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Ocular Complications Due to Cancer Treatment

Michael Ober · Camille A. Servodidio · David Abramson

Contents 6.6 : , and ...... 89 6.1 Introduction ...... 82 6.6.1 Anatomy and Physiology ...... 89 6.2 , Periorbital Skin and Tear Film ...... 82 6.6.2 Acute Radiation Effects ...... 89 6.2.1 Anatomy and Physiology ...... 82 6.6.3 Chronic Radiation Effects ...... 89 6.2.2 Acute Radiation Effects ...... 83 6.6.4 ...... 89 6.2.3 Chronic Radiation Effects ...... 83 6.6.5 Medical and Nursing Management . . . . . 89 6.2.4 Chemotherapy ...... 84 6.7 ...... 90 6.2.5 Medical and Nursing Management . . . . . 84 6.7.1 Anatomy and Physiology ...... 90 6.3 ...... 85 6.7.2 Acute Radiation Effects ...... 90 6.3.1 Anatomy and Physiology ...... 85 6.7.3 Chronic Radiation Effects ...... 90 6.3.2 Acute Radiation Effects ...... 85 6.7.4 Chemotherapy ...... 90 6.3.3 Chronic Radiation Effects ...... 85 6.7.5 Medical and Nursing Management . . . . . 90 6.3.4 Chemotherapy ...... 85 6.8 and ...... 90 6.3.5 Medical and Nursing Management . . . . . 85 6.8.1 Anatomy and Physiology ...... 90 6.4 ...... 86 6.8.2 Acute Radiation Effects ...... 90 6.4.1 Anatomy and Physiology ...... 86 6.8.3 Chronic Radiation Effects ...... 90 6.4.2 Acute Radiation Effects ...... 86 6.8.4 Chemotherapy ...... 91 6.4.3 Chronic Radiation Effects ...... 86 6.8.5 Medical and Nursing Management . . . . . 92 6.4.4 Chemotherapy ...... 87 6.9 Orbital Bones and Tissue ...... 92 6.4.5 Medical and Nursing Management . . . . . 87 6.9.1 Anatomy and Physiology ...... 92 6.5 ...... 87 6.9.2 Acute Radiation Effects ...... 92 6.5.1 Anatomy and Physiology ...... 87 6.9.3 Chronic Radiation Effects ...... 92 6.5.2 Acute Radiation Effects ...... 87 6.9.4 Chemotherapy ...... 93 6.5.3 Chronic Radiation Effects ...... 87 6.9.5 Medical and Nursing Management . . . . . 93 6.5.4 Chemotherapy ...... 88 6.10 Conclusion ...... 93 6.5.5 Medical and Nursing Management . . . . . 88 References ...... 93 06_Schwartz_Occular 27.01.2005 8:31 Uhr Seite 82

82 Chapter 6 M. Ober · C. A. Servodidio · D. Abramson

Figure 6.1 Cross-sectional anatomy of the eye

The tear film covers the anterior surface of the 6.1 Introduction conjunctiva and cornea. It serves the vital role of supplying the cornea with moisture, nutrients, en- The eye is composed of many tissues that vary great- zymes, immunoglobulins and protein signals, as well ly in their sensitivity to cytotoxic therapy. This chap- as allowing the maintenance of a clear, non-kera- ter highlights the ocular complications of cancer tinized epithelium in the visual axis. Furthermore, treatment and discusses the relevant anatomy and the tear film comprises the smooth outer refractive medical management. Each section discusses the ba- coating essential to vision by filling in corneal irreg- sic anatomy and physiology of a specific area of the ularities. The tear film consists of three layers. The eye (Fig. 6.1), common radiation and chemothera- aqueous layer is produced by the accessory lacrimal peutic complications and therapeutic management. glands found in the conjunctiva. Meibomian glands located within the tarsal plates produce an oily layer that sits on top of and acts to stabilize the aqueous 6.2 Eyelids, Periorbital Skin and Tear Film layer. The goblet cells of the conjunctiva produce the third, or mucous, layer. The overall function of the 6.2.1 Anatomy and Physiology tear film is vitally dependant on each of these indi- The thinnest skin in the body is located on the outer vidual layers, and a deficiency in any layer will surface of the eyelids. It is devoid of subcutaneous fat adversely affect the entire ocular surface. allowing for the accumulation of fluid to manifest The tears drain from the ocular surface via two rapidly as swelling. The upper and lower eyelids con- puncta located on the medial aspect of the upper and tain fibrous connective tissue, known as the tarsal lower lid margin. The puncta lead to the canaliculi plates, which function as structural support. The that empty into the lacrimal sac and, in turn, into are located on the anterior portion of the the nose via the nasal-lacrimal duct. eyelids and aid in protection of the eye. 06_Schwartz_Occular 27.01.2005 8:31 Uhr Seite 83

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Figure 6.2 Side effects of chemotherapy and radiation of the eye

6.2.2 Acute Radiation Effects fractionated over a 4-week period. Blisters and ede- ma may precede moist dermatitis. Symptoms include Madarosis, or loss of eyelashes, and erythema are the redness, peeling, burning, itching and pain [1] first side effects of (RT) involving (Fig. 6.2). the eye. Usually, eyelashes will grow back; however, permanent loss does occur. Erythema can occur 6.2.3 Chronic Radiation Effects within days of treatment (generally after doses of at least 20–30 Gy) and usually persists for a few days. The late effects of RT to the eyelids following doses Dermatitis is the most common acute side effect of from 30–60 Gy include madarosis, telangiectasia (di- RT. Dry dermatitis of irradiated skin can occur with lated, tortuous blood vessels; Fig. 6.3), hyperpigmen- doses greater than 20 Gy and often leads to desqua- tation, depigmentation, , hyperkeratosis, at- mation. Moist dermatitis, with exposure of the der- rophy, necrosis, ulceration and punctual occlusion. mis and associated serum leakage,can occur after the Although rarely seen today, lid deformities, such as fourth week of RT following doses of 40 Gy or more, ectropion (out-turning of margin), 06_Schwartz_Occular 27.01.2005 8:31 Uhr Seite 84

84 Chapter 6 M. Ober · C. A. Servodidio · D. Abramson

Figure 6.3 Telangiectasia of the conjunctival blood vessels

(in-turning of eyelid margin) and atrophy or con- with cicatricial eyelid malpositioning. Intravenous tracture, are seen when the tarsus has been included doxorubicin has also been associated with excessive in the radiation field. The time of onset ranges from 2 lacrimation. Paleness of the periorbital skin has been months to greater than 5 years after treatment. De- reported following mithramycin infusion, while struction or occlusion of the puncta may occur when drooping of the upper eyelid, known as , has the medial portions of the eyelid are irradiated, been reported following long-term corticosteroid which leads to impaired tear drainage. Lid necrosis, use [8]. exacerbated by excess sun exposure in areas previ- ously irradiated, may develop months to years after 6.2.5 Medical and Nursing Management treatment [2, 3]. The management for eyelid complications due to 6.2.4 Chemotherapy cancer treatment consists mainly of skin care,includ- ing the use of ultraviolet protection, meticulous hy- Many chemotherapeutic agents, such as cyclophos- giene with mild soaps, the use of skin lubricants, phamide, ifosfamide and methotrexate, alter the nor- avoiding skin sensitizing drugs (i.e. tetracyclines) mal tear film physiology either by causing inflamma- and occasionally corticosteroid and/or antibiotic tion of the lacrimal glands or by being excreted di- creams. Ptosis, tear drainage or eyelid position may rectly into tears, which leads to dry-eye symptoms require minor surgical manipulation by an ophthal- and inflammation around the eyelids and anterior mologist and should be referred in clinically signifi- segment of the eye [4].Patients treated with alkyl sul- cant cases [9]. The mainstay of dry eye therapy con- fonates, including busulfan and nitrosourea, have sists of tear replacement with artificial tears drops also reported developing dry eyes [5]. Both 5-fluo- and ointment. Patients with symptoms or at risk rouracil [6] and docetaxel [7] have been associated should be encouraged to use liberal amounts of arti- with stenosis of the punctum and tear (canalicular) ficial tears. Unpreserved artificial tears are preferred, drainage system. In addition, some patients receiving especially when they are used more than four times 5-fluorouracil develop excessive lacrimation along per day, due to the fact that the preservatives them- 06_Schwartz_Occular 27.01.2005 8:31 Uhr Seite 85

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selves can be irritating to the cornea, conjunctiva and 6.3.3 Chronic Radiation Effects eyelids.Further aids include punctal occlusion,warm compresses to eyelids and, in advanced cases, cy- Late effects of RT to the conjunctiva include pro- closporine drops. Patients with continued sympto- longed injection, telangiectasis, symblepharon (ad- matic or refractory dry eyes should be referred to an hesions between the bulbar and palpebral conjuncti- eye care professional without delay, as the conse- va) and subconjunctival hemorrhage, shortening of quences of hesitating could be permanent vision loss. the fornices, loss of goblet cells, keratinization and necrosis. Exposure to 30–50 Gy results in prolonged conjunctival injection, which develops in 1–2 years, 6.3 Conjunctiva followed by telangiectatic vessels 3–6 years later. These fragile vessels tend to rupture with minor trau- 6.3.1 Anatomy and Physiology ma, resulting in subconjunctival hemorrhage. The conjunctiva is a thin, transparent mucous mem- Chronic ulceration of the conjunctiva can be seen brane that lines both the posterior aspect of the eye- following treatment with 60 Gy. This leads to symble- lids (palpebral conjunctiva) and the anterior surface pharon formation, resulting in shortening of the for- of the eye (bulbar conjunctiva). The folds between nices, (turning of lashes onto the ocular the palpebral and bulbar conjunctiva are known as surface) and eyelid malpositioning. Goblet cell loss the superior and inferior fornices, respectively. Tis- occurs at relatively low doses,resulting in tear film in- sue is redundant in the fornices to allow for adequate stability and dry eye symptoms, while doses over movement of the . The main lacrimal gland, 50 Gy may result in keratinization of the conjunctiva. which functions during reflex tearing, empties into These keratin plaques constantly irritate adjacent the superior fornix, while the accessory lacrimal cornea, occasionally causing scarring and visual loss. glands, supplying basal tear secretion, are found Necrosis may occur after radioactive plaque therapy throughout the conjunctiva, concentrating in the for- for retinoblastoma patients, where doses to the con- nices. junctiva between 90–300 Gy are used [1–3, 10]. The conjunctiva contains a stratified non-kera- tinized epithelium overlying a stroma, known as the 6.3.4 Chemotherapy substantia propria. Goblet cells supplying the mucin layer of the tear film are found intermixed with the is a commonly reported symptom fol- epithelial cells. Besides acting as a physical barrier, lowing induction therapy with many medications,in- the conjunctiva aids in host defenses by hosting im- cluding cyclophosphamide, ifosfamide, nitrosoureas, mune cells as well as colonizing . cytosine arabinoside, doxorubicin, methotrexate, deoxycoformycin and mitomycin. 5-fluorouracil is 6.3.2 Acute Radiation Effects also associated with conjunctivitis and eye irritation. This usually occurs concurrently with the initiation Conjunctival inflammation (conjunctivitis), which of therapy and resolves within two weeks of treat- manifests as vascular injection with clear or mucoid ment cessation. The immunosuppressive effects of discharge tends to occur 1–3 weeks after the start of corticosteroids are believed to facilitate opportunis- radiation treatment. Edema of the conjunctiva, tic throughout the eye, including bacterial, known as chemosis, may occur simultaneously or in viral and fungal conjunctivitis [11]. isolation and usually lasts for a few days. Affected conjunctiva may also ulcerate leading to an increased 6.3.5 Medical and Nursing Management risk of . The duration of these signs may be prolonged when RT doses over 30 Gy are used [1, 2, Antibiotic eye drops, sometimes in combination with 10]. corticosteroids, are used for prolonged conjunctivitis and for conjunctival ulceration. Artificial teardrops 06_Schwartz_Occular 27.01.2005 8:31 Uhr Seite 86

86 Chapter 6 M. Ober · C. A. Servodidio · D. Abramson

often aid chronic conjunctival irritation by providing cells form a monolayer, which controls corneal hy- the lubrication necessary to replace lost tear volume dration via ionic pumps. Small changes in corneal and dilute toxic chemotherapeutic metabolites ex- hydration (thickness) drastically change the optical creted into the tear film. Vitamin A ophthalmic oint- properties of the cornea; therefore, the endothelial ment (tretinoin 0.01% or 0.1%) may reverse squa- pumps are essential to maintaining clear vision. En- mous metaplasia and loss of vascularization from dothelial cells can migrate to fill an area with damage, formation [12].Patients with infectious conjunc- but they do not regenerate; therefore, all loss of en- tivitis should be instructed to wash their hands fre- dothelial cells is permanent. Inflammation of the quently and take great care in interactions with cornea, known as , also increases the corneal others to prevent the spread of communicable dis- thickness and blurs vision. eases. In addition, sunglasses for protection from the sun and wind may be helpful in reducing symptoms. 6.4.2 Acute Radiation Effects Severe conjunctival reactions, such as symblepharon and forniceal shortening,may require ophthalmolog- The corneal epithelium is adversely affected after RT ic manipulations such as symblepharon lysis on a doses of 10–20 Gy. Early effects include epithelial de- repeated basis; or, alternatively, mucous membrane fects, keratitis and decreased corneal sensation. grafting with forniceal reconstruction may be neces- When the tear film production or integrity is re- sary. Ophthalmologic referral is therefore indicated. duced, the epithelial cells become fragile and loosely adherent to themselves and the underlying stromal bed, resulting in epithelial defects. Patients with this 6.4 Cornea problem will complain of ocular discomfort, foreign body sensation, excess reflex tearing and blurry 6.4.1 Anatomy and Physiology vision. Acute keratitis is often self-limited following The cornea is the transparent,avascular anterior por- exposure to 30 Gy,but,following treatment with up to tion of the eye that refracts and transmits light to the 50Gy, it may persist for months, along with conjunc- inner structures of the eye. Along with the overlying tivitis . Decreased corneal sensation may result from tear film, it provides approximately two thirds of the nerve damage and be exacerbated by impaired reflex refracting power of the eye. The conjunctiva borders tearing, which, in turn, diminishes the blink rate and the cornea in an area known as the limbus. This re- delays complaints from the patient [1, 10]. gion contains corneal stem cells; therefore, compro- mising this zone leads directly to the loss of corneal 6.4.3 Chronic Radiation Effects transparency and often its integrity. The cornea is an avascular tissue and thus depends on the limbal Late RT effects on the cornea include chronic epithe- vessels along with the tear film and aqueous fluid lial defects, neovascularization, keratinization, ede- from the anterior chamber for nutrients and waste ma, ulceration and perforation. Epithelial defects removal. may persist for months when radiation causes dam- The cornea consists of five specialized layers, age to corneal epithelial stem cells, accessory tear including, from anterior to posterior: epithelium, glands,goblet cells and/or corneal nerves.The cornea Bowman’s membrane,stroma,Descemet’s membrane responds to these non-healing areas with neovascu- and endothelium. The epithelium is stratified, non- larization and keratinization, both of which tem- keratinized and replaces itself every 5–7 days. The porarily or permanently decrease visual acuity. Ab- stroma contains approximately 90% of the overall normal blood vessels and chronic inflammation may corneal thickness, including a specialized superficial lead to lipid deposition within the corneal stroma, region known as Bowman’s membrane. Descemet’s further worsening vision.Damage to lacrimal glands, membrane is a tough, thickened basement mem- goblet cells and corneal sensation impairs host de- brane secreted by the endothelium. The endothelial fenses by limiting the cornea’s contact with tears and 06_Schwartz_Occular 27.01.2005 8:31 Uhr Seite 87

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their accompanying nourishment, lubrication, im- munoglobulins and enzymes. Colonization and inva- 6.5 Lens sion of the corneal surface by bacteria may accelerate 6.5.1 Anatomy and Physiology ulceration and perforation [1, 3, 10, 13]. The lens is the second clear, avascular refracting sur- 6.4.4 Chemotherapy face of the eye. It lies posterior to the iris and is sus- pended circumferentially by a ligament known as the Patients develop keratitis following treatment with zonule. This encapsulated structure is devoid of many chemotherapeutic agents, including chloram- nerves and vasculature and thus depends on the bucil, cyclophosphamide, methotrexate, nitrosoureas, aqueous and vitreous humor for nutrients. Through- 5-fluorouracil and deoxycoformycin [4]. Punctate out life, the mitotically active cells located within the corneal opacities and keratitis will occur acutely with anterior periphery of the lens migrate inward toward cytosine arabinoside therapy, usually resolving ap- the denser nucleus in the center. The cells of the lens proximately four weeks after completion. Both vin- are never shed; rather, they are incorporated into the cristine and vinblastine have been associated with nucleus. Thus, injured cells leave permanent, visible corneal hypoesthesia [14]. Patients undergoing long- defects. For this reason, the crystalline lens is partic- term tamoxifen treatment may acquire whirl-like ularly susceptible to the formation of a after corneal inclusions known as verticillata [15].In addi- cancer treatment. A cataract simply refers to the loss tion, the immunosuppressive effects of corticos- of optical clarity within the lens, a condition that can teroids are believed to facilitate opportunistic infec- vary widely in severity. tions throughout the eye, resulting in bacterial, viral and , as well as in corneal ulcers. 6.5.2 Acute Radiation Effects

6.4.5 Medical and Nursing Management On rare occasion, transient may occur in the weeks following RT as a result of increased water con- Artificial tears and ointment are important in main- tent within the lens. taining a healthy cornea following insults from can- cer treatment. Patients using these solutions more 6.5.3 Chronic Radiation Effects than four times daily should consider unpreserved formulations. Antibiotic drops are recommended for The posterior subcapsular cataract is the characteris- epithelial defects. Corticosteroid (dexamethasone) tic late complication of RT (Fig. 6.4). The lens is eye drops are often given prophylactically with an- the most radiosensitive structure within the eye timetabolite treatment, especially cytosine arabi- because of its perpetual mitotic activity and inability noside, to reduce corneal and conjunctival irritation. to remove injured cells or disperse heat efficiently. Steroid drops may also be used with specific types of The report on following radiation therapy sterile infiltrates for keratitis. Corneal infections and in 1957 by Merriam and Focht yielded results that ulcerations are treated with administration of antibi- remain clinically relevant today. They found the otic eye drops as frequently as every 15 minutes. Ban- threshold for cataract development to be a single dage contact lenses, along with antibiotic drops, may exposure to 200 rads, fractionated doses of 400 rads be used for non-healing epithelial defects. Emer- over 3 weeks to 3 months, or a total dose of 550 rads gency surgical intervention may be required when divided over more than 3 months. Furthermore, corneal perforation is pending or apparent, or when they reported that patients receiving a single treat- permanent central corneal scarring becomes evident. ment of 200 rads, fractionated doses of >1000 rads Patients should be instructed to avoid factors that over 3 weeks to 3 months, or 1100 rads over greater may contribute to eye irritation or dryness, such as than 3 months, developed cataracts 100% of the fans, wind, smoke or low-humidity situations. time [16]. The lens in children less than one year 06_Schwartz_Occular 27.01.2005 8:31 Uhr Seite 88

88 Chapter 6 M. Ober · C. A. Servodidio · D. Abramson

Figure 6.4 Radiation-induced cataract

of age is more sensitive to radiation, as compared 6.5.5 Medical and Nursing Management to the adult lens, presumably due to higher mitotic activity [10]. At the present time, there are no known medical treatments for the reversal of cataracts. Prevention of 6.5.4 Chemotherapy cataracts is best accomplished by fractionation of the RT dose,lens shielding during treatment and limiting The cataract is the most frequently reported side ef- exposure to toxic medications. Once a clinically sig- fect associated with corticosteroid use.The incidence nificant cataract develops, surgical extractions and of steroid-induced cataracts ranges from 15–52%, observation become the only options. Cataract ex- depending on dose and duration [17].Although vari- traction is elective in the vast majority of situations able, the approximate threshold for cataract forma- and depends upon the patient’s and family’s desires. tion is 10 mg prednisone daily for one year [18]. It Visual pathways in the brain develop only during a should be noted that steroid-induced cataracts have finite period of time. When the central nervous sys- been reported following treatment with systemic, tem is presented with altered visual stimuli during inhaled,topical and skin formulations.Some patients this critical period, such as through an opaque lens, treated with busulfan [19] also acquire cataracts, as the potential visual acuity is reduced.When this phe- do those receiving topical mitomycin C. Patients nomenon occurs, it is termed . The vital taking tamoxifen have been found to have a higher time begins before or at birth and is believed to end proportion of a specific class of cataract (posterior between age 7 and 13. Once development is complete, subcapsular) following years of treatment,which also alterations in the no longer change the may be indicative of lenticular toxicity [4, 20]. potential vision. When identified early in its course, amblyopia is potentially reversible. Visually impair- ing complications in children must therefore be recognized early. 06_Schwartz_Occular 27.01.2005 8:31 Uhr Seite 89

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neovascularization, also known as rubeosis iritis, 6.6 Uvea: Iris, Ciliary Body and Choroid occurs several months to years following RT with fractionated doses of 70–80 Gy over 6–8 weeks. The 6.6.1 Anatomy and Physiology abnormal vessels that result from this condition can The uvea consists of three structures with a common grow into the trabecular meshwork, thereby causing embryologic origin: the iris, ciliary body and intractable . Rubeosis iritis is believed to be choroid. The iris acts as the light aperture of the eye. caused by retinal ischemia, resulting in the liberation It is a muscular membrane with a central circular of vascular growth factors throughout the eye. Poste- opening (the ). Despite the wide variation in iris rior synechiae can also cause glaucoma by preventing color on the anterior surface, the posterior surface of fluid produced behind the iris from reaching the tra- the normal iris characteristically contains a thick lay- becular meshwork located anterior to the iris. Iris er of heavily pigmented cells that act to absorb and atrophy has been reported three years after high thus limit the influx of light. The size of the pupil is doses of beta-irradiation with 170–250 Gy [2, 3]. controlled by the autonomic nervous system with input from both sympathetic and parasympathetic 6.6.4 Chemotherapy systems. The ciliary body is a muscular structure located Corticosteroid treatment is known to cause an eleva- posterior to the iris and peripheral to the lens. The tion in intraocular pressure with the associated de- ciliary body produces the aqueous humor, the fluid velopment of glaucoma. Several factors may influ- that fills the anterior segment of the eye. This fluid ence a patient’s susceptibility to steroid-induced drains through a structure known as the trabecular glaucoma,including older age,genetic predisposition meshwork located anterior to the iris. As a result, the to glaucoma and length and increased dose of treat- fluid must travel through the pupil in order to exit the ment [21–23]. Generally, therapy for at least two eye. Any disruption to this flow will result in a back- weeks is required for increased intraocular pressure up of fluid and increased pressure within the eye, to manifest.Although the increased pressure induced known as glaucoma. The ciliary body is also respon- by corticosteroids usually resolves with cessation of sible for adjusting the tension on the zonule that al- the therapy, irreversible glaucoma has also been lows for lens . The choroid, located demonstrated [24]. In addition, corticosteroids have between the retina and sclera, is the posterior seg- been implicated in facilitating infective . ment of the uveal tract. It is a highly vascular struc- Severe uveal reactions have been reported follow- ture that supplies the outer retina with oxygen. ing intracarotid treatment with chemotherapeutic agents, including one case, with intracarotid cisplatin 6.6.2 Acute Radiation Effects infusion, of serous [25]. In addi- tion, one report found that 25% of patients treated Uveitis is an early effect of RT. It is caused by an in- with intracarotid mechlorethamine, a nitrogen mus- crease of vascular permeability,which leads to a leak- tard compound, developed an ipsilateral necrotizing age of protein and inflammatory cells [2]. Iritis (in- uveitis [26]. flammation of the iris) is dose-related and can occur after a fractionated dose of greater than 60 Gy over 6.6.5 Medical and Nursing Management 5–6 weeks. The medical management of non-infectious uveitis 6.6.3 Chronic Radiation Effects includes steroid ophthalmic drops and dilation drops (often Cyclogyl) to reduce inflammation,paralyze the Iris neovascularization, posterior synechiae (adhe- ciliary body for pain control and pull the iris away sions between the iris and the lens) and iris atrophy from the lens. Beta-blocker, alpha-agonist, carbonic are the major long-term complications of RT. Iris anhydrase inhibitors and prostaglandin analog eye 06_Schwartz_Occular 27.01.2005 8:31 Uhr Seite 90

90 Chapter 6 M. Ober · C. A. Servodidio · D. Abramson

drops all aid in lowering intraocular pressure. Photo- 6.7.5 Medical and Nursing Management coagulation of the iris (peripheral iridotomy) is occa- sionally needed to restore aqueous flow from produc- may benefit from systemic corticosteroid tion by the ciliary body to drainage in the trabecular therapy. More severe reactions, such as scleral melt- meshwork. Severe, unresponsive glaucoma may ing and ulceration, require close observation, treat- require surgical intervention to create an alternative ment with antibiotic drops and surgical repair with pathway for aqueous drainage. scleral grafting.Eye protection and the importance of avoiding trauma should be emphasized to patients.

6.7 Sclera 6.8 Optic Nerve and Retina 6.7.1 Anatomy and Physiology 6.8.1 Anatomy and Physiology The sclera is an acellular, avascular, collagenous pro- tective layer of the eye. It is continuous with the The retina is a thin, transparent structure that func- cornea at the limbus and covered anteriorly by the tions to convert light energy into electrical stimuli for conjunctiva. The superficial coating of the sclera, the brain to interpret. The macula, located temporal known as the episclera, consists of a loose, transpar- to the , is responsible for central vision and ent, vascular coating. contains the highest concentration of photoreceptors. The blood–retina barrier, which is analogous to the 6.7.2 Acute Radiation Effects blood–brain barrier, protects the retina. It is very sen- sitive to changes in vascular permeability that can lead The sclera may become inflamed 2–4 weeks after to swelling of the retinal layers (i.e. ). the initiation of RT. This condition is transient and The optic nerve contains 1,100,000 axons from the usually resolves on its own. superficial layer of the retina. These axons leave the eye through an area known as the optic disc and com- 6.7.3 Chronic Radiation Effects prise the pathway through which visual stimuli reach the brain. The sclera is able to tolerate doses of RT up to 900 Gy from an iodine or cobalt plaque when administered 6.8.2 Acute Radiation Effects over a period of four days to one week. Thinning, melting or atrophy of the sclera can occur several RT, either with 20–35 Gy fractionated over 2–4 weeks years after fractioned RT doses of 20–30 Gy. These or in doses in excess of 50 Gy, has been reported to scleral conditions are uncommon after RT for child- produce a transient retinal edema [1, 2]. hood tumors treated with external beam radiation, unless extremely high doses are used.Scleral perfora- 6.8.3 Chronic Radiation Effects tion may also occur, although it is rare [2]. Radiation (Fig.6.5) is a well-documented 6.7.4 Chemotherapy consequence of radiation treatment. It is character- ized by specific examination findings, including mi- There are no reported scleral complications when croaneurysms, hard exudates, cotton-wool spots, chemotherapy agents are used systemically; however, optic disc swelling, vascular occlusion, hemorrhages mitomycin C,which is used topically as adjunct treat- and neovascularization. These changes are clinically ment for ocular surface tumors, may lead to scleral indistinguishable from retinal changes due to dia- ulceration, scleritis and scleral calcification [4]. betes. Radiation retinopathy can develop as soon as 3 weeks, and as late as 15 years, following RT, although, typically, it occurs between 1 and 3 years. 06_Schwartz_Occular 27.01.2005 8:31 Uhr Seite 91

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Figure 6.5 Radiation retinopathy

Although as little as 15 Gy of external beam radiation visual loss due to retinopathy and has led to signs of retinopathy, 30–60 Gy are usually [32]. Intrathecal methotrexate has been reported to required.In the authors’experience,fewer than 5% of cause optic nerve atrophy, optic neuropathy, retinal children treated with external beam radiation for pigment changes and retinal edema [33]. Patients retinoblastoma develop radiation retinopathy. 50 Gy treated with Tamoxifen for a period greater than nine is regarded as the threshold for the development of months are susceptible to a crystalline retinopathy retinopathy following radioactive plaque exposure. and , although the visual impair- Either a history of diabetes mellitus or concurrent ment is generally reversible with cessation of treat- treatment with chemotherapy is believed to increase ment. In addition, bilateral with retinal susceptibility to radiation retinopathy [3, 27]. hemorrhages has been reported within three weeks of Tamoxifen initiation [34]. 6.8.4 Chemotherapy Corticosteroids have been implicated in the devel- opment of pseudotumor cerebri and its associated The optic nerve and retina are common sites for optic nerve swelling. In addition, the immunosup- chemotherapeutic complications. Retinal hemor- pressive effects of corticosteroids have been linked rhages, cotton wool spots and optic disc edema have to retinal infections. Plant alkaloids vincristine and all been reported following systemic nitrosoureas vinblastine may lead to visual loss and double vision [28], while intracarotid infusion has been implicated secondary to optic neuropathy, optic atrophy and in optic neuritis and atrophy [29]. In some patients cranial nerve palsies [35, 36].Acute optic neuropathy, treated systemically, cisplatin has produced optic along with cranial nerve palsy, may also follow neuritis, and retinal toxicity that mani- 5-fluorouracil treatment [4]. In addition, visual fests as [30]. Intracarotid infusion loss in the form of optic nerve damage has been can lead to visual loss from severe retinal and/or op- attributed to fludarabine, cyclosporine, paclitaxel, tic nerve ischemia,pigmentary retinopathy or exuda- nitrogen mustards and intrathecal cytosine arabi- tive retinal detachment [31]. Carboplatin has led to noside [37–40]. 06_Schwartz_Occular 27.01.2005 8:31 Uhr Seite 92

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6.8.5 Medical and Nursing Management

Retinal hemorrhages and cotton wool spots as part of radiation retinopathy will resolve without treatment; however, they are clear indications of retinal damage and are cause for ophthalmologic referral. Retinal edema manifests as blurred vision when it affects the macula. It is diagnosed by careful slit lamp biomi- croscopy with the aid of fluorescein angiography. Current treatment options include laser photocoagu- lation and corticosteroids. Neovascularization (both iris and retinal) is a manifestation of chronic retinal ischemia and is also treated with laser photocoagula- tion. Because diabetes mellitus and hypertension can mimic and/or potentiate radiation retinopathy, strict control of blood sugar and blood pressure should be emphasized. The treatment of optic disc edema and optic neu- ropathy is controversial. While the use of systemic Figure 6.6 corticosteroids and pressure-lowering medications Orbital bone suppression may be effective, observation is also a viable option.

6.9.3 Chronic Radiation Effects 6.9 Orbital Bones and Tissue Suppression of bony growth remains the most com- 6.9.1 Anatomy and Physiology mon orbital complication of chronic RT. The result is The orbital cavity is composed of seven bones: the especially noticeable in patients treated at a young maxilla, palatine, frontal, sphenoid, zygomatic, eth- age for retinoblastoma or rhabdomyosarcoma.A hol- moid and lacrimal bones. They form the shape of a lowing of the temporal bone, stunted vertical growth quadrilateral pyramid with the apex forming posteri- of the and saddle nose (flattening and shorten- orly and the medial walls parallel. The soft tissues of ing of the bridge of the nose) are typical features the orbit consist of the , orbital which occur years after a dose of 40–70 Gy to the fat,fascia and vascular structures.The function of the orbit,fractionated over a 3- to 7-week time period [2] orbital bones is to protect the eye, while the soft tis- (Fig. 6.6). The bony effects of radiation are reduced sues act to cushion the eye and optic nerve during when treatment is delayed until 6 months or, even movement. better, one year of age [3]. Furthermore, advanced ra- diation techniques allow greater precision in tissue 6.9.2 Acute Radiation Effects localization, thus sparing anterior segments of the eye and uninvolved bone. There are no known acute radiation effects to the Anophthalmic socket syndrome, or soft tissue at- orbital bones. rophy, and contracture of the socket following re- moval of the eye, has been documented after radio- therapy in patients treated for retinoblastoma [41]. Osteonecrosis rarely results after very high doses of radiotherapy, but may be associated with concurrent orbital infections. Most devastatingly, second, non- 06_Schwartz_Occular 27.01.2005 8:31 Uhr Seite 93

Ocular Complications Due to Cancer Treatment Chapter 6 93

ocular cancers may also develop in the radiation field, especially in retinoblastoma patients who are References predisposed to tumor formation [42]. 1. Haik BH, Jereb B, Abramson DH et al. (1983) Ophthalmic radiotherapy.In: Iliff NT (ed) Complications in ophthalmic surgery. Churchill Livingstone, New York, pp 4449–4485 6.9.4 Chemotherapy 2. Brady LW, Shields J, Augusburger JJ et al (1989) Complica- Intracarotid carboplatin concurrent with intra- tions from radiation therapy to the eye. Front Radiat Ther Oncol 23:238–250 venous etoposide may produce severe visual loss 3. Ober MD, Beaverson K, Abramson DH Ocular complica- secondary to severe orbital inflammation and optic tions.In:Wallace H,Green D (eds) Late effects of childhood nerve ischemia [43]. cancer. Arnold, London Both 5-fluorouracil and methotrexate therapy 4. Al-Tweigeri T, Nabholtz JM, Mackey JR (1996) Ocular toxi- have also led to clinically significant periorbital ede- city and cancer chemotherapy. A review. Cancer 78:1359– 1373 ma. Corticosteroids have been shown to cause a pro- 5. Sidi Y, Douer D, Pinkhas J (1977) Sicca syndrome in a trusion of the globe known as [44]. patient with toxic reaction to busulfan. JAMA 238:1951 Paralysis of the eye muscles (ophthalmoplegia) has 6. Straus DJ, Mausolf FA, Ellerby RA (1977) Cicatricial been reported with cyclosporine [45] and vin- ectropian secondary to 5-fluorouracil therapy. Med Pediatr cristine, due to cranial nerve palsy [14]. Oncol 3:15–19 7. Esmaeli B, Valero V, Ahmadi A et al (2001) Canalicular stenosis secondary to docetaxel (taxotere). A newly recog- 6.9.5 Medical and Nursing Management nized side effect. 108:994–995 8. Miller D, Pecxon JD (1965) Corticosteroid and functions in There is no medical treatment to reverse the retarda- the anterior segment of the eye. Am J Ophthalmol 59:31 tion of bone growth. Osteonecrosis may require sur- 9. Seiff SR, Shorr N, Adams T (1985) Surgical treatment of punctual-canalicular fibrosis from 5-fluorouracil therapy. gical debridement and antibiotics. Anophthalmic Cancer 56:2148–2149 socket syndrome is very difficult to treat and some- 10. Donnenfeld ED, Ingraham HJ,Abramson DH (1993) Effects times requires orbital reconstruction surgery. of ionizing radiation on the conjunctiva, cornea, and lens. Anophthalmic sockets with ocular prosthesis require In: Alberti WE, Sagerman RH (eds) Medical radiology. Radiotherapy of intraocular and orbital tumors. Springer, regular care and cleaning with gentle soaps.The orbit Berlin Heidelberg New York, pp 261–270 itself must be examined by a medical professional pe- 11. Palmer ML, Hyndiuk RA (2000) Toxicology of corticos- riodically for the development of second malignan- teroids and other antiinflammatory agents. In: Albert DM, cies. Finally, counseling should be available to pa- Jakobiec FA (eds) Principals and practice of ophthalmolo- tients regarding the disfiguring effects of radiation gy, 2nd edn. Saunders, Philadelphia, PA, pp 399–416 12. Tseng SC (1986) Topical treatment for severe dry-eye disor- on bone growth. ders. J Am Acad Dermatol 15:860–866 13. Blondi FC (1958) The late effects of x-radiation on the cornea. Trans Am Ophthalmol Soc 56:413–450 6.10 Conclusion 14. Albert DM,Wong VG, Henderson ES (1967) Ocular compli- cations of vincristine therapy.Arch Ophthalmol 78:709–713 15. Kaiser-Kupfer MI, Lippman ME (1978) Tamoxifen retino- The present and future outlook for the treatment of pathy. Cancer Treat Rep 62:315–320 children with primary ophthalmic tumors and other 16. Merriam GR, Focht EF (1957) A clinical study of radiation tumors involving the eye and its bony structures is cataracts and the relationship to dose. Am J Roentgenol encouraging. Cancers that were once uniformly fatal 77:759–785 are today viewed as treatable. Newer techniques in 17. Braver DA, Richards RD Good TA (1967) Posterior subcap- sular cataracts in steroid treated children. Arch Ophthal- radiotherapy, which provide the ability to conserve mol 77:161 vision and spare non-involved bone, together with 18. Loredo A, Rodriguez RS, Murillo L (1972) Cataracts after advancements in chemotherapy and surgery, offer short-term corticosteroid treatment. N Engl J Med 286:160 not only a longer lifespan, but also, improved quality of life. 06_Schwartz_Occular 27.01.2005 8:31 Uhr Seite 94

94 Chapter 6 M. Ober · C. A. Servodidio · D. Abramson

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