Few serious irreversible ocular side effects secondary to iodide preparations have been reported, except when these agents have been given intravenously. Intravenous I-131 can cause permanent obstruction of the lacrimal outflow system (Yuoness et al 2011; Cetinkaya et al 2007; Brockmann et al 2005; Shepler et al 2003; Kloos et al 2002; Omur et al 2011). Burns et al (2004) felt that this occurred at 3.4% incidence and 4.6% documented or suspected incidences. They felt that both of these percentages may have been low.

Kloos et al (2002) pointed out that I-131 may aggravate ocular sicca. All iodine products seem to be secreted in the tears. When I-131 is given intravenously, this concentrates in the lacrimal sac; and, if concentrations are high enough or there is a partial obstruction there already, radiation damage may cause scarring to occlude the passage. Graves disease has also been reported (Munigoti et al 2008; Tahrani et al 2007).

The severe retinal changes reported in the literature are secondary to a drug, septojod (iodines and iodates), that is no longer in use. It was the first drug recognized to cause retinal pigmentary degeneration (Duke-Elder et al 1972). When currently available products are given orally, retinal findings are probably nonexistent. Allergic reactions to these agents are of rapid onset and not uncommon. They may occur at small doses with responses occurring within minutes. A delayed hypersensitivity reaction may occur, causing iododerma with tender pustules, vesicles and nodular eyelid lesions. This reaction may be associated with keratoconjunctivitis sicca, hemorrhagic iritis and vitreous opacities.

Sildenafil (Viagra) has been studied far more extensively than tadalafil and vardenafil. In premarketing clinical trials, all three agents have a similar incidence of visual side effects; and all were proven transitory. Sildenafil citrate has been one of the largest selling prescription drugs in the world. The ocular side effects most commonly associated with sildenafil are a transitory bluish tinge to objects, hypersensitivity to light and minimal hazy vision. These reversible side effects may last from a few minutes to hours, depending on drug dosage. Visual changes are seen in approximately 3% of men taking the standard 50-mg dose and 11% of men taking 100 mg, with the incidence rising to 40% at a dose of 200 mg. At four times the recommended dose (200 mg) sildenafil causes minimal reversible ERG changes in b2 wave amplitude, both in phototopic and scotopic conditions, but with a less than 10% decrease in photopic implicit times in a- and b-waves. Although at normal dosage, a multicenter well-designed study (Cordell et al 2009) showed no ERG-related findings associated with daily administration of sildenafil or tadalafil over a six-month period. Conjunctival hyperemia, ocular pain and photophobia may occur. Chandeclerc et al (2004) has reported palpebral edema in one case with rechallenge data.

There has been a number of papers, both pro and con, on the relationship of erectile dysfunction drugs causing nonarteritic ischemic optic neuropathy (NAION). The FDA required the manufacturers to do a prospective study as to causality. This resulted in an FDA alert:

There are eight published cases of macular edema (Allibhai et al 2004; Gordon-Bennett 2012; Park 2007; Quiram et al 2005) and another seven in the National Registry (Fraunfelder et al 2005). Four of these cases have positive rechallenge of serous macular edema associated with erectile dysfunction drugs at normal or elevated dosages. Included are cases of chronic macular edema, which would not resolve until the drug was stopped. In total. there are now some 36 cases of retinal or macular edema in the literature and National Registry. While this data is interesting, the nature of non–drug-induced serous macular edema is recurrent and transitory. Further data is necessary; however, a few cases are suggestive, such as Aliferis et al (2012) with challenge-rechallenge data. The French et al (2010) case-control study of 111 men 59 years old and younger had no increased central serous choroidopathy versus the controls.

Multiple reports of retinal vascular accidents associated with the use of these drugs are given in the National Registry. Since this is not an uncommon finding in elderly patients, a positive association is not possible.

Gerometta et al (2011) showed a transient increase of intraocular pressure after taking sildenafil. Harris et al (2008) reviewed all studies of ocular blood flow with this class of drugs. Most studies suggest an increase in choroidal blood flow with a lesser effect in the retina. Vance et al (2011) document an increase in choroidal thickness. Ioannides et al (2009) reported 10 cases of acne rosacea in patients taking this drug.

In summary, a number of studies in following patients on these drugs long term or in a three-month double-blind crossover study (20–80 mg tid sildenafil for pulmonary arterial hypertension versus placebo) had complete ophthalmic exams, including contract sensitivity, visual fields and color vision and showed no permanent adverse ocular effects.

Recommendations

Over 200 million women have taken this group of drugs and still there is significant debate as to what side effects are real. This confusion is in large part due to their ever-changing formulation with newer contraceptives. A higher incidence of migraine, thrombophlebitis and intracranial hypertension probably occurs in women taking oral contraceptives than in a comparable population. There is some evidence that combination oral contraceptives, which contain more progestins, have fewer side effects than those that contain mainly estrogens. There is an increased risk of venous thrombosis in patients on these medications. Risk factors include personal history of venous thrombosis, gross obesity and abnormalities of the hemostatic mechanism (Vandenbroucke et al 2001). Arterial thrombosis may be less likely but aging, smoking and hypertension may increase patient risk. Schwartz et al (1999) reported that both ischemic and hemorrhagic stroke associated with the “pill” were double over controls if the woman had a history of migraine headaches. In a few cases, the courts have ruled that there is a cause-and- effect relationship between the use of oral contraceptives and retinal vascular abnormalities. In selected patients with retinal vascular abnormalities, there should probably be informed consent or even the consideration of not taking the drug. If retinal vascular abnormalities develop, the use of these drugs in that patient may need to be reevaluated. With long-term use, there are data that suggest there can be decreased color perception, mainly blue and yellow, and prolonged photo stress recovery times. This is seldom clinically identified. If a patient has a transient ischemic attack, the oral contraceptive may need to be discontinued since the incidence of strokes is significantly increased. In the National Registry and the literature, there are cases that implicate these drugs in causing macular edema. A number of these patients have been rechallenged with recurrence of the edema. Rait et al (1987) stated that most patients with acute macular neuroretinopathy have been taking oral contraceptive medication in addition to other possible causative factors. They postulate the “pill” as a possible cofactor. There is a suggestion that pregnancy causes progression of retinitis pigmentosa. Since these oral contraceptives cause a pseudopregnancy, there is a question of whether they may also cause progression of this retinal disease. However, there is no proof of this, and most researchers feel these agents are safe for the retinitis pigmentosa patient to use.

Garmizo et al (2008) and Orlin et al (2010) have described patients on various estrogo-progestogens that develop bluish-green or turquoise corneal deposits in a dusting or lacy pattern. These are worse inferiorly in the mid periphery cornea. These differ from a Kaiser-Fleischer ring by having a clear cornea between the deposit and the limbus. If the drugs are stopped, these deposits regress and disappear. In numerous studies, oral contraceptives have been associated with elevated serum copper levels (Schenker et al 1971).

The National Registry has received numerous case reports of cataracts possibly related to the administration of oral contraceptives. Recent data by Klein et al (1994) show no evidence to support this. In fact, oral contraceptives may even have a modest protective effect on the lens. Benitez et al (1997) and Harding (1994) both support Klein’s data in well-designed studies. However, recently Cumming et al (1997), in the Blue Mountain Eye Study, have supported the hypothesis that estrogen and/or progestin may be involved in cataract development. The problem in part is the lack of an easy, accurate way to grade lenses. The Swedish Mammography Cohort study (30,861 participants) showed that women taking hormone replacement therapy for some time showed a significant positive risk of having cataract surgery versus controls (Lindblad et al 2010). They also showed that this risk was even greater if >1 alcoholic drink was consumed each day. There is a relationship of oral contraceptives and contact-lens intolerance. Candela et al (1989) found increased tear mucus production in patients on these drugs. Since there are estrogen receptors in the cornea and retina, changes can be expected. For example, Giuffre et al (2007) have shown changes in corneal thickness during menstruation. Deschenes et al (2010) showed increased blood flow in the retina in females on postmenopausal hormone replacement. Tomlinson et al (2001) could not confirm this. Mayer (1944) found transitory decreased accommodation on diethylstilbestrol. There are a number of case reports in the literature and in the National Registry of retrobulbar and optic neuritis, optic nerve pathology with various visual field abnormalities, pupillary abnormalities, uveitis, transient myopia, exophthalmos, paralysis of extraocular muscles and nystagmus. A clear cause-and-effect relationship between these events and the drug is difficult to prove. Most of these reports were from patients who were in the age range usually associated with multiple sclerosis.

Having said all of the above, Vessey et al (1998) in two large UK cohort studies suggested that oral-contraceptive use does not increase the risk of eye disease, with the possible exception of retinal vascular lesions. However, based on the literature and National Registry data, our classifications are our “best guesses” at this time.

The Pasquale et al (2011) study of 79,440 females who took ≥5 years of oral contraceptive showed a modest increased risk of primary open-angle glaucoma (POAG). Hulsman et al (2001), in a study of 3,078 females and in those who had an earlier onset of menopause, reported that those females had a higher risk of POAG. Pasquale et al (2013), in 3,430 controls of both genders, found only in females an estrogen metabolism single nucleotide polymorphism panel that was associated with POAG.

Abramov et al (2005) in a small study showed that hormone replacement therapy and life-long estrogen and progesterone exposure does not seem to affect intraocular pressure (IOP) or cause an increased risk of IOP. Tint et al (2010) reported that IOP was significantly lower in females taking hormonal therapy (HT). Therefore, there is data supporting HT increasing and even a decrease of IOP on HT. Further research is necessary to answer this question.

Generic Name:

Estradiol.

Proprietary Names:

Alora, Climara, Delestrogen, Depo-Estradiol, Divigel, Elestrin, Estrace, Estraderm, Estrasorb, Estring, EstroGel, Evamist, Femring, Femtrace, Gynodiol, Inofem, Menostar, Vagifem, Vivelle, Vivelle-Dot.

Primary use

This naturally occurring estrogen is administered in tablets, transdermal patches and vaginal creams, and used in the management of menopause, vulval and vaginal atrophy, ovarian failure, uterine bleeding, and prevention of osteoporosis.

Levonorgestrel is twice as potent as, and more commonly used than, norgestrel. The documented side effects mentioned here are primarily all for levonorgestrel. Alder et al (1995) reported 57 cases of intracranial hypertension or papilledema from a spontaneous reporting system; and there are an additional 70 cases known to the manufacturer (Weber et al 1995), all possibly due to levonorgestrel. Alder’s series of patients were female with a mean age of 23 years (range 16–34 years), with a mean levonorgestrel treatment of 175 days (range 9–616 days) before the onset of intracranial hypertension. Visual field defects (primarily blind spots) were present in at least 12 cases. Diplopia, usually due to 6th-nerve paresis, was present in 16 cases. However, there were at least 140 cases of blurred vision reported with patients taking this agent. Of course, the problem with this type of data is that intracranial hypertension occurs in this age group of persons without obesity at a rate of approximately 3.3 per 100,000 per year; therefore, a report of 57 cases with much of the data being incomplete is suspect for causality.

The drug first came on the market in 1991, and in 1994 the manufacturer first released the possible association of this drug with intracranial hypertension. They stated that in patients who have vision disturbances or headaches, especially headaches that change in frequency, pattern, severity or persistence, it is particularly important to view the optic nerves. Also, they suggest that patients who develop papilledema or intracranial hypertension have the implants removed. While not a proven association, one should probably remove the implants if optic nerve findings occur. Brittain et al (1995) reported myasthenia gravis occurring after insertion of a levonorgestrel implant and improving after its removal. Levonorgestrel has been associated with acute attacks of pophyria with various ocular and acute ocular findings. These include retinal edema, cotton-wool spots, hemorrhages and scleral ulcers. Partial 3rd-nerve palsy, ptosis and mydriasis can occur.

There are 108 cases in the National Registry of problems with accommodation while on levonorgestrel.

Clomifene appears to have a unique effect on the retina that may occur in up to 10% of patients. This consists of any or all of the following: flashing lights, glare, various colored lines (often silver), multiple images, prolonged afterimages, “like looking through heat waves,” objects have “comet” tails, phosphene stimulation and scintillating scotomas identical to migraine. Racette et al (2010) reported that all 8 patients with ocular side effects in their study had bilateral reduction in flicker sensitivity. These may occur as early as 48 hours after taking this agent and are reversible after stopping the medication. Transitory and prolonged decreased vision has also been reported. After years of prolonged use, vision loss in the 20/40–60 range may occur (etiology unknown), which may be slow to recover. Purvin (1995) reported three cases of irreversible prolonged visual disturbances (palinopsia), as described above. Cases in the National Registry support this. Bilateral acute reversible loss of vision, even in the light perception range, is a rare event. Mydriasis is common, but of a mild degree and reversible. Of clinical significance are the unilateral or bilateral scotomas and visual field constriction seen with this drug. It is of interest that classic scintillating scotoma seems to occur secondarily to clomifene. Some of these side effects required discontinuing the medication. The causes of these are unclear but Padron Rivas et al (1994) and several cases in the National Registry suggest the possibility of an optic neuritis for some of these effects. These are in females, most in the multiple sclerosis age group, and a cause-and-effect relationship is conjecture. Usually, the patient refuses to take further medication; and, if the drug is continued, the long-term sequelae are unclear. Decreased contact-lens wear may be due to clomifene’s ability to inhibit mucus production. Monocular and binocular diplopias have been reported, but are not well documented. While the literature contains references to the cataractogenic potential of this agent, a drug-related cause has not been proven. There is one well-documented case in the National Registry of this agent causing bilateral elevated intraocular pressure. Myers et al (2008) reported a single case of bilateral uveitis in a 30 year old with polycystic ovary syndrome after starting clomifene. The drug was stopped with full recovery in three weeks. Three months later, the drug was restarted and within eight days bilateral uveitis returned (Myers et al 2008). Lawton (1994) reported a case suggestive of anterior ischemic optic neuropathy on the basis that the drug may cause increased blood viscosity. Retinal vascular occlusions have been reported, but usually with complicating medical problems (Viola et al 2011; Politou et al 2009). This drug also has ocular teratogenic effects. It has been reported that about 1% of patients are forced to stop taking it secondary to ocular side effects.

Lee et al (2004) found a possible association of glaucoma and thyroid disease in the Blue Mountains Eye Study. This was particularly true in patients currently treated with levothyroxine. They stated, however, that further evaluation of this potential association is warranted. There are numerous articles suggesting that this group of drugs can cause intracranial hypertension. Prepubertal and peripubertal hypothyroid children may be the most susceptible to intracranial hypertension when beginning this group of drugs. Sundaram et al (1985) reported petit mal status epilepticus with rapid rhythmic eyelid fluttering and blinking occurring in a patient approximately 1 week after starting levothyroxine therapy. Lledo Carreres et al (1992) reported a case of toxic internuclear ophthalmoplegia after the use of these agents for weight loss. Visual hallucinations have appeared soon after initiation of thyroid replacement therapy in hypothyroid patients, usually in patients with an underlying psychiatric disorder. Other than the CNS changes, most ocular findings clear within a few months of discontinuing the medication.