Ординатура / Офтальмология / Английские материалы / Electrophysiology of Vision_Lam_2005

of early subtle bull’s-eye maculopathy. Areas of localized decreased multifocal ERG responses are found bilaterally in patients with hydroxychloroquine maculopathy, and clinically asymptomatic patients may have decreases in multifocal ERG responses (Fig. 15.3) possibly indicating a preclinical stage of drug-related toxicity or pharmacologic actions of the drug (43–46).

Because of the localized nature of toxic retinopathy from chloroquine or hydroxychloroquine especially in the early stages, neither full-field ERG or EOG are diagnostically useful although both tests will demonstrate abnormalities in advance cases (47). Full-field ERG is usually normal or only mildly reduced in chloroquine or hydroxychloroquine maculopathy. With progression to diffuse retinal involvement, fullfield ERG abnormalities become evident. In general, full-field ERG cone response is more likely to be affected than rod response. However, with advance cases, all components of the full-field ERG are affected, and both full-field ERG and EOG become non-detectable or minimally recordable (41). For instance, Weiner et al. (48) documented marked impairment of virtually all components of the full-field ERG, both scotopically and photopically, in two patients with advanced hydroxychloroquine retinopathy and cumulative doses of about 1800 and 2900 g. Of interest, the autoimmune disease that is being treated by these agents may itself produce mild ERG and EOG impairment. Sassaman et al. (49) found smaller foveal ERG responses in patients with untreated systemic lupus erythematosus compared to normals. In the same report, the authors also noted mild full-field ERG alterations in systemic lupus erythematosus patients treated with hydroxychloroquine with no apparent retinopathy compared to untreated patients; this finding may imply that treated patients had more severe systemic lupus erythematosus which produced the full-field ERG alterations than untreated patients or that altered ERG responses from retinal dysfunction occur before any visible retinopathy. With regard to EOG, several authors found reduced EOG light-peak to dark-trough amplitude ratios in untreated patients with

autoimmune disease and in patients treated with chloroquine or hydroxychloroquine (47,50). In the latter study, Pinckers and Broekhuyse (47) studied 918 rheumatoid arthritis patients and found EOG abnormality rates of 20%, 23%, and 37% in the untreated, hydroxychloroquine-treated, and chloroquine retinopathy groups, respectively. The authors concluded that EOG is not a method of choice in detecting early toxic retinopathy in these patients, because impaired EOG is found in untreated patients and was not sensitive enough to determine.

THIORIDAZINE (MELLARIL ),

CHLORPROMAZINE, AND OTHER

PHENOTHIAZINES

Thioridazine (Mellaril ) is a phenothiazine derivative used in the treatment of psychiatric disorders. Symptoms of thiorida- zine-induced toxic retinopathy include decreased visual acuity, visual field loss, and night blindness. In the early stage, the macula and sometimes other regions of the retina acquire a granular appearance. With time, these changes evolve into patchy areas of pigmentary disturbance that may be hypopigmented or hyperpigmented. Binding of phenothiazines to melanin granules is implicated as the etiology of the toxic retinopathy. If toxicity is detected early, visual loss may be reversed with drug cessation, but in advance cases, visual loss is irreversible and may continue to progress even after discontinuation of the medication (51–53). The risk of developing thioridazine retinopathy is related to daily and cumulative dosage. The risk of toxic retinopathy is generally low for dosages below the recommended maximal total daily dose of 800 mg but retinal toxicity may still rarely occur (54). Pigmentary deposits of the skin, cornea and lens are also common with 800 mg thioridazine daily for over 44 months (55).

The diagnosis of thioridazine-induced toxic retinopathy as well as other phenothiazine-induced retinopathy is arrived on the basis of visual symptoms, visual field defects, retinal

appearance, and ERG findings. Serial periodic assessment is helpful in patients suspected of thioridazine-induced toxic retinopathy.

In thioridazine-induced toxic retinopathy, virtually all scotopic and photopic components of the full-field ERG are affected to a various degree correlating to the extent of pigmentary retinopathy. However, in some cases, Marmor (51) has shown that visual function parameters including the full-field ERG may improve despite visible progression of the pigmentary retinopathy. With continued progression, full-field ERG eventually becomes non-detectable and EOG light-peak absent. Filip and Balik (56) demonstrated acute thioridazine-induced full-field ERG changes and found an impaired a-wave and b-wave in 10 normal volunteers 90 min after ingestion of 50 mg of thioridazine as compared to baseline, but the ERG was performed only after 5 min of dark adaptation and 5 min of light adaptation, respectively, Miyata et al. (57) reported reduced amplitudes of the O2, O3, and O4 wavelets of the oscillatory potentials and delayed peak time of the O2 wavelet in 28 patients treated with thioridazine, one of whom had visible pigmentary retinopathy. However, the authors reported results only from the combined rod–cone full-field ERG response obtained only after 15 min of dark adaptation. Godel et al. (58) examined the effect of thioridazine cessation on the full-field ERG and found improved ERG amplitudes in two patients and no improvement in one patient. In general, EOG tends to parallel ERG responses and the extent of thioridazine-induced pigmentary retinopathy. Also VEP is likely to parallel ERG findings and macular function. However, Saletu et al. (59) reported prolonged and reduced flash VEP responses in 21 hyperkinetic children who were treated only with up to 80 mg thioridazine daily for 8 weeks. Since such brief regimen is unlikely to produce retinal toxicity, these results suggest that thioridazine may have a physiologic effect on the VEP.

Chlorpromazine is a phenothiazine derivative used for psychiatric disorders and has far less ocular toxic effect than thioridazine (60). The risk of pigmentary retinopathy increases significantly with prolonged treatment of over

800 mg chlorpromazine daily (55). Pigmentary deposits of the skin, conjunctiva, cornea, and lens can also occur with chlorpromazine therapy. Siddall (55) found pigmentary retinopathy in 13 (26%) of 50 patients treated with chlorpromazine alone as compared with 13 (46%) of 28 patients treated with a combination of chlorpromazine and other phenothiazine derivatives including thioridazine. Of the 13 patients with chlorpromazine-induced pigmentary retinopathy, nine had retinal granularity and four had fine pigmentary clumping which was reversed with reduced chlorpromazine dosage. Visual loss as well as the corresponding pigmentary retinopathy were less severe in the chlorpromazine only group.

Of note, despite the binding of phenothiazines to melanin granules and the occurrence of associated pigmentary retinopathy, EOG is not of value in the early detection of phenothia- zine-induced retinopathy. In a study of 203 eyes of patients less than age 46 treated with phenothiazines including perazine, thioridazine, levo-mepromazine, and promethazine, Henkes (61) found that of the 92 eyes with ‘‘just visible’’ retinal pigmentary changes, 20 eyes had reduced EOG light-peak to dark-trough amplitude ratios, and of 18 eyes with ‘‘clearly visible’’ pigmentary retinopathy, only 12 had reduced EOG ratios. Based on these data, Henkes (61) concluded that EOG was not sensitive enough to detect early phenothiazine retinopathy. Likewise, in a study of 99 female patients, less than age 45, initially treated with phenothiazine derivatives, Alkemade (62) found 15 (15%) patients with pigmentary retinopathy, and of these, only nine of the 13 patients who had EOG testing had reduced EOG.

QUININE

Quinine, an alkaloid originally derived from the bark of the South American cinchoma tree, is used in the treatment of malaria and nocturnal muscle cramps. Quinine toxicity occurs with overdose from over-medication, attempted suicide, attempted abortion, or exposure to quinine filler in illegal narcotics. Symptoms of acute quinine poisoning include

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nausea, vomiting, tinnitus, deafness, blindness, and confusion. These symptoms usually occur with an ingestion of greater than 4 g of quinine with the mean fatal dose being in the range of 8 g. However, rare idiosyncratic sensitivity to quinine at lower dosages may occur. Treatment is aimed at reducing quinine serum levels.

With non-lethal acute quinine toxicity, severe visual loss occurs within hours after ingestion followed often by partial central visual improvement over days to weeks and marked persistent loss of peripheral vision. Ocular findings include large non-reactive pupils, retinal arteriolar narrowing, retinal edema, and the development of optic nerve head pallor. If needed, visual electrophysiologic tests may help in assessing visual function particularly in those who test unreliably subjectively with visual acuity and fields. The mechanism of visual dysfunction from quinine toxicity is not completely understood. Retinal dysfunction with abnormal ERG response is evident in humans as well as animals (63). The development of optic nerve head pallor has led to the speculation of retinal ganglion cell dysfunction.

Clinical and visual electrophysiologic findings in quinine toxicity are variable depending on the severity of toxicity and degree of recovery. In addition, studies of electrophysiologic findings in quinine toxicity consist mostly of case reports with differences in methodology. In general, during the early stage of acute quinine toxicity when severe acute visual loss occurs, the full-field ERG may be normal or demonstrate both rod and cone response impairment with absent oscillatory potentials. Over the next few days, some visual improvement usually occur, and impaired full-field ERG becomes more apparent with a greater selective reduction in b-wave so that a negative ERG pattern with b-wave to a-wave amplitude ratio of less than 1 is common (Fig. 15.4). The cone ERG response is generally more impaired than the rod response, and absent oscillatory potentials persist. Subsequently over weeks and months as the vision stabilizes, the ERG may improve or may demonstrate delayed slow progression of impairment. With regard to EOG and VEP, reduced EOG light-peak to dark-trough amplitude ratio and increased VEP latency occur

Figure 15.4 Full-field responses of a patient with persistent visual impairment from quinine toxicity. The cone responses are more impaired than the rod responses. The scotopic combined rod–cone response demonstrates a relatively selective reduction in b-wave such that the b- to a-wave amplitude ratio is less than one (‘‘negative ERG’’). The oscillatory potentials are essentially absent.

in the early stage of quinine toxicity and may show some subsequent improvement.

Several studies have documented electrophysiologic findings during the early phase of quinine toxicity. Brinton et al. (64) found slowed but increased a-wave, reduced and delayed b-wave, and absent oscillatory potentials for the scotopic combined rod–cone full-field ERG response in a patient with no light perception 18 h after ingestion of about 4 g of quinine, but the ERG was performed only after 15 min of dark

adaptation. The next day, the patient’s central vision improved, and the ERG a-wave and b-wave returned to normal in a few days, but a late progressive decrease in b-wave amplitude was noted within 6 months of follow-up. Visual acuity recovered to 20=15 in each eye but visual fields remained severely constricted with peripheral vision consisting of temporal islands only. The EOG amplitude ratio was initially 1.3 in each eye but improved to 1.6 by day nine. The pattern VEP showed persistent increased latency. In contrast, Yospaiboon et al. (65) reported small a-wave, nondetectable b-wave, and non-detectable oscillatory potentials for the scotopic combined rod–cone full-field ERG response and non-detectable VEP in a patient with no light perception after ingesting 12.6 g of quinine over 1 week for the treatment of malaria, but the ERG was performed after only 15 min of dark adaptation. After 21 weeks of follow-up, gradual partial a-wave and b-wave recovery and near complete VEP recovery were observed concomitantly with a visual acuity recovery to 20=30. Further, Canning and Hague (66) noted normal fullfield ERG amplitude to presumably scotopic blue, red, and white stimuli, reduced ERG oscillatory potentials, markedly reduced pattern ERG, non-detectable pattern VEP to grading stimuli, and small but not delayed flash VEP in a patient with visual acuity of 6=18 right eye and 6=24 left eye with markedly constricted visual fields one day after ingesting 9 g of quinine. After 66 days, the full-field ERG amplitudes became reduced, the reduced pattern ERG persisted, and the pattern VEP became detectable with increased latency.

Several other studies have further provided electrophysiologic responses after the acute phase of quinine toxicity. Moloney et al. (67) documented improved scotopic variableintensity stimuli response function of the full-field ERG from day 10 to 24 months in a patient with light perception vision after ingesting 6 g of quinine. However, despite an eventual visual acuity of 20=30 in each eye, reduced full-field ERG cone response and reduced oscillatory potentials persisted with rod response improving after 12 months. The EOG at day 10 had no light peak but eventually improved to a light-peak to darktrough amplitude ratio of 1.8 at 24 months. Flash VEP

response was absent at day 10 but improved to near normal after 60 days. In another case report, Bacon et al. (68) found increased a-wave and absent b-wave for the scotopic combined rod–cone full-field ERG response, reduced EOG lightpeak and dark-trough amplitude ratio of 1.3, and delayed pattern VEP with P2 component at 125–145 ms in a patient 4 weeks after ingestion of 10 g of quinine. When these tests were repeated 10 weeks after quinine toxicity, only a modest improvement was found with a small detectable full-field ERG b-wave and slightly improved VEP latency. Of interest, Franc¸ois et al. (69) found a relatively selective b-wave impairment with a negative pattern full-field ERG, greater photopic than scotopic impaired full-field ERG response, absent ERG oscillatory potentials, and reduced EOG in three patients examined at 15 months, 36 years and 37 years, respectively, after quinine toxicity. Similar findings were also noted by Behrman and Mushin (70) in a 10-month follow-up of a patient ingested 24 g of quinine but this patient was also on central nervous system medications for schizophrenia.

DEFEROXAMINE (DESFERRIOXAMINE)

Deferoxamine, also called desferrioxamine, is an iron chelator used for the treatment of iron overload. Patients with hematologic conditions such as beta-thalassemia major requiring frequent transfusions may develop hemosiderosis or iron overload that if left untreated may produce diabetes, cardiac disease, and hepatic dysfunction. Deferoxamine treatment in these patients dramatically increases urinary iron excretion. Other indications of deferoxamine have included acute iron intoxication, removal of iron deposits in synovial membranes in rheumatoid arthritis, and as a challenge test to diagnose aluminum overload in chronic renal failure. Deferoxamine is generally tolerated and is administered subcutaneously, intramuscularly, or intravenously (71). However, adverse toxic effects of deferoxamine therapy may involve visual, auditory, cutaneous, cardiovascular, respiratory,

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gastrointestinal, and nervous systems. Ocular signs of deferoxamine toxicity include cataract, pigmentary retinopathy, and optic neuropathy. The mechanism of deferoxamine toxicity is not completely understood. The fact that deferoxamine also chelates other metals such as copper, zinc, cobalt, and nickel has been implicated as a potential cause of toxicity (72). Patients with preexisting blood–retinal barrier breakdown associated with diabetes, rheumatoid arthritis, metabolic encephalopathy, and renal failure are at increased risk of developing deferoxamine-induced retinopathy (73). Ocular histopathology of deferoxamine toxicity reveals degenerative retinal pigment epithelial cells and thickened Bruch’s membrane (74). The relationship between deferoxamine dosage and the development of induced toxic retinopathy is highly variable. In a recent study of 16 patients with deferoxa- mine-induced retinal toxicity, the duration of deferoxamine therapy before presentation of 13 of the patients was known and varied from 4 weeks to 10 years, and the total dosage of deferoxamine was calculable in six patients and ranged from 243 to 10,950 g with a mean of 2785 g (73). Moreover, irreversible and reversible visual loss from optic nerve hyperemia, cystoid macular edema, and pigmentary retinopathy have been reported with a single small dose of deferoxamine (40 mg=kg) used as an aluminum overload challenge test in patients with chronic renal failure and on dialysis (75,76).

Visual symptoms of deferoxamine toxicity include decreased vision, impaired color vision, and night blindness. Ocular findings include cataract, pigmentary retinopathy, and optic neuropathy. Concomitant deferoxamine-induced deafness may occur. The earliest sign of deferoxamine retinopathy is often a subtle opacification or loss of transparency of the outer retina and retinal pigment epithelium followed by development of retinal pigment epithelium pigment mottling (73). With time, macular or peripheral retinal pigmentary alterations occur (77,78). Late hyperfluorescence of the affected region of the retina on fluorescein angiography is a reliable sign of active toxic retinopathy (73). Following deferoxamine cessation, visual improvement may or may not

improve, and retinal pigmentary changes may progress or develop despite improvement in visual function (78,79). Isolated optic neuropathy associated with deferoxamine use is likely to be less frequent than deferoxamine-induced retinopathy. In a series of eight patients with deferoxamine ocular toxicity reported by Lakhampal et al. (78), five of six patients with ‘‘presumed’’ retrobulbar optic neuropathy also had macular pigmentary degeneration.

The diagnosis of deferoxamine-induced ocular toxicity is arrived on the basis of visual symptoms, visual field defects, ophthalmoscopy, and fluorescein angiography. Visual electrophysiologic tests including full-field ERG, focal ERG, EOG, pattern ERG, and VEP are also of diagnostic value to determine earlier or more widespread injury than is suggested by ophthalmoscopic examination alone (73).

Visual electrophysiologic findings in deferoxamine toxicity are variable and are generally related to the severity of toxicity (77). Full-field ERG ranges from normal in mild cases to marked reduced and prolonged rod and cone responses in severe cases (73,78). Likewise, EOG may be normal or demonstrate a substantial impaired light rise with marked reduced light-peak to dark-trough amplitude ratio (73,78). Impaired VEP may reflect toxic retinopathy, optic neuropathy or both. In a study of 120 beta-thalassemia patients undergoing long-term deferoxamine treatment, Triantafyllou et al. (80) found impaired pattern VEP in 27% of the patients, which was mostly reversible with modification of deferoxamine treatment. Similarly, Taylor et al. (81) noted prolonged pattern VEP in 21% of 77 patients on chronic deferoxamine therapy and without clinical apparent retinopathy. Further, in a study of 43 patients with betathalassemia undergoing long-term deferoxamine treatment, Arden et al. found no or only mild abnormal retina appearance but pattern ERG abnormalities were much more pronounced than full-field or EOG findings. Of interest, siderosis or iron overload itself may also produce electrophysiologic alterations. For example, Gelmi et al. (82) found that thalassemia major patients treated with transfusions, who have no visual symptoms and had never received high