” ies, asteroid hyalosis was present in 1% of vation from sources exogenous to the Upon , the asteroid bodies surveyed people.4,5 Ophthalmoscopically, vitreous.11 “sway” within the vitreous, but they always return to their origin. Management • Two conditions are often confused Asteroid hyalosis is considered a with asteroid hyalosis: synchisis scintil- benign condition. Although it is pro- lans and amyloidosis. gressive, it never leads to severe vision • Synchisis scintillans (a.k.a. choles- loss, and even the mild symptoms men- terol bulbi) is an extremely rare condi- Two views of asteroid hyalosis. tioned above are infrequent. The vast tion that occurs in severely diseased eyes. majority of cases merely require docu- This condition also presents with refrac- asteroid hyalosis appears as multiple, dis- mentation. More often than not, this tile crystals in the vitreous, although crete, refractile yellow or yellow-white disorder poses a greater challenge to the these particles are actually composed of particles (asteroid bodies, Benson’s bod- physician’s conducting a thorough exam- cholesterol. They are not attached to the ies) suspended within the vitreous. In ination, since it can obscure details of the vitreal framework and therefore tend to early stages, these bodies are less numer- underlying retina. Hence, intervention is settle out inferiorly after eye movement. ous and tend to accumulate in the inferi- considered only in patients being man- Because this condition occurs in end- or vitreous. Advanced cases can be so aged for glaucoma or retinal disease (e.g., stage , pathologists, rather dense that the examiner’s view of the those who have , than clinical optometrists or ophthal- posterior fundus is impaired. Asteroid retinal tear or detachment). Vitrectomy mologists, typically make the diagnosis hyalosis has been reported to have a is typically performed in these of synchisis scintillans. strong positive association in patients instances.1-3,16 • Amyloidosis of the vitreous is also with diabetes mellitus.6-10 Additionally, Clearly, asteroid hyalosis is more prob- quite rare and occurs typically after age systemic arterial and ather- lematic to the examiner than the patient. 40. Those with a positive familial histo- osclerotic vascular disease have been Asteroid hyalosis changes the optical ry of amyloidosis usually present earlier associated with asteroid hyalosis.8,10 quality of the vitreous and can cause an than those without family history (as However, a number of reports refute the incorrect reading from automated tech- much as 20 years earlier on average). associations between asteroid hyalosis nologies such as autorefraction and A- Patients characteristically demonstrate and systemic diseases.4-6 scan ultrasonography.17 Thus, in addition bilateral involvement, with granular, to compromising ability to visualize fun- strand-like opacities that are concentrat- Pathophysiology dus details, the presence of asteroid bod- ed within the central vitreous. These Asteroid bodies represent small cal- ies can lead to erroneous axial length strands or membranes are anchored to cium soaps (calcium-laden lipids) sus- measurements, refractions, and intraocu- the posterior lens surface in about half of pended within and attached to the lar lens power calculations.17-18 Also in all patients. Small, yellow-white bodies hyaluronic acid framework of the vitre- consideration of intraocular lens implan- dot the vitreal strands. ous body. Chemically, they have been tation, it has been documented that sili- • The density of asteroid hyalosis found to contain calcium oxalate cone lenses can calcify when implanted does not correlate with visual dysfunc- monohydrate and calcium hydrox- in eyes with asteroid hyalosis, making sil- tion. If a patient presents with signifi- yphosphate. There are structural and icone an unacceptable material choice for cantly diminished acuity (e.g., 20/40 or elemental similarities of asteroid bodies these subjects.19-21 worse), asteroid hyalosis is not to blame. with hydroxyapatite. Calcium may also Fortunately, there are options for fun- Continue examining the patient until be bound to phosphate groups in the dus examinations in cases in which the actual etiology is found.

APRIL 15, 2009 REVIEW OF OPTOMETRY 33A 001_ro0409_handbook 4/2/09 9:42 AM Page 34

1. Olea Vallejo JL, Muñoz Corrales E, Mateos Poch JM, coherence tomography in asteroid hyalosis. Retina With fluorescein , the et al. Vitrectomy for asteroid hyalosis. Arch Soc Esp 2006;26(6):661-5 Oftalmol 2002;77(4):201-4 25. Browning DJ, Fraser CM. Optical coherence tomog- will hyperfluoresce early in 2. Parnes RE, Zakov ZN, Novak MA, et al. Vitrectomy in raphy to detect in the presence of aster- the angiogram, showing a characteristic patients with decreased visual acuity secondary to aster- oid hyalosis. Am J Ophthalmol 2004;137(5):959-61 balloon-appearance with late-phase oid hyalosis. Am J Ophthalmol 1998;125(5):703-4 5 3. Lambrou FH Jr, Sternberg P Jr, Meredith TA, et al. leakage. In cases of extensive hemor- Vitrectomy when asteroid hyalosis prevents laser photo- RETINAL ARTERIAL rhage, indocyanine green (ICG) coagulation. Ophthalmic Surg 1989;20(2):100-2 MACROANEURYSM angiography can better identify the 4. Fawzi AA, Vo B, Kriwanek R, et al. Asteroid hyalosis 10 in an autopsy population: The University of California at focal aneurysmal dilatation. Los Angeles (UCLA) experience. Arch Ophthalmol Signs and Symptoms Several causes of vision loss may occur 2005;123(4):486-90 Most patients developing retinal arte- from retinal arterial macroaneurysm. Of 5. Mitchell P, Wang MY, Wang JJ. Asteroid hyalosis in an older population: The Blue Mountains Eye Study. rial macroaneurysms (RAMs) are older, course, leakage and rupture leading to 1-6 Ophthalmic Epidemiol 2003;10(5):331-5 typically between 50 and 80 years old. macular edema, exudation and hemor- 6. Moss SE, Klein R, Klein BE. Asteroid hyalosis in a RAMs rarely occur in younger patients, rhage are the most obvious. However, population: The Beaver Dam eye study. Am J Ophthalmol 2001;132(1):70-5 but when they do, there is often an asso- retinal arterial macroaneurysm rupture 7 7. Akram A, Niazi MK, Ishaq M, et al. Frequency of dia- ciated systemic disease. There appears also has been strongly associated with betics in asteroid hyalosis patients. J Ayub Med Coll to be a female the development of macular holes and Abbottabad 2003;15(3):10-1 8. Bergren RL, Brown GC, Duker JS. Prevalence and preponder- retinal detachment, which can leave 4-6 association of asteroid hyalosis with systemic diseases. ance. The patients with profound vision loss Am J Ophthalmol 1991;111(3):289-93 most com- despite complete resolution of the leak- 9. Jones WL, Twamley CR. Documented acquired 18-24 asteroid hyalosis in a case of early diagnosed diabetes mon comor- age from aneurysmal rupture. mellitus. Optom 200;72(5):315-21 bidity is sys- Additionally, retinal arterial macroa- 10. Yazar Z, Hanioglu S, Karakoç G, et al. Asteroid temic arterial neurysms have been seen in association hyalosis. Eur J Ophthalmol 2001;11(1):57-61. 11. Kador PF, Wyman M. Asteroid hyalosis: hypertension, with retinal telangiectasias, arterial Retinal arterial macroaneu- 5,25 Pathogenesis and prospects for prevention. Eye rysm with notable vascular occurring in emboli and retinal vein occlusion. 2008;Mar 14 [Epub ahead of print]. dilation and hemorrhage. approximate- 12. Komatsu H, Kamura Y, Ishi K, et al. Fine structure and morphogenesis of asteroid hyalosis. Med Electron ly 80% or Pathophysiology 3,5,8,9 Microsc 2003;36(2):112-9 more of patients. There is also an Retinal arterial macroaneurysms are 13. Adenis JP, Leboutet MJ, Loubet R. Asteroid increased incidence of cardiovascular acquired out-pouchings of the retinal hyalopathy. Ultrastructural study of 3 cases. J Fr 5,6 5 Ophtalmol 1984;7(8-9):529-34 disease and arteriosclerosis. arterioles. These balloon-like formations 14. Streeten BW. Vitreous asteroid bodies. Ophthalmoscopically, there will be a are caused by a break in the internal elas- Ultrastructural characteristics and composition. Arch dilatation of a major arterial branch tic lamina of the arteriole wall through Ophthalmol 1982;100(6):969-75 15. Winkler J, Lünsdorf H. Ultrastructure and composi- within the first three bifurcations. which serum, lipids and blood exude into tion of asteroid bodies. Invest Ophthalmol Vis Sci Retinal arterial macroaneurysms are typ- the surrounding 2001;42(5):902-7 ically unilateral, but may be multifocal.3,5 retina.26 However, there 16. Boissonnot M, Manic H, Balayre S, et al. Role of vit- rectomy in patients with a decrease in visual acuity sec- In many cases of unruptured retinal arte- is no associated micro- ondary to asteroid hyalosis. J Fr Ophtalmol rial macroaneurysms, the patient vasculopathy as typi- 2004;27(7):791-4 remains asymptomatic and the discovery cally seen in diabetic 17. Wong SC, Sampath R. Erroneous automated refrac- tion in a case of asteroid hyalosis. J Cataract Refract is made during a routine fundus exami- retinopathy. Aging Surg 2002;28(9):1707-8 nation. Often, however, by the time the arterioles demonstrate A small, almost 18. Allison KL, Price J, Odin L. Asteroid hyalosis and patient presents, significant leakage has subclinical an increase in intimal axial length measurement using automated biometry. J RAM. Cataract Refract Surg 1991;17(2):181-6. occurred and the surrounding area man- collagen and replace- 19. Fuchihata M, Saito Y, Kitaguchi Y, et al. Calcification ifests exudates and extensive pre-, intra- ment of medial muscle on the posterior surface of an implanted silicone intraoc- and/or subretinal hemorrhage. Vitreous fibers by collagen, making them less elas- ular lens in a patient with asteroid hyalosis. Nippon Ganka Gakkai Zasshi 2006;110(9):736-40 hemorrhage also may occur upon rup- tic. It has been postulated that this loss of 10-17 20. Werner L, Kollarits CR, Mamalis N, et al. Surface cal- ture. Occasionally, spontaneous pul- elasticity makes arterioles more suscepti- cification of a 3-piece silicone intraocular lens in a patient sation of an unruptured aneurysm may ble to dilatation from elevated hydrostat- with asteroid hyalosis: a clinicopathologic case report. 5 Ophthalmol 2005;112(3):447-52. be noted. When there is extensive hem- ic pressure occurring in hypertension. 21. Foot L, Werner L, Gills JP, et al. Surface calcification orrhage, it is often difficult to identify The strong association of retinal macroa- of silicone plate intraocular lenses in patients with aster- retinal macroaneurysm as the cause. In neurysm with hypertension points to this oid hyalosis. Am J Ophthalmol 2004;137(6):979-87. 22. Hampton GR, Nelsen PT, Hay PB. Viewing through such cases, neovascularization is often systemic disease as a possible contributo- the asteroids. Ophthalmol 1981;88(7):669-72 misdiagnosed as the source. ry mechanism affecting the vessel wall. 23. Win PH, Young TA. Optos Panoramic200A fluores- If the focal dilatation is not ophthal- cein angiography for proliferative diabetic retinopathy with asteroid hyalosis. Semin Ophthalmol 2007;22(2):67-9 moscopically apparent, fluorescein Management 24. Hwang JC, Barile GR, Schiff WM, et al. Optical angiography can illuminate the RAM. The natural course of RAM typically

34A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 35 VITREOUS AND RETINA involves spontaneous sclerosis and neurysm rupture as they have the greatest features in 34 patients. Eye 2006;20(9):1011-20. 31 4. Lavin MJ, Marsh RJ, Peart S, et al. Retinal arterial occlusion, particularly after hemorrhag- potential for residual visual morbidity. macroaneurysms: a retrospective study of 40 patients. Br 5,6,26-30 ing. Periodic observation is indicated Submacular surgery to remove accumu- J Ophthalmol 1987;71(11):817-25. if there is no vision loss or threat of macu- lated hematoma should be performed 5. Panton RW, Goldberg MF, Farber MD. Retinal arterial macroaneurysms: Risk factors and natural history. Br J lar hemorrhage. Asymptomatic, non- within several days of the development of Ophthalmol 1990;74(10):595-600. leaking macroaneurysms may be moni- submacular hemorrhage to prevent per- 6. Rabb MF, Gagliano DA, Teske MP. Retinal arterial tored at four- to six-month intervals. If manent photoreceptor damage. Alter- macroaneurysms. Surv Ophthalmol 1988;33(2):73-96. 7. Yilmaz G, Cakmakçi S, Aydin P. Retinal arterial there is leakage in the form of exudation nately, pneumatic displacement of the macroaneurysm in a young patient with chronic renal fail- and/or hemorrhage that does not threaten submacular hematoma can help reduce ure. Eur J Ophthalmol 2000;10(3):264-5. the macula, then monitoring at one- to permanent vision loss. Evacuation of the 8. Colucciello M. Retinal vascular disease in hyperten- sion. Risk factor modification optimizes vision outcomes. three-month intervals is indicated. submacular hemorrhage through surgery Postgrad Med 2005;117(6):33-8, 41-2. However, if hemorrhage threatens or must be done as soon as possible, since 9. Sekuri C, Kayikcioglu M, Kayikcioglu O. Retinal artery involves the macula, or persistent macu- permanent vision loss will develop within macroaneurysm as initial presentation of hypertension. Int 10,12,17,34 J Cardiol 2004;93(1):87-8. lar edema exists, then direct photocoagu- several days. 10. Zhao P, Hayashi H, Oshima K, et al. Vitrectomy for lation of the macroaneurysm is indicat- macular hemorrhage associated with retinal arterial ed.1,4-6,27,29 In these cases, moderately Clinical Pearls macroaneurysm. Ophthalmol 2000;107(3):613-7. 11. Townsend-Pico WA, Meyers SM, Lewis H. intense photocoagulation is applied • In cases of unexplained vitreous Indocyanine green angiography in the diagnosis of retinal directly to the macroaneurysm so as not pre-, intra- or subretinal hemorrhage, arterial macroaneurysms associated with submacular and to produce complete occlusion of the consider retinal macroaneurysm as the preretinal hemorrhages: A case series. Am J Ophthalmol 2000;129(1):33-7. involved artery. Alternately, to avoid cause. If the characteristic balloon 12. Tonotsuka T, Imai M, Saito K, et al. Visual prognosis potential arterial occlusion, perianeurys- appearance is not readily observable for symptomatic retinal arterial macroaneurysm. Jpn J mal laser application can be performed. ophthalmoscopically, fluorescein or ICG Ophthalmol 2003;47(5):498-502. 13. Gedik S, Gür S, Yilmaz G, Retinal arterial macroa- In the event a non-hemorrhagic macroa- angiography may aid diagnosis by more neurysm rupture following fundus neurysm is observed to be spontaneously clearly identifying the aneurysm. If the and treatment with Nd:YAG laser membranectomy. pulsating, immediate direct photocoagu- diagnosis is not in question, then Ophthalmic Surg Lasers Imag 2007;38(2):154-6. 14. Zghal-Mokni I, Nacef L, Yazidi B, et al. Clinical and lation is indicated, since rupture is likely. angiography is not indicated. progressive features of macular hemorrhage secondary to The visual prognosis for eyes with • Retinal arterial macroaneurysm, retinal artery macroaneurysms. J Fr Ophtalmol ruptured or leaking retinal arterial along with exudative macular degenera- 2007;30(2):150-4 15. Arthur SN, Mason J, Roberts B, et al. Secondary macroaneurysm depends on the degree tion and polypoidal choroidal vascu- acute angle-closure glaucoma associated with vitreous and type of macular involvement. In lopathy, can cause hemorrhage any- hemorrhage after ruptured retinal arterial macroaneurysm. most cases, gradual and spontaneous where from the subretinal strata to the Am J Ophthalmol 2004;138(4):682-3. 16. Vaidya AR, Shah NJ. A ruptured retinal arterial involution is concurrent with hemor- vitreous. Consider retinal arterial macroaneurysm presenting as subhyaloid haemorrhage. 5,6,12,31 rhage resorption. Eyes with vitreous macroaneurysm when multiple layered Indian J Ophthalmol 2002;50(1):56-8. hemorrhage or premacular subhyaloid hemorrhages are present. 17. Humayun M, Lewis H, Flynn HW, et al. Management of submacular hemorrhage associated with retinal arterial hemorrhage typically recover good vision, • There is a high rate of mortality in macroaneurysms. Am J Ophthalmol 1998;126(3):358-61. but the vision in those with submacular patients with retinal arterial macroa- 18. Tashimo A, Mitamura Y, Ohtsuka K, et al. Macular hemorrhage with or without premacular neurysm due to cardiovascular disease. hole formation following ruptured retinal arterial macroa- 12 neurysm. Am J Ophthalmol 2003;135(4):487-92. hemorrhage generally remains poor. Patients discovered to have RAM should 19. Saito K, Iijima H. Visual prognosis and macular Early vitrectomy is recommended for be referred for systemic evaluation. At the pathology in eyes with retinal macroaneurysms. Nippon RAM-related vitreous hemorrhage, to very least, a fasting blood glucose, com- Ganka Gakkai Zasshi 1997;101(2):148-51. 20. Mitamura Y, Terashima H, Takeuchi S. Macular hole allow for observation of the fundus, par- plete blood count with differential, fasting formation following rupture of retinal arterial macroa- 10 ticularly the macula. lipid profile, blood pressure evaluation neurysm. Retina 2002;22(1):113-5. In cases where significant preretinal and electrocardiogram are indicated. 21. Takahashi K, Kishi S. Serous macular detachment associated with retinal arterial macroaneurysm. Jpn J hemorrhage has occurred, resolution and • Retinal macroaneurysms can occur Ophthalmol 2006;50(5):460-4. drainage can be greatly assisted by also in a venule, but this is much rarer 22. Ciardella AP, Barile G, Schiff W, et al. Ruptured retinal Nd:YAG laser rupture of the internal lim- than occurrence in an arteriole. arterial macroaneurysm associated with a stage IV macu- lar hole. Am J Ophthalmol 2003;135(6):907-9. iting membrane in front of the hemor- • Physical exertion can cause ruptur- 23. Tashimo A, Mitamura Y, Sekine N, Rhegmatogenous 12,19,32,33 rhage. Laser photodisruption of the ing of retinal arterial macroaneurysms. retinal detachment after rupture of retinal arterial macroa- posterior hyaloid membrane releases the neurysm. Am J Ophthalmol 2003;136(3):549-51. 1. Attali P, Sterkers M, Coscas G. Retinal arterial macroa- 24. Colucciello M, Nachbar JG. Macular hole following preretinal hemorrhage into the vitreous neurysms. J Fr Ophtalmol 1984;7(11):697-710. ruptured retinal arterial macroaneurysm. Retina space, where it can be more easily resorbed 2. Gurwood AS, Nicholson CR. Retinal arterial macroa- 2000;20(1):94-6. or surgically removed. More concerning neurysm: A case report. J Am Optom Assoc 25. Abu-El-Asrar AM. Retinal arterial macroaneurysm at 1998;69(1):41-8. the site of a retinal artery embolus. Eye 2001;15(Pt and urgent are submacular hemorrhages 3. Moosavi RA, Fong KC, Chopdar A. Retinal artery 5):655-7. that develop from retinal arterial macroa- macroaneurysms: clinical and fluorescein angiographic 26. Theodossiadis PG, Emfietzoglou I, Sfikakis, PP, et al.

APRIL 15, 2009 REVIEW OF OPTOMETRY 35A 001_ro0409_handbook 4/2/09 9:42 AM Page 36

Simultaneous bilateral visual loss caused by rupture of bifurcation.5,7 Bilateral involvement is appears chalk-like.4 Cholesterol emboli retinal arterial macroaneurysms in a hypertensive patient. Acta Ophthalmol Scand 2005;83(1):120-2. uncommon, but there may be multiple are the most commonly encountered 27. Tachfouti S, Lezrek M, Karmane A, et al. Retinal arte- emboli within the same eye. The emboli (80% of all emboli); fibrin-platelet rial macroaneurysm: spontaneous occlusion after rupture. can have a reflective or refractile appear- emboli represent 14% of emboli, while In connection with a case. Bull Soc Belge Ophtalmol 2004;(294):5-11. ance; a dull, bulky, chalky appearance; or calcific emboli account for just 6% of vis- 8 28. Ohno-Matsui K, Hayano M, Futagami S, et al. may appear long and white within a ves- ible retinal emboli. Spontaneous involution of a large retinal arterial macroa- sel.1,5,7 Over time, retinal emboli tend to Patients frequently have concurrent neurysm. Acta Ophthalmol Scand 2000;78(1):114-7. 29. Badii G, Messmer EP. Spontaneous regression of an dislodge and move down the vascular tree. hypertension, a history of smoking and acquired arterial macroaneurysm of the retina. Klin One large population study found the elevated cholesterol levels. The stress on Monatsbl Augenheilkd 1992;200(5):537-8. 10-year cumulative incidence of retinal the arteries induced by hypertension leads 30. Brown DM, Sobol WM, Folk JC, et al. Retinal arterio- 2 lar macroaneurysms: Long-term visual outcome. Br J emboli was 1.5%. Another large popu- to reduced elasticity of the vessels. Ophthalmol 1994;78(7):534-8. Cholesterol deposition then 31. Yang CS, Tsai DC, Lee FL, et al. Retinal arterial occurs within the vessel walls and macroaneurysms: risk factors of poor visual outcome. Ophthalmologica 2005;219(6):366-72. an atheroma forms, with subse- 32. Raymond LA. Neodymium:YAG laser treatment for quent arterial narrowing. hemorrhages under the internal limiting membrane and Turbulent blood flow over the posterior hyaloid face in the macula. Ophthalmol. 1995;102(3):406-11 atheroma can lead to plaque 33. Iijima H, Satoh S, Tsukahara S. Nd:YAG laser pho- ulceration, which allows small todisruption for preretinal hemorrhage due to retinal Examples of retinal emboli lodged in the arterial system. particles to break off and flow macroaneurysm. Retina 1998;18(5):430-4. 34. Oie Y, Emi K. Surgical excision of retinal macroa- within the bloodstream. This neurysms with submacular hemorrhage. Jpn J lation based study found asymptomatic accounts for the majority of cholesterol Ophthalmol 2006;50(6):550-3. retinal emboli in 1.4% of the study pop- emboli. The origin of most cholesterol ulation. There was an increase in preva- emboli is thought to be ulcerated athero- RETINAL EMBOLI lence associated with age, with a preva- matous plaques in the internal or com- lence of 0.8% in persons aged younger mon carotid artery. Fibrin-platelet emboli Signs and Symptoms than 60 years, 1.4% for those aged 60 to typically arise from a mural thrombus, Patients observed to have retinal 69 years, 2.1% for those aged 70 to 79 and calcific emboli are thought to arise emboli are typically elderly and often years, and 1.5% for those aged 80 years from cardiac valvular structures.4,14 have a concurrent history of hyperten- or older.8 There is a greater prevalence in Once an embolus has broken off from sion, diabetes, carotid artery disease, men than women.8 Another report its point of origin, it travels the arterial peripheral vascular disease, hypercholes- noted a 3% incidence in retinal emboli in system until it encounters a vessel whose terolemia, hyperlipidemia, smoking and an older population.9 Notably, these .1-4 The patient is often large population studies involved prima- asymptomatic, and the plaques are often rily whites; there is a lower prevalence of found upon routine eye exam. However, asymptomatic retinal emboli in Hispanic the patient may have previously experi- and Asian peoples.1,10 However, the tran- enced transient episodes of monocular sient nature of retinal emboli makes it vision loss (amaurosis fugax).5,6 Rarely, difficult to determine the true preva- patients will have experienced a transient lence, and most population studies likely ischemic attack with hemiparesis, pares- underestimate the actual prevalence. thesia, and/or aphasia. These episodic bouts of amaurosis fugax may be quite Pathophysiology A rarely captured view of a plaque at the optic frequent, and may last from several sec- Retinal emboli are heterogeneous. nerve head, which can induce a central retinal onds to several minutes. Rarely does the One type of embolus is composed of vein occlusion. patient have any lasting visual deficits. cholesterol and typically lodges at a ves- Frequently, patients who describe expe- sel bifurcation. These cholesterol emboli caliber is too small to allow it to flow any riencing amaurosis fugax will not exhib- are refractile in appearance and are farther. This causes the plaque to lodge it retinal emboli upon examination, but sometimes known as Hollenhorst within that vessel. If blood flow is signif- may have arteriolar narrowing and plaques.11-13 Another type of embolus is icantly impaired distal to the blockage, sheathing.5 long and dull and appears similar to then ischemia to that tissue will ensue. If Ophthalmoscopically, an intra-arterio- toothpaste within the arteriole lumen. the embolus lodges within a retinal arte- lar plaque will be evident. Emboli can This type of emboli is composed of fib- riole, then retinal ischemia with corre- occur along the course of the vessel in the rin and platelet aggregates.4 The third sponding loss of vision occurs. The result retina or at the or at a vessel type of retinal emboli is calcific and may be a retinal artery occlusion. In the

36A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 37 VITREOUS AND RETINA case of cholesterol emboli, however, the with symptomatic retinal emboli.6 tomatic retinal emboli. blockage often quickly dislodges without Interestingly, there is no consensus on 1. Cheung N, Lim L, Wang JJ, et al. Prevalence and risk factors of retinal arteriolar emboli: The Singapore Malay permanent impairment of vision. the need for carotid ultrasonography in Eye Study. Am J Ophthalmol 2008; Jul 18 [Epub ahead of Instead, the patient may experience a patients with asymptomatic retinal print]. brief interruption of vision and/or visual emboli, since the majority of these 2. Klein R, Klein BE, Moss SE, et al. Retinal emboli and cardiovascular disease: The Beaver Dam Eye Study. 5 field (amaurosis fugax). Multiple bouts patents do not have high-grade carotid Trans Am Ophthalmol Soc 2003;101:173-80. of amaurosis fugax may indicate multiple .4,7,11,13,16 3. Wong TY, Larsen EK, Klein R, et al. Cardiovascular risk emboli. In cases where the patient is There is increased risk of and factors for retinal vein occlusion and arteriolar emboli: The Atherosclerosis Risk in Communities & Cardiovascular asymptomatic, yet a retinal embolus is decreased survivorship with the appear- Health studies. Ophthalmol 2005;112(4):540-7. visible, there is unlikely permanent ance of a retinal embolus. A large pop- 4. Mitchell P, Wang JJ, Smith W. Risk factors and signifi- ischemia. This is because many emboli, ulation study collecting data over 10 to cance of finding asymptomatic retinal emboli. Clin Experiment Ophthalmol 2000;28(1):13-7. particularly cholesterol, are malleable 12 years found that 30% of patients 5. Amick A, Caplan LR. Transient monocular visual loss. permitting blood flow. with retinal emboli died, with 4% dying Compr Ophthalmol Update 2007;8(2):91-8. from stroke-related complications and 6. Wijman CA, Gomes JA, Winter MR, et al. Symptomatic and asymptomatic retinal have 16 Management 16% from cardiovascular causes. different mechanisms. Stroke 2004;35(5):e100-2. There is no direct treatment for These death rates were higher than 7. Wong TY, Klein R. Retinal arteriolar emboli: epidemiol- asymptomatic visible retinal emboli. In those for age-matched people not hav- ogy and risk of stroke. Curr Opin Ophthalmol 2002;13(3):142-6. fact, because blood flow is often uninter- ing retinal emboli. Most available data 8. Mitchell P, Wang JJ, Li W, et al. Prevalence of asymp- rupted, flowing around or through an suggests that retinal emboli in other- tomatic retinal emboli in an Australian urban community. apparently complete blockage, ocular wise asymptomatic people are associat- Stroke 1997;28(1):63-6. 9. Cugati S, Wang JJ, Rochtchina E, et al. Ten-year inci- intervention is not necessary.The proper ed with a higher risk of stroke and dence of retinal emboli in an older population. Stroke approach to managing asymptomatic stroke mortality, independent of con- 2006;37(3):908-10. retinal emboli is truly unknown. Retinal ventional risk factors.7 10. Hoki SL, Varma R, Lai MY, et al. Prevalence and associations of asymptomatic retinal emboli in Latinos: emboli causing acute arterial occlusion, There is no clear indication for The Los Angeles Latino Eye Study (LALES). Am J if detected in time, can be vaporized or in patients with Ophthalmol 2008;145(1):143-8. dislodged by Nd:YAG laser; however, asymptomatic retinal emboli, even with 11. Hollenhorst RW. Significance of bright plaques in the retinal arterioles. JAMA. 1961 Oct 7;178:23-9 15 this procedure is still being refined. For concurrent high grade carotid steno- 12. Dunlap AB, Kosmorsky GS, Kashyap VS. The fate of all cases of retinal emboli, the concern sis.4,7,17-19 For these patients, carotid patients with retinal artery occlusion and Hollenhorst must be subsequent embolization with endarterectomy is generally not consid- plaque. J Vasc Surg 2007;46(6):1125-9. 13. Bunt TJ. The clinical significance of the asympto- ensuing permanent retinal infarct or ered. There does seem to be a benefit to matic . J Vasc Surg 1986;4(6):559-62. cerebrovascular accident with the per- carotid endarterectomy in patients with 14. Palmiero P, Maiello M, Nanda NC. Retinal emboliza- manent sequelae of stroke. symptomatic retinal emboli and high- tion of bicuspid aortic valve calcification. Echocardiog 2004;21(6):541-4. 20 A retinal embolus is an indication of grade carotid stenosis. 15. Opremcak E, Rehmar AJ, Ridenour CD, et al. significant systemic vascular disease. The Restoration of retinal blood flow via translumenal Nd:YAG most common associated systemic dis- Clinical Pearls embolysis/embolectomy (TYL/E) for central and branch retinal artery occlusion. Retina 2008;28(2):226-35. eases are hypertension, cardiovascular • Asymptomatic retinal emboli can 16. Wang JJ, Cugati S, Knudtson MD, et al. Retinal arte- disease and stroke.2-4,7-10 In many studies, be difficult to detect ophthalmoscopical- riolar emboli and long-term mortality: Pooled data analysis the prevailing risk factor for retinal ly. Older male patients with a history of from two older populations. Stroke 2006;37(7):1833-6. 17. O’Donnell BA, Mitchell P. The clinical features and 1,3,4,7-10 emboli is smoking. In that the hypertension and smoking are at the associations of retinal emboli. Aust NZ J Ophthalmol presence of asymptomatic retinal emboli greatest risk for retinal emboli. The reti- 1992; 20:11-17. indicate potential risk for further embol- nal arterial tree should be examined 18. Schwarcz TH, Eton D, Ellenby MI, et al. Hollenhorst plaques: retinal manifestations and the role of carotid ic disease, a preventative approach dic- most closely in these patients. endarterectomy. J Vasc Surg 1990;11(5):635-41. tates that all modifiable risk factors— • Asymptomatic retinal emboli are 19. Wolintz RJ. Carotid endarterectomy for ophthalmic especially smoking—be altered. Patients not highly associated with severe carotid manifestations: is it ever indicated? J Neuroophthalmol 2005;25(4):299-302. should be evaluated by an internist, vas- stenosis. Carotid ultrasonography is not 20. European Carotid Surgery Trialists’ Collaborative cular surgeon or cardiologist for hyper- an especially vital test for these patients. Group. Endarterectomy for moderate symptomatic tension, , diabetes • Patients with asymptomatic retinal carotid stenosis: Interim results from the MRC European Carotid Surgery Trial. Lancet 1996;347:1591-3. and carotid artery disease. A complete emboli are typically not surgical candi- physical with stress echocardiogram, dates, especially if they are older than 70. fasting glucose, lipid levels, blood chem- • The most significant modifiable istry with cardiac enzymes, magnetic risk factor for retinal emboli is smok- resonance angiography, transthoracic ing. Smoking cessation is crucial in Signs and Symptoms and transesophageal echocardiography reducing the risk of future embolic A patient with hypertensive retinopa- may be indicated, especially for patients phenomenon in patients with asymp- thy suffers from hypertension, although

APRIL 15, 2009 REVIEW OF OPTOMETRY 37A 001_ro0409_handbook 4/2/09 9:42 AM Page 38

the condition may be unknown to the oles, resulting in acute focal inner retinal Managing patients with severe hyper- patient and the eye exam may yield the ischemia.4,5 Acute elevation in blood pres- tension and extremely elevated BP has first clue to this potentially asympto- sure causes smooth muscle necrosis and led to an algorithm in which patients are matic systemic disease.1 Most common- breakdown of the blood-retina barrier, classified as having either hypertensive ly, the patient is middle-aged or older.2 resulting in retinal hemorrhages.6,16,17 emergency or hypertensive urgency. In addition, hypertension is more com- In extreme cases, a macular exudative Patients with extremely elevated BP but mon and severe in African Americans star and disc edema develops. The mech- no evidence of end organ damage are than in whites.3 Patients with only anism behind this phenomenon is poorly said to have a hypertensive urgency; oral hypertensive retinopathy and no other understood, but it may be associated with antihypertensive medications are used to hypertensive ocular complications are a hypertension-related increase in lower BP over 24 to 48 hours by a pri- nearly always visually asymptomatic. mary care physician. Patients with Findings in hypertensive retinopathy extremely elevated BP and acute include arteriolosclerosis (artery narrow- end organ damage (cardiovascu- ing with increased arteriole light reflex, lar, cerebrovascular, or renal) are secondary to thickening within the blood diagnosed as having hypertensive vessel wall, arteriovenous crossing emergency and require immediate changes with venous constriction and treatment with a titratable short- banking, arteriolar color changes and Two examples of hypertensive retinopathy. acting IV antihypertensive additional vessel damage with scar for- agent.19,20 mation), cotton wool spots and flame and is therefore con- In that the eye is considered an “end shaped hemorrhages within the nerve sidered true .1,3,17 organ,” the presence of retinopathy and fiber layer. Intraretinal hemorrhages Arteriolosclerotic changes in the reti- extremely elevated BP would technically occur less commonly. Rarely will there be nal microvasculature will persist even if be considered a . retinal or macular edema, and then only systemic blood pressure is reduced. Some Most clinicians don’t equate retinal hem- in the most severe cases. In advanced hypertensive retinopathy classification orrhages and cotton wool spots as a crisis cases, there will be a macular star or cir- schemes do not include the arterioloscle- situation. However, a patient presenting cinate pattern (ring of exudates from the rotic changes as these vessel findings can with disc edema and macular exudative disc to the macula) and disc edema.4-7 occur in non-hypertensive people.9 The star is suffering from malignant hyper- One study noted a greater incidence of other hypertensive retinopathy changes tension and should be considered as hypertensive retinopathy in women and will resolve over time with the reduction being in medical crisis. This patient 40% of hypertensive patients demon- of systemic blood pressure (BP).18 Cotton needs immediate consult with a primary strating some degree of retinopathy.8 wool spots will develop in 24–48 hours care physician and, most likely, immedi- There may also be concomitant comor- with the elevation of BP,and will resolve in ate transport to a hospital emergency bidities in the form of subclinical and two to 10 weeks with the lowering of BP.4,5 room. It must be reiterated, though, that clinical stroke, cognitive impairment, there are many causes of papilledema. renal dysfunction and cardiovascular Management Other causes, such as an intracranial mortality.9-13 Severe and atypical cases of Management of hypertensive retinopa- mass lesion, must also be considered in hypertensive retinopathy have been asso- thy involves appropriate treatment of the the patient with hypertension. However, ciated with pheochromocytoma.14,15 underlying hypertension. A large popula- in a case in which BP is extremely elevat- tion study indicated that pharmacologic ed (e.g., 250/150mm Hg) and there is Pathophysiology BP reduction resulted in a lower incidence disc edema with a macular star, malig- The findings in hypertensive retinopa- of retinopathy.18 Medical co-management nant hypertension is the likely cause. thy all stem from hypertension-induced with the primary physician is paramount. changes to the retinal microvasculature. The ophthalmic examination may be the Clinical Pearls Hypertension leads to a lying down of first time that a patient is discovered to • For cotton wool spots to develop cholesterol into the tunica intima of have retinopathic changes consistent from hypertension, autoregulatory mech- medium and large arteries. This leads to with hypertension. In that patients anisms must first be overcome. The an overall reduction in the lumen size of demonstrating hypertensive retinopathy patient must have at least some chronic these vessels. Arteriolosclerosis leads to also have a greater risk of subclinical and readings of 110mm Hg diastolic or high. focal closure of the retinal microvascula- clinical stroke, cognitive impairment, • Fluorescein angiography is not ture. This gives rise to microinfarcts (cot- renal dysfunction and cardiovascular indicated in cases of hypertensive ton wool spots) and superficial hemor- mortality, independent of blood pressure retinopathy, since it will yield little diag- rhages. Cotton wool spots represent levels and control, referral for additional nostic information. occlusions of the terminal retinal arteri- evaluation may be appropriate.9-13 • Hypertensive retinopathy presents

38A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 39 VITREOUS AND RETINA with a “dry” retina (i.e., few hemorrhages, Ophtalmol 1983;6(12):995-1005. layers—may be seen within the affected 17. Hammond S, Wells JR, Marcus DM, et al. 1,3,5 rare edema, rare exudates and multiple cot- Ophthalmoscopic findings in malignant hypertension. J area. In some forms of the disease, 1-4 ton wool spots), whereas diabetic retinop- Clin Hypertens (Greenwich) 2006;8(3):221-3. lipid exudates are present. athy presents with a “wet” retina (multiple 18. Klein R, Klein BE, Moss SE The relation of systemic Although a variety of complex classifi- hypertension to changes in the retinal vasculature: The hemorrhage, multiple exudates, extensive Beaver Dam Eye Study. Trans Am Ophthalmol Soc cation schemes are described in the liter- edema, and few cotton wool spots). 1997;95:329-48. ature, there are essentially two forms of • The presence of hypertensive 19. Marik PE, Varon J. Hypertensive crises: challenges idiopathic juxtafoveal retinal telangiecta- and management. Chest 2007;131(6):1949-62. retinopathy or disc edema in a poorly 20. Haas AR, Marik PE. Current diagnosis and manage- sia (IJRT): unilateral and bilateral. The controlled hypertensive patient are ment of hypertensive emergency. Semin Dial unilateral form, described by Yanuzzi as important findings, because they indi- 2006;19(6):502-12. Type 1 or aneurysmal telangiectasia, cate end organ damage. For this reason, occurs almost exclusively in males and is comprehensive ophthalmic evaluation IDIOPATHIC JUXTAFOVEAL asymptomatic until after age 40.4 In this complete with dilation is mandatory. We RETINAL TELANGIECTASIA group, lipid exudate is common, while do not defer dilation on patients with pigment plaques and retinal crystals are markedly elevated BP. Standard dilation Signs and Symptoms rare. The bilateral form, also known as with 2.5% phenylephrine and 1% tropi- Patients with idiopathic juxtafoveal Type 2 or perifoveal telangiectasis, occurs camide will not affect a patient’s BP. retinal telangiectasia (IJRT) are typically equally in males and females.1-4 Type 2 40 years of age or older. They may have IJRT is typically discovered between the 1. Lourenço S, Murinello A, Loureiro C, et al. Malignant a coincident history of ischemic vascular ages of 40 and 60 years, with a mean age hypertension, severe hypertensive retinopathy and malig- diseases such as diabetes or hyperten- of 55-59 years.3,4 In this form of the dis- nant nephroangiosclerosis. Rev Port Cardiol 2008;27(3):373-9. sion, but these do not appear to be ease, parafoveal atrophy, right-angle 2. Wong TY. Fred Hollows lecture: Hypertensive causative factors.1-4 IJRT may present venules, RPE pigment plaques and reti- retinopathy—a journey from funduscopy to digital imag- with a wide range of visual impact, from nal crystals are the prevailing signs.4 ing. Clin Experiment Ophthalmol 2006;34(5):397-400. 3. Lip GY, Beevers M, Beevers DG. Complications and totally asymptomatic to substantially survival of 315 patients with malignant-phase hyperten- impaired; in most cases Pathophysiology sion. J Hypertens 1995;13(8):915-24. however, patients IJRT is probably best defined as an 4. Schmidt D. The mystery of cotton-wool spots—a review of recent and historical descriptions. Eur J Med retain functional acuity acquired capillary ectasia (i.e., a focal Res 2008;13(6):231-66. of 20/200 or better.1 expansion or outpouching) and dilation 5. Hayreh SS, Servais GE, Virdi PS. Cotton-wool spots Metamorphopsia may in the parafoveal region, leading to vas- (inner retinal ischemic spots) in malignant arterial hyper- tension. Ophthalmologica 1989;198(4):197-215. be a subjective com- cular incompetence. The telangiectatic 6. Hayreh SS, Servais GE. Retinal hemorrhages in malig- plaint. The key fundus vessels develop microaneurysms, which nant arterial hypertension. Int Ophthalmol 1988;12(2): Fundus photo of findings in IJRT subsequently leak fluid, blood, and occa- 137-45. idiopathic juxta- 7. Hayreh SS. Classification of hypertensive fundus foveal retinal involve a focal area of sionally, lipid. Some have described changes and their order of appearance. Ophthalmologica telangiectasia. diminished retinal IJRT as a variant of Coat’s disease, 1989;198(4):247-60. transparency (i.e., gray- although this is a more accurate depic- 8. Besharati MR, Rastegar A, Shoja MR, et al. Prevalence of retinopathy in hypertensive patients. Saudi ing) and/or small retinal hemorrhages tion of the Type 1 form than the Type 2 Med J 2006;27(11):1725-8. just temporal to the fovea. Dilated capil- form.4,6 While the precise etiology is 9. Wong TY, McIntosh R. Systemic associations of retinal laries may also be noted within this area, unknown, it has been speculated that microvascular signs: A review of recent population-based studies. Ophthalmic Physiol Opt 2005;25(3):195-204. and while this is often difficult to visual- chronic venous congestion caused by 10. Wong TY, McIntosh R. Hypertensive retinopathy ize ophthalmoscopically, the abnormal obstruction of the retinal veins as they signs as risk indicators of cardiovascular morbidity and capillary pattern is readily identifiable cross retinal arteries at the horizontal mortality. Br Med Bull 2005;73-74(1):57-70. 1-3 2,3,7 11. Shiga T, Owada K, Hoshino T, et al. An analysis of risk with fluorescein angiography. raphe may be a contributory factor. factors for asymptomatic . Intern Med Areas of focal RPE hyperplasia, i.e. Histopathologically, the affected vessels 2008;47(1):1-6. pigment plaques, often develop in 12. Baker ML, Hand PJ, Wang JJ, et al. Retinal signs and stroke: Revisiting the link between the eye and brain. the paramacular region as a Stroke 2008;39(4):1371-9. response to these abnormal vessels. 13. Kwon HM, Kim BJ, Oh JY, et al. Retinopathy as an Other signs of IJRT include right indicator of silent brain infarction in asymptomatic hyper- tensive subjects. J Neurol Sci 2007 Jan 31;252(2):159-62. angle venules, representing an 14. Petkou D, Petropoulos IK, Kordelou A, et al. Severe unusual alteration of the vasculature bilateral hypertensive retinopathy and in in the paramacular area, with vessels a patient with pheochromocytoma. Klin Monatsbl Augenheilkd 2008;225(5):500-3. taking an abrupt turn toward the 15. Pawlowski P, Mrugacz M, Bakunowicz-Lazarczyk A. macula as if being dragged.1 Also, OCT of IJRT; evident is an intraretinal cystic area adja- Hypertensive retinopathy in child with pheochromocy- retinal crystals—fine, refractile toma. Klin Oczna 2005;107(1-3):124-6. cent to an abnormal blood vessel, enhanced by accu- 16. Chaine G, Kohner EM. Hypertensive retinopathy. J Fr deposits in the superficial retinal mulation of retinal pigment.

APRIL 15, 2009 REVIEW OF OPTOMETRY 39A 001_ro0409_handbook 4/2/09 9:42 AM Page 40

have been observed to display diffuse 21 years showed deterioration of vision 2. Gass JD, Oyakawa RT. Idiopathic juxtafoveolar retinal telangiectasis. Arch Ophthalmol 1982;100(5):769-80. pericyte degeneration, as their lumens in more than 84% of eyes, either due to 3. Gass JD, Blodi BA. Idiopathic juxtafoveolar retinal become occluded by abnormal basement intraretinal edema and serous retinal telangiectasis. Update of classification and follow-up membrane material.8 These findings are detachment (Type 1) or pigmented RPE study. Ophthalmol 1993;100(10):1536-46. 11 4. Yannuzzi LA, Bardal AM, Freund KB, et al. Idiopathic very similar to those seen in diabetic scar formation or CNV (Type 2). macular telangiectasia. Arch Ophthalmol. 2006;124(4): retinopathy, although there is no estab- Historically, laser photocoagulation has 450-60. lished link between IJRT and diabetes.9 been the recommended treatment early 5. Moisseiev J, Lewis H, Bartov E, et al. Superficial retinal refractile deposits in juxtafoveal telangiectasis. Am J In recent years, optical coherence in the course of Type I IJRT to help sus- Ophthalmol 1990;109(5):604-5. tomography has been helpful in identi- pend the exudative process and diminish 6. Wu J, Ferrucci S. Idiopathic juxtafoveal retinal telang- fying more detailed fundus morphology macular edema.2,3 In contrast, laser ther- iectasia. Optom 2008;79(11):653-62. 7. Tasca J, Grogg JA. Idiopathic juxtafoveolar retinal associated with IJRT. One such finding apy is not considered a viable treatment telangiectasia: a review and case report. Clin Eye Vis Care is that there is often progressive foveal option for Type 2 IJRT, unless frank 2000;12(1-2):79-87. atrophy through the late stages of this neovascularization is evident on fluores- 8. Green WR, Quigley HA, de la Cruz Z, Cohen B. 10 2,3,12 Parafoveal retinal telangiectasis: light and electron disease. It is thought that this collec- cein angiography. In fact, laser thera- microscopy studies. Retina 2005;25(5 Suppl):S162- tive loss of retinal cells may induce py may actually enhance vessel ectasia S170. intraretinal neovascularization and, and promote intraretinal fibrosis in these 9. Millay RH, Klein ML, Handelman IL, et al. Abnormal 12 glucose metabolism and parafoveal telangiectasia. Am J ultimately, subretinal or choroidal neo- individuals. Ophthalmol 198;102(3):363-70. vascularization (CNV). However, it Today, additional therapies include 10. Paunescu LA, Ko TH, Duker JS, et al. Idiopathic should be noted that not all patients surgical removal of CNV, photodynamic juxtafoveal retinal telangiectasis: New findings by ultra- high-resolution optical coherence tomography. will develop CNV, as IJRT often spon- therapy with verteporfin and treatment Ophthalmol 2006;113(1):48-57. 11 taneously arrests. with anti-VEGF drugs such as beva- 11. Watzke RC, Klein ML, Folk JC, et al. Long-term cizumab.14-16 However, these treatment juxtafoveal retinal telangiectasia. Retina 2005;25(6):727-35. 12. Park DW, Schatz H, McDonald R, Johnson RN. Grid Management modalities should be considered only in laser photocoagulation for macular edema in bilateral The most crucial aspect of managing cases of marked and rapid vision loss juxtafoveal telangiectasis. Ophthalmol 1997;104(11): patients with IJRT is recognition of the secondary to macular edema or CNV. 1838-46. 13. Berger AS, McCuen BW, Brown GC, et al. Surgical clinical signs. This condition is relatively Otherwise, a conservative approach is rec- removal of subfoveal neovascularization in idiopathic uncommon and has only been described ommended, since many of these patients juxtafoveolar retinal telangiectasis. Retina 1997;17(2):94-8. in the literature during the past 25 years; will stabilize without intervention. 14. Potter MJ, Szabo SM, Chan EY, et al. Photodynamic therapy of a subretinal neovascular membrane in type 2A hence, many practitioners may not be idiopathic juxtafoveolar retinal telangiectasis. Am J familiar with or experienced in diagnos- Clinical Pearls Ophthalmol 2002;133(1):149-51. ing the disorder. IJRT must be part of • IJRT may also be referred to by var- 15. Snyers B, Verougstraete C, Postelmans L, et al. Photodynamic therapy of subfoveal neovascular mem- the differential in any case of idiopathic ious names, including idiopathic juxta- brane in type 2A idiopathic juxtafoveolar retinal telangiec- paramacular hemorrhage, vasculopathy, foveolar, macular, perifoveal or parafoveal tasis. Am J Ophthalmol 2004;137(5):812-9. macular edema or focal pigment hyper- telangiectasis, depending on the source. 16. Gamulescu MA, Walter A, Sachs H, et al. Bevacizumab in the treatment of idiopathic macular trophy, especially in those patients with- All refer to the same syndrome. telangiectasia. Graefes Arch Clin Exp Ophthalmol out a history of retinopathy or contribu- • IJRT is commonly underdiagnosed. 2008;246(8):1189-93. tory systemic disease. The findings may appear very similar to Diagnosis of IJRT may be aided by diabetic retinopathy, and many cases the use of ancillary testing. OCT can have been incorrectly ascribed to diabet- OCULAR ISCHEMIC help to identify the abnormal vessels, ic retinopathy. Unfortunately, this misdi- SYNDROME pigment plaques, retinal crystals, foveal agnosis has also occurred in patients who atrophy and intraretinal cysts associated were not diabetic. Recognition of this con- Signs and Symptoms with this disorder.6,7,10 Likewise, fluores- dition can save a patient from unnecessar- As the name implies, ocular ischemic cein angiography is beneficial in identify- ily undergoing extensive medical testing. syndrome (OIS) results when the blood ing the anomalous vasculature, particu- • Consider IJRT in cases of mild para- supply to eye is diminished.1-4 It is a pro- larly in the early stages of Type 2 disease. macular dot and blot hemorrhages in gressive disorder in which chronic While some have argued that angiogra- patients without ischemic vascular disease hypoperfusion to the eye and orbit pro- phy is essential in making a definitive such as diabetes and hypertension. Also, duces poor ocular hemodynamics, result- diagnosis, others suggest that such test- consider this diagnosis in cases of macular ing in a plethora of anterior and posteri- ing may be unnecessary when a diagnosis and paramacular RPE hyperplasia where or segment findings, including loss of is apparent via less invasive means.1-4,6 no other cause can be identified. vision, exfoliation syndrome (with the The natural history of IJRT suggests possibility of exfoliation glaucoma), pre- 1. Abujamra S, Bonanomi MT, Cresta FB, et al. Idiopathic a slowly progressive disorder. A retro- juxtafoveolar retinal telangiectasis: Clinical pattern in 19 mature cataractogenesis, corneal edema, spective series of 20 patients over 10 to cases. Ophthalmologica 2000;214(6):406-11. anterior chamber cellular response, ocu-

40A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 41 VITREOUS AND RETINA lar hypotony, dilated but non-tortuous nation of markedly reduced ocular blood OIS does not often lead to increased retinal vessels, mid-peripheral intra-reti- flow coupled with increased vascular IOP.5,10 Rather, because of the low perfu- nal hemorrhages secondary to venous resistance within the retrobulbar circula- sion pressure and propensity for ciliary stasis, cotton wool spots, spontaneous tion of the central retinal and posterior body anoxia, poor aqueous secretion will retinal arterial pulsation, cherry red mac- ciliary circulation.10 Chronic hypoxia result in relative hypotony.5,10 New iris ula and ischemia inciting the growth of affects the iris and ciliary body produc- vessels are weak and leaky, promoting a neovascularization in both the posterior ing hypoperfusion leading to relative cellular inflammatory response with the and anterior segment.1-6 ocular hypotony, secondary to decreased potential to worsen any developing neo- Impaired blood flow in the ophthalmic aqueous production.5,8 Further, a vascular glaucoma.10 Diabetes mellitus is and can induce histopathologic study has demonstrated also known to aggravate carotid occlu- lenticular stress, which may incite prema- that ciliary body atrophy, derived from sive disease and can hasten the progres- ture cataractogenesis, true lens exfoliation chronic ischemia, is plausible.5 sion of developing ocular ischemic syn- syndrome and exfoliation glaucoma.5 (GCA) is a sys- drome (OIS) and retinopathy.8 Severe carotid stenosis may be associated temic vasculopathy in which an excessive with reduced ocular perfusion, which can fibroproliferative response leads to vas- Management be quantitatively evaluated by observing cular luminal narrowing.9 Alternately, The acute ocular management of OIS arterial pulsation upon ophthalmody- this vascular closure can be distinguished includes gonioscopy to obtain angle sta- namometry (ODM).7 Induced rubeosis from the typical OIS atherosclerotic tus, topical and oral steroidal and nons- irides and neovascularization of the angle teroidal anti-inflammatory prepa- may or may not produce raised intraocu- rations to quell inflammation, lar pressure (IOP) with variable amounts topical cycloplegics to reduce pain, of cornea edema and iritis, ectropion uvea topical ocular hypotensive medica- (eversion of the papillary margin), painful tions if IOP is raised and ocular vision loss with eye and head pain, pho- laser surgical therapy to address tophobia and lacrimation (secondary to neovascular proliferation. A sys- ocular and arterial nociceptor stimulation Mid-peripheral retinal hemorrhages and dilated, non- temic evaluation is also critical to via inflammation and ischemia).8,9 As the tortuous veins in ocular ischemic syndrome. identify additional impending asso- condition develops and the ciliary body ciated cardiovascular or cerebrovas- becomes hypoxic, aqueous production occlusion suggesting that it has a differ- cular complications.3,13 In patients sus- often reduces, causing the IOP in the ent response pattern to arterial injury.9 In pected of having OIS, evaluation should affected eye to drop, producing a relative GCA, macrophages at the vessel’s tunica include a complete blood count with dif- hypotony despite angle closure from neo- media/tunica intima border secrete ferential and platelets, an erythrocyte vascularization. As the condition unfolds platelet derived growth factors (PDGF), sedimentation rate, c-reactive protein, and worsens, inflammatory debris in the which drive the process.9 As the affected lipid panel, carotid artery evaluation anterior chamber and neovascularization vessels lose their ability to support perfu- using transcranial Doppler, magnetic res- of the iris and angle may impede aqueous sion, ischemic optic neuropathy and onance imaging, magnetic resonance egress to the point where IOP rises well ocular ischemic syndrome occur distal to angiography and vascular angiography.3 above normal levels.1 Since the syndrome the event.5,9 Anticoagulant and antiplatelet med- is associated with systemic age-related The underlying ischemia encourages ications are a staple of managing sys- vascular processes, its presence carries an the release of ocular neovascular growth temic cardiovascular and cerebrovascular increased risk both of cardiovascular factors.4-11 This initiates new vessel disease.2 If giant cell arteritis is the sus- complications and cerebrovascular dis- growth in the form of fibrovascular pro- pected cause, immediate treatment or ease.2 liferative membranes, which form on prompt referral to a neurologist or both the retina and the iris surface.8,12 neuro-ophthalmologist is indicated for Pathophysiology When iris neovascularization reaches induction of appropriate anti-inflamma- OIS is traditionally caused by athero- the angle, its contractile nature pulls the tory therapy (intravenous methylpred- sclerotic stenotic processes of the ipsilat- iris into tight apposition with Schwalbe’s nisolone or high-dose oral pred- eral internal carotid artery or ophthalmic ring, covering the trabecular meshwork nisone).5,14 Patients with giant cell artery.1-10 These changes are produced by and occluding the angle.8,12 This second- arteritis will require long-term oral classic age-related vascular changes or ary angle closure is often called “zipper- steroid regimens with plans for extended vascular-inflammatory disease.2,8,10 ing” and may eventually result in elevat- monitoring for ocular and non-ocular External carotid stenosis is a rare but ed IOP and neovascular glaucoma. complications.5,14 Generally, vision is not reported alternate etiology.5,8 The mech- However, anterior chamber rubeosis and recovered. Treatment is geared toward anism of damage results from a combi- neovascular angle closure secondary to recognizing OIS as a possible result of

APRIL 15, 2009 REVIEW OF OPTOMETRY 41A 001_ro0409_handbook 4/2/09 9:42 AM Page 42

GCA and preventing additional loss in • Because of its appearance, OIS is RETINAL ARTERY OCCLUSION the fellow eye. often mistaken for diabetic retinopathy. In patients with OIS who develop Unilateral, asymmetric presentation in Signs and Symptoms neovascularization, panretinal photoco- the absence of lipid should create suspi- Acute retinal artery occlusion is a agulation (PRP) can be used to decrease cion for OIS over diabetic retinopathy. potentially blinding ophthalmic emer- the retinal demand for oxygen, thereby gency.1,2 Artery occlusions are catego- indirectly reducing the need for the faulty 1. Hayreh SS. Neovascular glaucoma. Prog Retin Eye rized into branch, central, cilioretinal, or Res 2007;26(5):470-85. 15 vascular supply. 2. Chen CS, Miller NR. Ocular ischemic syndrome: ophthalmic, depending on the location New research in Review of clinical presentations, etiology, investigation, of the blockage.3 They are not the result the area of combi- and management. Compr Ophthalmol Update of a single disease, but instead manifest a 2007;8(1):17-28. nation treatment 3. Marx JL, Hreib K, Choi IS, et al. Percutaneous carotid combination of chronic systemic abnor- using PRP and artery angioplasty and stenting for ocular ischemic syn- malities.2,3 As such, no definitive epi- External view of OIS; the vascular endo- drome. Ophthalmol. 2004;111(12):2284-91. demiology for retinal artery occlusion note congestion of 4. Foncea Beti N, Mateo I, Díaz La Calle V, et al. The ocu- conjunctival vascula- thelial growth fac- lar ischemic syndrome. Clin Neurol Neurosurg has been determined. Rather, it falls ture and dense lentic- tor inhibitor beva- 2003;106(1):60-2. under the epidemiology of systemic ular opacification. cizumab resulted 5. Schmidt D. Ocular ischemia syndrome—a malignant heart disease, cardiovascular disease, course of giant cell arteritis. Eur J Med Res in rapid decrease 2005;10(6):233-42. smoking, obesity and other chronic or of IOP and swift regression of neovascu- 6. Detorakis ET, Achtaropoulos AK, Drakonaki EE, et al. episodic contributors including subacute larization, possibly identifying a new Hemodynamic evaluation of the posterior ciliary circulation bacterial endocarditis, tumors, leukemia, in exfoliation syndrome and exfoliation glaucoma. Graefes 15 approach to the problem. Arch Clin Exp Ophthalmol 2007;245(4):516-21. corticosteroid injection, polyarteritis Percutaneous carotid angioplasty with 7. Cohn EJ Jr, Sandager GP, Benjamin ME, et al. nodosa, , blunt trauma, radiation stenting has been successfully developed Assessment of ocular perfusion after carotid endarterec- exposure, optic nerve drusen, amniotic tomy with color-flow duplex scanning. J Vasc Surg 3,4 for treating OIS resulting from intracra- 1999;29(4):665-71. fluid embolism and abuse. nial .3,16 Another 8. Ino-ue M, Azumi A, Kajiura-Tsukahara Y, et al. Ocular The majority of patients with retinal modality for relieving the effects of ischemic syndrome in diabetic patients. Jpn J Ophthalmol artery occlusion are older.3 Patients pres- 1999;43(1):31-5. reduced ocular circulation from carotid 9. Kaiser M, Weyand CM, Björnsson J, et al. Platelet- ent with a chief complaint of sudden, artery disease is carotid endarterecto- derived growth factor, intimal hyperplasia, and ischemic my.17-19 Although it has had mixed sup- complications in giant cell arteritis. Arthritis Rheum 1998;41(4):623-33. port as a treatment for OIS, most reports 10. Munch IC, Larsen M. The ocular ischemic syndrome. in the literature support its position in Ugeskr Laeger 2005;167(35):3269-73. the armamentarium of procedures 11. Alizai AM, Trobe JD, Thompson BG, et al. Ocular ischemic syndrome after occlusion of both external designed to improve outcomes for carotid arteries. J Neuroophthalmol 2005;25(4):268-72. OIS.6,18,19 In instances in which OIS is 12. Buettner H, Machemer R. Histopathologic findings in caused by non-giant cell vasculostenotic human eyes after pars plana vitrectomy and lensectomy. Arch Ophthalmol 1977;95(11):2029-33. pathology, reestablishing the appropriate 13. Furino C, Guerriero S, Boscia F, et al. In vivo evidence vascular supply reduced ocular sequelae of hypotrophic ciliary body in ocular ischemic syndrome and symptoms.12,15,17-19 by ultrasound biomicroscopy. Ophthal Surg Lasers Imag 2007;38(6):505-7. 14. Hayreh SS, Zimmerman B, Kardon RH. Visual Central retinal artery occlusion. Clinical Pearls improvement with corticosteroid therapy in giant cell • Intracranial carotid artery stenosis arteritis. Report of a large study and review of literature. painless vision loss.1-4 In many instances, Acta Ophthalmol Scand 2002;80(4):355-67. is a rare cause of ocular ischemic syn- 15. Ehlers JP, Spirn MJ, Lam A, et al. Combination intrav- the loss is noticed upon waking. drome. Carotid angioplasty and stenting itreal bevacizumab/panretinal photocoagulation versus However, when a branch retinal artery is now permits lesions to be treated that panretinal photocoagulation alone in the treatment of neo- involved or a cilioretinal artery is pres- vascular glaucoma. Retina 2008;28(5):696-702. were previously not amenable to 16. Kawaguchi S, Sakaki T, Iwahashi H, et al. Effect of ent—preserving central vision—patients endarterectomy. carotid artery stenting on ocular circulation and chronic may complain of shadows in their visual • Giant cell arteritis must always be ocular ischemic syndrome. Cerebrovasc Dis 2006;22(5- field. Some may report that they have 6):402-8. considered as the cause of ocular 17. Wolintz RJ. Carotid endarterectomy for ophthalmic experienced episodes of transient visual ischemic syndrome cases in patients manifestations: Is it ever indicated? J Neuroophthalmol loss before the current episode.3-5 older than 60 years. 2005;25(4):299-302. Concurrent pain is more suggestive of 18. Kawaguchi S, Okuno S, Sakaki T, et al. Effect of • Lack of perfusion creates a stagnant carotid endarterectomy on chronic ocular ischemic syn- underlying ocular ischemic syndrome blood in the peripheral retinal microvas- drome due to internal carotid artery stenosis. Neurosurg (carotid circulation) rather than retinal cular circulation. This leads to mid- 2001;48(2):328-32. artery occlusion.6 Although the etiology 19. Kawaguchi S, Sakaki T, Uranishi R, et al. Effect of peripheral dot and blot hemorrhages, the carotid endarterectomy on the . Acta of retinal artery obstructions is primarily hallmark of OIS. Neurochir (Wien) 2002;144(5):427-32. embolic, they are not always visible.2

42A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 43 VITREOUS AND RETINA As artery occlusions develop, the fun- edema and necrosis present within min- tion. Anecdotally, the potential for duscopic appearance will vary. Blood utes of the event.3 achieving any restoration of vision is flow is impeded and retinal function When partial or complete retinal greatest when the blockage is dislodged becomes compromised immediately, arterial occlusion occurs, tissue ischemia within 100 minutes of the onset of the although initially the retina may appear begins. Retinal ischemia initiates the first symptoms.3,16 Although frequently unaffected.1-5 As the ischemia evolves, process of neovascularization in both the unsuccessful, emergent treatments are retinal arteries may visibly narrow, anterior and posterior segments.11 designed to increase retinal perfusion by demonstrating segmented interrupted Interestingly, neovascular complications re-establishing retinal blood flow.1-4,16 flow known as “box car vessels.” Over The traditional mechanism of increas- time, the retina may appear pale and ing intraocular pressure in the eye by swollen.1-5 Nerve fiber layer hemorrhag- aggressive digital palpation with sudden es may be present in the parapapillary release is designed to stimulate retinal area.3 The classic macular “cherry red autoregulatory mechanisms. Here, as

spot” seen in central retinal artery occlu- Image courtesy of Dr. Joe Overstreet the retinal tissues sense the general sion occurs as a result of the absence of hypoxia created by the digitally applied foveal photoreceptors and thinner anato- force, the retinal vasculature dilates to my in the macular region.3 The intact increase blood flow. When intraocular choroidal circulation is highlighted by pressure drops as the force is removed, the surrounding retinal pallor, making it aqueous is forced from the eye, which stand out.1-10 decreases resistance to incoming blood. Following acute injury, the retinal The hope is that the emboli will be dis- appearance may resolve over the course of Cilio-retinal artery occlusion. lodged and move farther down the reti- six weeks, but function rarely returns.1-4 nal arterial system, permitting reperfu- Rare instances however, have been report- from retinal artery occlusion are infre- sion of the critical retinal area.3 Other ed in which visual function improves quent when compared to other causes strategies for dislodging the embolus over time with or without treatment.2,7 such as retinal vein occlusion and dia- include decreasing the resistance to ocu- The formation of neovascularization on betes, because artery occlusion causes the lar blood flow by reducing intraocular the retina and iris is a possibility.1-3,11 retinal tissue to die rather than starve. pressure via topical and oral medication Hypertension is clearly a major risk or paracentesis. An alternate strategy Pathophysiology factor for the development of microvas- involves stimulating retinal vascular Calcific emboli are most likely to culopathy in general.13 As such, it dilation by increasing blood carbon cause retinal artery occlusion and are increases the risk for retinal vascular dioxide levels, either by having the often cardiac in origin. Emboli from var- events such as retinal vein occlusion, patient breathe into a paper bag or by ious sources travel through the vascular retinal artery occlusion and ischemic having him or her breathe a carbogen system, becoming lodged inside a retinal optic neuropathy.13 Sickle-cell disease mixture (95% oxygen, 5% carbon diox- vessel, partially or completely obstruct- has also been noted as an etiology of reti- ide) or with sublingual nitroglycerine.3 ing the flow of blood to distal tissues.2,4 nal artery occlusion.14 Although most Unfortunately, such heroic measures Multiple reports in the literature cite eti- cases are the result of cardiac, carotid, rarely improve the final outcome. ologies related to malfunctioning clot- vascular, hemodynamic and autoim- Patients with artery occlusion must ting factors in blood, such as antiphos- mune diseases, in rare instances retinal receive a complete systemic evaluation to pholipid disease, factor VIII artery occlusions have occurred in uncover the underlying cause of the abnormality, and with protein S and C healthy individuals with no attributable occlusion.4,15 Evaluation should include a alteration as an underlying source.7-9 systemic etiology found.7,15 Additionally, complete blood count with differential Amniotic fluid embolism has also been some cases of central retinal artery and platelets, an erythrocyte sedimenta- recorded as an unusual but plausible occlusion are caused not by emboli but tion rate (ESR), C-reactive protein source of retinal emboli.10 by thrombi from giant cell arteritis (CRP), lipid panel, carotid artery evalua- As the oxygen-sensitive retinal ele- (GCA). This condition must be consid- tion using transcranial Doppler, pro- ments lose their source of sustenance, ered as a possible cause of retinal artery thrombin time, activated partial thrombo- they quickly begin to fail, creating symp- occlusion in older patients to prevent fel- plastin time, protein S, protein C, toms of variable visual phenomena or low eye vision loss.2,3 antiphospholipid antibody testing, anti- complete painless vision loss.1-7 Retinal nuclear antibody and tissue is extremely sensitive to oxidative Management testing, echocardiogram and trans- stress.12 The inner layers of the retina The key to visual recovery in any reti- esophageal echocardiogram.8,9,15,17-20 In succumb to ischemia, with intracellular nal arterial occlusion is timely interven- older patients with systemic symptoms

APRIL 15, 2009 REVIEW OF OPTOMETRY 43A 001_ro0409_handbook 4/2/09 9:42 AM Page 44

suggestive of GCA, obtaining ESR and potential for spontaneous visual 4. Opremcak E, Rehmar AJ, Ridenour CD, et al. Restoration of retinal blood flow via translumenal Nd:YAG CRP is emergently required. improvement, even without interven- embolysis/embolectomy (TYL/E) for central and branch In general, anticoagulation therapy is tion. Over a 27 year period, Hayreh and retinal artery occlusion. Retina 2008;28(2):226-35. the staple of treating patients with artery Zimmerman noted spontaneous visual 5. Schmidt D, Hetzel A, Geibel-Zehender A, et al. Systemic diseases in non-inflammatory branch and cen- occlusion secondary to coagulopathy, improvement in some patients with tral retinal artery occlusion—an overview of 416 patients. hyperviscosity, cardiac or carotid CRAO, dependent upon the classifica- Eur J Med Res 2007;12(12):595-603. sources.15,17-20 In cases involving GCA, tion and etiology of the occlusion.26 6. Chen CS, Miller NR. Ocular ischemic syndrome: Review of clinical presentations, etiology, investigation, lupus or antiphospholipid antibody syn- and management. Compr Ophthalmol Update drome, immunosupressants may be Clinical Pearls 2007;8(1):17-28. appropriate.18 • Giant cell arteritis, , 7. Chung YR, Kim JB, Lee K, et al. Retinal artery occlu- sion in a healthy pregnant patient. Korean J Ophthalmol Intra-arterial thrombolysis (IAT) rep- retinal vein occlusion, infectious neu- 2008;22(1):70-1. resents an aggressive approach to treat- roretinitis, vitreous hemorrhage sec- 8. Greven CM, Weaver RG, Owen J, et al. Protein S defi- ing retinal arterial occlusions, with the ondary to proliferative retinopathy, reti- ciency and bilateral branch retinal artery occlusion. Ophthalmol 1991;98(1):33-4. potential to produce superior visual out- nal detachment and retinal vasculitis are 9. Nelson ME, Talbot JF, Preston FE. Recurrent multiple- comes compared with conventional all potential sources of monocular branch retinal arteriolar occlusions in a patient with protein treatments.21-24 The use of intravenous vision loss. C deficiency. Graefes Arch Clin Exp Ophthalmol 1989;227(5):443-7. and intra-arterial thrombolytic agents • Cilioretinal arteries take their blood 10. Kim IT, Choi JB. Occlusions of branch retinal arteri- such as urokinase has been investigated supply from the , often emerging oles following amniotic fluid embolism. Ophthalmologica for more than 20 years, but there from the temporal optic nerve and aid- 2000;214(4):305-8. 11. Konareva-Kostianeva M. Neovascular glaucoma. remains insufficient evidence to support ing in the supply of retinal tissues in the Folia Med (Plovdiv) 2005;47(2):5-11. its routine use.21-24 A potential side effect vicinity of the macula. In the event that 12. Kergoat H, Hérard ME, Lemay M. RGC sensitivity to of the treatment is vitreous hemor- a central retinal artery occlusion occurs mild systemic hypoxia. Invest Ophthalmol Vis Sci 2006;47(12):5423-7. 23 rhage. A prospective controlled clinical in the presence of a cilioretinal artery, 13. Wong TY, Mitchell P. The eye in hypertension. Lancet trial is ongoing in Europe, with the goal these vessels can partially preserve func- 2007;369(9559):425-35. of providing reliable information and tion over the area of their distribution, as 14. Liem RI, Calamaras DM, Chhabra MS, et al. Sudden- onset blindness in sickle cell disease due to retinal artery 22 guidelines on this treatment. long as the occlusion does not also affect occlusion. Pediatr Blood Cancer 2008;50(3):624-7. Hyperbaric oxygen therapy is a pri- the choroidal circulation. 15. Winterkorn JM, Mack P, Eggenberger E. Transient mary or adjunctive therapeutic modality • Patients with primary antiphos- visual loss in a 60-year-old man. Surv Ophthalmol 2008;53(3):301-5. that is currently in off-label trials for eye pholipid antibody syndrome may devel- 16. Hayreh SS, Zimmerman MB, Kimura A, et al. Central diseases.25 Increasing evidence has op retinal artery occlusions and may retinal artery occlusion. Retinal survival time. Exp Eye Res demonstrated safety and efficacy for use also exhibit episodes of amaurosis 2004;78(3):723-36. 17. Suvajac G, Stojanovich L, Milenkovich S. Ocular in retinal artery occlusion among other fugax, transient ischemic attack and manifestations in antiphospholipid syndrome. Autoimmun conditions.25 A newly proposed tech- anterior ischemic optic neuropathy, cil- Rev 2007;6(6):409-14. nique using Nd:YAG laser to photodis- ioretinal artery occlusion, central retinal 18. Coroi M, Bontas E, Defranceschi M et al. Ocular manifestations of antiphospholipid (Hughes’) syndrome— rupt emboli within the central retinal artery occlusion and ophthalmic artery minor features? Oftalmologia 2007;51(3):16-22. artery and branch retinal arteries may occlusion. Amaurosis fugax, retinal vas- 19. Coroi M, Bontas E, Visan R, et al. Ocular help achieve rapid reperfusion of the reti- cular and optic neuropathy and antiphospholipid antibodies—where we stand? Oftalmologia 2007;51(3):8-15. 4 na. Translumenal Nd:YAG embolysis are considered the ocular hallmark signs 20. Schmidt D, Hetzel A, Geibel-Zehender A. Retinal (TYL) or embolectomy (TYE) have of Hughes’ syndrome. Testing for arterial occlusion due to embolism of suspected cardiac been reported as potential procedures autoimmune factors and antiphospho- tumors—report on two patients and review of the topic. Eur J Med Res 2005;10(7):296-304. that can be deployed quickly in cases of lipid antibody syndrome is especially 21. Noble J, Weizblit N, Baerlocher MO, et al. Intra-arte- retinal nonperfusion secondary to embol- important in younger patients with rial thrombolysis for central retinal artery occlusion: A sys- ic blockage.4 In one study, following retinal artery occlusion. tematic review. Br J Ophthalmol 2008;92(5):588-93. 22. Biousse V, Calvetti O, Bruce BB, et al. Thrombolysis TYL, Snellen visual acuity improved by • Heroic measures to restore retinal for central retinal artery occlusion. J Neuroophthalmol an average of 4.7 lines in 17 of 19 perfusion typically fail in the majority of 2007;27(3):215-30. patients (89%), and 11 of the patients these cases because many patients delay 23. Weber J, Remonda L, Mattle HP, et al. Selective intra-arterial fibrinolysis of acute central retinal artery 4 (58%) gained greater than 4 lines. seeking treatment. occlusion. Stroke 1998;29(10):2076-9. Vitreous hemorrhage and subhyaloid 24. Vallée JN, Paques M, Aymard A, et al. Combined hemorrhage are potential complications 1. Pokhrel PK, Loftus SA. Ocular emergencies. Am Fam central retinal arterial and venous obstruction: Emergency Physician 2007;76(6):829-36. ophthalmic arterial fibrinolysis. Radiol 2002;223(2):351-9. 4 of this treatment, however. 2. Hayreh SS. Prevalent misconceptions about acute 25. Oguz H, Sobaci G. The use of hyperbaric oxygen It should be noted that while retinal retinal vascular occlusive disorders. Prog Retin Eye Res therapy in ophthalmology. Surv Ophthalmol artery occlusion significantly deprives 2005;24(4):493-519. 2008;53(2):112-20. 3. Duker JS. Retinal arterial obstruction. In: Yanoff M, 26. Hayreh SS, Zimmerman MB. Central retinal artery the retina of oxygen with tissue death Duker JS. Ophthalmology (2nd ed). St Louis, MO: Mosby, occlusion: visual outcome. Am J Ophthalmol. 2005 rapidly esuing, there still remains the 2004, pp. 854-61. Sep;140(3):376-91.

44A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 45

NEURO-OPHTHALMIC DISEASE NEURO-OPHTHALMIC DISEASE

DORSAL MIDBRAIN brain) contains many structures that can element of managing patients with DMS SYNDROME be compromised, resulting in the numer- is determining the underlying etiology. ous clinical signs seen in the syndrome. Treatment options are dictated by the Signs and Symptoms DMS represents a supranuclear palsy that specific condition. Today, pinealomas are Dorsal midbrain syndrome (DMS), primarily affects conjugate vertical eye most commonly managed by surgical also known as Parinaud’s syndrome, pre- movements. It results from damage to the excision with radiation. Chemotherapy is tectal syndrome, Sylvian aqueduct medial longitudinal fasciculus (MLF), an alternative or adjuvant therapy, depend- syndrome or Koerber-Salius-Elschnig mainly at the level of the superior collicu- ing upon the nature of the tumor. All cases syndrome, presents with findings that lus. The rostral interstitial nucleus of the of DMS warrant prompt referral to a qual- include a vertical gaze disturbance with MLF (riMLF) controls vertical gaze; the ified neurologist and/or neurosurgeon. paresis, spastic-paretic accommodation, superior colliculus controls vertical sac- convergence-retraction and cades and houses the intercalated neu- Clinical Pearls light-near dissociated (LND) .1-7 rons, which are associated with pupillo- • The initial presentation of DMS There may also be bilateral lid retraction motor function. Downgaze paralysis may involve loss of upward saccades in without lid lag on down gaze (Collier’s results from bilateral lesions involving the isolation of other findings. Pupillomotor sign), as well as vertical diplopia due to uni- regions located just caudal, medial and dysfunction is another early sign. All of lateral or bilateral fourth cranial nerve dorsal to the upper poles of the red nuclei, the abovementioned signs need not be palsies.8-10 Patients will present variably with while upgaze paralysis results from unilat- present to implicate damage to the dor- these signs and symptoms, and not every eral lesions in or near the posterior com- sal midbrain. symptom will be present in every patient. missure. Combined downgaze and • Hydrocephalus often ensues in cases Because of the inability to converge upgaze paralysis results from bilateral of DMS because of aqueductal stenosis. the eyes, coupled with the accommoda- lesions involving the region related to the In these cases, patients may present with tive dysfunction, patients presenting whole riMLF on both sides.13 Probable associated symptoms of headache, nausea with this condition most often complain destruction of the olivary pretectal nucle- and vomiting, transient visual obscura- of a newfound difficulty with reading or us and the nucleus of the like- tions, tinnitus, alterations of mental sta- recent onset diplopia. Headache may be ly abolishes the pupillary light reflex.11 tus and gait disturbance. Papilledema is reported in cases that have associated Occasionally, damage will involve the typically observed in these patients. intracranial hypertension.11 Clinical test- midbrain at the level of the inferior col- • DMS is often confused with myas- ing reveals an inability to look upwards. liculus.The trochlear nuclei (cranial nerve thenia gravis in its early stages because of Initially, only upward saccades are lost, IV) are located in this area, ventral to the its variable presentation. Pupil involve- but eventually upward pursuit move- cerebral aqueduct. Their motor fibers ment is never associated with myasthe- ments fail as well. This finding may be leave the nuclei and decussate within the nia gravis, however, and ocular motility vague, however, and is best elicited by anterior medullary vellum. Involvement dysfunctions improve following rest. using an optokinetic nystagmus drum or in this area gives rise to unilateral and Also, ptosis is a common early finding in tape to test upgaze.1-7 Downgaze paresis bilateral cranial nerve palsies.8-10 myasthenia gravis that is not encoun- may occur as well, although it occurs less Most often, DMS is associated with tered in DMS. frequently. Accommodative difficulties pinealoma, a compressive lesion of the • When patients present with pupils range from intermittent spasms on pineal gland that impinges on the struc- that do not react to light, near function attempted upgaze to complete accom- tures of the dorsal midbrain in the pre- must be assessed. If the pupils react modative paresis. Convergence-retrac- tectal area.2,6 Midbrain infarction and properly to near, vertical saccades must tion nystagmus is easily elicited in these closed head trauma are common etiolo- be examined. When vertical saccades are patients. Upon attempted upward sac- gies.4,9-11 Other reported causes include abnormal, DMS should be ruled out. cades, the eyes demonstrate retro dis- obstructive hydrocephalus, congenital 1. Oishi A, Miyamoto K, Yoshimura N. Dorsal midbrain placement into the orbit, with an associ- aqueductal stenosis, metastatic cancer, syndrome induced by midbrain neurosarcoidosis. Jpn J ated nystagmus.1,5,7 mesencephalic hemorrhage, multiple Ophthalmol 2008;52(3):236-8. Bilateral LND pupils are a hallmark sclerosis, A-V malformations, infective 2. Allmer DM, Golis TA. Dorsal midbrain syndrome sec- ondary to a pineocytoma. Optom 2001;72(4):234-8. 12 sign of DMS. The pupils demonstrate endocarditis, posterior fossa aneurysm, 3. Kato I, Okada T, Akao I, et al. Vertical gaze palsy no reactivity to light, but do react slowly neurosarcoidosis and neurosyphilis.1,4,8,14-19 induced by midbrain lesions and its structural imaging. to accommodative stimuli. Less com- Auris Nasus Larynx 1998;25(4):339-47. 4. Clark JM, Albers GW. Vertical gaze palsies from medi- monly, skew deviations and downbeat Management al thalamic infarctions without midbrain involvement. nystagmus may be noted. Once DMS is diagnosed, neuroimag- Stroke 1995;26(8):1467-70. ing of the midbrain must be obtained 5. Serdaru M, Gray F, Lyon-Caen O, et al. Parinaud’s syn- drome and tonic vertical gaze deviation. 3 anatomo-clinical Pathophysiology (preferably MRI with contrast medium) observations. Rev Neurol (Paris) 1982;138(8-9):601-17. The dorsal mesencephalon (mid- to ascertain the cause. The most critical 6. Spalice A, Parisi P, Iannetti P. Paroxysmal tonic up

APRIL 15, 2009 REVIEW OF OPTOMETRY 45A 001_ro0409_handbook 4/2/09 9:42 AM Page 46

gaze: Physiopathological considerations in three addition- widely. From an al cases. J Child Neurol 2000;15(1):15-8. 7. Baloh RW, Furman JM, Yee RD. Dorsal midbrain syn- ophthalmic stand- drome: Clinical and oculographic findings. Neurol point, patients may 1985;35(1):54-60. present with an array 8. Mielke C, Alexander MS, Anand N. Isolated bilateral palsy as the first clinical sign of a metasta- of visual symptoms, tic bronchial carcinoma. Am J Ophthalmol 2001;132(4): including diminished 593-4. acuity, color desatu- 9. Bhola R, Olson RJ. Dorsal midbrain syndrome with bilateral superior oblique palsy following hem- ration, field loss and orrhage. Arch Ophthalmol 2006;124(12):1786-8. even diplopia (if the Patient diagnosed with pituitary macroadenoma. The only visible finding is subtle blurring of the disc margin. 10. Barr DB, McFadzean RM, Hadley D, et al. Acquired cavernous sinus is bilateral superior oblique palsy: A localising sign in the 5 dorsal midbrain. Eur J Ophthalmol 1997;7(3):271-6. involved). The classic defect produce Cushing’s disease (hyperadren- 11. Maramattom BV, Wijdicks EF. Dorsal mesencephalic is a bi-temporal hemianopia that is more alism).4 Rarely, tumors can secrete thyroid syndrome and acute hydrocephalus after subarachnoid dense from superior to inferior, although stimulating hormone (TSH), producing hemorrhage. Neurocrit Care 2005;3(1):57-8. 12. Wilhelm BJ, Wilhelm H, Moro S, et al. Pupil response a variety of field defects can occur, signs and symptoms of thyrotoxicosis, components: studies in patients with Parinaud’s syn- including such non-localizing entities as including heat intolerance, sweating, drome. Brain 2002;125(Pt 10):2296-307. peripheral constriction and arcuate sco- tachycardia, fine tremor and weight 13. Pierrot-Deseilligny CH, Chain F, Gray F, et al. 5-7 9 Parinaud’s syndrome: Electro-oculographic and anatomi- tomas. Less common ocular manifes- loss. Despite this vast array of potential cal analyses of six vascular cases with deductions about tations include nystagmus and photo- signs and symptoms, a significant pro- vertical gaze organization in the premotor structures. phobia.7,8 Funduscopically, patients with portion of pituitary adenomas are silent Brain 1982;105(Pt 4):667-96. 14. Quint DJ, Cornblath WT, Trobe JD. Multiple sclerosis may display a com- and discovered only by chance during presenting as Parinaud syndrome. AJNR Am J pletely normal optic nerve, though long- unrelated brain imaging; the term inci- Neuroradiol 1993;14(5):1200-2. standing chiasmal compression may lead dentaloma has been proposed for such 15. Tijssen CC. Perinaud syndrome as sign of acute obstructive hydrocephalus: Recovery after acute ventricu- to primary optic atrophy and the devel- non-functioning, asymptomatic pitu- lostomy. Ned Tijdschr Geneeskd 2002;146(33):1563. opment of disc pallor.5 Optic disc edema itary adenomas.9,10 16. Costantino A, Black SE, Carr T, et al. Dorsal midbrain is not a characteristic finding of this dis- syndrome in multiple sclerosis with magnetic resonance imaging correlation. Can J Neurol Sci 1986;13(1):62-5. ease state. Pathophysiology 17. Dumas P, Chassagne M, Vallat JM, et al. Dorsal mid- A variety of systemic signs and symp- The pituitary gland is situated within brain syndrome from giant aneurysm of the posterior toms can accompany pituitary adeno- the sella turcica of the sphenoid bone, at fossa. Neurol 1984;34(5):702-3. 18. Coppeto JR, Lessell S. Dorsal midbrain syndrome mas. Mass effects of the expanding neo- the base of the skull.The anterior lobe of from giant aneurysm of the posterior fossa: Report of two plasm include headache, seizures or the pituitary gland secretes six hor- cases. Neurol 1983;33(6):732-6. cerebrospinal fluid rhinorrhea (i.e., drip- mones: thyroid stimulating hormone 19. Miller NR. Late improvement in upward gaze in a 9 patient with hydrocephalus related Parinaud dorsal mid- ping of CSF from the nose). Depending (TSH), adrenocorticotropic hormone brain syndrome. Br J Ophthalmol 2006;90(1):123. on the location and severity of the (ACTH), follicle stimulating hormone tumor, numerous hormonal changes (FSH), leutenizing hormone, growth PITUITARY ADENOMA may occur. Prolactinomas—tumors that hormone (GH) and prolactin.2 The pos- produce excessive levels of prolactin— terior pituitary gland secretes vasopressin Signs and Symptoms are the most common form of pituitary and oxytocin. The cavernous sinuses, Pituitary adenomas are a common adenoma, and cause amenorrhea (the which contain III and IV, type of intracranial tumor.The prevalence loss of menstruation), galactorrhea (the the ophthalmic and maxillary divisions in the general population, based upon spontaneous flow of milk from the of cranial nerve V, cranial nerve VI and meta-analysis of the prevailing literature, breast) and infertility is about 17%.1 Pituitary tumors demon- in females; in males, strate a peak incidence between the ages prolactinomas cause of 30 and 60 years and are considered rare hypogonadism, in individuals younger than age 20.2 decreased libido and There is no substantial gender difference impotence.9 Tumors in overall incidence, although on average, that secrete excess women seem to be affected at a substan- growth hormone tially earlier age than men.2,3 There are no cause gigantism in reported geographic or race differences; children and acro- however, pituitary adenomas account for megaly in adults.4,9 a greater percentage of intracranial Adrenocorticotrophic tumors in African Americans.4 hormone (ACTH)- Clinical presentations can vary secreting adenomas Bitemporal visual field loss is pathognomonic for chiasmal disease.

46A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 47 NEURO-OPHTHALMIC DISEASE

the internal carotid artery are located lat- Management Complications of transphenoidal resec- eral to the pituitary gland. Patients who present with signs or tion include cerebrospinal fluid rhinor- Pituitary adenomas are typically symptoms indicative of chiasmal pathol- rhea (discharge from nasal mucous benign, slow-growing neoplasms of ogy, such as pituitary adenoma, warrant membranes), diabetes insipidus and epithelial origin.11 In most cases, they prompt neuroimaging and medical con- sinusitis.13 arise from the adenohypophysis (the sultation. The preferred radiologic tech- As an alternative (or adjunctive treat- anterior lobe of the pituitary gland) and nique is high-resolution dynamic mag- ment) to surgery, fractionated radiother- are capable of producing both systemic netic resonance imaging (MRI). apy offers a non-invasive option to arrest and visual signs. The is sit- Contrast enhancement with gadolinium tumor growth in pituitary tumors. The uated approximately 8–13mm above the helps to further delineate pituitary irreg- usual dose is 50 Gy ± 5 Gy and may be pituitary gland. The nasal retinal fibers ularities, and is crucial in diagnosing delivered via several techniques, includ- of each eye (representing temporal visu- microadenomas.12 Computed tomogra- ing external proton beam, cobalt al field) cross, proceeding into the con- phy (CT) scanning can also be used to gamma-knife or linear accelerator focal tralateral optic tract, while temporal reti- delineate pituitary abnormalities and stereotactic technology.9 Potential com- nal fibers (representing nasal visual field) may actually be superior in demonstrat- plications associated with this form of continue posteriorly uncrossed. Inferior ing calcification within the tumor mass; therapy include radiation-induced nasal fibers (representing superior tem- however, MRI is substantially better hypopituitarism, cerebrovascular acci- poral field) decussate within the chiasm than CT at depicting the complex dent, optic nerve damage and non-spe- anteriorly and superior nasal fibers (rep- anatomy and delicate structures sur- cific neurological dysfunction.14 resenting inferior temporal field) decus- rounding the sella.9 Patients with any Medical therapy is primarily limited to sate posteriorly. indication of hormonal abnormalities prolactinomas and somatotrophic Upwardly growing pituitary tumors should undergo pituitary function test- tumors, although in such cases tremen- that reach appropriate sizes can impinge ing, preferably by a pituitary endocrinol- dous efficacy has been noted, to the point on the anterior notch of the chiasm at ogist. A consultation may be of excluding other, more invasive treat- its lowest lying aspect, producing the required in cases of substantial neurolog- ment options. Key medical therapies classic bitemporal , with ic symptoms, such as seizure, nystagmus, include dopamine agonists (e.g., increased density superiorly. Since memory disturbance or impairment of bromocriptine, cabergoline and quinago- tumor growth is usually asymmetrical, the senses. lide) for hyperprolactinemia, and somato- the field loss between two eyes is also Therapeutic intervention is aimed at statin analogues (e.g., octreotide and lan- typically asymmetrical. reducing the tumor mass and normaliz- reotide) and GH antagonists (e.g., Pituitary adenomas are differentiated ing hormonal secretion. The three treat- pegvisomant) for acromegaly. The clinically by size and by the presence or ment modalities that are employed with dopamine agonists have particularly absence of hormonal hypersecretion. regularity include surgery, radiation and impressive outcomes in 85–90% of Microadenomas, defined as 10mm or medical (i.e., pharmacologic) therapy. patients, but, unfortunately they are less in diameter without sellar enlarge- The preferred treatment in any given plagued by substantial adverse side ment, have little impact on the visual sys- case depends upon the age and health of effects, including nausea and vomiting, tem or gland function. Macroadenomas, the patient, the size and invasiveness of postural hypotension and dizziness, which by definition are 10mm or larger, the tumor, and the degree of hormone headache, constipation and depressive have the capacity to expand beyond the production by the tumor. reactions.2 Thus, despite their efficacy, sella turcica and induce mass effect Surgical intervention for pituitary these drugs are often intolerable to symptoms, such as headache and visual adenomas is indicated when there is evi- patients. Also, the practitioner must real- disturbances.9 Macroadenomas include dence of tumor enlargement, especially ize that the effects of these agents persist (in order of most common to least com- when growth is accompanied by com- only as long as therapy is continued; mon): non-secreting adenomas, prolactin pression of the optic chiasm, cavernous hence, these medications must be contin- secreting (chromaphobe) adenomas, sinus invasion or the development of ued for life, unless other forms of therapy growth hormone secreting (acidophil) pituitary hormone deficiencies. A trans- are used. adenomas, ACTH secreting (basophil) sphenoidal or subfrontal transcranial adenomas and FSH or TSH secreting approach may be used, though the trans- Clinical Pearls adenomas.2,9 Secreting tumors are usually sphenoidal technique is preferred by the • Although pituitary adenomas are diagnosed by internists and endocrinolo- vast majority of skilled pituitary neuro- considered benign, they have the capacity gists. Non-secreting tumors are often surgeons.9 Visual improvement follow- to cause significant morbidity in vision diagnosed by eyecare practitioners ing treatment is often dramatic, with the and other organ systems. In a small per- because they produce visual symptoms in greatest degree of improvement occur- centage of patients, pituitary tumors may the absence of systemic signs. ring within the first few months. be malignant. By definition, these are

APRIL 15, 2009 REVIEW OF OPTOMETRY 47A 001_ro0409_handbook 4/2/09 9:42 AM Page 48

referred to as pituitary carcinomas and 8. Kawasaki A, Purvin VA. Photophobia as the present- nomena without affecting acuity, and ing visual symptom of chiasmal compression. J represent pituitary tumors with evidence Neuroophthalmol 2002;22(1):3-8. typically includes other neurologic of subarachnoid, brain, or systemic 9. Chanson P, Salenave S. Diagnosis and treatment of pitu- symptoms. In some cases, TIA presents metastasis.12 itary adenomas. Minerva Endocrinol 2004;29(4):241-75. with no visual involvement, and these 10. Chanson P, Young J. Pituitary incidentalomas. • The differential diagnosis of pitu- Endocrinologist 2003;13(2):124-35. patients typically present to a neurologist itary tumor includes 11. Minniti G, Esposito V, Piccirilli M, et al. Diagnosis and or hospital emergency room. The pat- (a slow-growing tumor arising from ves- management of pituitary tumours in the elderly: A review tern demonstrated is often diagnostic for based on personal experience and evidence of literature. 3 tigial remnants of Rathke’s pouch), Eur J Endocrinol 2005;153(6):723-35. location. may be monocular and gliomas; all of these 12. Kaltsas GA, Nomikos P, Kontogeorgos G, et al. or binocular, idiopathic, altitudinal, sec- can impinge on the chiasm and present Clinical review: Diagnosis and management of pituitary toral or homonymous.3 Monocular, sec- carcinomas. J Clin Endocrinol Metab 2005;90(5):3089-99. with a similar ophthalmic picture. 13. Ahmed S, Elsheikh M, Stratton IM, et al. Outcome of toral episodes indicate involvement in 3 Clinical masqueraders can include chron- transphenoidal surgery for acromegaly and its relationship the carotid/ocular circulation. Binocu- ic retrobulbar optic neuritis, toxic/nutri- to surgical experience. Clin Endocrinol (Oxf) lar, homonymous events signify a 1999;50(5):561-7. tional optic neuropathy, uncorrected 14. Gillam MP, Molitch ME, Lombardi G, et al. Advances retrochiasmal effect and posterior or ver- , normal tension glaucoma in the treatment of prolactinomas. Endocr Rev tebral circulatory issue. Like AF, TIA is and age-related . Misdiag- 2006;27(5):485-534. a sign of vascular disease, making its epi- nosis is often attributable to an inade- demiology similar to that of AF.1-11 quate history, failure to correlate systemic AMAUROSIS FUGAX AND TIA is on a continuum with AF but is signs and visual symptoms, or failure to TRANSIENT ISCHEMIC ATTACK considered its own entity because of the perform adequate testing or follow up. length of time the events last and because • Bilateral tilted disc syndrome can Signs and Symptoms it reflects influence on more than one result in a superior bi-temporal field The word amaurosis originates from neurologic area. AF is strictly a local ocu- defect similar to that seen in pituitary the Greek meaning “darkness.”1 The lar event; TIA represents the beginning adenoma. Careful ophthalmoscopic eval- word fugax originates from the Latin of a territorial issue. As the name implies, uation should be performed before more meaning “fleeting.” Hippocrates was the TIA affects a sector of neurologic tissue invasive testing (such as MRI or pituitary first to use the term amaurosis fugax to momentarily and temporarily, secondary function testing) is ordered. However, connote blindness in the absence of any to an event or process that interrupts cir- bitemporal field loss respecting the verti- apparent lesion of the eye.1 Today, the culation.1-11 When the effects of an cal meridian warrants neuroradiologic term is used to describe an event of episode remain permanently, they cross investigation even in the presence of tilt- monocular vision loss lasting from sec- the line into the category of cerebrovas- ed disc syndrome. onds to minutes.1-4 cular accident or stroke. • In pregnant women, bi-temporal Amaurosis fugax (AF) almost always visual field loss and headache may signal presents as sudden, painless vision loss, Pathophysiology (rapid degeneration lasting seconds to minutes, without evi- AF and TIA share the common etiol- with hemorrhagic necrosis of the pituitary dence of headache, secondary to an ogy of interrupted blood flow either to gland). Pituitary apoplexy is a potentially embolic event or hemodynamic insuffi- the eye or areas of the brain which sub- life-threatening condition and warrants ciency, frequently leaving some perma- serve vision.4-8 Patients with common prompt referral for an MRI with or with- nent remnant.1-9 AF may forecast carotid artery stenosis may be susceptible out lumbar puncture to rule out subarach- impending retinal hemorrhages, cotton to transient hemodynamic insufficiency noid hemorrhage from this type of tumor. wool spots, central retinal vein occlusion, of the retina as a result of simultaneous anterior ischemic optic neuropathy, reti- reductions in blood supplies from both 1. Ezzat S, Asa SL, Couldwell WT, et al. The prevalence nal artery occlusion, ophthalmic artery the external carotid artery and the inter- of pituitary adenomas: A systematic review. Cancer occlusion or cerebrovascular accident nal carotid artery.2,3 2004;101(3):613-9. 6,10 2. Davis JR, Farrell WE, Clayton RN. Pituitary tumours. (CVA). It is a sign of beginning, TIA may be caused by papilledema, Reproduc 2001;121(3):363-71. impending or worsening vascular dis- epilepsy, hypertension, diabetes, cardiac 3. Faglia G. Epidemiology and pathogenesis of pituitary ease.11 As such, its epidemiology is non- disease, pregnancy, seizures, blood coag- adenomas. Acta Endocrinol (Copenh) 1993;129(Suppl 1):S1-S5. specific and is associated with the sys- ulopathy and hyperviscosity syndromes, 4. Monson JP. The epidemiology of endocrine tumours. temic illnesses that induce it, along with the toxic effects of medications, hyper- Endocr Relat Cancer 2000;7(1):29-36. smoking, hyperlipidemia and age older lipidemia, as well as thrombosis and 5. Kitthaweesin K, Ployprasith C. Ocular manifestations of 1-12 11-20 suprasellar tumors. J Med Assoc Thai 2008;91(5):711-5. than 64 years. emboli. Disorders of clotting, hyper- 6. Bynke H. Pituitary adenomas and their ocular mani- Transient ischemic attack (TIA) may coagulopathy and hyperviscosity, such as festations: Evidence of cases and clinical findings be characterized by monocular or binoc- antiphospholipid antibody syndrome, 1946–1984. Neuroophthalmol 1986; 6:303-11. 7. Foroozan R. Chiasmal syndromes. Curr Opin ular vision loss lasting minutes to hours, should be considered in young people Ophthalmol 2003;14(6):325-31. may induce other noticeable visual phe- experiencing either phenomenon.6,14

48A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 49 NEURO-OPHTHALMIC DISEASE

Spontaneous dissection of the cervical management will vary with ultimate the setting of a normal neuro-oph- internal carotid artery causes territory cause.1-25 Obviously, work must be done thalmic examination.5-7 ischemia and symptoms on the side of in the area of the modifiable risk fac- dissection. Local signs and symptoms tors: stopping smoking, reducing cho- Clinical Pearls include head, facial or neck pain, lesterol, lowering blood pressure, man- • Important clinical questions for Horner’s syndrome, pulsatile tinnitus, aging diabetes and maintaining a patients presenting with the chief com- cranial nerve palsy (III, IV, V and VI), proper weight. The medical evaluation plaint of an episode of sudden painless headache, ischemic stroke in 80–84%, should include a complete blood count vision loss include: transient ischemic attack in 15–16%, with differential and platelets, an ery- – What activities preceded the amaurosis fugax in 3%, ischemic optic throcyte sedimentation rate (ESR), C- episode? neuropathy in 4% and retinal infarct in reactive protein (CRP), lipid panel, – Was it one eye or both? 1%.15 have also been carotid artery evaluation using transcra- – Was vision completely lost dur- reported to induce episodes of transient nial Doppler, prothrombin time, acti- ing the episode? visual interruption via the mechanism of vated partial thromboplastin time, pro- – Was vision blacked out or blurry? intermittent compression.9 tein S, protein C, antiphospholipid – How long did the episode last? Retinal migraine is characterized by antibody testing, antinuclear antibody – When vision returned, did it its vasospastic etiology.3,5-8 Although the and lupus anticoagulant testing, come back suddenly or gradually? International Headache Society diag- echocardiogram and transesophageal – Did the episode leave any per- nostic criteria for retinal migraine echocardiogram.16-19 Older patients, manent loss? requires reversible visual loss, irreversible especially those demonstrating systemic – Has this happened before, and if visual loss may be part of the retinal symptoms suggestive of giant cell so, how many times? migraine spectrum, representing an ocu- arteritis (jaw claudication, pain upon – If the episodes are new, what is lar form infarction.8 palpation of the temporal forehead, their frequency, and is the frequency Light-induced amaurosis fugax is a anorexia, loss of appetite), should changing? manifestation of ocular ischemic syn- undergo ESR and CRP immediately.23 – Did a headache occur after the drome (carotid occlusive syndrome) Ocular management should include episode? occurring when significant, bilateral, detailed, dilated inspection of the poste- • Retinal migraine is classically seen carotid artery disease has developed.4 rior pole to rule out the presence of in women of childbearing age and The frequency of amaurotic episodes emboli and perimetry to determine any includes classic, cluster or complicated seems to be significantly higher in cases visual field loss. Neuroimaging, such as headache with .6 It typically is involving common carotid artery steno- magnetic resonance imaging and mag- characterized by monocular visual phe- sis compared against internal carotid netic resonance angiography, may be nomena lasting less than one hour. artery stenosis and indicates advanced indicated to ascertain a cause. • Acephalic retinal migraine can disease.2 The systemic management for TIA produce variable visual symptoms in Giant cell arteritis (GCA) is a possi- and AF resulting from vascular disease is the absence of headache, further com- ble cause of TIA and AF in the elder- oral anticoagulant therapy. Management plicating the diagnosis. ly.21 In a classic report on the subject, for systemic autoimmune disease is oral • Light-induced AF from ocular examining biopsy-proven GCA in a anti-inflammatory therapy with or with- ischemic syndrome is often an indica- prospective study of 170 patients over a out immune modulation.6 Surgical man- tion that timely carotid surgical inter- 12-year period, amaurosis fugax agement of carotid artery disease can be vention is indicated because of the occurred in 30.6% of patients. This accomplished via percutaneous angio- major risk for stroke. underscores the need to consider GCA plasty with stenting or endarterecto- • Amaurosis fugax is a significant in all patients experiencing transient my.9,24 Patients experiencing AF will symptom with a much higher associa- vision loss. Uncovering GCA as the need consultation from an internist or tion to extracranial CVA than either cause of TIA or AF may save patients cardiologist to determine the underlying Hollenhorst plaque or artery occlusion. from certain catastrophic vision loss cause. Patients experiencing TIA are It warrants immediate investigation. from central retinal artery occlusion best managed by a neurologist. • Recurrent bouts of AF in elderly (CRAO), anterior ischemic optic neu- AF must be differentiated from patients may indicate the presence of ropathy (AION) or cerebrovascular monocular visual loss labeled retinal GCA and impending permanent vision accident.21,22 migraine.5,6 A true retinal migraine is a loss from retinal artery occlusion or diagnosis of exclusion that produces a ischemic optic neuropathy. Management fully reversible monocular visual distur- • AF and TIA are straws that tell us AF and TIA are symptoms of an bance (classic aura vs. other episodic phe- which way the intracranial wind is underlying vasculopathic process.1-8 The nomena) in concert with a headache in blowing.

APRIL 15, 2009 REVIEW OF OPTOMETRY 49A 001_ro0409_handbook 4/2/09 9:42 AM Page 50

1. Friel JP. Amaurosis. In: Friel JP. Dorland’s Illustrated Medical Dictionary (26th ed). Philadelphia, PA: W.B. CRANIAL NERVE III PALSY CN III palsy. Patients may additionally Saunders, 1985, p. 54. have contralateral intention tremor, cere- 2. Hoya K, Morikawa E, Tamura A, et al. Common carotid Signs and Symptoms bellar ataxia or contralateral hemiplegia, artery stenosis and amaurosis fugax. J Stroke Cerebrovasc Dis 2008;17(1):1-4. A patient with acute cranial nerve depending upon the cause and location of 3 3. Hedges TR. Neuro-ophthalmic emergencies: Vascular (CN) III palsy will usually present with a damage to CN III. disorders. In: Yanoff M, Duker JS. Ophthalmology (2nd sudden onset of unilateral ptosis (or rarely, Patients developing acute CN III palsy ed). St Louis, MO: Mosby, 2004, pp. 1401-9. 4. Kaiboriboon K, Piriyawat P, Selhorst JB. Light-induced a bilateral ptosis if the damage occurs to tend to be older; CN III palsy is uncom- 7 amaurosis fugax. Am J Ophthalmol 2001;131(5):674-6. the third nerve nucleus) and ophthalmo- mon in children, though it does occur. 5. Hill DL, Daroff RB, Ducros A, et al. Most cases labeled There is often concurrent diabetes and/or as “retinal migraine” are not migraine. J Neuroophthalmol 3,6,7,11 2007;27(1):3-8. hypertension. Occasionally, there will 6. Coroi M, Bontas E, Visan R, et al. Ocular migraine and be head trauma associated with the devel- antiphospholipid antibodies—where we stand? opment of CN III palsy.12 Oftalmologia 2007;51(3):8-15. 7. Kunkel RS. Migraine aura without headache: benign, but a diagnosis of exclusion. Cleve Clin J Med Pathophysiology 2005;72(6):529-34. The third cranial nerve arises in the 8. Grosberg BM, Solomon S, Lipton RB. Retinal migraine. Curr Pain Headache Rep 2005;9(4):268-71. dorsal mesencephalon with distinct 9. Amick A, Caplan LR. Transient monocular visual loss. paired subnuclei that give rise to fibers Compr Ophthalmol Update 2007;8(2):91-8. Left cranial nerve III palsy. that pass through the brainstem, sub- 10. Dunlap AB, Kosmorsky GS, Kashyap VS. The fate of patients with retinal artery occlusion and Hollenhorst arachnoid space, cavernous sinus and plaque. J Vasc Surg 2007;46(6):1125-9. plegia, frequently accompanied by signif- orbit to ultimately innervate the levator 11. Murray S, Bashir K, Lees KR, et al. Epidemiological icant eye or head pain dependent upon palpebrae superioris, superior rectus, infe- aspects of referral to TIA clinics in Glasgow. Scott Med J 1-4 2007;52(1):4-8. the cause. The patient often complains rior rectus, medial rectus and inferior 12. Bajwa R, Jay WM, Asconapé J. Neuro-ophthalmo- of double vision, though in some cases the oblique muscles. All subnuclei innervate logic manifestations of epilepsy. Semin Ophthalmol diplopia may masked by the ptosis which ipsilateral structures with the exception of 2006;21(4):255-61. 13. Carter JE. Anterior ischemic optic neuropathy and obscures the vision in the affected eye; the superior rectus (innervating the con- stroke with use of PDE-5 inhibitors for erectile dysfunction: however, if the lid is manually elevated, tralateral eye) and the levator palpebrae cause or coincidence? J Neurol Sci 2007;262(1-2):89-97. the patient will experience diplopia. superioris, which has a single subnuclei 14. Suvajac G, Stojanovich L, Milenkovich S. Ocular 3,13 manifestations in antiphospholipid syndrome. Autoimmun Acuity is typically unaffected unless the innervating both eye lid muscles. In Rev 2007;6(6):409-14. provoking lesion occurs in the superior concert with the third cranial nerve 15. Baumgartner RW, Bogousslavsky J. Clinical manifes- orbital fissure causing simultaneous cra- nucleus is the Edinger-Westphal nucleus, tations of carotid dissection. Front Neurol Neurosci 2005;20(1):70-6. nial nerve II involvement. which controls the pupil sphincter and 16. Winterkorn JM, Mack P, Eggenberger E. Transient CN III palsy produces a noncomitant ciliary body muscles. Pupillary fibers trav- visual loss in a 60-year-old man. Surv Ophthalmol exotropic, hypotropic eye position (down el the course with CN III. 2008;53(3):301-5. 17. Hayreh SS, Zimmerman MB, Kimura A, et al. Central and out). There is limitation of elevation, Third nerve palsy results from damage retinal artery occlusion. Retinal survival time. Exp Eye Res depression and adduction. There is an to the anywhere along 2004;78(3):723-36. underaction of the superior, inferior, and its route from the nucleus in the dorsal 18. Coroi M, Bontas E, Defranceschi M, et al. Ocular manifestations of antiphospholipid (Hughes)’ syndrome— medial recti muscles and inferior oblique mesencephalon, its fascicles in the brain- 1-3 minor features? Oftalmologia 2007;51(3):16-22. muscle. The underaction of these mus- stem parenchyma, the nerve root in sub- 19. Schmidt D, Hetzel A, Geibel-Zehender A. Retinal cles may be complete or incomplete.5-7 arachnoid space, the cavernous sinus or arterial occlusion due to embolism of suspected cardiac 3,13 tumors—report on two patients and review of the topic. Total involvement of the levator palpe- the posterior orbit. Damage to the Eur J Med Res 2005;10(7):296-304. brae superioris and all extraocular mus- third nerve nucleus results in an ipsilater- 20. Liberman A, Karussis D, Ben-Hur T, et al. Natural cles subserved by CN III is termed a al third nerve palsy with contralateral course and pathogenesis of transient focal neurologic complete CN III palsy. Patients with superior rectus underaction and bilateral symptoms during pregnancy. Arch Neurol 2008;65(2):218-20. some degree (but not total paralysis) of ptosis. Damage to the third nerve fasci- 21. Hayreh SS, Podhajsky PA, Zimmerman B. Ocular the extraocular muscles are said to have cles emerging from the CN III subnu- manifestations of giant cell arteritis. Am J Ophthalmol an incomplete CN III palsy.3 In any case clear complex and passing through the 1998;125(4):509-20. 22. Nesher G, Berkun Y, Mates M, et al. Risk factors for of CN III palsy, the pupil may be dilated parenchyma of the mesencephalon can cranial ischemic complications in giant cell arteritis. and minimally reactive to light (pupillary result in an ipsilateral third nerve palsy Medicine (Baltimore) 2004;83(2):114-22. involvement), totally reactive and normal with contralateral hemiparesis (Weber’s 23. Biousse V, Trobe JD. Transient monocular visual loss. Am J Ophthalmol 2005;140(4):717-21. (pupillary non-involvement) or may be syndrome), contralateral intention tremor 24. Sadek M, Hynecek RL, Sambol EB, et al. Carotid sluggishly responsive (partial pupillary (Benedikt’s syndrome) or ipsilateral cere- angioplasty and stenting, success relies on appropriate involvement).3,4,7-10 bellar ataxia (Nothnagel’s syndrome). patient selection. J Vasc Surg 2008;47(5):946-51. 25. Goldstein LB, Simel DL. Is this patient having a Various neurological signs may present Vascular infarct, metastatic disease and stroke? JAMA 2005;293(19):2391-402. concomitantly with the development of demyelinization are the common causes

50A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 51 NEURO-OPHTHALMIC DISEASE

of brainstem involvement.7,13 Damage to the third nerve in the cav- regeneration develops, MRI/MRA is Once the CN III fascicles emerge ernous sinus, or required to rule out the presence of a mass from the brainstem, they form the nerve posterior orbit is unlikely to present as an in the subarachnoid space.3 proper and travel through the subarach- isolated palsy due to the confluence of Children younger than 14 years rarely noid space parallel to the posterior com- other structures within these areas. have , and the majority of third municating artery. Damage to the third Cavernous sinus involvement will also nerve palsies in this age group are trau- nerve within the subarachnoid space pro- include possible concurrent pareses of matic or congenital.7 If the patient is duces an isolated third nerve palsy. The cranial nerve IV, VI and V1, as well as an younger than 50 years and has a non- main concern in an isolated CN III palsy ipsilateral Horner’s syndrome. The most pupillary-involved, isolated third nerve occurring within the subarachnoid space common causes of damage in these areas palsy, intracranial angiography is indicat- is compression of the nerve by an include metastatic disease, inflammation, ed, since ischemic vasculopathy is less expanding aneurysm of the posterior herpes zoster, carotid artery aneurysm, likely than aneurysm to occur in this age communicating artery. Additionally pituitary adenoma, pituitary apoplexy and group. If an adult patient of any age pres- aneurysmal compression can occur from sphenoid wing .2,3,7 ents with complete or incomplete isolated the internal carotid, basilar, anterior com- third nerve palsy with pupillary involve- municating or temporal arteries, though Management ment, it should be considered a medical to a lesser extent than from the posterior Management of third nerve palsy in emergency and the patient should under- communicating artery.8,9,14-16 Approxi- the adult depends upon the associated go immediate MRA/MRI or intracranial mately 15% of isolated CN III palsies findings and etiology. In complicated angiography. In these cases, the cause is occurring secondary to damage within third nerve palsies in which other neural likely an aneurysm at the junction of the the subarachnoid area are the result of structures are involved, the patient should internal carotid and posterior communi- aneurysms.11 Vasculopathic infarct, often undergo MRI scanning to ascertain the cating arteries or at the tip of the basilar associated with concurrent diabetes or etiology. The scan should be directed to artery. If the aneurysm ruptures, Tthe hypertension, accounts for 35% of cases the anatomical location as dictated by the patient may die from subarachnoid hem- of isolated CN III palsy.11 associated findings described above.3 orrhage and brainstem herniation Aneursymal compression is marked In cases of isolated, complete third through the foramen magnum. by head or retro-orbital pain and aniso- nerve palsies with no pupillary involve- In cases of CN III palsy caused by coria with ipsilateral pupil dilation as the ment and in which the patient is older subarachnoid aneurysm, immediate neu- than 50 years, the main cause is predom- rosurgical intervention is necessary. inantly ischemic vascular infarct. Giant Common endovascular treatment cell arteritis is also a potential etiology. involves direct clipping of the aneurysm Tumor and aneurysm also can produce or embolization with detachable coils.16-17 isolated lesions without pupillary involve- ment, although this is rare.3 Magnetic res- Clinical Pearls onance imaging (MRI) and magnetic res- • Isolated third nerve palsy resulting Right cranial nerve III palsy. onance angiography (MRA), erythrocyte from ischemic vasculopathy will sponta- sedimentation rate, C-reactive protein, neously resolve and recover over a period expanding aneurysm compresses the blood pressure measurement, complete of three to six months. If the palsy fails pupillomotor fibers within CN III as blood count with differential, blood glu- to resolve in this time, then neuroradio- well as pain-sensitive dura and other cose testing, antinuclear antibody testing logic studies must be undertaken once such structures. Approximately one- and syphilis serology are indicated. Close again to determine the true etiology. third of patients with CN III palsy from pupil observation is required, as pupil • Complete and total CN III palsy in vascular infarct manifest a small degree involvement may be delayed by five to an adult older than age 50 without pupil of of typically less than 1mm. seven days. This is especially true for involvement is rarely ever caused by an In contradistinction, aneurysmal com- patients with incomplete CN III palsy aneurysm. pression typically causes more than 2mm with pupil sparing, because these patients • Patients manifesting an incomplete of anisocoria.11 Additionally, patients are more likely to have an incipient CN III palsy should be suspected of hav- developing CN III palsy from aneurys- aneurysm developing.5 In ischemic vascu- ing a developing aneurysm. mal compression initially may not pres- lar CN III palsy, the pupil will not evolve, • Myasthenia gravis can mimic virtu- ent with anisocoria or pupil involve- aberrant regeneration will not occur and ally any cranial neuropathy, including ment.5,8-10 These patients typically the palsy will spontaneously improve or isolated non-pupillary involved third present initially with an incomplete palsy resolve over the course of three to six nerve palsies. It must remain a possible that evolves and develops pupil dilation months.3,11 If the palsy shows no improve- diagnosis when encountering a third over several days.3,7, 11 ment over six to eight weeks or if aberrant nerve palsy, especially when the course is

APRIL 15, 2009 REVIEW OF OPTOMETRY 51A 001_ro0409_handbook 4/2/09 9:42 AM Page 52

variable or atypical. nerve dysfunction in cases of oculomotor palsy. Jpn J ately preceding development of the CN Ophthalmol 2008;52(1):32-5. • There will always be pain in 12. Takeuchi S, Takasato Y, Masaoka H, et al. Brain IV palsy. The trauma need not be major; aneurysmal compression. In ischemic Nerve 2008;60(5):555-8. relatively minor injuries can precipitate vascular CN III palsies, however, pain is 13. Adams ME, Linn J, Yousry I. Pathology of the ocular CN IV palsy.2,3,12-14 In cases of longstand- motor nerves III, IV, and VI. Neuroimaging Clin N Am frequent but may be absent, and it is typ- 2008;18(2):261-82. ing decompensated CN IV palsy, the ically less severe than with aneurysmal 14. White JB, Layton KF, Cloft HJ. Isolated third nerve inciting trauma may have been many compression. palsy associated with a ruptured anterior communicating years antecedent. artery aneurysm. Neurocrit Care 2007;7(3):260-2. • Consider GCA as a cause of CN 15. Aiba T, Fukuda M. Unilateral oculomotor nerve pare- III palsy in older patients. sis associated with anterior communicating artery Pathophysiology • Ischemic vascular CN III palsy aneurysm rupture—two case reports. Neurol Med Chir The fourth cranial nerve nucleus is (Tokyo) 2003;43(10):484-7. does not progress to develop aberrant 16. Asakura K, Tasaki T, Okada K. A case of unruptured located in the dorsal mesencephalon. regeneration. anterior temporal artery aneurysm showing pupil-sparing Nerve fibers decussate and exit the brain • Anisocoria in ischemic infarction oculomotor palsy. No Shinkei Geka 1986;14(6):777-82. stem dorsally into the subarachnoid 17. Inamasu J, Nakamura Y, Saito R, et al. Early resolu- CN III palsy is nominal, typically less tion of third nerve palsy following endovascular treatment space. The nerve then courses around the than 1mm between the eyes. In con- of a posterior communicating artery aneurysm. J brain to enter the cavernous sinus, supe- tradistinction, the anisocoria from Neuroophthalmol 2002;22(1):12-4. rior orbital fissure and orbit to innervate 18. Ahn JY, Han IB, Yoon PH, et al. Clipping vs. coiling of aneurysmal compression typically posterior communicating artery aneurysms with third the . Damage to exceeds 2mm. nerve palsy. Neurol 2006;66(1):121-3. the fourth nerve nucleus or its fascicles • Pupil-involved CN III palsy in within the brain stem produces a con- adults is one of the few true medical tralateral , along with emergencies seen in eye care. These CRANIAL NERVE IV PALSY the possible associated signs of light-near patients must be sent to the hospital dissociated pupils, retraction nystagmus, immediately for neurosurgical consult. Signs and Symptoms upgaze palsy, Horner’s syndrome and/or A patient with cranial nerve (CN) IV internuclear ophthalmoplegia. Bilateral 1. Satyarthee GD, Mahapatra AK. Unusual neuro-oph- thalmic presentation of anterior communicating artery palsy will typically present with com- fourth nerve palsies are possible as well. aneurysm with third nerve paresis. J Clin Neurosci plaints of vertical diplopia, which worsens The main causes of damage to the fourth 2004;11(7):776-8. if the patient tries to read. There may be nerve in this area are hemorrhage, infarc- 2. Bahmani Kashkouli M, Khalatbari MR, Yahyavi ST, et al. Pituitary apoplexy presenting as acute painful isolated an inability to look down and in. There tion, trauma, hydrocephalus and unilateral third cranial nerve palsy. Arch Iran Med may also be a component of horizontal demyelinization.9,14 2008;11(4):466-8. diplopia as a lateral phoria becomes man- The fourth nerve is especially prone to 3. Yanovitch T, Buckley E. Diagnosis and management of 1-4 third nerve palsy. Curr Opin Ophthalmol 2007;18(5):373-8. ifest due to the vertical dissociation. trauma as it exits the brain stem and 4. Delengocky T, Bui CM. Complete ophthalmoplegia The chin is often tucked downwards courses through the subarachnoid space. with pupillary involvement as an initial clinical presentation (moved into the field of the dysfunction- In contrast to third nerve palsies with an of herpes zoster ophthalmicus. J Am Osteopath Assoc 2008;108(10):615-21. al muscle) as well. The patient may note etiology in subarachnoid space, fourth 5. Takahashi M, Kase M, Suzuki Y, et al. Incomplete ocu- greater diplopia or visual discomfort nerve palsies are rarely the result of lomotor palsy with pupil sparing caused by compression when head tilting toward the side of the aneurysmal compression.The most com- of the oculomotor nerve by a posterior communicating posterior cerebral aneurysm. Jpn J Ophthalmol palsy. Commonly, the patient develops a mon causes of damage to the fourth 2007;51(6):470-3. compensatory head tilt opposite to the nerve in this region are trauma and 6. Capó H, Warren F, Kupersmith MJ. Evolution of oculo- affected superior oblique muscle. ischemic vasculopathy.3 motor nerve palsies. J Clin Neuroophthalmol 1992;12(1):21-5. Visual acuity is unaffected and there is Due to the large number of other neu- 7. Richards BW, Jones FR Jr, Younge BR. Causes and very rarely any concurrent pain. Ocular ral structures that accompany the fourth prognosis in 4,278 cases of paralysis of the oculomotor, motility testing with the alternate cover nerve as it travels through the cavernous trochlear, and abducens cranial nerves. Am J Ophthalmol 1992;113(5):489-96. test will reveal a hyperphoric or hyper- sinus and superior orbital fissure, it is 8. Kasoff I, Kelly DL Jr. Pupillary sparing in oculomotor tropic deviation that will increase in con- unlikely that patients will exhibit isolated palsy from internal carotid aneurysm. Case report. J tralateral gaze, reduce in ipsilateral gaze, fourth nerve palsy from damage within Neurosurg 1975;42(6):713-7. 9. Kissel JT, Burde RM, Klingele TG, et al. Pupil-sparing increase on ipsilateral head tilt and these areas. More likely, there will be a oculomotor palsies with internal carotid-posterior com- decrease on contralateral head tilt. In concomitant palsy of cranial nerves III municating artery aneurysms. Ann Neurol bilateral cranial nerve IV palsy, the patient and VI. Common causes of damage to 1983;13(2):149-54. 10. Saito R, Sugawara T, Mikawa S, et al. Pupil-sparing will manifest a hyperdeviation which the fourth nerve in these areas are herpes oculomotor nerve paresis as an early symptom of unrup- reverses in opposite gaze. The hyperdevi- zoster, inflammation of the cavernous tured internal carotid-posterior communicating artery ation increases on ipsilateral head tilt.5-8 sinus or posterior orbit, meningioma, aneurysms: Three case reports. Neurol Med Chir (Tokyo) 2008;48(7):304-6. Frequently there is concurrent hyper- metastatic disease, pituitary adenoma 11. Akagi T, Miyamoto K, Kashii S, et al. Cause and prog- tension and/or diabetes.9-11 Often, there and carotid cavernous fistula.15 Trauma to nosis of neurologically isolated third, fourth, or sixth cranial will be a history of head trauma immedi- the head or orbit can cause damage to the

52A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 53 NEURO-OPHTHALMIC DISEASE

trochlea with resultant superior oblique management beyond periodic observa- 8. Straumann D, Bockisch CJ, Weber KP. Dynamic aspects of trochlear nerve palsy. Prog Brain Res muscle dysfunction. tion and either occlusion or press-on 2008;171:53-8. 2,3 Trauma and vascular disease are consid- prism therapy is required. In some 9. Park UC, Kim SJ, Hwang JM, et al. Clinical features ered the main causes of acquired CN IV cases, recovery does not occur.2,3 In these and natural history of acquired third, fourth, and sixth cra- 14,15 nial nerve palsy Eye 2008;22(5):691-6. palsy. However, there have been num- cases, permanent prism (ground into the 10. Trigler L, Siatkowski RM, Oster AS, et al. Retinopathy erous reports of other potential causes of spectacle lenses), muscle surgery or botu- in patients with diabetic ophthalmoplegia. Ophthalmol isolated CN IV palsy, including multiple linum injections may be considered.22 2003;110(8):1545-50. 11. Acaroglu G, Akinci A, Zilelioglu O. Retinopathy in sclerosis, polycythema vera, -scratch patients with diabetic ophthalmoplegia. Ophthalmologica 15-21 disease and, rarely, metastatic disease. Clinical Pearls 2008;222(4):225-8. • Cases of true vertical diplopia can 12. Dhaliwal A, West AL, Trobe JD, et al. Third, fourth, and sixth cranial nerve palsies following closed head Management be considered a fourth nerve palsy until injury. J Neuro-ophthalmol 2006;26(1):4-10. A fourth nerve palsy often presents proven otherwise. 13. Ishizaki E, Kurokawa Y. A case of solitary and unilat- suddenly but may additionally result from • If the presenting motility of a eral trochlear nerve palsy due to a blunt head impact. Rinsho Shinkeigaku 2003;43(9):571-3. decompensation of a longstanding or patient is a hyperdeviation in one eye 14. de Camargo GB, Hida WT, Goldchmit M, et al. congenital palsy. To differentiate these that increases on opposite gaze and ipsi- Paralytic strabismus: Review of 24 years at “Santa Casa two types of palsies, old photographs of lateral head tilt, the cause is nearly de São Paulo.” Arq Bras Oftalmol 2007;70(4):585-7. 15. Richards BW, Jones FR Jr, Younge BR. Causes and the patient (such as a drivers license) always CN IV palsy. prognosis in 4,278 cases of paralysis of the oculomotor, should be examined. A patient with a • Myasthenia gravis can mimic CN trochlear, and abducens cranial nerves. Am J Ophthalmol decompensated longstanding palsy will IV palsy and must always be considered. 1992;113(5):489-96. 16. Tsuda H, Ito T, Yoshioka M, et al. Isolated trochlear present with a compensatory head tilt. • Bilateral CN IV palsy localizes nerve palsy in herpes zoster ophthalmicus. Intern Med Further, patients with decompensated damage to the dorsal mesencephalon. 2007;46(8):535-6. longstanding fourth nerve palsies will • In children, nearly all cases of isolat- 17. Mielke C, Alexander MS, Anand N, et al. Isolated bilateral trochlear nerve palsy as the first clinical sign of a have an exaggerated vertical fusional abil- ed fourth nerve palsy are either congeni- metastatic bronchial carcinoma. Am J Ophthalmol ity. Longstanding fourth nerve palsies tal or traumatic. In adults, nearly all iso- 2001;132(4):593-4. typically have a benign course and no fur- lated acquired fourth nerve palsies can be 18. Lavin PJ, Donahue SP, Jacobson DM, et al. Isolated trochlear nerve palsy in patients with multiple sclerosis. ther management is necessary. ascribed to trauma or vascular disease. Neurol 2000;55(2):321-2. In the case of complicated fourth Rarely is tumor or aneurysm a cause.The 19. Jacobson DM, Moster ML, Eggenberger ER, et al. nerve palsies—those that present with majority of fourth nerve palsies follow a Isolated trochlear nerve palsy in patients with multiple sclerosis. Neurol 1999;53(4):877-9. other concurrent neurological dysfunc- benign course. 20. Jones MM, Clement CI, Rowe DB. Isolated trochlear tion—the patient should undergo neuro- • When encountering isolated fourth nerve palsy as a presenting feature of primary poly- radiological studies dictated by the nerve palsy, delay prescribing permanent cythemia rubra vera. Clin Experiment Ophthalmol 2004;32(3):339-40. accompanying signs and symptoms. In prisms for at least three months to allow 21. Müller D, Neubauer BA, Waltz S, et al. the case of isolated fourth nerve palsies for the palsy to recover. Otherwise, Neuroborreliosis and isolated trochlear palsy. Eur J caused by recent trauma, the patient glasses with permanent Paediatr Neurol 1998;2(5):275-6. 22. Bagheri A, Eshaghi M. Botulinum toxin injection of should undergo neuroradiological studies can induce vertical diplopia should the the for the treatment of superior of the head to dismiss the possibility of a palsy recover. oblique muscle palsy. J AAPOS 2006;10(5):385-8. concurrent . If 1. Staubach F, Lagrèze WA. Oculomotor, trochlear, and the fourth nerve palsy is not associated palsies. Ophthalmologe 2007;104(8): with recent trauma, a history of past trau- 733-46. CRANIAL NERVE VI PALSY ma should be investigated. If the fourth 2. Akagi T, Miyamoto K, Kashii S, et al. Cause and prog- nosis of neurologically isolated third, fourth, or sixth cra- nerve palsy is the result of previous trau- nial nerve dysfunction in cases of oculomotor palsy. Jpn Signs and Symptoms ma and has recently decompensated, the J Ophthalmol 2008;52(1):32-5. A patient with isolated, unilateral, diplopia can be managed by the place- 3. Hoya K, Kirino T. Traumatic trochlear nerve palsy fol- acute onset cranial nerve (CN) VI palsy lowing minor occipital impact—four case reports. Neurol ment of vertical prisms in spectacles. If Med Chir (Tokyo) 2000;40(7):358-60. will present with horizontal uncrossed the patient is elderly and has a fourth 4. von Noorden GK, Murray E, Wong SY. Superior diplopia that worsens at distance in nerve palsy of recent origin, an ischemic oblique paralysis. A review of 270 cases. Arch either right or left gaze depending upon Ophthalmol 1986;104(12):1771-6. vascular evaluation should be undertaken 5. Baumeister E. Contribution to the diagnosis of the involved eye.The patient will have an to determine whether he or she has dia- trochlear paresis (first description of Bielschowsky head- abduction deficit in the involved eye and betes and hypertension. Giant cell arteri- tilt test). Strabis 2003;11(2):129-30. either an non-comitant esophoric or 6. Simonsz HJ, Crone RA, van der Meer J, et al. 1,2 tis should also be considered and appro- Bielschowsky head-tilt test—I. Ocular counterrolling and esotropic posture. If the palsy is isolat- priate history and testing should then Bielschowsky head-tilt test in 23 cases of superior ed, there will be neither visual acuity nor occur. If the palsy is caused by vascular oblique palsy. Vision Res 1985;25(12):1977-82. visual field loss. There may be some 7. Gräf M, Krzizok T, Kaufmann H. Head-tilt test in uni- infarct, then it will spontaneously resolve lateral and symmetric bilateral acquired trochlear nerve degree of head or retro-orbital pain pres- over three to six months and no further palsy. Klin Monatsbl Augenheilkd 2005;222(2):142-9. ent, dependent upon the cause.

APRIL 15, 2009 REVIEW OF OPTOMETRY 53A 001_ro0409_handbook 4/2/09 9:42 AM Page 54

There are three distinct demographic noid space, ascends the clivus and enters patient profile and palsy. In one large groups that develop CN VI palsy. Most the cavernous sinus. Within the sub- population-based study, the four most patients developing acute CN VI palsy arachnoid space, the sixth nerve may be common causes were idiopathic, hyper- are older. This group often has a concur- stretched against the clivus if the brain tension alone, coexistent diabetes and rent history of hypertension and/or dia- stem herniates through the foramen hypertension and trauma.6 betes.3-5 The peak incidence occurs in the magnum due to increased intracranial Detailed presenting and medical his- seventh decade of life.6 Children are also pressure.This may induce a bilateral sixth tory must be obtained as well as a neuro- prone to develop CN VI palsy.The cause nerve palsy (which is often intermittent) logic examination upon presentation. may range from benign, such as viral ill- and papilledema.13 The sixth nerve pass- Each case of CN VI palsy should be ness or trauma, to malignant.7-11 The es over the petrous apex of the temporal classified as traumatic or non-traumatic. third group consists of adults aged 20–50 bone; damage here can result in a sixth Non-traumatic cases should be subdi- years. This group is more likely to have nerve palsy, facial pain, and hearing loss. vided as neurologically isolated or non- neurologically complicated CN VI This is the result of inflammation of the neurologically isolated.6 Additionally, palsies involving other cranial nerves.12,13 temporal bone (Gradenigo’s syndrome) patients should be ascribed to one of In contrast to older adults, vascular dis- or nasopharyngeal carcinoma.16,21 Within three groups: children, young adults, and ease such as diabetes and hypertension the cavernous sinus, the sixth nerve is older adults.6 are uncommon in this group, which typ- joined by the oculosympathetic nerves, as A non-neurologically isolated sixth ically exhibits more serious conditions well as CN III, IV and VI. Damage here nerve palsy involving any of the above- such as central (CNS) mentioned neurological signs indicates mass lesions and multiple sclerosis.13-15 the need for an MRI of the suspect area Because various cancers have been as well as a cerebrospinal fluid analysis. associated with CN VI palsy, patients Non-neurologically isolated CN VI may present with a pre-existing history of palsies are commonly caused by cere- malignant disease. However, CN VI palsy brovascular accidents involving the , may be the premonitory sign of cancer in aneurysm (typically within the cav- some patients. Carcinoma in particular ernous sinus) or .6 While neu- has been associated with the development rologically complicated CN VI palsy has of CN VI palsy, either through direct a high likelihood of a serious cause such Cranial nerve VI palsy with resultant abduction invasion from the nasopharnyx or metas- deficit. as neoplasm, isolated CN VI palsy actu- tasis from the prostate or other sites.16-21 ally has a very low risk (2% in one series) Other less common associations with CN will yield a and Horner’s of being caused by a neoplasm.6 VI palsy include herpes zoster, temporal syndrome, as well as possibly concurrent In children, sixth nerve palsy can arteritis, Lyme disease, sarcoidosis, pitu- CN III and IV palsy.19,20,29 The etiology occur from a presumed viral cause and itary tumor, aneurysm, inflammation and may be aneurysm, meningioma, pituitary has an excellent prognosis.9,10 However, ophthalmoplegic migraine.22-28 adenoma, inflammation or fistula.30-33 nearly one-half of all CN VI palsies in The sixth nerve is also vulnerable to children result from neoplastic disease, Pathophysiology ischemic infarct from diabetes and notably pontine glioma.8,11 Thus, neuro- CN VI arises in the pons in close asso- hypertension; this remains a prime cause logic evaluation and consultation is ciation with the and parame- of isolated sixth nerve palsy. urgent in this group, and the cause of the dian pontine reticular formation (PPRF). Although CN VI can be affected in palsy should not be presumed benign.11 Because of this arrangement, damage to many areas through its course from the In younger adults, CN VI palsy is the sixth nerve within the brain stem can pons to the orbit, a significant number of likely to be caused by serious underlying produce a sixth nerve palsy along with a cases will have no conclusive etiology, disease. In this group, CNS mass lesions facial nerve palsy or internuclear oph- despite extensive medical evaluation.2-4,6,13 and multiple sclerosis account for 33% thalmoplegia. Associated findings may As many as one-third of CN VI palsies and 24% of CN VI palsies, respectively. also include leg paralysis with sixth nerve will remain idiopathic.6 13 Idiopathic CN VI palsies account for palsy (Raymond’s syndrome) or leg 13% of cases and vascular disease only paralysis, facial paralysis and sixth nerve Management 4%.13 It should be noted that CN VI palsy (Millard-Gubler syndrome). These The most important consideration in palsy caused by CNS mass lesions in additional findings identify the location the management of patients with acute young adults involve other cranial neu- of damage as the pons, in which ischemic onset CN VI palsy involves identifying ropathies and are not isolated. Thus, infarct, tumor and demyelinization are the causative factor efficiently and cost- neuroimaging is highly recommended in the common causes.3,4 effectively. Doing so involves under- this group. CN VI travels through the subarach- standing common causes for each In adults older than 50 years with an

54A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 55 NEURO-OPHTHALMIC DISEASE

isolated sixth nerve palsy, an evaluation and lateral rectus underaction can be said cle palsy, facial numbness and ataxia as the initial mani- festation of multiple sclerosis. J Natl Med Assoc for ischemic vascular diseases such as only to have an abduction deficit. A neg- 2008;100(5):572-4. diabetes and hypertension should be ative forced duction test ascribes the 16. Marchese-Ragona R, Maria Ferraro S, Marioni G, et undertaken, since these are the most motility to CN VI palsy. al. Abducent nerve paralysis: first clinical sign of clivus 2-6 metastasis from tonsillar carcinoma. Acta Otolaryngol likely causes. If the patient is older • There is a very low risk of acute iso- 2008;128(6):713-6. than 60 years, an erythrocyte sedimenta- lated CN VI palsy being caused by a 17. Malloy KA. Prostate cancer metastasis to clivus tion rate (ESR) should be ordered to rule neoplasm in an older adult. causing cranial nerve VI palsy. Optom 2007;78(2):55-62. 18. O’Boyle JE, Gardner TA, Oliva A, et al. Sixth nerve out giant cell arteritis. In cases of isolat- • Acute CN VI palsies in children are palsy as the initial presenting sign of metastatic prostate ed CN VI palsy in older adults with a often harbingers of serious disease such cancer. A case report and review of the literature. J Clin history of diabetes or hypertension, neu- as cancer, and they must be promptly Neuroophthalmol 1992;12(3):149-53. 19. Hirao M, Oku H, Sugasawa J, et al. Three cases of roimaging and other extensive evalua- investigated. abducens nerve palsy accompanied by Horner syndrome tion can be deferred, unless the palsy • Non-neurologically isolated CN VI Nippon Ganka Gakkai Zasshi 2006;110(7):520-4. progresses, fails to improve over three palsies are often associated with CNS 20. Tsuda H, Ishikawa H, Asayama K, et al. Abducens nerve palsy and Horner syndrome due to metastatic tumor months, or other neurologic complica- mass lesions and should be promptly in the cavernous sinus. Intern Med 2005;44(6):644-6. tions develop. Ischemic vascular palsies evaluated. 21. Ilhan O, Sener EC, Ozyar E. Outcome of abducens typically progress over several days, but • Acute CN VI palsy in a young adult nerve paralysis in patients with nasopharyngeal carcino- ma. Eur J Ophthalmol 2002;12(1):55-9. progression over two weeks warrants is not commonly caused by microvascu- 22. Arai M, Katsumata R. Temporal arteritis presenting 6 neurioimaging. lar infarct but by more serious disease with headache and abducens nerve palsy. Report of a Spontaneous recovery of CN VI palsy such as multiple sclerosis and CNS mass case. Rinsho Shinkeigaku 2007;47(7):444-6. 23. Berlit P. Isolated and combined pareses of cranial is common, especially if the etiology is lesions; therefore, it should be promptly nerves III, IV and VI. A retrospective study of 412 patients. idiopathic, traumatic or microvascu- investigated. J Neurol Sci 1991;103(1):10-5. lar.3,4,6,13,34 Resolution of CN VI palsy is 24. Kim SH, Lee KC, Kim SH. Cranial nerve palsies 1. Goodwin D. Differential diagnosis and management of accompanying pituitary tumour. J Clin Neurosci typically complete by three to six acquired sixth cranial nerve palsy. Optom 2006;77(11): 2007;14(12):1158-62. months, although some cases may take 534-9. 25. Nagasawa H, Iseki C, Wada M, et al. Abducens longer to resolve. CN VI palsies associ- 2. Staubach F, Lagrèze WA. Oculomotor, trochlear, and nerve palsy as the first manifestation of cavernous sinus abducens nerve palsies. Ophthalmologe 2007;104(8): sarcoidosis. Rinsho Shinkeigaku 2005;45(1):38-40. ated with CNS mass lesions tend to have 733-46. 26. Iwao K, Kobayashi H, Okinami S. Case of herpes a worse prognosis for spontaneous 3. Richards BW, Jones FR Jr, Younge BR. Causes and zoster ophthalmicus with abducent palsy: the cause and recovery.6,13 In cases where complete prognosis in 4,278 cases of paralysis of the oculomotor, magnetic resonance imaging findings. Nippon Ganka trochlear, and abducens cranial nerves. Am J Ophthalmol Gakkai Zasshi 2006;110(3):193-8. recovery does not occur, Fresnel prism 1992;113(5):489-96. 27. Kindstrand E. Lyme borreliosis and cranial neuropa- correction may alleviate diplopia and 4. Rush JA, Younge BR. Paralysis of cranial nerves III, IV, thy. J Neurol 1995;242(10):658-63. visual discomfort. More aggressive ther- and VI. Cause and prognosis in 1,000 cases. Arch 28. Vasconcelos LP, Stancioli FG, Leal JC, et al. Ophthalmol 1981;99(1):76-9. Ophthalmoplegic migraine: A case with recurrent palsy of apy in non-remitting cases includes stra- 5. Acaroglu G, Akinci A, Zilelioglu O. Retinopathy in the abducens nerve. Headache 2008;48(6):961-4. bismus surgery or medial rectus injection patients with diabetic ophthalmoplegia. Ophthalmologica 29. Tsuda H, Ishikawa H, Kishiro M, et al. Abducens nerve with botulinum toxin (Botox).35-37 2008;222(4):225-8. palsy and postganglionic Horner syndrome with or without 6. Patel SV, Mutyala S, Leske DA, et al. Incidence, asso- severe headache. Intern Med 2006;45(14):851-5. ciations, and evaluation of sixth nerve palsy using a pop- 30. Kupersmith MJ, Stiebel-Kalish H, Huna-Baron R, et Clinical Pearls ulation-based method. Ophthalmol 2004;111(2):369-75. al. Cavernous carotid aneurysms rarely cause subarach- • The etiology of isolated CN VI 7. Janssen K, Wojciechowski M, Poot S, et al. Isolated noid hemorrhage or major neurologic morbidity. J Stroke abducens nerve palsy after closed head trauma: a pedi- Cerebrovasc Dis 2002;11(1):9-14. palsy in the adult is undetermined in a atric case report. Pediatr Emerg Care 2008;24(9):621-3. 31. Wu HC, Ro LS, Chen CJ, et al. Isolated ocular motor significant number of cases, despite full 8. Broniscer A, Laningham FH, Sanders RP, et al. Young nerve palsy in dural carotid-cavernous sinus fistula. Eur J diagnostic evaluation. age may predict a better outcome for children with diffuse Neurol 2006;13(11):1221-5. pontine glioma. Cancer 2008 1;113(3):566-72. 32. Lee KY, Kim SM, Kim DI. Isolated bilateral abducens • Vasculogenic CN VI palsies can be 9. Cohen HA, Nussinovitch M, Ashkenazi A, et al. Benign nerve palsy due to carotid cavernous dural arteriovenous expected to progress over several days, abducens nerve palsy of childhood. Pediatr Neurol fistula. Yonsei Med J 1998;39(3):283-6. but they will not worsen over two or 1993;9(5):394-5. 33. Ogawa G, Tanabe H, Kanzaki M, et al. Two cases of 10. Vallée L, Guilbert F, Lemaitre JF, et al. Benign paraly- idiopathic carotid-cavernous fistula with headache and more weeks. Such a clinical course sug- sis of the 6th cranial nerve in children. Ann Pediatr (Paris) ophthalmoplegia. Rinsho Shinkeigaku 2007;47(8):516-8. gests alternate etiologies. 1990;37(5):303-5. 34. Holmes JM, Droste PJ, Beck RW. The natural histo- • Myasthenia gravis may mimic a 11. Lee MS, Galetta SL, Volpe NJ, et al. Sixth nerve ry of acute traumatic sixth nerve palsy or paresis. J palsies in children. Pediatr Neurol 1999;20(1):49-52. AAPOS 1998;2(5):265-8. sixth nerve palsy and should always be 12. Brinar VV, Habek M, Ozretiç D, et al. Isolated non- 35. Kao LY, Chao AN. Subtenon injection of botulinum considered in the differential diagnosis, traumatic abducens nerve palsy. Acta Neurol Belg toxin for treatment of traumatic sixth nerve palsy. J Pediatr especially if the palsy takes on a variable 2007;107(4):126-30. Ophthalmol Strabis 2003;40(1):27-30. 13. Peters GB 3rd, Bakri SJ, Krohel GB. Cause and 36. Holmes JM, Leske DA, Christiansen SP. Initial treat- course with exacerbations and remis- prognosis of nontraumatic sixth nerve palsies in young ment outcomes in chronic sixth nerve palsy. J AAPOS sions. However, routine diagnostic test- adults. Ophthalmol 2002;109(10):1925-8. 2001;5(6):370-6. ing is not indicated unless the patient’s 14. Barr D, Kupersmith MJ, Turbin R, et al. Isolated sixth 37. Gómez De Liaño Sánchez P , Villarejo Díaz-Maroto I, nerve palsy: an uncommon presenting sign of multiple Gómez De Liaño Sánchez R, et al. Treatment of sixth history suggests myasthenia gravis. sclerosis. J Neurol 2000;247(9):701-4. nerve palsy of traumatic or tumor etiology using botulinum • A patient with horizontal diplopia 15. Mitchell JP, Beer J, Yancy A, et al. Lateral rectus mus- toxin. Arch Soc Esp Oftalmol 2000;75(7):471-6.

APRIL 15, 2009 REVIEW OF OPTOMETRY 55A 001_ro0409_handbook 4/2/09 9:42 AM Page 56

OCULOSYSTEMIC DISEASE

MYASTHENIA GRAVIS gia and slurred speech, the presence of reserved for immunocompetent fluctuating dysphonia (changing of the patients with generalized MG who Signs and Symptoms voice tone) is an under-recognized lack muscle AChR binding, AChR Myasthenia gravis (MG) takes its sign.3 “Dropped head sign” or weakness modulating or MuSK antibodies at meaning from the Greek words myo, in the neck muscles creating an inabil- presentation and again at a follow-up meaning muscle, and asthenia, mean- ity to raise the head has also been rec- 12 months later.14 ing weakness.1 The condition is char- ognized as a potential sign of impend- The predilection of myasthenia to acterized as a chronic autoimmune ing MG.9 Myasthenic crisis is the attack ocular muscles may be related to disease of the neuromuscular junction catastrophic failure of the skeletal mus- differences between limb muscle and which leads to varying degrees of cles involved in respiration.10 Patients extraocular muscle physiology, func- weakness and fatigability in the skele- in myasthenic crisis develop acute res- tion or antigenicity.15 In simpler terms, tal muscles.2,3 It affects men and piratory failure and require prompt air- the autoantibodies involved in the women equally, though mostly older way protection in the form of ventila- pathophysiology, for reasons that men and women in their second or tion support.12 remain unclear, prefer the receptors of third decade.3,4 It is not known to be the eye muscles to the skeletal muscles genetically transmitted.3-5 Prevalence Pathophysiology of the body.15 rates for MG approach 1 in 5,000 MG results from an antibody- MG has a well-established associa- individuals.6 The disease may affect mediated, T-cell–dependent immuno- tion with thymus gland pathology and any muscle of the body, including the logic attack on the endplate region of the paraneoplastic syndrome thymo- muscles of the eye. MG may involve the postsynaptic membrane.6 As the ma.13 Thymoma (tumorous infiltration just the muscles of the body without receptors which receive the neuro- of the gland by nonmalignant or affecting the muscles of the eye (gen- transmitter acetylcholine become malignant cells) is found in approxi- eralized myasthenia) or just the mus- degraded, the signal intended to mately 10–15% of patients with myas- cles of the eye without affecting the invoke a muscle movement cannot be thenia gravis.15,16 muscles of the body (ocular myasthe- propagated or maintained, and acetyl- nia).2-8 Some of the classic systemic choline is blocked from reaching the Management symptoms of the disorder include dif- post-synaptic receptors.13 Subsequently, There are four easy clinical tests for ficulty in swallowing () and an enzyme, acetylcholinesterase, MG that can be performed in the slurred speech.2-7 Ocular signs and degrades acetylcholine and the com- office. In the sleep test, the patient is symptoms include intermittent pupil ponent parts are sequestered into the asked to rest with eyes closed for 20 sparing and diplop- presynaptic membrane to formulate minutes. As the acetylcholine builds ia, ptosis of the eyelid, and the pathog- new acetylcholine for the next action up in the presynaptic membranes, pre- nomonic Cogan’s lid twitch (over- potential. This leads to an inability to existing weaknesses will improve for a shooting of the affected eyelid on move muscles, rapid fatiguing and loss short time. In another test, the patient upgaze with a final ptotic resting posi- of stamina.13 is asked to look up (for ocular MG) or tion after prolonged fixation in down A subset of myasthenia gravis to keep the arms up (for general MG). gaze).2-9 patients are seronegative for anti- As patients fatigue, they become Generalized myasthenia gravis will acetylcholine receptor (anti-AChR) unable to continue and the eyelid or develop in more than 50% of patients antibodies.12 They are referred to as arms will drift down. Additionally for presenting with , typi- seronegative myasthenics.12 These ocular MG, the patient can be asked to cally within two years.2,7 The conversion patients are instead seropositive for squeeze eyes closed, or, for systemic rate to the generalized form is as high as antibodies against the muscle-specific MG, to squeeze the examiner’s finger. 90% within three years of the onset of kinase (anti-MuSK-positive).12 Just If they lack strength or they fatigue ocular symptoms.2,7,10 If MG affects only because an individual is seronegative quickly, it becomes apparent that MG the eye for four years, it rarely will after one test does not mean they will may be involved. For patients with progress to systemic involvement. remain so.12 In one study, 15.2% of ptosis or ophthalmoplegia, the ice- Late-onset MG is a phenomenon of patients initially determined to be pack test can be employed. In this sit- elderly men that is often misdiag- seronegative became seropositive 12 uation, a bag of crushed ice covered in nosed.3 While the involvement of months later, yielding an ultimate a towel is placed over the affected eye, oropharyngeal musculature has been seronegativity rate of 8.2%.14 The clas- with eyelid closed, for two minutes. well described as symptoms of dyspha- sification of seronegative MG is Lowering the temperature slows the

56A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 57 OCULOSYSTEMIC DISEASE

action of acetylcholinesterase, allowing ods lasting at least two years in approx- atypical course of myasthenia gravis. Proc West 19 Pharmacol Soc 2007;50:140-2. acetylcholine a longer duration in the imately 70% of patients. Thym- 3. Montero-Odasso M. Dysphonia as first symptom of synaptic cleft and a greater opportuni- ectomy may be required in selected late-onset myasthenia gravis. J Gen Intern Med ty to interact with post-synaptic recep- cases.20 Age, gender, onset of symp- 2006;21(6):C4-6. 4. Ferrero S, Esposito F, Biamonti M, et al. Myasthenia tors with a subsequent improvement in toms, the duration of the disease, the gravis during pregnancy. Expert Rev Neurother function. response to medicinal preparations and 2008;8(6):979-88. The abovementioned in-office tests the presence of thymoma help to 5. Ortiz S, Borchert M. Long-term outcomes of pedi- atric ocular myasthenia gravis. Ophthalmol 2008; greatly increase the index of suspicion determine whether thymectomy is 115(7):1245-1248. 21 for MG. Definitive testing is necessary appropriate. Owing to improved 6. Juel VC, Massey JM. Myasthenia gravis. Orphanet J to make a conclusive diagnosis. This diagnostic testing and immunothera- Rare Dis 2007;2(1):44. 7. Kupersmith MJ, Latkany R, Homel P. Development involves pharmacologic testing with py, the prognosis for MG is favorable of generalized disease at 2 years in patients with ocular edrophonium chloride (Tensilon™, with less than 5% mortality and a myasthenia gravis. Arch Neurol 2003;60(2):243-8. ICN, Costa Mesa, CA) that elicits nearly normal life expectancy.6 8. Kusner LL, Puwanant A, Kaminski HJ. Ocular myas- thenia: diagnosis, treatment, and pathogenesis. unequivocal improvement in strength Neurologist 2006;12(5):231-9. and function, electrophysiological test- Clinical Pearls 9. Kusuhara T, Nakajima M, Imamura A. Ocular myas- ing with repetitive nerve stimulation • Myasthenia gravis never affects the thenia gravis associated with euthyroid ophthalmopa- thy. Muscle Nerve 2003;28(6):764-6. and/or single-fiber electromyography pupil. If there is ptosis and ophthalmo- 10. Monsul NT, Patwa HS, Knorr AM, et al. The effect (SFEMG) that demonstrates a pri- plegia, and the pupil is affected, MG is of prednisone on the progression from ocular to gener- mary postsynaptic neuromuscular junc- not the cause. alized myasthenia gravis. J Neurol Sci 2004;217(2): 131-3. tional disorder and serologic assay of • Eaton-Lambert myasthenic syn- 11. Yaguchi H, Takei A, Honma S, et al. Dropped head acetylcholine receptor (AChR) or mus- drome resembles late-onset MG; how- sign as the only symptom of myasthenia gravis. Intern cle-specific tyrosine kinase (MuSK) ever, its pathophysiology occurs in the Med 2007;46(11):743-5. 5,12 12. Szczeklik W, Jankowski M, Wegrzyn W, et al. antibodies. presynaptic endplate, not the post Acute in patients with Guillain-Barré Once MG has been confirmed, addi- synaptic. Although it produces systemic syndrome and myasthenic crisis treated with plasma- tional laboratory work should include a signs similar to those of MG, Eaton- pheresis in the intensive care unit. Pol Arch Med Wewn 2008;118(4):239-42. computed tomography scan (CT) of the Lambert patients do not fatigue upon 13. Cole RN, Reddel SW, Gervásio OL, et al. Anti- chest, antinuclear antibody testing working, rarely exhibit eye signs and MuSK patient antibodies disrupt the mouse neuromus- (ANA), a rheumatoid factor test (RF) have a pathology linked to paraneoplas- cular junction. Ann Neurol 2008;63(6):782-9. 14. Chan KH, Lachance DH, Harper CM, et al. and a thyroid panel (T3, T4, TSH), tic (small-cell lung carcinoma and oth- Frequency of seronegativity in adult-acquired generalized since it has been associated with other ers) or autoimmune systemic disease, myasthenia gravis. Muscle Nerve 2007;36(5):651-8. autoimmune diseases.17 making this element an essential com- 15. Tormoehlen LM, Pascuzzi RM. Thymoma, myas- thenia gravis, and other paraneoplastic syndromes Treatment must be individualized ponent of the laboratory work in suspi- Hematol Oncol Clin North Am 2008;22(3):509-26. for each patient, and may include cious cases. 16. Lee BW, Ihm SH, Shin HS, et al. Malignant thymo- inhibitors (Mestinon™, • MG becomes unpredictable in ma associated with myasthenia gravis, Graves’ dis- ease, and SIADH. Intern Med 2008;47(11):1009-12. pyridostigmine, Valeant, Aliso Viejo, pregnant women, with life-threatening 17. Burden G, Bryant SA. Myasthenia gravis. In: CA) and immune modulation with sequelae possible. These patients Burden G, Bryant SA. Laboratory and Radiologic Tests corticosteroids, azathioprine, cyclo- require frequent and regular progress for Primary Eye Care. Boston: Buterworth-Heinemann, 6,18 1997, p. 30. sporine and mycophenolate mofetil. evaluations. 18. Barton JJ, Fouladvand M. Ocular aspects of myas- Rapid, temporary improvement may • The ice-pack test works exception- thenia gravis. Semin Neurol 2000;20(1):7-20. be achieved for myasthenic crises and ally well with ptosis as the presenting 19. Kupersmith MJ, Ying G. Ocular motor dysfunction and ptosis in ocular myasthenia gravis: Effects of treat- episodic exacerbations with either weakness, but it is less effective and ment. Br J Ophthalmol 2005; 89(10):1330-4. steroids, plasma exchange (PEX) or diagnostic when ophthalmoparesis is 20. Mahadeva B, Phillips LH 2nd, Juel VC. intravenous immunoglobulin (IVIg).6 the presenting sign. Autoimmune disorders of neuromuscular transmission. Semin Neurol 2008;28(2):212-27. One report demonstrated that pred- • The late great Dr. Larry Gray used 21. Cardone A, Congedo E, Aceto P, et al. nisone significantly lowered the con- to remind us of the testing for MG by Perioperative evaluation of myasthenia gravis. Ann Ital version rate from pure ocular MG to saying, “Sleep ’em, tease ’em, squeeze Chir 2007;78(5):359-65. systemic MG.7 The benefit of 50–60 ’em and freeze ’em.” mg of daily prednisone followed by MULTIPLE SCLEROSIS tapered doses to 10mg or less has also 1. Friel JP. Myasthenia. In: Friel JP. Dorland’s Illustrated demonstrated stabilizing/resolving Medical Dictionary (26th ed). Philadelphia, PA: W.B. Signs and Symptoms Saunders, 1985, p. 856. power for ptosis and diplopia for peri- 2. Labana SS, Qureshi S, Nandakumar T, et al. An Multiple sclerosis (MS) is the most

APRIL 15, 2009 REVIEW OF OPTOMETRY 57A 001_ro0409_handbook 4/2/09 9:42 AM Page 58

common cause of immunologic inflam- Romberg’s sign is a disequilibrium precisely certain of the etiology of MS. mation that initiates the process of associated with cerebellar dysfunction; The disease seems to develop in demyelination, the loss of insulating it causes patients to be unable to main- patients who demonstrate genetic sus- ceptibility, although there are likely sev- eral environmental triggers that play a role in its pathogenesis. Based upon animal models of experimental autoim- mune encephalomyelitis, MS appears to involve autoantigens within the CNS that recruit microglial cells and macro- phages; in turn, these cells activate cytokines (e.g., interferon-gamma and tumor necrosis factor alpha), comple- ment and other immunomodulatory regulators to spur an inflammatory reaction.2 This response specifically tar- gets oligodendrocytes and results in myelin disruption. When the myelin sheath becomes damaged, saltatory This MS patient had a history of optic neuritis in his right eye several years before being diagnosed. nerve conduction is disturbed, resulting in motor impairment. There is also evi- myelin sheath about the body’s nerve tain balance when their eyes are closed.5 dence that a smaller subset of MS axons.1,2 MS affects approximately From an ophthalmic perspective, the patients may have a primary disorder 400,000 Americans and nearly 2 million most frequently encountered ocular within the oligodendrocytes that is people worldwide.2 The classic MS manifestation of MS is optic neuritis reminiscent of virus or toxin-induced patient is a white female in her child- (ON). ON is often the initial present- demyelination.11 bearing years; women between the ages ing sign of MS as well.6-8 Internuclear The characteristic pathology of MS of 20 and 40 have a twofold greater inci- ophthalmoplegia (INO) has a well doc- involves multicentric, multiphasic CNS dence than men, and white individuals umented association with MS. In fact, a inflammation and demyelination.2 (particularly those of northern Euro- higher percentage of young female There is a predilection for specific areas pean descent) are especially vulnerable.2 patients experiencing INO eventually of the nervous system including the MS tends to present insidiously and develop MS than those who have suf- optic nerve and periventricular white produces a wide variety of neurological fered an episode of optic neuritis.9,10 matter of the , brain stem, complaints, but the most common ini- Other ocular manifestations associated basal ganglia and spinal cord. On aver- tial symptoms appear to be weakness in with MS include acquired pendular age, patients experience clinical relapses one or more limbs, parasthesias, optic nystagmus, central vestibular nystag- every one to two years during the so- neuritis (demyelinating optic neuropa- mus (i.e., downbeat and upbeat), peri- called relapsing-remitting phase of the thy), diplopia and vertigo.2 Patients odic alternating nystagmus, supranu- disease, although studies using serial may also experience classic dysfunc- clear gaze palsies (i.e., dorsal midbrain magnetic resonance imaging (MRI) tions associated with demyelinating syndrome) and isolated ocular motor suggest that inflammatory lesions are disease, including Uhthoff ’s phenome- abnormalities (i.e., abducens palsy).9 practically continuous throughout this non, L’Hermitte’s phenomenon and Pars planitis also demonstrates a rela- period.12 In later stages of MS, active Romberg’s sign. Uhthoff ’s phenome- tively high association with MS.10 inflammation appears to diminish, non is characterized by impairment of although disability often continues to vision with increased body temperature. Pathophysiology advance, suggestive of a more chronic, It is often encountered when taking a MS is defined by recurrent bouts of degenerative process.12,13 Speculation hot shower or during vigorous exercise.3 central nervous system (CNS) inflam- exists that consecutive tissue injury in L’hermitte’s phenomenon is noted as a mation that results in damage to both MS ultimately exceeds a critical thresh- radiating neck pain (sometimes the myelin sheath surrounding axons old beyond which the nervous system described as an electric shock wave) and the axons themselves.1-10 As with can no longer compensate. At this point upon flexure of the cervical vertebrae.4 most autoimmune disorders, no one is the disease becomes primarily degener-

58A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 59 OCULOSYSTEMIC DISEASE

ative in nature and is referred to as sec- two or more MRI lesions consistent tonic spasms.21 ondary progressive MS.2 with MS plus positive CSF finding or Ongoing disease-modifying therapy second clinical attack; consists primarily of immunomodula- Management • One attack with objective clinical tory agents. The major drugs used in Four decades ago, Schumacher and evidence of at least two lesions plus dis- the United States include interferon associates suggested that the core diag- semination in time on MRI or second beta-1b (Betaseron® subcutaneous; nosis of MS involved CNS lesions dis- clinical attack; Schering, Berlin) and interferon beta- seminated in space and time, as well as • One attack with objective clinical 1a (Avonex® intramuscular; Biogen, the elimination of alternative diag- evidence of one lesion, plus dissemina- Cambridge, MA; Rebif® subcutaneous; noses.14 Despite the numerous proce- tion in space shown on MRI or two or Serono, Geneva). Also widely used is dures that have been added to our diag- more MRI lesions consistent with MS glatiramer acetate (Copaxone® subcu- nostic armamentarium since that time, plus positive CSF finding and dissemi- taneous; Teva; Petach Tikva, Israel). In there exists today no single, absolute nation in time shown on MRI or sec- randomized, placebo-controlled trials, pathognomonic criterion for MS. The ond clinical attack; all of these medications were shown to diagnosis ultimately must be a clinical • Insidious neurologic progression decrease the rate of clinical relapses by decision, based upon the presenting suggestive of MS plus one year of dis- about 30–40%, and they also reduced signs and symptoms, as well as the sup- ease progression determined retrospec- the number of new lesions appearing on porting laboratory and radiographic tively or prospectively and two of the magnetic resonance imaging.22-25 findings. following: positive brain MRI result Mitoxantrone (Novantrone® intra- Serologic testing of the cerebral (nine T2 lesions or at least four T2 venous infusion; Serono USA, spinal fluid is often helpful in a diagno- lesions with positive Visual Evoked Rockland, MA) is a newer immuno- sis of MS. Oligoclonal IgG bands have Potential), positive spinal cord MRI suppressant medication that has been found to be prevalent in patients result with two focal T2 lesions, and demonstrated efficacy in progressive suffering from MS.15 Moreover, MRI is positive CSF findings. MS. It is typically administered every perhaps the single greatest diagnostic Treatment for patients with MS three months, although it may be given and prognostic tool in the management involves management of acute attacks monthly for the first few doses to of MS today. Clinically definite MS and symptoms and prevention of patients with very active disease. demonstrates multiple periventricular relapses and progression. In this regard, Unfortunately, side effects and potential and discrete cerebral hemisphere white it is crucial to initiate disease-modify- toxicities, including cardiac toxicity, matter lesions known as plaques; these ing therapy as soon as possible. Current limit the use of Novantrone® to are sometimes referred to as “unidenti- therapies are aimed at eliminating the patients with secondary progressive MS fied bright objects” or “UBOs” because immune dysfunction and resultant neu- or very active relapsing-remitting MS.26 of their appearance on MRI. ral damage with the goal of preventing In 2001, new recommendations the long-term risk of clinically signifi- Clinical Pearls regarding diagnostic criteria for MS cant disability. • Certain clinical and/or demo- were published by an international Acute attacks (and those resulting in graphic risk factors such as age of onset, panel of experts.16-18 The “McDonald ON) are usually treated with intra- gender, CNS involvement, course of criteria” allowed for MRI evidence in venous methylprednisolone 1000 mg disease and attack frequency can aid cli- the diagnosis of MS in patients who daily for three days, followed by a taper- nicians in determining the prognosis experienced a single acute clinical ing dose of oral prednisone over several for a patient with MS. Individuals with episode.16 Subsequent revisions of these weeks. Although protocols vary, this is a favorable prognosis fit the following McDonald criteria were published in the most widely used regimen accord- profile: age of onset younger than 40 2005, and updated further by Swanton ing to current sources.19,20 In addition, years, female, optic neuritis or other and associates in 2006.17,18 Today, most 4-aminopyridine and 3,4-diaminopyri- sensory symptoms at onset, relapsing/ clinicians rely on the following to make dine may prove useful for the sympto- remitting disease course and a low a diagnosis of MS: matic treatment of some multiple scle- attack frequency. Individuals with an • At least two attacks with objective rosis patients. Pemoline may be an unfavorable prognosis are those whose clinical evidence of at least two lesions; alternative to amantadine for the con- age of onset is older than 40 years, male, • At least two attacks with objective trol of fatigue, and acetazolamide may have motor or cerebellar symptoms, clinical evidence of one lesion plus dis- be an alternative to carbamazepine and neurologic findings at onset, a progres- semination in space shown on MRI or phenytoin for the treatment of painful sive course of the disease and a high

APRIL 15, 2009 REVIEW OF OPTOMETRY 59A 001_ro0409_handbook 4/2/09 9:42 AM Page 60

number of attacks. Premyelinating oligodendrocytes in chronic lesions of and seventh decades of life represent multiple sclerosis. N Engl J Med 2002;346(3):165-73. • The association between optic neu- 14. Schumacher GA, Beebe GW, Kibler RF, et al. age peaks of incidence, with a slight 3 ritis and MS has been previously Problems of experimental trials of therapy in multiple preponderance for women. The natural demonstrated and is well documented. sclerosis: Report by the panel on the evaluation of history of the disease remains poorly experimental trials of therapy in multiple sclerosis. Ann 1-4 However, a number of other types of NY Acad Sci 1965;122:552-68. defined. In fact, the ocular aspects of demyelinating disorders have been asso- 15. Harrington MG, Kennedy PG. The clinical use of the disease may remit or improve spon- ciated with optic neuritis. These include cerebrospinal fluid studies in demyelinating neurological taneously.3 The ocular conditions char- diseases. Postgrad Med J 1987;63(743):735-40. acute transverse myelitis, Gullain-Barré 16. McDonald WI, Compston A, Edan G, et al. acteristic of the disease may exist in the syndrome, Devic’s neuromyelitis optica, Recommended diagnostic criteria for multiple sclerosis: Charcot-Marie-Tooth syndrome, multi- guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50(1):121-7. focal demyelinating neuropathy and 17. Polman CH, Reingold SC, Edan G, et al. Diagnostic acute disseminated encephalomyelitis. criteria for multiple sclerosis: 2005 revisions to the • At one time, when a patient pre- “McDonald Criteria.” Ann Neurol 2005;58(6):840-6. 18. Swanton JK, Fernando K, Dalton CM, et al. sented with an acute optic neuropathy Modification of MRI criteria for multiple sclerosis in or INO suggestive of demyelinating patients with clinically isolated syndromes. J Neurol disease, there was no great hurry to Neurosurg Psych 2006;77(7):830-3. 19. Murray TJ. Diagnosis and treatment of multiple confirm a diagnosis of MS because no sclerosis. BMJ 2006;332(7540):525-7. effective treatments were available. 20. Beck RW, Cleary PA. Optic neuritis treatment trial. Today there are a number of medica- One-year follow-up results. Arch Ophthalmol 1993;111(6):773-5. tions that reduce the incidence and 21. Noseworthy JH. Clinical trials in multiple sclerosis. Graves' Disease is evident in this patient with thyroid ophthalmopathy. recurrence of neurological deficits and Curr Opin Neurol Neurosurg 1993;6(2):209-15. impairment and delay the onset of 22. The IFNB Multiple Sclerosis Study Group, University of British Columbia MS/MRI Analysis Group. clinical MS. Hence, if MS is suspected, Interferon beta-1b in the treatment of multiple sclerosis: absence of clinical or biochemical evi- 2,3 testing should be conducted immedi- Final outcome of the randomized, controlled trial. dence of thyroid dysfunction. When ately to confirm the diagnosis. Neurol 1995;45(7):1277-85. the systemic and ocular condition exist 23. Galetta SL. The controlled high risk Avonex multi- ple sclerosis trial (CHAMPS Study). J Neuroophthalmol together, they may follow completely 2-6 1. Peterson LK, Fujinami RS. Inflammation, demyelina- 2001;21(4):292-5. different clinical courses. tion, neurodegeneration and neuroprotection in the 24. Johnson KP, Brooks BR, Cohen JA, et al. The hallmark sign of TO is bilateral, pathogenesis of multiple sclerosis. J Neuroimmunol Copolymer 1 reduces the relapse rate and improves 2007;184(1-2):37-44. disability in relapsing-remitting multiple sclerosis: non-pulsatile proptosis secondary to 2. Inglese M. Multiple sclerosis: New insights and Results of a phase III multicenter, double-blind, place- tendon sparing extraocular muscle trends. AJNR Am J Neuroradiol 2006;27(5):954-7. bo-controlled trial. Neurol 1995;45(7):1268-76. enlargement.1-4 Other important find- 3. Stutzer P, Kesselring J. Wilhelm Uhthoff: A phenom- 25. PRISMS Study Group. Randomised double-blind enon 1853 to 1927. Int MS J 2008;15(3):90-3. placebo-controlled study of interferon beta-1a in relaps- ings include impaired ocular motility 4. Boneschi FM, Colombo B, Annovazzi P, et al. ing/remitting multiple sclerosis. Lancet 1998;352(9139): and ophthalmoplegia with resultant Lifetime and actual prevalence of pain and headache in 1498-504. diplopia, firm resistance to globe multiple sclerosis. Mult Scler 2008;14(4):514-21. 26. Avasarala JR, Cross AH, Clifford DB, et al. Rapid 5. Pearce JM. Romberg and his sign. Eur Neurol onset mitoxantrone-induced cardiotoxicity in secondary retropulsion, eyelid retraction, poor 2005;53(4):210-3. progressive multiple sclerosis. Mult Scler 2003;9(1):59-62. upper eyelid tracking upon downgaze 6. Chan JW. Optic neuritis in multiple sclerosis. Ocul (Von Graefe’s sign), variable diplopia, Immunol Inflamm 2002;10(3):161-86. 7. Soderstrom M. Optic neuritis and multiple sclerosis. possibly impaired visual acuity and Acta Ophthalmol Scand 2001;79(3):223-7. THYROID OPHTHALMOPATHY visual field defects, sight loss secondary 8. Pirko I, Blauwet LK, Lesnick TG, et al. The natural to corneal exposure-related keratopathy history of recurrent optic neuritis. Arch Neurol 7,8 2004;61(9):1401-5. Signs and Symptoms or compressive optic neuropathy. 9. Rucker JC. Efferent visual dysfunction from multiple Graves’ disease, Graves orbitopathy, Thyroid-associated dermopathy sclerosis. Int Ophthalmol Clin 2007;47(4):1-13. dysthyroid orbitopathy, thyroid eye dis- with fluid infiltration in the lower 10. Chen L, Gordon LK. Ocular manifestations of multi- ple sclerosis. Curr Opin Ophthalmol 2005;16(5):315-20. ease and thyroid ophthalmopathy (TO) extremities, particularly the pretibial 11. Lucchinetti CF, Brück W, Rodriguez M, et al. are all synonymous terms connoting an area of the leg (pretibial myxedema), Distinct patterns of multiple sclerosis pathology indi- autoimmune disorder characterized by the dorsum of the foot, rarely the hand, cates heterogeneity on pathogenesis. Brain Pathol 1,2 1996;6(3):259-74. multiple systemic manifestations. elbow, upper arm and forearm, and 12. Confavreux C, Vukusic S. Accumulation of irre- Thyroid ophthalmopathy manifests acropachy (clubbing of the fingers and versible disability in multiple sclerosis: from epidemiolo- in approximately 50% of patients with toes) almost always occurs in advanced gy to treatment. Clin Neurol Neurosurg 2006;108(3): 5,6 327-32. systemic thyroid dysfunction with stages of systemic thyroid disease. 13. Chang A, Tourtellotte WW, Rudick R, et al. advanced effects in 3–5%.3 The fifth These two indicators often occur in the

60A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 61 OCULOSYSTEMIC DISEASE

presence of progressing ophthalmopa- trate orbital tissues, further kindling the because ophthalmopathy can develop in thy.5 The curiosity of thyroid disease is cascade of inflammation.9,10 Finally, the setting of an underactive, hyperactive its often unpredictable nature. As an although originally thought to repre- or normally functioning thyroid gland, example, dermopathy has been sent a separate pathway for inflamma- contingencies for treating glandular mal- observed in many cases without any tion, antibodies that develop against the function and eye signs and symptoms clinical ophthalmopathy.5 extraocular muscles are now considered must be developed separately.1-4,7,17-25 a secondary consequence of global Laboratory testing should include Pathophysiology extraocular muscle inflammation.9 assays for the levels of triidothyronine The etiology of the disorder is mul- Thyroglobulin (Tg) may also be (T3), thyroxine (T4), thyroid stimulat- tifactorial and secondary to newly dis- involved in the pathogenesis of TO.13,14 ing hormone (TSH), thyroid peroxi- covered heritable abnormalities that Following its release from the cytokine dase antibodies, thyroglobin antibodies, interfere with immune regulation.1 Not stimulated thyroid, Tg may have the thyrotropin receptor antibodies and all of the mechanisms responsible for ability to elicit autoimmune aggression thyroid stimulating immunoglobulins.2,3 the systemic and/or ocular manifesta- in orbital tissues and extraocular mus- Ultrasonography can be used to assess tions are understood.2 Research regard- cles by becoming complexed with gly- the condition of the extraocular mus- ing the clinical manifestations of thy- cosaminoglycans, infiltrating the tissues cles, and computed tomography (CT) is roid ophthalmopathy traditionally and then serving as a binding site for generally considered the accepted point to a combination of increased the other previously mentioned modality. Magnetic resonance imaging orbital fat and extraocular muscle vol- cytokines.13,14 Previously viewed as the (MRI) may be used for those requiring ume within the orbital space.1,2,9-12 TO is main mechanism of pathogenesis, Tg a detailed view of the soft tissues of the a slowly progressive disease in which a has recently been confirmed by research entire orbit.18 Monitoring of proptosis malfunctioning immune system acti- as playing a secondary role.13 should be done either with an exoph- vates thyrotropin receptor-specific T- Environmental triggers, such as thalmometer or photographs. cells and B cells.11 This activation pro- smoking, can also induce or hasten Resultant proptosis may require duces autoantibodies.10 Orbital ophthalmopathy.3,15 Because smoking is monitoring only. Any signs and symp- fibroblasts residing within orbital tis- a modifiable risk factor, it must be toms associated with ocular surface sues succumb to autoimmune attack included in the historical questioning compromise can be managed with effi- when these antibodies bind both to and then approached in management. cient hydration.25,26 Artificial tear solu- their thyrotropin receptors (TSHr) and Hashimoto’s autoimmune thyroiditis tions and ointments may remedy most insulin-like growth factor-1 (IGF-1) (HAT) is the most common cause of symptoms.25,26 Punctual occlusion can receptors.9-12 It appears that orbital thyroid diseases in children and adoles- be used to retard drainage as well. fibroblasts act as sentinel cells, initiating cents.16 It is also is the most common Patients with increased symptoms upon lymphocyte recruitment and tissue cause of acquired hypothyroidism with waking may have lagophthalmos. In remodeling.6 Evidence suggests that or without goiter.16 It is capable of these instances, they should be coun- when the autoantibodies bind to the inducing the orbital changes consistent seled to use a blindfold to create an thyrotropin receptor sites, they stimu- with thyroid orbitopathy.16 enclosed, moist environment and pre- late a subset of these cells to undergo vent exposure-based . adipogenesis, thus increasing orbital Management In the most severe cases, moisture adipose tissue volume.9,10 Auto- Thyroid cancer should be considered chambers can be created for waking antibodies that bind to the insulin-like when examining patients with suspect- hours by affixing face-conforming plas- growth factor-1 receptors appear to ed TO.10 Prognosis for the disease, tic barriers to the temples of the impact pathogenesis through recruit- when diagnosed promptly, is excellent patient’s spectacles. Affixed Fresnel or ment and activation of additional T- in the long term,with low rates of mor- ground-in prisms may improve fusion cells and by upregulating the produc- tality.12 Unlike other cancers of the in patients with ophthalmoparesis and tion of hyaluronan (hyaluronic acid), a head and neck, it tends toward delayed diplopia.26 In rare instances, congestion cytokine that plays a key role in the metastasis to regional lymph nodes.17 of the orbit can lead to raised intraocu- development of inflammation and Since the hallmark sign of TO is a lar pressure. Here, topical hypotensives increased orbital tissue swelling.9,10 bilateral, symmetrical, proptotic appear- may be appropriate. Simultaneously, the process stimulates an ance, laboratory testing and imaging is Clinical trials with oral antihista- overproduction of thyroid hormones.9-12 indicated to understand the potential mine and anti-leukotriene prepara- Activated T-cells continue to infil- etiology in suspicious cases.18 However, tions, traditionally used in treating

APRIL 15, 2009 REVIEW OF OPTOMETRY 61A 001_ro0409_handbook 4/2/09 9:42 AM Page 62

nasal itching, rhinorrhea and conges- consensus and standardization, with a orbits, making them appear proptotic. tion, have demonstrated some effec- varying quality of published reports.24,27 Checking old photographs of patients tiveness for patients with mild-to- At best, offers an to chronicle their habitual appearance moderate thyroid eye disease and option for patients with extraocular is a helpful tool for determining base- orbital congestion.19 A six-week course motility impairment; however, mixed line appearance. of oral cetirizine (10mg q.a.m.) and results have been presented in clinical • Thyroid ophthalmopathy is gen- oral montelukast (10mg q.p.m.) in a trials, indicating that proptosis, eyelid erally symmetric and bilateral. A meas- series of patients with significant oph- retraction and soft tissue changes may urement difference of 6mm or more thalmopathy yielded subjective improve- not improve with radiation treat- between the eyes is ominous and not ment in tearing, dryness and itching in ment.5,24,27 Given the risk of radiation consistent with TO. 50% of subjects compared to controls, retinopathy vs. the controversial gains • Cases involving thyroid dysfunc- although it was less effective for against symptoms, patients should be tion should be referred to an endocri- diplopia and proptosis.19 appropriately educated before consider- nologist. 24 Oral and intravenous steroids have ing this solution. 1. Kim N, Hatton MP. The role of genetics in Graves’ been demonstrated as successful thera- Orbital decompression by trans- disease and thyroid orbitopathy. Semin Ophthalmol pies for cases of moderate-to-severe palpebral fat removal is a proven, reli- 2008;23(1):67-72. 2. Sergott RC, Glaser JS. Graves’ ophthalmopathy. A .20,21,26 ophthalmopathy. Work has shown able, effective and safe method of clinical and immunologic review. Surv Ophthalmol that blocking the CD-20 receptor on B relieving the compressive complica- 1981;26(1):1-21. lymphocytes has significantly affected tions of TO. The results were first 3. Wiersinga WM, Bartalena L. Epidemiology and pre- vention of Graves’ ophthalmopathy. Thyroid the clinical course of TO, resulting in described in 1988, and the procedure 2002;12(10):855-60. rapid reduction of inflammation and has developed a track record for lasting 4. Ben Simon GJ, Syed HM, Douglas R, et al. proptosis.20 results, improvement in visual function Extraocular muscle enlargement with tendon involve- ment in thyroid-associated orbitopathy. Am J Experimental use of infliximab (anti- and development of patient well-being, Ophthalmol 2004;137(6):1145-7. tumor necrosis factor alpha) has also with benefits outweighing risk.7 5. Fatourechi V, Bartley GB, Eghbali-Fatourechi GZ, et been investigated in TO patients sec- al. Graves’ dermopathy and acropachy are markers of severe Graves’ ophthalmopathy. Thyroid 2003;13(12): ondary to its ability to decrease inflam- Clinical Pearls 1141-4. mation.22 Although the option is a rea- • Thyroid eye disease can occur in 6. Hasani-Ranjbar S, Mohajeri-Tehrani MR. Localized sonable alternative to surgical the presence of hyperthyroid, hypothy- myxedema of the toe: A rare presentation of graves’ dermopathy. Arch Iran Med 2008;11(3):326-9. approaches, the data on this new strat- roid or euthyroid states. Hyperthyroid 7. Richter DF, Stoff A, Olivari N. Transpalpebral decom- egy is currently limited with respect to is marked by unexplained weight loss, pression of endocrine ophthalmopathy by intraorbital thyroid eye disease and orbital inflam- nervousness and tachycardia; hypothy- fat removal (Olivari technique): Experience and progres- sion after more than 3000 operations over 20 years. 22 matory conditions. roidism is marked by intolerance to Plast Reconstr Surg 2007;120(1):109-23. In cases in which TO is associated cold, premature fatigue and depression. 8. Gaddipati RV, Meyer DR. Eyelid retraction, lid lag, with an overactive thyroid gland, vari- • The classic “NOSPECS” pneu- lagophthalmos, and von Graefe’s sign quantifying the eyelid features of Graves’ ophthalmopathy. Ophthalmol ous antithyroid medications can be monic permits an easy-to-recall system 2008;115(6):1083-8. employed, with or without the possi- of staging: N=no signs or symptoms, 9. Khoo TK, Bahn RS. Pathogenesis of Graves’ oph- bility of radioiodine treatment.25,26 O = only signs such as the “stare” or thalmopathy: The role of autoantibodies. Thyroid 2007;17(10):1013-8. Some indications suggest that the use Von Graefe’s sign but no symptoms, 10. Garrity JA, Bahn RS. Pathogenesis of graves oph- of radioiodine treatment may worsen S = soft tissue involvement (resistance thalmopathy: implications for prediction, prevention, ophthalmopathy.3,23,26 A concomitant to retropulsion, conjunctival edema, and treatment. Am J Ophthalmol 2006;142(1):147-53. 11. Prabhakar BS, Bahn RS, Smith TJ. Current per- course of oral steroids is frequently fullness of the eyelids, injection of the spective on the pathogenesis of Graves’ disease and used to mitigate this effect.3,23,26 The horizontal recti insertions), P=propto- ophthalmopathy. Endocr Rev 2003;24(6):802-35. combination of corticosteroid treat- sis, E=extraocular muscle involvement, 12. Karasek M, Lewinski A. Etiopathogenesis of Graves’ disease. Neuro Endocrinol Lett 2003;24(3- ment and external beam radiation to C=corneal involvement, S=sight loss. 4):161-6. the thyroid gland is another effective • The classic Dalrymple’s sign is 13. Lisi S, Botta R, Agretti P, et al. Poorly specific bind- modality in which multiple mecha- characterized by eye lid retraction and ing of thyroglobulin to orbital fibroblasts from patients with Graves’ ophthalmopathy. J Endocrinol Invest 21 nisms can be placated. “stare,” Moebius, sign is marked by an 2005;28(5):420-4. Orbital radiation is a controversial inability to converge, and Gifford’s sign 14. Marinò M, Lisi S, Pinchera A, et al. Glycosa- local treatment modality for patients is marked by difficulty in everting the minoglycans provide a binding site for thyroglobulin in orbital tissues of patients with thyroid-associated oph- 24,27 with severe thyroid ophthalmopathy. eyelids. thalmopathy. Thyroid 2003;13(9):851-9. The literature demonstrates a lack of • Many patients have shallow 15. Zhang Q, Yang YM, Lv XY. Association of Graves’

62A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 63 OCULOSYSTEMIC DISEASE

disease and Graves’ ophthalmopathy with the polymor- Oculocutaneous albinism (OCA), tagmus, strabismus and photophobia, phisms in promoter and exon 1 of cytotoxic T lympho- cyte associated antigen-4 gene. J Zhejiang Univ Sci B also known as oculodermal albinism, is in the setting in which pigmentation 6 2006;7(11):887-91. a group of inherited defects of melanin of skin and hair is relatively normal. 16. Lorini R, Gastaldi R, Traggiai C, et al. Hashimoto’s biosynthesis characterized by reduc- Incomplete albinism or albinoidism is Thyroiditis. Pediatr Endocrinol Rev 2003;1(Suppl 2):S205-S211. tion in pigmentation of the hair, skin characterized by variable manifesta- 2 17. Cognetti DM, Pribitkin EA, Keane WM. and eyes. The clinical spectrum of tions of the albino condition, owing to Management of the neck in differentiated thyroid can- OCA ranges from OCA1A, the most a genetic variation.7 cer. Surg Oncol Clin N Am 2008;17(1):157-73. 18. Lennerstrand G, Tian S, Isberg B, et al. Magnetic severe type, which demonstrates a resonance imaging and ultrasound measurements of complete lack of melanin production Pathophysiology extraocular muscles in thyroid-associated ophthal- throughout life, to milder forms such All types of OCA have been estab- mopathy at different stages of the disease. Acta Ophthalmol Scand 2007;85(2):192-201. as OCA1B, OCA2, OCA3 and lished as inherited autosomal recessive 2 19. Lauer SA, Silkiss RZ, McCormick SA. Oral mon- OCA4, each of which shows some disorders. The four genes determined telukast and cetirizine for thyroid eye disease. Ophthal pigment accumulation over time.2 The to be responsible for the different Plast Reconstr Surg 2008;24(4):257-61. 20. Salvi M, Vannucchi G, Campi I, et al. New clinical manifestations of OCA types of the disease are TYR, OCA2, 2 immunomodulators in the treatment of Graves’ oph- include congenital nystagmus, iris TYRP1 and MATP. Because of the thalmopathy. Ann Endocrinol 2008;69(2):153-6. hypopigmentation and translucency, clinical overlap in forms of albinism, 21. Zoumalan CI, Cockerham KP, Turbin RE, et al. Efficacy of corticosteroids and external beam radiation varying degrees of strabismus, reduced molecular techniques must be in the management of moderate to severe thyroid eye stereoscopic vision, reduced pigmenta- employed to establish a specific sub- disease. J Neuroophthalmol 2007;27(3):205-14. tion of the retinal pigment epithelium type.2 Studies have shown that ocular 22. Prendiville C, O’Doherty M, Moriarty P, et al. The use of infliximab in ocular inflammation. Br J (RPE), foveal hypoplasia, reduced albinism may constitute a clinically Ophthalmol 2008;92(6):823-5. visual acuity (20/60 to mild presentation of 23. Sisson JC, Schipper MJ, Nelson CC, et al. 20/400), varying refrac- oculocutaneous albi- Radioiodine therapy and Graves’ ophthalmopathy. J Nucl Med 2008;49(6):923-30. tive errors, color vision nism resulting from 24. Bradley EA, Gower EW, Bradley DJ, et al. Orbital impairment and debili- mutations either in the radiation for graves ophthalmopathy: A report by the tating photophobia.2 TYR (OCA1) or American Academy of Ophthalmology. Ophthalmol 6 2008;115(2):398-409. Patients with OCA OCA2 (P) genes. The 25. Modjtahedi SP, Modjtahedi BS, Mansury AM, et al. have a normal lifespan genetic mutation Pharmacological treatments for thyroid eye disease. with normal develop- responsible for HPS Drugs 2006;66(13):1685-700. 2 4 26. Wiersinga WM. Management of Graves’ ophthal- ment and fertility. External view of ocular albinism. remains unknown. The mopathy. Nat Clin Pract Endocrinol Metab 2007 Some forms of OCA CHS1/LYST gene has May;3(5):396-404. have systemic associations.3-5 Herman- been associated with Chediak-Higashi 27. Gorman CA, Garrity JA, Fatourechi V, et al. A 5 prospective, randomized, double-blind, placebo-con- sky-Pudlak syndrome (HPS), for syndrome. Mutations in the OA1 trolled study of orbital radiotherapy for Graves’ ophthal- example, is an autosomal-recessive dis- gene on the short arm of the X chro- mopathy. Ophthalmol 2001;108(9):1523-34. order characterized by oculocutaneous mosome are known to cause X-linked albinism, platelet dysfunction and ocular albinism known as the ALBINISM multisystem tissue lysosomal ceroid Nettleship-Falls variant.8 deposition.3,4 It is most common in the The common denominator of Signs and Symptoms Puerto Rican population.3 Chediak- decreased vision in patients with Albinism is a genetic condition Higashi syndrome is a albinism is decreased associated with defects in melanin pro- rare autosomal recessive foveal volume and macular duction or storage, causing maldevel- disorder in which hypoplasia.1,9-11 This find- opment of the and fovea, patients show hypopig- ing is compatible with a reduced retinal cell numbers and mentation, recurrent infec- reduction or loss of gan- abnormal routing of ganglion cell tions, mild coagulation glion cell numbers.1,2 This nerve fibers within the optic chiasm defects and varying neu- is a different process than and visual pathway.1 The prevalence of rologic problems.5 Ocular albinism - fundus. the one that merely pro- all forms of albinism varies with esti- Ocular albinism (OA) duces an anatomical lack mates at approximately one in 17,000 is characterized as a group of genetic of foveal pit, which is not a requirement persons.2 This suggests that one in 70 disorders presenting with reduced pig- for foveal cone specialization.9,10 New people carry a gene for albinism in one mentation only of the eye in associa- research suggests that the observation form or another.2 tion with decreased visual acuity, nys- of no foveal pit be known by the specif-

APRIL 15, 2009 REVIEW OF OPTOMETRY 63A 001_ro0409_handbook 4/2/09 9:42 AM Page 64

ic term as fovea plana.9,10 Patients may nase positive OCA, there is activity of Winchester optical, Scranton, PA) or be fovea plana without the effects of the enzyme, but melanin that is pro- the option for protective UV shields™ foveal hypoplasia, as seen in albinotic duced cannot be sequestered into (Fieldale, VA, CP films) or NOIR maculopathy.9,10 melanosomes. In tyrosinase-negative shields™ (South Lion, MI, NOIR Since the foveal region contains the OCA, inactivity of the enzyme pre- medical technologies). Prescribing the highest cell density in the human reti- vents melanin formation.17,18 maximum correction, especially in na, a large area of the visual cortex is younger patients, will maximize visual dedicated to its representation.10,11 In Management acuity and minimize the amblyogenic cases of both aniridia and albinism, the When a patient with fair skin and effects of large astigmatic or asymmet- fovea does not properly develop, caus- minimal fundus pigmentation presents ric corrections. In cases of strabismus ing its corresponding cortical repre- with or without the presence of com- (with or without an accommodative or sentations to be reduced.1,11 Analysis promised visual acuity, the possibility refractive component) or where visual reveals that regionally specific decreas- of albinism should be considered.1-11,19 acuity cannot be corrected to the val- es in grey matter at the occipital poles A complete family history, including ues obtained via laser interferometry, in patients with albinism corresponds investigation of family photographs, must be considered, with an to the cortical representation of the may help uncover a genetic link previ- appropriate surgical referral or referral central visual field and correlates to ously not realized. Since albinism has for binocular evaluation and training. most of the compromises in visual linkage to systemic syndromes, its exis- Surgical results are variable, and unfor- function.1 Patients with albinism have tunately, because a facet of this disease additional chiasmal irregularities and induces axons to aberrantly cross in the alterations in the hemispheric projec- chiasm, visual training may not be tions.1,11 Misrouting of the fibers at the effective.20,21 The literature confirms optic chiasm, where the majority of evidence that surgery on the extraocu- fibers cross to the contralateral side, lar muscles in patients with albinism produces an abnormal decussating pat- exhibits independent neurologic and tern.9-11 This reflects the disturbance visual results.20 A positive angle kappa within the retina controlled in part by seems to be another clinical feature of the dysfunction of melanin metabo- the disorder. Surgeons must consider lism.12 It also is the predominant rea- this when planning extraocular muscle son most of these patients lack true surgery, particularly when preoperative binocularity and often present with Ocular albinism - fundus. testing indicates the potential for a some strabismus. binocular outcome.21 Foveal hypoplasia is related to poor tence cannot be dismissed simply In cases in which traditional specta- fundus pigmentation in the region.13 because the patient reports no clinical cles do not alleviate visual disabilities, Melanocytes are pigment-producing symptoms. In cases of high suspicion, low vision rehabilitation along with cells residing primarily in hair follicles, referral for genetic counseling/testing orientation and mobility rehabilitation the skin and the eyes.13 Pigmentation (tyrosinase hair bulb assay) may be services may provide magnifying is achieved inside melanocytes when indicated, both for the welfare of the devices (full-field full-diameter micro- melanin is produced from the amino patient and to understand the risk to scopes, prism half-eye microscopes, acid tyrosine and sequestered within potential future generations of the stand magnifiers, handheld micro- specialized organelles known as mela- patient’s family.2,16 scopes, telemicroscopes, telescopes and nosomes.13 Normal foveal develop- Ocular management for all forms of closed circuit televisions) as well as ment requires a proper underlying albinism begins with appropriate spec- supportive aides (acetate filters to substrate; that is, a normally pigment- tacle correction. Consideration includes increase the contrast of printed materi- ed RPE. The enzyme tyrosinase, a refractive error and protection from als, large print books, enlarged clocks). type I membrane glycoprotein, plays a the harmful rays of the sun. Spectacle Prescribing practitioners and rehabili- key role in the initiation of the corrections should be designed consid- tation specialists each have a role in the melanogenesis process in humans.14-16 ering either sun specific lenses, photo- management of these patients. Mutations in the human tyrosinase chromic lenses (Transitions, Pinnelas The nystagmus in patients with gene cause the tyrosinase negative form Park, FL, Transitions Optical Inc.; albinism is often termed “searching of oculocutaneous albinism.15 In tyrosi- Photogray™, Corning Optical via nystagmus.”22,23 Research supports that

64A REVIEW OF OPTOMETRY APRIL 15, 2009 001_ro0409_handbook 4/2/09 9:42 AM Page 65 OCULOSYSTEMIC DISEASE

acuity development in these cases is Clinical Pearls 7. Hall AJ, Sesebe T, Lopes Cardozo R, et al. A high- frequency albinism variant on the gulf coast of Papua. directly related to the visual sensory • The differential diagnosis for PNG Med J 1981;24(1):35-9. defects and not the nystagmus.20,22,23 albinism in general includes ocular 8. Rudolph G, Meindl A, Bechmann M, et al. X-linked The nystagmus develops secondary to albinism, albinoidism, the Hermansky- ocular albinism (Nettleship-Falls): A novel 29-bp dele- tion in exon 1. Carrier detection by ophthalmic exami- the poor ability to stabilize fixation as a Pudlak variant (albinism + bleeding nation and DNA analysis. Graefes Arch Clin Exp result of the compromised fovea. The disorder), the Chediak-Higashi variant Ophthalmol 2001;239(3):167-72. characteristics of searching nystagmus (Albinism + susceptibility to infection), 9. Izquierdo NJ, Emanuelli A, Izquierdo JC, et al. Foveal thickness and macular volume in patients with include bilaterality, conjugate horizon- Griscelli syndrome (albinism + oculocutaneous albinism. Retina 2007;27(9): 1227-30. tal uniplanar movements and an accel- immunodeficiency) and Waardenburg 10. Marmor MF, Choi SS, Zawadzki RJ, et al. Visual erating slow phase. Unfortunately, no syndrome type II (facial anomalies, insignificance of the foveal pit: Reassessment of foveal hypoplasia as fovea plana. Arch Ophthalmol single ocular motor characteristic can heterochromia of the iris, fundus 2008;126(7):907-13. differentiate a benign form of infan- pigmentation variation and congenital 11. Neveu MM, von dem Hagen E, Morland AB, et al. tile/searching nystagmus from one sensorineural deafness). The fovea regulates symmetrical development of the visual cortex. J Comp Neurol 2008;506(5):791-800. with an alternate neurological etiology. • Genetic detection in carriers and 12. Schmitz B, Krick C, Käsmann-Kellner B. Clinicians must therefore consider the obtaining a prenatal diagnosis is plausi- Morphology of the optic chiasm in albinism. host of clinical features and rule out the ble when a history of the disease is Ophthalmologe 2007;104(8):662-5. 13. Neveu MM, Holder GE, Sloper JJ, et al. Optic chi- 22,23 need for neurologic consultation. identified in the family line. asm formation in humans is independent of foveal Patients with OCA are especially • Albinoidism or ocular albinism development. Eur J Neurosci 2005;22(7):1825-9. vulnerable to the harmful rays of the may be present in patients with normal 14. Goding CR. Melanocytes: the new black. Int J Biochem Cell Biol 2007;39(2):275-9. sun because they lack protective mela- visual acuity who possess the complaint 15. Schallreuter KU, Kothari S, Chavan B, et al. nin.1,11,24 This puts them at risk for of photophobia. In these cases, the Regulation of melanogenesis—controversies and new developing skin lesions that have both patient should be questioned regarding concepts. Exp Dermatol 2008;17(5):395-404. 16. Popescu CI, Paduraru C, Dwek RA, et al. Soluble cosmetic and systemic health implica- the pigmentation and tanning status of tyrosinase is an endoplasmic reticulum (ER)–associated tions and that increase their risk for family members. degradation substrate retained in the ER by calreticulin developing skin cancers.5 Patients with • Strabismus cases undergoing sur- and BiP/GRP78 and not calnexin. J Biol Chem 2005;280(14):13833-40. any form of albinism must have regu- gical correction have a poor prognosis 17. Chaki M, Mukhopadhyay A, Chatterjee S, et al. lar skin evaluations and must be because of the dysfunctional hard- Higher prevalence of OCA1 in an ethnic group of east- informed about the need for strict and wiring (mal-decussating fibers). ern India is due to a founder mutation in the tyrosinase gene. Mol Vis 2005;11(7):531-4. 1,24 consistent sun protection strategies. • Medications with antiplatelet 18. Francis E, Wang N, Parag H, et al. Tyrosinase mat- Work is underway to develop a foveal properties can produce significant ill uration and oligomerization in the endoplasmic reticu- hypoplasia grading system using optical effects on HPS patients and should be lum require a melanocyte-specific factor. J Biol Chem 2003;278(28):25607-17. 25 coherence tomography (OCT). The avoided. 19. Kutzbach BR, Summers CG, Holleschau AM, et al. same group is undertaking the task of • Patients with extremely blond Neurodevelopment in children with albinism. attempting to correlate visual acuity to fundus may be misdiagnosed with Ophthalmol 2008;115(10):1805-8, 20. Hertle RW, Anninger W, Yang D, et al. Effects of iris transillumination, macular trans- albinism. Patients with albinism will extraocular muscle surgery on 15 patients with oculo- parency and foveal hypoplasia in young have reduced acuity and nystagmus. cutaneous albinism (OCA) and infantile nystagmus syn- albinism patients.25 This could provide drome (INS). Am J Ophthalmol 2004;138(6):978-87. 1. von dem Hagen EA, Houston GC, Hoffmann MB, et 21. Merrill KS, Lavoie JD, King RA, et al. Positive angle patients and guardians with valuable al. Retinal abnormalities in human albinism translate into kappa in albinism. J AAPOS 2004;8(3):237-9. prognostic information. a reduction of grey matter in the occipital cortex. Eur J 22. Weiss AH, Kelly JP. Acuity development in infantile The traditional treatment for Neurosci 2005;22(10):2475-80. nystagmus. Invest Ophthalmol Vis Sci 2007;48(9): 2. Grønskov K, Ek J, Brondum-Nielsen K. 4093-9. Chediak-Higashi syndrome is a bone Oculocutaneous albinism. Orphanet J Rare Dis 23. Abadi RV, Bjerre A. Motor and sensory character- marrow transplant to remedy the 2007;2(11):43. istics of infantile nystagmus. Br J Ophthalmol hematologic and immune defects.5 3. Feliciano NZ, Rivera E, Agrait E, et al. Hermansky- 2002;86(10):1152-60. Pudlak syndrome: dental management considerations. 24. Lund PM, Taylor JS. Lack of adequate sun protec- Unfortunately, nothing is currently J Dent Child (Chic) 2006;73(1):51-6. tion for children with oculocutaneous albinism in South available to alter the neurologic prob- 4. Iannello S, Fabbri G, Bosco P, et al. A clinical variant Africa. BMC Public Health 2008;8(6):225. lems.5 The treatment for Hermansky of familial Hermansky-Pudlak syndrome. MedGenMed 25. Seo JH, Yu YS, Kim JH, et al. Correlation of visual 2003;5(1):3. acuity with foveal hypoplasia grading by optical coher- Pudlak syndrome ranges from transfu- 5. Kaplan J, De Domenico I, Ward DM. Chediak- ence tomography in albinism. Ophthalmol 2007;114(8): sion of platelets to medicating with Higashi syndrome. Curr Opin Hematol 2008;15(1):22-9. 1547-51. antifibrinolytics to clotting factor 6. Hutton SM, Spritz RA. A comprehensive genetic 26. Nurden P, Nurden AT. Congenital disorders associ- study of autosomal recessive ocular albinism in ated with platelet dysfunctions. Thromb Haemost replacement therapy and stem-cell Caucasian patients. Invest Ophthalmol Vis Sci 2008;99(2):253-63. transplantation.3,26 2008;49(3):868-72.

APRIL 15, 2009 REVIEW OF OPTOMETRY 65A