Ординатура / Офтальмология / Английские материалы / Clinical Ophthalmology A Systematic Approach 7th Edition_Kanski, Bowling_2011

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•Because keratopathy does not affect vision its presence is not an indication to discontinue treatment. Other toxic effects of amiodarone are anterior subcapsular lens deposits and optic neuropathy (see below).

Fig. 20.1 Drug-induced keratopathies. (A) Vortex; (B) chlorpromazine; (C) argyrosis; (D) chrysiasis

(Courtesy of L Zografos – fig. C)

Chlorpromazine

Chlorpromazine (Largactil) is used as a sedative and to treat psychotic illnesses. Some patients on long-term therapy may develop innocuous, subtle, diffuse yellowish-brown granular deposits in the endothelium, Descemet membrane and deep stroma occurring only in exposed cornea of the interpalpebral fissure (Fig. 20.1B). Other toxic effects are anterior lens capsule deposits and retinopathy (see below).

Argyrosis

Argyrosis is a discoloration of ocular tissues secondary to silver deposits, and may be iatrogenic or from occupational exposure. Keratopathy is characterized by greyish-brown granular deposits in Descemet membrane (Fig. 20.1C). The conjunctiva may also be affected.

Chrysiasis

Chrysiasis is the deposition of gold in living tissue, occurring after prolonged administration, usually in the treatment of rheumatoid arthritis. Virtually all patients on continuous chrysotherapy who have received a total dose of gold compound exceeding 1500 mg develop corneal deposits.

•Corneal chrysiasis is characterized by dust-like or glittering purple granules scattered throughout the epithelium and stroma, more concentrated in the deep layers and the periphery (Fig. 20.1D). These findings are innocuous and not an indication for cessation of therapy. In some cases the deposits clear after stopping treatment whilst in others they may persist for years.

•Other toxic effects of gold are innocuous lens deposits and occasionally marginal keratitis.

Amantadine

Amantadine (Symmetral) is an oral agent used in the treatment of Parkinson disease and related conditions. Some patients, on doses of 200–400 mg/day, develop diffuse white punctate opacities that may be associated with epithelial oedema, 1–2 weeks after commencement of therapy. The changes resolve with discontinuation of treatment.

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Lens

Steroids

Steroids, both systemic and topical, are cataractogenic.

•The lens opacities are initially posterior subcapsular (Fig. 20.2A); later the anterior subcapsular region becomes affected. The relationship between weekly systemic dose, duration of administration, total dose and cataract formation is unclear. It is thought that patients on less than 10 mg prednisolone (or equivalent), or treated for less than 4 years may be immune.

•Although it is believed that children may be more susceptible to the cataractogenic effects of systemic steroids, individual (genetic) susceptibility may also be of relevance. It has therefore been suggested that the concept of a safe dose be abandoned.

•Patients who develop lens changes should be certain that dosage is the minimum consistent with control of the underlying disease, and if possible be considered for alternate day therapy.

•Early opacities may regress if therapy is discontinued; alternatively progression may occur despite withdrawal and warrant surgical intervention.

Fig. 20.2 (A) Steroid-induces posterior subcapsular cataract; (B) anterior capsular deposits due to chlorpromazine

Other drugs

1Chlorpromazine may cause the deposition of innocuous, fine, stellate, yellowish-brown granules on the anterior lens capsule within the pupillary area in 50% of patients who have received a cumulative dose of 1000 g (Fig. 20.2B). The deposits persist despite discontinuation of the drug.

2Busulphan (Myleran), used in the treatment of chronic myeloid leukaemia, may occasionally cause lens opacities.

3Gold, used in the treatment of rheumatoid arthritis, causes innocuous anterior capsular deposits in about 50% of patients on treatment for longer than 3 years.

4Allopurinol, used in the treatment of hyperuricaemia and chronic gout, increases the risk of cataract formation in elderly patients, if the cumulative dose exceeds 400 g or duration of administration exceeds 3 years.

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Uveitis

Rifabutin

Rifabutin is used mainly in the management and prophylaxis of Mycobacterium avium complex infections in AIDS patients with low CD4 counts. It is also used to treat tuberculosis in combination with other drugs in immunocompetent patients. Drugs that inhibit metabolism of rifabutin through the cytochrome p-450 pathway (clarithromycin and fluconazole), will increase the risk of uveitis.

1 AAU is typically unilateral and frequently associated with hypopyon; associated vitritis may be mistaken for endophthalmitis.

2Treatment involves withdrawal of the drug or reduction of dose.

Cidofovir

Cidofovir is used in the management of CMV retinitis in AIDS patients.

1AAU with few cells but a marked fibrinous exudate may develop following several intravenous infusions. Vitritis is common and hypopyon may occur with long-term administration.

2Treatment with topical steroids and mydriatics is usually successful, avoiding the need to discontinue therapy.

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Retina

Antimalarials

Drugs

Antimalarials are excreted from the body very slowly and are melanotropic drugs that become concentrated in melanin-containing structures of the eye, such as the RPE and choroid.

1Chloroquine retinotoxicity is related to the total cumulative dose. The normal daily dose is 250 mg; a cumulative dose of less than 100 g or treatment duration under 1 year is rarely associated with retinal damage. The risk of toxicity increases significantly when the cumulative dose exceeds 300 g (i.e. 250 mg daily for 3 years). However, there have been reports of patients receiving cumulative doses exceeding 1000 g who did not develop retinotoxicity. If possible, chloroquine should be used only if other agents are ineffective.

2Hydroxychloroquine is much safer than chloroquine and if the daily dose does not exceed 400 mg the risk of retinotoxicity is negligible. Physicians should therefore be encouraged to use hydroxychloroquine instead of chloroquine whenever possible. The risk of toxicity is increased if a daily dose over 6.5 mg/kg is administered for longer than 5 years, although even then the risk is still very small.

Retinopathy

Chloroquine retinopathy can be divided into the following stages:

1Premaculopathy is characterized by normal visual acuity and a scotoma to a red target located between 4° and 9° from fixation. Amsler grid testing may also show a defect. However, the most sensitive test is assessment of colour vision to detect both mild blue-yellow and protan red-green defects. The two most sensitive tests for detecting these defects are the Adams Desaturation-15 test and the Hardy-Rand-Rittler test. Other colour vision tests such as the Ishihara do not appear to be as sensitive. If the drug is discontinued, visual function usually returns to normal.

2Early maculopathy is the next stage, if treatment is not discontinued. It is characterized by a modest reduction of visual acuity (6/9–6/12). Fundus examination shows a subtle ‘bull's eye’ macular lesion characterized by a central foveolar island of pigment surrounded by a depigmented zone of RPE atrophy, which is itself encircled by a hyperpigmented ring (Fig. 20.3A). The lesion may be more obvious on FA than ophthalmoscopy because the RPE atrophy gives rise to a RPE ‘window’ defect, similar to that seen in cone dystrophy (see Fig. 15.17). This stage may progress even if the drug is stopped.

3Moderate maculopathy is characterized by moderate reduction of visual acuity (6/18–6/24) and an obvious ‘bull's eye’ macular lesion (Fig. 20.3B).

4Severe maculopathy is characterized by marked reduction of visual acuity (6/36–6/60) with widespread RPE atrophy surrounding the fovea (Fig. 20.3C).

5End-stage maculopathy is characterized by severe reduction of visual acuity and marked atrophy of the RPE with unmasking of the larger choroidal blood vessels. The retinal arterioles may also become attenuated and pigment clumps develop in the peripheral retina (Fig. 20.3D).

Fig. 20.3 Progression of chloroquine retinopathy (see text)

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(Courtesy of S Milenkovic – fig. A; Moorfields Eye Hospital – fig. B)

Screening

Screening of patients routinely on hydroxychloroquine is unnecessary although some authorities have recommended annual screening if the patient has been on medication for over 6 years.

•In clinical practice chloroquine can also be given safely to patients without the need for repetitive routine examinations by ophthalmologists or the use of specialized tests.

•Asking about symptoms and pre-treatment recording of near visual acuity and ophthalmoscopy by the prescribing doctor is all that is required. The patient can be given an Amsler grid to use once a week. Near visual acuity should be checked at annual review. If symptoms occur or an abnormality is found, then the opinion of an ophthalmologist should be sought.

•The ophthalmologist can, if necessary, perform more sophisticated tests such as visual fields, macular threshold, colour vision testing, contrast sensitivity, FA and electro-oculography. Recent reports suggest that multifocal electroretinography (see Ch. 15) may be useful in detecting early toxicity.

Phenothiazines

1Thioridazine (Melleril) is used to treat schizophrenia and related psychoses. The normal daily dose is 150–600 mg. Doses which exceed 800 mg/day for just a few weeks may be sufficient to cause reduced visual acuity and impairment of dark adaptation. The clinical signs of progressive retinotoxicity are as follows:

•‘Salt-and-pepper’ pigmentary disturbance involving the mid-periphery and posterior pole.

•Plaque-like pigmentation and focal loss of the RPE and choriocapillaris (Fig. 20.4A).

•Diffuse loss of the RPE and choriocapillaris (Fig. 20.4B).

2Chlorpromazine (Largactil). The normal daily dose is 75–300 mg. Retinotoxicity may occur if very much larger doses are used over a prolonged period. It is characterized by nonspecific pigmentary granularity and clumping.

Fig. 20.4 Thioridazine retinopathy. (A) Pigmented plaques and focal loss of the RPEand choriocapillaris; (B) diffuse atrophy of the RPEand choriocapillaris

(Courtesy of K Jordan)

Drug-induced crystalline maculopathies

1Tamoxifen (Nolvadex, Emblon, Noltan and Tamofen) is a specific anti-oestrogen used in the treatment of selected patients with

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breast carcinoma. It has few systemic side-effects and ocular complications are uncommon. The normal daily dose is 20–40 mg.

•Retinotoxicity and visual impairment may develop in some patients on higher doses and rarely in patients on normal doses.

•Retinopathy is characterized by bilateral, superficial, fine, yellow, crystalline deposits in the inner layers of the retina and punctate grey lesions in the outer retina and RPE (Fig. 20.5A). Visual impairment is thought to be caused by maculopathy associated with foveolar cyst formation.

•A rare side-effect is optic neuritis, reversible on cessation of therapy.

2Canthaxanthin is a carotenoid used to enhance sun tanning. If used over prolonged periods of time it may cause the deposition of innocuous glistening yellow inner retinal deposits arranged symmetrically in a doughnut shape at the posterior poles (Fig. 20.5B). The deposits are slowly reversible.

3Methoxyflurane (Penthrane) is an inhalant general anaesthetic. It is metabolized to oxalic acid which combines with calcium to form an insoluble salt which is deposited in tissues including the RPE. Prolonged administration may lead to renal failure and secondary hyperoxalosis. Ocular involvement is characterized by mild visual impairment associated with calcium oxalate crystals scattered throughout the retina that may later be associated with RPE hyperplasia at the posterior pole (Fig. 20.5C).

4Nitrofurantoin is an antibiotic used in the treatment of urinary tract infections. Long-term use may result in slight visual impairment associated with superficial and deep glistening intraretinal deposits distributed in a circinate pattern throughout the posterior pole.

Table 20.1 -- Other causes of macular crystals

•Primary hyperoxaluria

•Bietti corneoretinal crystalline dystrophy

•Cystinosis

•Sjögren–Larsson syndrome

•Gyrate atrophy

•Acquired parafoveal telangiectasis

•Talc-cornstarch emboli

•West African crystalline maculopathy

Fig. 20.5 Drug-induced crystalline retinopathies. (A) Tamoxifen; (B) canthaxanthin; (C) oxalosis

(Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby, 1997)

Other drugs

1Interferon-alpha is used in a variety of systemic conditions including Kaposi sarcoma, haemangioma in infancy, high-risk

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cutaneous melanomas, metastatic renal cell carcinoma, leukaemia, lymphoma and chronic hepatitis C. Systemic adverse effects include constitutional symptoms, neutropenia and thrombocytopenia.

•Retinopathy characterized by cotton wool spots and intraretinal haemorrhages (Fig. 20.6A) may develop in some patients, particularly those on high-dose therapy. FA shows focal areas of capillary non-perfusion (Fig. 20.6B).

•The condition usually resolves spontaneously with cessation of therapy and in the majority of patients the visual prognosis is good.

•Less common ocular side-effects include CMO, oculomotor nerve palsy, optic disc oedema and retinal vein occlusion.

2Desferrioxamine is an iron chelating agent used in the treatment of chronic iron overload, to prevent haemosiderosis in patients with haematological conditions requiring regular transfusion. It is most commonly administered as a slow subcutaneous infusion.

•Presentation is with rapid visual loss although the fundi may be normal or show only mild macular greying.

•Within several weeks mottled pigmentary changes develop (Fig. 20.7A) that are associated with reduced ERG amplitudes and reduced EOG light-peak to dark-trough ratios.

•FA shows punctate hyperfluorescence (Fig. 20.7B).

3Nicotinic acid, a cholesterol-lowering agent, has a number of side effects, including cutaneous flushing, pruritus, nausea and abdominal pain.

•A small minority of patients develop cystoid maculopathy suggestive of cystoid macular oedema (Fig. 20.8) but without leakage on fluorescein angiography.

•The macular changes cause a mild reduction of visual acuity and occur when doses greater than 1.5 g daily are used, but resolve with discontinuation of the drug.

Fig. 20.6 (A) Interferon retinopathy; (B) FA shows focal areas of capillary non-perfusion

(Courtesy of P Gili)

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Fig. 20.7 (A) Desferrioxamine retinopathy; (B) FA shows diffuse punctate hyperfluorescence

(Courtesy of R Bates)

Fig. 20.8 Nicotinic acid maculopathy

(Courtesy of J Donald M Gass, from Stereoscopic Atlas of Macular Diseases, Mosby, 1997)

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Optic nerve

Ethambutol

Ethambutol (Myambutol, Mynah) is used in combination with isoniazid and rifampicin in the treatment of tuberculosis. Ocular toxic effects include optic neuritis, colour vision abnormalities and visual field defects. Toxicity is doseand duration-dependent; the incidence is up to 6% at a daily dose of 25 mg/kg and rare with a daily dose not exceeding 15 mg/kg. Toxicity typically occurs within 3–6 months of starting treatment. Isoniazid may also rarely cause toxic optic neuropathy, particularly when given in combination with ethambutol.

1Presentation of optic neuritis is with abrupt visual impairment.

2Signs include normal or slightly swollen optic discs with splinter-shaped haemorrhages.

3Visual field defects are of two types.

•Central type involves the maculopapular bundle and results in decreased visual acuity, central or centrocaecal scotomas and impairment of blue-yellow colour vision.

•Peripheral type causes peripheral visual field constriction and red-green dyschromatopsia.

4Prognosis is good following cessation of treatment although recovery may take up to 12 months. A minority of patients develop permanent visual impairment as a result of optic atrophy.

5Screening should be every 4 weeks when the dose is more than 15 mg/kg and every 3–6 months for lower doses. The drug should be stopped immediately if symptoms develop.

Amiodarone

Optic neuropathy, probably demyelination, is rare and not dose-related. It affects just over 1% of patients during the initial 8 years of therapy and just under 2% during the subsequent 10 years.

1Presentation is with insidious unilateral or bilateral visual impairment.

2 Signs are bilateral optic disc swelling that may persist for a few months after medication is stopped.

3Visual field defects may be mild and reversible or severe and permanent.

4Prognosis is variable because cessation of the drug may not inevitably bring about improvement.

5Screening is not appropriate because there is no way to identify those at risk. Patients should, however, be warned of the small risk of toxicity and to report any suggestive symptoms.

6Differential diagnosis includes non-arteritic anterior ischaemic optic neuropathy (NAION), which also affects patients with systemic vascular disease. However, amiodarone optic neuropathy typically has a more insidious onset, milder visual loss, a longer duration of disc oedema and is more commonly bilateral than NAION.

Vigabatrin

Vigabatrin is used as a second-line antiepileptic drug for the treatment of uncontrolled complex partial seizures and as first line monotherapy for infantile spasms (West syndrome).

1Presentation is months or years after starting treatment with bilateral concentric or binasal visual field defects. The defects persist if treatment is stopped but do not progress if medication is continued. This suggests that the defects are idiosyncratic rather than a dose-related effect.

2Ophthalmoscopy is usually normal although a small percentage of patients may show a variety of changes including peripheral atrophy, nasal (inverse) optic disc atrophy, arteriolar narrowing, abnormal macular reflexes and surface wrinkling.

3Screening. Baseline visual field examination is recommended prior to starting treatment. Reassessment is made thereafter every 6 months for 3 years and then annually if no abnormality is detected.

Topiramate

Topiramate is an anticonvulsant also used in the treatment of migraine. It can cause acute angle-closure glaucoma with associated myopia due to ciliochoroidal effusion.

1 Presentation is usually within a month of starting treatment with blurred vision, and sometimes haloes, ocular pain and redness. 2 Signs include shallowing of the anterior chamber and raised intraocular pressure.

3 Treatment consists of reducing the intraocular pressure and stopping the drug.

4Prognosis is usually good provided the complication is recognized.

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