Ординатура / Офтальмология / Английские материалы / Electrophysiology of Vision_Lam_2005

Gentamicin

Ethambutol

Cisplatin

Indomethacin

VITAMIN A DEFICIENCY

Vitamin A is a fat-soluble vitamin that is absorbed by the small intestine and transported to the liver where it is stored as vitamin A ester. Vitamin A is delivered to the target tissues by retinol binding protein, a transport protein produced by the liver, as vitamin A alcohol (retinol). In the retina, retinol is stored in the retinal pigment epithelium and enters the outer segments of the photoreceptors as 11-cis retinol where it is transformed to 11-cis retinaldehyde (retinal) and combined with the protein opsin to form the light sensitive rhodopsin. Therefore, vitamin A deficiency may arise from inadequate nutritional intake, poor intestinal absorption, impaired liver storage, ineffective retinol binding protein transport, or impaired conversion of retinol to retinaldehyde.

Children are especially susceptible to vitamin A deficiency from malnutrition, and the major cause of blindness in children worldwide is xerophthalmia due to vitamin A deficiency (1). Night vision impairment from retinal dysfunction in affected individuals is common. The reason why certain persons are affected in impoverished communities while the majority is spared remains unclear, and the condition is often accompanied by generalized malnutrition with multiple dietary deficiencies.

In developed countries, vitamin A deficiency from malnutrition is extremely rare, and the condition occurs most commonly from poor intestinal absorption (e.g., congenital or post-surgical short bowel syndrome and Crohn’s disease) and liver dysfunction (e.g., alcoholism, liver failure). In some cases, treatment with oral vitamin A supplements may be ineffective and intravenous treatment is necessary.

In the 1950s, Dhanda (2) using early ERG techniques in India found reduced and non-detectable ERG responses in

patients with xerophthalmia and night blindness due to vitamin A deficiency. After oral vitamin A, the night blindness resolved rapidly with ERG responses returning to normal at a slower rate. The xerosis patches, on the other hand, were more refractive to treatment. Children younger than age 15 are particularly prone to develop night blindness from vitamin A deficiency. Multiple scattered retinal gray-white spots may occur with prolonged vitamin A deficiency, but at the onset of night blindness, the retina usually appears normal. The dark adaptation threshold curves in vitamin A deficiency are prolonged and show delayed initial cone dark adaptation followed by a marked prolongation of early rod adaptation (‘‘rod plateaux’’) but normal final rod threshold is eventually reached (3).

Studies in developed countries where vitamin A deficiency occurs in the setting of liver dysfunction (4,5), intestinal bypass (6,7), Crohn disease (8), cystic fibrosis (9), and abetalipoproteinemia (10) have shown reduced ERG responses as well as abnormal dark adaptometry. Rod ERG responses are more reduced than cone ERG responses in vitamin A deficiency, but both can be substantially reduced depending on the stage of the disease (Fig. 15.1). Implicit times are less prolonged than those in rod–cone dystrophy (retinits pigmentosa), and the shape of the dark-adapted bright-flash combined rod–cone response may have some similarity to the light-adapted cone response (7). Dark adaptometry reveals elevated rod and cone thresholds (8). With vitamin A supplementation, ERG responses and dark adapting thresholds improve. In the central retina, the cone function recovers more quickly than rod function, while in the retinal periphery the opposite occurs perhaps because of regional differences in rod–cone density and rod–cone competition for available vitamin A during visual pigment regeneration (8).

In general, ERG and dark adaptometry are useful in supporting the diagnosis of vitamin A deficiency and in following patients who are refractive to treatment. Serum vitamin A level remains the first ancillary test of choice when the condition is suspected. Nevertheless, ERG and dark adaptometry

Figure 15.1 Full-field ERG responses of an 8-year-old boy with nutritional retinopathy due to malabsorption from short gut syndrome. The patient had vitamin A and vitamin E deficiency. The scotopic rod and combined rod–cone responses were more impaired than the photopic cone responses. The oscillatory potentials were also reduced.

are beneficial especially in cases where xerophthalmia is not obvious or when long-term follow-up is necessary because the deficiency is the result of chronic intestinal or liver disorders.

NUTRITIONAL OPTIC NEUROPATHY

Optic neuropathy related to deficiency of nutrient to the optic nerve is called nutritional optic neuropathy. Other names for

the disorder include nutritional amblyopia and tobacco– alcohol amblyopia. The condition may be caused by malnutrition and in some cases, is associated with tobacco and alcohol use. Rapid onset of bilateral loss of central vision with cecocentral scotomas is followed by the development of optic nerve head pallor. A deficiency of B complex vitamins appears to be the underlying cause in some causes, but causative factors may be multiple. Prognosis is generally favorable, if malnutrition is rectified and use of alcohol and tobacco are discontinued in the early stage of the disease. Reversible VEP abnormalities in patients with nutritional optic neuropathy have been reported (11–13). Impairments of VEP are more likely to occur with lower contrast pattern stimulus, and P1 latency may not necessary increase in some patients (14).

METALLIC INTRAOCULAR FOREIGN BODIES— OCULAR SIDEROSIS

Metallic intraocular foreign bodies may produce progressive visual loss by continued release of dissolving toxic material. The extent and rapidity of the induced ocular toxicity depend on the type of metal, size, and location. For instance, coppercontaining foreign bodies usually produce severe ocular toxicity (ocular chalcosis) with rapid loss of vision and diminishing ERG responses but aluminum foreign bodies typically are associated with mild ocular toxicity. Ocular toxicity from iron-containing foreign bodies may result in ocular siderosis (siderosis bulbi) with clinical features such as tonic pupil, iris heterochromia, cataract, and progressive pigmentary retinopathy. Symptoms of ocular siderosis include decreased central and peripheral vision and impaired night vision.

When the risks of surgical removal of the metallic intraocular foreign body appear to outweigh the likelihood of ocular toxicity, periodic examinations and serial ERGs are recommended. If progressive loss of visual function due to ocular toxicity is detected, prompt removal of the foreign body is indicated (15,16). Full-field ERG in early ocular siderosis is normal or may demonstrate a transient supernormal

response (17,18). Damage from the impact of the foreign body such as retinal edema or retinal detachment may also result in transient as well as permanent reduced ERG responses and should be considered in ERG interpretation. Over time, full-field ERG responses become reduced and prolonged, often with more scotopic than photopic impairment (Fig. 15.2). A greater selective decrease in b-wave amplitude as compared to a-wave occurs and is most notable on the scotopic combined rod–cone bright flash response (19). The oscillatory potentials also decrease correspondingly indicating more dysfunction of the inner retina. With further progression, a negative ERG pattern with b-wave to a-wave amplitude ratio of less than 1 may occur and the ERG eventually becomes non-detectable.

In early ocular siderosis, visual function and ERG responses improve after foreign body removal. In more advance cases, improvements are variable but visual acuity and ERG responses are likely to stabilize with removal of the foreign body (18). Of interest, in patients with ocular siderosis and cataract, reduced or non-detectable full-field ERG responses do not preclude a visual acuity of 20=25 or better after cataract extraction and foreign body removal despite persisting visual field defects (16,20). Impairment of EOG also occurs with ocular siderosis but has not been extensively studied.

Figure 15.2 (Facing page) Visual fields and full-field ERG responses of a 44-year-old man with a retained metallic foreign body in the left eye for 10 years. Visual acuity was 20=20 right eye and 20=60 left eye. Visual fields showed nasal constriction in the left eye. Ophthalmoscopy revealed normal appearance of the maculas and the optic nerve heads. Full-field ERG responses were markedly asymmetric indicating toxic retinopathy of the left eye. The scotopic rod and combined rod–cone responses of the left eye were more impaired than the photopic cone responses. The scotopic combined rod–cone response demonstrated a relatively selective reduction in b-wave such that the b- to a-wave amplitude ratio is less than 1 (‘‘negative ERG’’). The oscillatory potentials were essentially absent. Prompt removal of the metallic foreign body was recommended.

METHANOL POISONING

Methanol (methyl alcohol) is a toxic chemical used as an industrial solvent and is also found in automotive antifreeze fluid. Methanol may be found in home-brewed alcohol or used unethically as a cheap substitute for ethanol in alcoholic drinks. Absorption of methanol can occur through the skin, lung, and gastrointestinal tract. Methanol poisoning can result in permanent blindness and death, and absorption of as little as 10 ml of methanol can cause blindness. Methanol is primarily oxidized to formaldehyde by hepatic alcohol dehydrogenase, and formaldehyde is then rapidly converted by aldehyde dehydrogenase to formic acid, which is subsequently oxidized to carbon dioxide by a hepatic folate dependent pathway. The accumulation of formic acid not only produces severe metabolic acidosis but also inhibits mitochondrial cytochrome oxidase, which results in dysfunction of the photoreceptors, Mu¨ ller cells, and axoplasmic flow of the retrolaminar optic nerve (21–24).

Patients with methanol toxicity usually report a history of recent alcohol ingestion and have headache, nausea, vomiting, and weakness. Visual symptoms typically occur 12–48 hr after methanol ingestion and is variable ranging from mild blurred vision to complete blindness (25). The degree of impaired pupillary light reaction is an important prognostic indicator of visual outcome and death (25). Ocular findings include hyperemia of the optic nerve, followed by peripapillary retinal edema which subsequently spreads radially as greyish streaks throughout the retina accompanied commonly by retinal vein engorgement. Over weeks, some visual recovery may occur, and the optic nerve head becomes atrophic and occasionally develops glaucomatous-like cupping (25,26). Treatment strategies of methanol toxicity have principally been directed at inhibiting alcohol dehydrogenase.

In general, visual electrophysiologic tests may help in detecting retinal and optic nerve dysfunction due to methanol toxicity. The findings of ERG and VEP are variable and dependent on degree of toxicity and stage of recovery (27– 29). Virtually all components of the standard full-field ERG,

both scotopically and photopically, are likely to be impaired during the acute stage of methanol toxicity. Because photoreceptors as well as Mu¨ ller cells are sensitive to damage from formic acid, both a- and b-wave are impaired (27,28,30). However, a relatively selective impairment of b-wave has been reported and a negative pattern ERG may occur with a b-wave to a-wave amplitude ratio of less than 1 on scotopic combined rod–cone response (31). Further, an increased a-wave and a reduced b-wave in the acute stage of methanol poisoning have been documented in humans as well as primates during acute toxicity (32,33). With visual recovery, the full-field ERG improves (27). In methanol toxicity, VEP responses are likely to be impaired in part from retinal dysfunction, but reports of VEP in methanol toxicity are sparse. Responses of VEP ranging from normal to transient reduction of pattern VEP with normal latency have been noted (27,29).

SYNTHETIC RETINOIDS—ISOTRETINOIN (ACCUTANE )

Analogues of vitamin A such as isotretinoin (Accutane ), a synthetic retinoid, are used in the treatment of acne and other dermatologic diseases. Impaired night vision, abnormal dark adaptation, and reduced scotopic ERG responses have been reported with isotretinoin use and are reversed with cessation of the medication (34,35). The pathogenesis is likely related to the synthetic retinoid competing for normal vitamin A binding sites on the retinol binding protein or on the target cell surface. In light of the number of persons on synthetic retinoids, the frequency of significant retinal toxicity is relatively low, and mass screening is impractical and unnecessary. However, detailed clinical work-up is warranted in those with visual symptoms.

CHLOROQUINE=HYDROXYCHLOROQUINE

Chloroquine and its derivative hydroxychloroquine (Plaquenil ) are medications used in the treatment of

malaria, rheumatoid arthritis, systemic lupus erythematosus, and Sjo¨gren’s syndrome. The clinical features of toxic retinopathy from chloroquine and hydroxychloroquine include reduced visual acuity, peripheral visual loss, pigmentary macular atrophy often acquiring a bull’s eye appearance, peripheral retinal changes, and eventual optic nerve atrophy. Binding of chloroquine and hydroxychloroquine to melanin granules in the ciliary body, retina, and choroid has been implicated as a cause of the toxicity but the exact mechanism is unclear (36). Toxic retinopathy is more frequent with the use of chloroquine than with hydroxychloroquine. In general, the incidence of hydroxychloroquine retinal toxicity from more recent studies ranges from less than 1% to up to 6% (37–40). The risk of toxicity increases with higher daily dosages and is likely to be related to the amount of total cumulative dosage. Patients with normal retinal function placed on hydroxychloroquine at a maximal daily dosage of 6.5 mg=kg are safe from retinal toxicity for the first six years of treatment (40). In general, visual loss from toxic retinopathy may be reversible with discontinued use of these medications if toxicity is detected early, but in some cases, visual loss is irreversible and continues to progress even after drug cessation (41,42).

In most cases, serial periodic automated static perimetry of the central 10-degree visual field and multifocal ERG testing at the start of the treatment and periodically thereafter as indicated is the preferred method of detecting maculopathy from chloroquine or hydroxychloroquine. In additional

Figure 15.3 (Facing page.) Multifocal ERG of a 55-year-old woman treated with hydroxychloroquine, 200 mg twice daily for 5 years. The patient was asymptomatic and had 20=20 vision in each eye. Ophthalmoscopy was normal. Multifocal ERG showed impaired responses centrally. Notable decreases in response density of the center and perifoveal concentric rings are apparent. Clinically asymptomatic patients on hydroxychloroquine may have decreases in multifocal ERG responses possibly indicating a preclinical stage of drug-related toxicity.