Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

Figure 35-8 Characteristic bull’s eye maculopathy associated with chloroquine toxicity.

The zone of depigmentation is, in turn, surrounded by another ring of pigment. Although this clinical picture can vary in intensity, it is pathognomonic of chloroquine retinopathy and is referred to as a “bull’s eye” maculopathy (Figure 35-8).

Variations of RPE disturbances can occur but most often appear as well-circumscribed areas of RPE atrophy in the macular area, which may resemble a macular hole (Figure 35-9). A high degree of bilateral symmetry between eyes is generally noted, but occasionally the toxicity can affect one eye more than the other.

Some patients with chloroquine retinopathy may have retinal changes resembling retinitis pigmentosa. Chloroquine retinopathy does exhibit peripheral RPE hyperplasia, but, in contrast to retinitis pigmentosa, the pigment does not tend to accumulate around the retinal veins.

Figure 35-9 Retinal pigment epithelial atrophy in macular area as a consequence of chloroquine therapy.

Figure 35-10 Peripheral retinal pigment epithelial hyperplasia characteristic of pseudoretinitis pigmentosa in 42-year-old man with chloroquine toxicity.

The peripheral lesions can occur with or without simultaneous macular involvement (Figure 35-10). Other changes include attenuated retinal vessels, optic atrophy, peripheral visual field loss, abnormal color vision, and a subnormal electroretinogram (ERG). The fact that the dark-adaptation threshold is normal, or only minimally abnormal, further differentiates this condition from retinitis pigmentosa.

Although the visual fields may be normal even in the presence of definite macular pigmentary changes, visual field loss generally correlates well with the degree of retinal damage.The typical visual field defects in chloroquine retinopathy consist of central or paracentral scotomata, which may become confluent and form a complete ring.

In the early stages of retinopathy, electrodiagnostic studies tend to be of little value in detecting early toxicity. Both the ERG and EOG can be normal or abnormal. Advanced cases of retinopathy, however, usually exhibit markedly abnormal, or even extinguished, ERGs. This is especially true in cases involving the retinal periphery. Multifocal electroretinography may show decreased electrical responses in the macular areas of patients who have normal standardized Ganzfeld ERG results.

Although it is possible for patients with chloroquine maculopathy to be asymptomatic, extensive macular damage often leads to symptoms of decreased visual acuity, metamorphopsia, and visual field disturbances. Pericentral ring scotomas can cause reading difficulty.Although color vision is normal in the early stages of chloroquine toxicity, more extensive macular damage can lead to severe impairment of color vision. Dark adaptation is typically normal, an important feature distinguishing the peripheral retinal changes from those seen in retinitis pigmentosa.

Risk factors for the development of retinopathy are related to daily dosage, duration of treatment, serum drug levels, and patient age, size, and amount of body fat.

The incidence of retinopathy increases with patient age, and in older patients retinal toxicity appears to be correlated with total drug dosage.

The risk of retinopathy associated with hydroxychloroquine is considerably less than that associated with chloroquine. In one study retinal toxicity occurred in only 4 of 99 patients receiving hydroxychloroquine in a daily dosage of 400 mg for at least 1 year. No patient, however, sustained significant vision loss, and the abnormalities were reversible after the medication was discontinued. In some cases the macular changes may be reversible without recurrence even if the medication is reinstituted. Despite early diagnosis and withdrawal of medication, permanent visual field defects can occur.The risk of retinal toxicity seems to be minimal if the daily dose of hydroxychloroquine is less than 6.5 mg/kg of body weight, the duration of treatment is less than 5 years, and renal function is norma1 (Table 35-11).

Etiology

Although the precise mechanisms of chloroquine and hydroxychloroquine toxicity are not well understood, it is known that metabolic effects are noted in the retinal photoreceptors. Both agents reversibly bind to melanin in the RPE, and this binding may serve to concentrate and prolong the toxicity, even after the drug is discontinued. Although the periphery can be affected, the effects of chloroquine and hydroxychloroquine center primarily in the maculae.This suggests a relationship to cone metabolism or possibly to light absorption as a contributing factor. This can lead to degenerative changes of the RPE. The destructive process within the RPE leads to migration of pigment-laden cells from the RPE to the outer nuclear and outer plexiform layers. The foveolar cones are often spared, which explains the ophthalmoscopic appearance

seen in cases of bull’s eye maculopathy.Attenuation of the retinal arterioles along with optic nerve pallor is thought to be secondary to the extensive retinal damage.

Management

Recommendations for screening procedures for chloroquine or hydroxychloroquine toxicity have been quite variable both in frequency of examination and in types of required tests at each visit. Although examination for sight-threatening adverse effects of these medications is critical, evidence, costs, and risk-to-benefit ratios necessitate a balance of all these factors.

Patients should receive baseline examinations after starting therapy and should be examined periodically for evidence of retinal changes. Early retinopathy has been shown to be reversible if drug dosage is reduced or discontinued; however, others show a continued progression despite drug discontinuation. Baseline examination of the fundus is especially important because drug-induced maculopathy can resemble age-related macular disease. This examination should include a full ophthalmic examination, including visual acuity,Amsler grid, and Humphrey central 10-2 visual field testing. Color vision and fundus photography are useful tests. Fluorescein angiography and ERG testing are not undertaken unless another condition is to be differentiated.

Controversy has existed over the length of time to follow-up, ranging from every 3 months to infrequently. Once treatment has started, follow-up examinations should be based on risk factors (see Table 35-11). The current Preferred Practice Pattern indicates that patients at low risk of developing retinopathy can be monitored based on age; that is, at least once in the span between 20 and 29 years, at least twice between 30 and 39 years, every 2 to 4 years between 40 and 64 years of age, and

every 1 to 2 years over the age of 65. Patients using the drug for greater than 5 years and patients determined to have other risk factors should have yearly examinations. Individual patient factors must always be considered, and the patient should be informed and the record clear regarding counseling and examination findings. Patients should be counseled that there is a small risk of toxicity within the initial 5-year period and, indeed, at all if they have a low-risk profile. Emphasis should be made, however, that they should return before their next scheduled appointment if they notice any change in visual acuity,Amsler grid appearance, color perception, or dark adaptation problems or if they develop liver or kidney problems or are given an increased dosage.

Testing of contrast sensitivity is an additional screening procedure that may detect early macular dysfunction, particularly in patients younger than 40 years of age. Color vision should be evaluated with a color vision test designed to detect both mild blue-yellow and protan redgreen deficiencies. Tests that meet these criteria are the Standard Pseudoisochromatic Plates Part 2 and theAmerican Optical Hardy-Rand-Ritter.

Cessation of the drug is the only management option if toxicity is suspected. Because these drugs are often critical to the management of the patient’s disease, this decision should be made with the patient and his or her internist or rheumatologist. Early changes may be discussed with the patient and the caregivers and an active decision made to either continue or discontinue the drug. In the former case, close follow-up is suggested (at least every 3 months). Even after discontinuation visual loss may continue despite drug cessation, so those patients with obvious bull’s eye maculopathy or vision loss should also be reexamined within 3 months and on a continual basis several years after drug cessation.

Thioridazine

Chlorpromazine (Thorazine) and thioridazine (Mellaril), both phenothiazine derivatives, are used for their antipsychotic effects in the control of severely disturbed or agitated behavior and in schizophrenia. Thioridazine has a higher incidence of antimuscarinic effects but a lower incidence of extrapyramidal symptoms. Pigmentary changes of the retina have been reported occasionally in association with chlorpromazine therapy, although it is recognized that only thioridazine produces retinal toxicity.

Clinical Signs and Symptoms

Thioridazine can cause significant retinal toxicity, leading to reduced visual acuity, changes in color vision, and disturbances of dark adaptation.These symptoms typically occur 30 to 90 days after initiation of treatment. The fundus often appears normal during the early stages of symptoms, but within several weeks or months a pigmentary

Figure 35-11 Retinal pigment epithelial hyperplasia and atrophy in 33-year-old man with thioridazine retinopathy.

retinopathy develops, characterized by fine clumps of pigment developing first in the periphery and progressing toward the posterior pole (Figure 35-11). In milder cases the pigment remains fine and peppery, but in more severe cases the pigment can form plaque-like lesions with multiple confluent areas of hypopigmentation and choroidal atrophy. Retinal edema can also occur, but the optic disc and retinal vasculature are usually normal.

It is now recognized that the primary clinical factor associated with thioridazine retinopathy is the daily dose of drug. Before becoming aware of the dose-related retinal toxicity, dosages exceeding 1,600 mg daily were commonly prescribed. Few cases of pigmentary retinopathy have been reported, however, with daily dosages of less than 800 mg.

Depending on the severity of toxicity, retinal function can return to normal with reduction or discontinuation of the drug, but the pigmentary changes are often permanent. Severe cases may result in permanent impairment of visual acuity, visual field, and dark adaptation. The pigmentary retinopathy may even progress after the drug therapy has been discontinued, and some cases of progressive retinopathy have been noted later, occurring from 4 to 10 years after discontinuation of thioridazine.

Etiology

Thioridazine and other phenothiazines bind to melanin in the uveal tract, especially in the choroid. Drug uptake by the choroid occurs even in patients whose serum levels of thioridazine are in the nontoxic range. Such drug binding may be retinotoxic by damaging the choriocapillaris, thus leading to changes in the overlying RPE.

Management

Because the danger of retinal toxicity from thioridazine is significantly correlated with daily dosage, patients should be placed on dosages of less than 800 mg daily. Patients should receive careful fundus examinations during the first 2 to 4 months of therapy and every 6 months thereafter. Electrodiagnostic tests such as ERG and EOG are generally of no value in detecting early retinopathy. If symptoms or objective signs of retinal toxicity are observed, consideration should be taken with the patient’s prescribing physicians for prompt discontinuation of the medication to improve the chances of resolution. Because the pigmentary retinopathy may be progressive even after thioridazine has been discontinued, patients should receive follow-up examinations on an annual basis.

Cardiac Glycosides

Digitoxin and digoxin, both digitalis derivatives, have been widely used in the treatment of congestive heart disease and certain cardiac arrhythmias.Visual symptoms associated with digitalis may include dimming vision, flickering or flashing scotomas, and significant disturbances of color vision.

Clinical Signs and Symptoms

The most common symptoms reported by patients are changes in color vision and impaired vision.These symptoms can take many forms and include the visual phenomena listed in Box 35-4. A common symptom is snowy vision (objects appear to be covered with frost or snow), and this observation is intensified in brightly illuminated environments. There is also evidence that digoxin may contribute to rhegmatogenous retinal detachment by decreasing the normal adhesion of the retina to the RPE.

Complaints of color vision disturbances are common with both digoxin and digitoxin, but color vision impairment can often be detected even in patients without

Box 35-4 Visual Symptoms in Digitalis

Intoxication

Dyschromatopsia, including yellow or blue tinge to vision and/or colored halos

Colored spots surrounded by coronas Snowy, hazy, or blurred vision

Dimming of vision Flickering or flashes of light Glare sensitivity

From Weleber RG, Shutts WT. Digoxin retinal toxicity. Clinical and electrophysiological evaluation of a cone dysfunction syndrome. Arch Ophthamol 1981;99:1568–1572.

symptoms. Both the incidence and severity of color vision impairment tend to correlate with the plasma glycoside level. Figure 35-12 shows the results of color vision testing in patients receiving therapeutic dosages and those with toxic serum levels of digoxin.Approximately 80% of patients with digoxin intoxication demonstrate generalized color vision deficiencies, but detectable color vision impairment or other visual symptoms can occur even at normal therapeutic drug levels (Figure 35-13). In contrast, patients treated with digitoxin in therapeutic concentrations usually show no significant color vision abnormality. This difference may be related to plasma protein binding or to different distributions in the retina. Digoxin can also interact with quinidine, which raises the digoxin level approximately twofold.

The prevalence of digitalis intoxication is from 16% to 20%. Color vision disturbances are especially common and may occur before, simultaneously with, or after the onset of cardiac toxicity. Although color vision disturbances are associated with cardiac glycoside toxicity decreased visual acuity without the accompanying classic symptom of xanthopsia is also common.

Visual symptoms may occur as soon as 1 day after drug administration, but often occur within 2 weeks of initial therapy. Occasionally, ocular toxicity does not appear until after several years of treatment. Once the serum level is decreased or digitalis therapy is discontinued, however, visual symptoms quickly subside, usually within several weeks.

Etiology

The precise mechanism whereby digoxin produces a toxic effect may involve inhibition of Na+K+-activated adenosine triphosphatase, an enzyme that plays a vital role in maintaining normal cone receptor function. This would explain the drug-induced interference with both dark adaptation and color vision.

Management

Patients taking cardiac glycosides should be monitored for visual symptoms, including color vision changes, flashing or flickering lights, and other entoptic phenomena. Although the Panel D-15 test can be useful for evaluating color vision, the Farnsworth-Munsell 100-hue test has been shown to be particularly sensitive for detecting digi- talis-induced color vision deficiencies. Detectable changes in color vision should warrant consultation with the prescribing physician with regard to potential digitalis intoxication.

Sildenafil

The erectile dysfunction group of drugs,of which sildenafil is most common, are potent inhibitors of cyclic guanosine monophosphate–specific phosphodiesterase type 5 (PDE-5). The other two available drugs are tadalafil (Cialis) and

vardenafil (Levitra).When orally administered, these drugs are effective and generally well-tolerated treatments for men with erectile dysfunction. The drugs enhance the effect of nitric oxide by inhibiting PDE-5, which is responsible for the degradation of cyclic guanosine monophosphate in the corpus cavernosum. Sexual stimulation causes local release of nitric oxide, and inhibition of PDE-5 causes increased levels of cyclic guanosine monophosphate in the corpus cavernosum, which results in smooth muscle relaxation and inflow of blood.Although these drugs are highly selective for PDE-5, they retain some affinity for phosphodiesterase type 6 (PDE-6), an enzyme found in the retina. Inhibition of PDE-6 may provide the basis for ocular side effects that can occur in men who use these drugs.Tadalafil is more specific to PDE-5 and therefore may produce less visual adverse effects.

DIGOXIN SERUM CONCENTRATION (ng/ml)

Figure 35-13 Mean total error scores on FarnsworthMunsell 100-hue test according to digoxin serum concentration ranges. (Modified from Rietbrock N, Alken RG. Color vision deficiencies: a common sign of intoxication in chronically digoxin-treated patients. J Cardiovasc Pharmacol 1980; 2:93–99.)

Clinical Signs and Symptoms

In a battery of vision function tests,sildenafil has been given at dosages up to twice the maximum recommended dosage. Mild, transient, dose-related impairment of color vision has been detected.The peak effect occurs near the time of peak plasma drug levels, at 30 minutes to 2 hours after ingestion. Visual side effects are reported to occur in 3% to 10% of users. OADRs considered “certain” by WHO criteria include bluish-tinged or occasionally pinkor yellowish-tinged vision and that dark colors appear darker; blurred or hazy vision; changes to light perception, including increased sensitivity to light and flashing lights; conjunctival hyperemia, ocular pain; and transient ERG changes. Most visual symptoms last several minutes to a few hours.Other OADRs for these agents listed as “possible” include nonarteritic ischemic optic neuropathy (see Drugs Affecting the Optic Nerve, below) and mydriasis, retinal vascular accidents, and subconjunctival hemorrhage, all of which may be related to the activities undertaken during use of the drugs.

Etiology

The visual effects associated with the PDE-5 inhibitor therapies are consistent with cross-inhibition of the enzyme PDE-6, which is involved in retinal phototransduction.

Management

Visual symptoms are mild and transient. Patients can be reassured that no permanent or clinically significant visual impairment has been associated with sildenafil use. Some patients with retinitis pigmentosa have genetic disorders of retinal PDEs. Because there is no safety information on administering sildenafil to these patients, the drug should be used with caution in patients with retinitis pigmentosa.

Oral Contraceptives

Two large cohort studies in the United Kingdom involving 63,000 women noted no notable increase in the following

conditions, including lacrimal disease: conjunctivitis, keratitis, iritis, strabismus, cataract, glaucoma, and retinal detachment.There was consistent evidence, however, of a notable increase in risk of retinal vascular lesions in oral contraceptive users. The relative risk of retinal vascular lesions in oral contraceptive users was 2.0 to 2.4. This included all retinal vascular abnormalities, including vascular occlusion, vein thrombosis, and retinal hemorrhage.Women are counseled not to smoke when on oral contraceptives. If a retinal vascular lesion is detected on dilated fundus examination, it should be monitored in a reasonable time, depending on the nature of the abnormality, the location, and threat to vision. The patient and the prescribing practitioner should be informed of the lesion and discussions undertaken as to the risk-to-bene- fit ratio of continued treatment.

Nonsteroidal Anti-Inflammatory Agents

NSAIDs are commonly used for their analgesic, antiinflammatory, and antipyretic actions in the treatment of arthritis, musculoskeletal disorders, dysmenorrhea, and acute gout.Although these drugs are widely used and are often used for prolonged periods, retinal toxicity is rare.

Clinical Signs and Symptoms

Salicylates are well known to have anticoagulant properties. In high dosages or with prolonged use these drugs can cause retinal hemorrhage.

Most of the reported cases of retinopathy associated with NSAIDs have involved indomethacin therapy. Although there have been no epidemiologic studies investigating the relationship between indomethacin and retinopathy, there is evidence that the drug can induce pigmentary changes of the macula and other areas of the retina.The lesions usually consist of discrete pigment scattering of the RPE perifoveally, as well as fine areas of depigmentation around the macula. In some cases the pigmentary changes are more marked in the periphery of the retina. Depending on the amount of retinal involvement, the ERG and EOG can be normal or abnormal. Likewise, the amount of retinopathy dictates whether changes occur in visual acuity, dark adaptation, and visual fields. Acquired color vision deficiencies of the blue-yellow type have been reported.

No definite relationship has been established between the dosage of indomethacin and retinal toxicity. When drug therapy is discontinued, however, most of the functional disturbances associated with the retinopathy usually improve, although the pigmentary changes of the retina are generally irreversible.Significant improvement of color vision, visual acuity, dark adaptation, and visual fields may require at least 6 to 12 months after discontinuation of drug therapy.

Etiology

Most investigators have speculated that indomethacin may have a direct or indirect effect on the RPE, but the

precise mechanism has not been clarified. The localization of the retinotoxic effect to the RPE is supported by changes observed in the ERG and EOG in patients with indomethacin retinopathy.

Management

Patients taking salicylates or indomethacin in high dosages or for prolonged periods should be monitored for evidence of retinal hemorrhage or pigmentary changes, especially in the macular area. Evaluation of color vision may be helpful in identifying patients with early retinotoxic effects associated with indomethacin. Once retinal toxicity is documented, the prognosis for improved retinal function is good, provided indomethacin therapy is decreased or discontinued. Drug therapy, however, should be changed only on the advice of the prescribing physician.

Clomiphene

Clomiphene citrate (Clomid) is an orally administered nonsteroidal agent widely used for treatment of infertility. Visual side effects associated with clomiphene therapy include nonspecific blurring of vision and various entoptic phenomena, including flashes of light, scintillations, heat waves, and prolonged afterimages. The symptoms can occur as early as several days after treatment is started and usually disappear within several days to several weeks after treatment is discontinued. Cases have been reported, however, in which patients remained symptomatic from 2 to 7 years after discontinuing the medication.

Antineoplastic Agents

Tamoxifen

Tamoxifen citrate (Nolvadex), an orally administered nonsteroidal antiestrogen, is one of the most effective antitumor agents for the palliative treatment of metastatic breast carcinoma in postmenopausal women.This drug has been in clinical use since 1970 without serious side effects in most patients. It is used both alone and in combination with other agents. OADRs are reported to be as high as 6.3%; however, in low doses retinopathy is rare (0.9%).

Clinical Signs and Symptoms

Tamoxifen retinopathy has been documented in many patients, and the retinal findings include white or yellow refractile opacities in the macular and perimacular area, with or without macular edema (Figure 35-14). Although the lesions are usually more numerous in the macular area, they can also extend to the ora serrata. The lesions occur at all levels of the sensory retina, and many appear superficial to the retinal vessels. The patient may be asymptomatic or may experience reduced visual acuity associated with the macular lesions, and the visual fields can show abnormalities.

Although tamoxifen is far less likely to induce ocular toxicity at the normal dosage level of 20 mg daily, retinopathy does occur, although it is usually asymptomatic.With high dosages (e.g., 90 to 120 mg twice daily), toxic effects can be observed within 17 to 27 months, as the total cumulative dose exceeds 90 g.

The most important difference between high-dose and low-dose toxicity is the extent of reversibility after discontinuing the drug. Patients taking 20 mg twice daily may demonstrate regression of retinopathy and improvement in visual symptoms.

Etiology

It has been suggested that high-dose tamoxifen therapy causes widespread axonal degeneration, primarily in the paramacular area. The yellow-white lesions seen on fundus examination appear to represent products of the axonal degeneration and are confined to the nerve fiber and inner plexiform layers. However, others have compared this drug with other amphiphilic compounds such as chloroquine, chlorpromazine, thioridazine, and tilorone, all of which bind to polar lipids, inhibiting catabolism of the lipids and causing accumulation of drug–lipid complexes in lysosomes.

Management

Because tamoxifen retinopathy can occur at relatively low total doses of drug, it is important to obtain a baseline examination within the first year after therapy is begun. This should include best-corrected visual acuity, visual fields and Amsler grid evaluations, and fundus examination. It is important to monitor symptomatic

patients carefully during therapy, because macular compromise can result in irreversible loss of vision. Annual examinations are sufficient if normal drug dosages are administered. However, patients receiving higher than normal dosages, ranging from 80 mg once daily to 120 mg twice daily, should be monitored every 6 months. The prevalence of ocular toxicity from lowdose tamoxifen therapy (10 mg twice daily) appears to be low, and some investigators have suggested therefore that no special ocular screening is required in these patients. If retinopathy is detected in visually asymptomatic patients, tamoxifen therapy may be continued, in consultation with the patient’s oncologist.

Carmustine

Carmustine (BCNU) is a commonly used chemotherapeutic agent for the treatment of various malignant neoplasms, including metastatic malignant melanoma, malignant gliomas of the central nervous system, metastatic breast cancer, and leukemia. It has been administered by infusion into the internal carotid artery as a method of increasing bioavailability of the drug to brain tumors within the supply of this vessel. This has led to ocular toxicity in some patients.

Clinical Signs and Symptoms

Retinal toxicity usually begins within 2 to 14 weeks after intra-arterial infusion of BCNU. Approximately 65% of patients develop retinal complications (Box 35-5). It is common to have loss of vision from the retinopathy, and visual acuity can be reduced to 20/60, to light perception, or even to no light perception. A definite relationship

Box 35-5 Retinal Complications of

Carmustine Use

Retinal infarction

Retinal periarteritis

Retinal periphlebitis

Changes of retinal pigment epithelium

Branch retinal artery occlusion

Nerve fiber layer hemorrhages

Macular edema

between dosage of BCNU and retinopathy has not been established.

Etiology

The retinal toxicity resulting from intracarotid BCNU is probably related to the increased flow of drug into the ophthalmic artery. The precise mechanism whereby BCNU causes retinal toxicity is unknown, but several investigators have suggested that the drug may be toxic to the retinal and choroidal vasculature, causing segmental intraretinal vasculitis with or without vascular obstruction.This process would lead to nerve fiber layer infarcts and retinal hemorrhage.

Management

As previously mentioned, the retinotoxic effects of intracarotid BCNU can be largely minimized or avoided by using an infusion catheter that is advanced beyond the origin of the ophthalmic artery. If retinal complications develop, the risk-to-benefit ratio must be considered regarding the advisability of continued therapy.

Miscellaneous Chemotherapeutic Agents

Various other systemic chemotherapeutic agents have been associated with retinotoxic effects. Use of interferon-α, for example, has resulted in various retinal effects, including cotton-wool spot formation, macular edema, capillary nonperfusion, arteriolar occlusion, and intraretinal hemorrhage. Cisplatin and etoposide have induced retinal toxicity in both adults and children.

Vigabatrin

Vigabatrin is an effective anticonvulsant medication that selectively increases brain and retinal γ-aminobutyric acid.

Clinical Signs and Symptoms

Vigabatrin-induced visual field constriction is well documented. The visual field constriction is bilateral, usually asymptomatic, and characteristically consists of concentric peripheral field loss with temporal and macular sparing. Field loss occurs in 30% to 50% of patients and appears to be irreversible in most cases.Visual acuity and color vision can also be affected, and the best method to detect

dyschromatopsia appears to be the Farnsworth-Munsell 100-hue test. Visual symptoms can develop from several months to several years after initiation of drug therapy.

Electrodiagnostic testing may reveal normal or abnormal responses on ERG and visual evoked potential tracings, but the EOG seems to be the most sensitive electrophysiologic test.The results of electroretinography suggest reduced inner retinal cone responses and impairment of Müller and amacrine cells. The visual symptoms associated with vigabatrin therapy may represent selective vulnerability of the retina to the γ-aminobutyric acidergic effects of the medication.

Management

Patients taking this drug should have regular peripheral visual field examinations,and consideration should be given to electrodiagnostic testing, especially electrooculography.

Isotretinoin

Isotretinoin, or 13-cis-retinoic acid, is widely used for the treatment of recalcitrant cystic acne. Although this drug more commonly affects the external tissues of the eye, causing ocular surface dryness,there is sufficient evidence to designate that this agent has a “certain” retinotoxic effect, causing nyctalopia. It also has a “probably/likely” designation for reversible decreases in color vision.

Clinical Signs and Symptoms

Impairment of dark adaptation with or without excessive glare sensitivity has been reported with isotretinoin therapy in doses of 1 mg/kg of body weight daily.These complaints may be associated with an abnormal ERG or abnormal EOG. Once therapy is discontinued, both the abnormal dark adaptation and abnormal ERG usually resolve within several months.

Etiology

Although the precise mechanism explaining the effect on dark adaptation is unclear, it has been suggested that the drug could become incorporated into the rod photoreceptor elements during the process of outer disc shedding and renewal. Isotretinoin may compete for normal retinol binding sites on cell surfaces or transport molecules, which would account for the reduced retinal sensitivity. Though not proven, more recently it has been speculated that a preexisting hypovitaminosis A may predispose a patient placed on isotretinoin to nyctalopia. This may be because the isotretinoin likely binds to the sites where retinol normally would bind, but it does not subsequently biotransform to physiologically active rhodopsin, slowly affecting the photoreceptors.

Management

Patients taking isotretinoin should be monitored for changes in night vision.A history of night vision impairment should suggest more definitive evaluation procedures, such

as visual field testing, dark adaptometry, and electroretinography. If retinal function is documented to be abnormal, the drug should be withdrawn in consultation with the prescribing physician. Once drug therapy has been discontinued, retinal function should be monitored for improvement. These patients also must be monitored for dry eye and more unlikely events such as intracranial hypertension.

Inhaled Corticosteroids

The use of inhaled steroids has been associated with the development of central serous chorioretinopathy. In susceptible patients the systemic absorption of inhaled steroids may be sufficient to induce macular detachment and reduced central visual acuity associated with central serous chorioretinopathy.

Quinine

Historically, quinine has been used for the treatment of malaria, but it is now used primarily for the management of nocturnal leg cramps and myotonia congenita. Quinine toxicity has been recognized for more than 150 years,and overdosage of quinine is still encountered in patients who attempt self-induced abortion or suicide.Accidental ingestion of quinine can lead to serious side effects. Among the various features of quinine toxicity, acute vision loss is one of the most significant and dangerous.

Clinical Signs and Symptoms

Mild toxic reactions are characterized by slight reduction of visual acuity, “flickering” of vision, color vision decrease, impaired night vision, tinnitus, weakness, or confusion. In more severe cases, symptoms consist of sudden complete loss of vision, dizziness, and even deafness. Coma with circulatory collapse characterizes the most severe form of quinine toxicity. Patients may complain of impairment of night vision, but color vision is usually normal. The visual fields usually demonstrate concentric constriction. Improvement of the visual fields after the acute episode may require days or months,but the field loss may show no recovery and become permanent.

Patients presenting with acute quinine overdose frequently have no light perception in either eye, and pupils are often dilated and nonreactive to light. Ophthalmoscopic examination of the fundus soon after acute quinine overdose may reveal a normal fundus but also may reveal constriction of the arterioles, optic disc pallor, venous dilation, or retinal edema.

The visual prognosis for patients with acute quinine toxicity is guarded. Visual acuity can improve from no light perception to 20/20 within days to several weeks or months. As vision recovers there is progressive constriction of the retinal vessels, and the optic disc becomes pale. Although central vision often returns to normal levels, the visual fields can remain constricted, and night and color vision changes can be permanent.

In general, the maximum daily dosage of quinine should not exceed 2 g;quinine toxicity is common in dosages over 4 g. The lethal oral dose in adults is approximately 8 g. Toxic reactions to relatively small dosages of quinine are probably idiosyncratic in nature but can result in a clinical picture similar to that caused by higher dosages.

Etiology

Our current understanding of the pathogenesis of quinine retinal toxicity is derived primarily from various electrodiagnostic studies that have demonstrated that quinine probably has a direct toxic effect on the photoreceptors and ganglion cells. Moreover, fluorescein angiographic studies have shown no significant circulatory disturbances. Damage to the RPE is indicated by an abnormal EOG, the increased visibility of the choroid in the late stages of toxicity, and the increased background fluorescence seen on angiography.Visual evoked potential findings confirm the conduction abnormality in the nerve fiber layer associated with the secondary optic atrophy.

Management

Because central vision tends to recover spontaneously even without treatment, patients with acute quinine toxicity should generally be managed by supportive measures alone. Hyperbaric oxygen has been used in an attempt to increase oxygen delivery to the retina. The use of oral activated charcoal or any other gastric decontamination procedures does not improve clinical outcome and may, in fact,be harmful to the patient. It is important to emphasize preventive measures, such as patient education and dispensing of quinine in child-resistant containers.

After the acute episode, patients can be monitored for improvement in visual acuity, visual fields, and fundus appearance.

Talc

Tablets of medication intended for oral use contain inert filler materials such as talc (magnesium silicate),corn starch, cotton fibers, and other refractile and nonrefractile substances. Long-term drug abusers are known to prepare a suspension of medication for injection by dissolving the crushed tablet of cocaine,heroin,methylphenidate,or other narcotic in water. They then boil the solution and filter it through a crude cigarette or cotton filter before injecting the solution intravenously, subcutaneously, or intramuscularly. The talc particles eventually embolize to the retinal circulation and produce a characteristic form of retinopathy.

Clinical Signs and Symptoms

Fundus examination reveals multiple tiny, yellow-white, glistening particles scattered throughout the posterior pole but concentrated in the capillary bed and small arterioles of the perimacular area (Figure 35-15).The distribution and position of the particles remain stationary over time. In addition to these characteristic lesions, some

Figure 35-15 Talc retinopathy characterized by numerous yellow-white intra-arteriolar particles scattered throughout perimacular area.

patients can have macular edema, venous engorgement, punctate and flame-shaped hemorrhages, and arterial occlusion. Foreign body granulomas of the retina have also been described.

Retinal neovascularization as a consequence of talc injection can occur in the retinal periphery as neovascular tufts in the shape of sea fans at the junction of the perfused and nonperfused retina.This is a potentially serious complication of talc emboli, because it can lead to retinal detachment, massive vitreal hemorrhage, and optic disc neovascularization.

Most patients have no significant visual symptoms, and visual acuity is normal. Some patients, however, report blurring of vision and blind spots in the visual fields and occasionally can have severe reduction of visual acuity associated with macular ischemia or fibrosis. Neither the extent of drug abuse nor the degree of filtration of the prepared suspension appears to be correlated with visual symptoms.

The extent of talc particles observed in the posterior pole appears to correlate with the duration of drug abuse and with the cumulative number of tablets injected. Often, the drug abuser injects from 10 to 40 tablets daily, and some abusers inject as many as 100 tablets daily for several years.Talc retinopathy is usually not found in drug abusers who have injected less than 9,000 tablets, but it is consistently found in most patients who have injected more than 12,000 tablets.

A variant of talc retinopathy has been referred to as “microtalc” retinopathy. This appears as fine refractile deposits distributed in the superficial retinal layers of the

posterior pole adjacent to the vascular arcades. These lesions were usually associated with retinal nerve fiber defects and were seen exclusively in patients with a history of free-basing crack cocaine. Visual field changes that mimic glaucoma can occur.

Other clinical signs of drug abuse may be present. These include weight loss, disheveled physical appearance, poor mental status, drug-seeking behavior, unusual infections, repetitive lost prescriptions, burns to hand and face, and “doctor shopping.”

Etiology

As the talc, cornstarch, and other insoluble tablet fillers embolize to the lungs, they become trapped within the pulmonary tissues and eventually cause pulmonary hypertension.This leads to the development of collateral vessels that allow part of the venous return to bypass the lungs and enter the left side of the heart, where the particles are further embolized to the eye and other organs of the body. The presence of talc particles in the eye indicates that substantial foreign body damage has occurred in the lungs.

The talc particles are more numerous in the perimacular region than in other areas of the retina, probably because of the rich blood supply and greater blood flow in that area. The particles lodge in the walls of the precapillary arterioles and capillaries, producing focal occlusion of these vessels in the retina and choroid. The occlusions are caused primarily by the cellular reaction to the emboli.

The neovascular lesions of talc retinopathy are thought to be associated with peripheral arteriolar nonperfusion, which leads to retinal ischemia and secondary neovascularization. Such a pathogenesis is quite similar to that seen in sickle cell retinopathy and is confirmed by the predominantly supertemporal location of the neovascular proliferation. Macular fibrosis with significant visual loss has also been associated with talc retinopathy.

Microtalc dusting of the retina may represent minute crystalline deposits of crack cocaine’s adulterants lodged in the retinal microcirculation, the inner retinal layers, or both. It has been hypothesized that the retinal nerve fiber layer changes seen in these patients may occur from ischemia induced by focal drug-induced vasospasm of the short posterior ciliary arteries.

Management

Because of the implications of the diagnosis, the practitioner must rule out other conditions that may have a similar clinical appearance. The differential diagnosis includes Gunn dots, multiple cholesterol emboli, drusen, and Stargardt disease.

Once the diagnosis has been established, appropriate drug abuse counseling should be given to prevent further risk of severe pulmonary or ocular complications. Consideration should also be given to pulmonary consultation, because patients with eye findings usually have