Ординатура / Офтальмология / Английские материалы / Electrophysiology of Vision_Lam_2005

doses of deferoxamine, may exhibit ERG and VEP findings that resemble early siderosis bulbi.

VIGABATRIN

Vigabatrin is an antiepileptic medication used for complex partial, secondarily generalized seizures, and infantile spasm. Vigabatrin increases concentration of g-aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system, by interfering with the production of the enzyme g-aminobutyric transaminase which inactivates GABA. However, GABA is also an important inhibitory neurotransmitter in the retina, and GABA receptors are found on photoreceptor terminals and horizontal, bipolar, and amacrine cells of the inner retina. Bilateral visual field constriction, often concentric or binasal, from toxic retinopathy occurs in about one-third of patients on vigabatrin therapy; however, only about 10% of vigabatrin patients have visual symptoms such as reduced peripheral vision, blurred vision, and impaired color vision (83–86). Vigabatrin produces accumulation of GABA in the retina but precise mechanisms of vigabatrininduced retinopathy are not well understood. Three subtypes of GABA receptors, type A, B, and C are known, and subtypes of GABA-ergic rod bipolar, cone bipolar, and amacrine cells have been identified. However, subtypes of GABA receptors are not necessarily evenly distributed. For instance, bipolar cells express both GABAA and GABAC receptors but the ratio of GABAC to GABAA receptors is greater in rod bipolar cells than cone bipolar cells. Activation of GABAC receptors increases ERG b-wave, and activation of GABAA receptors decreases ERG b-wave, but vigabatrin also produces GABA accumulation in Mu¨ ller cells which are involved in generating the ERG b-wave (87–89).

The retinal appearance is usually normal in vigabatrininduced retinopathy. Rarely, the retina may show narrow retinal arterioles, surface wrinkling retinopathy, and abnormal macular reflexes (85). The diagnosis of vigabatrin-induced retinopathy is typically made on the basis of visual symptoms,

bilateral concentric or binasal visual field constriction, and progressive deterioration of full-field ERG responses. Visual impairment may persist even after cessation of vigabatrin therapy (90,91).

While impaired full-field ERG responses are commonly found in vigabatrin-treated patients, the impaired ERG responses may be the result of not only the toxic effect of vigabatrin but also the non-toxic pharmacological effect of vigabatrin (92). Therefore, in vigabatrin-treated patients who are visually asymptomatic with stable visual fields and abnormal ERG responses, the abnormal ERG responses could be due to physiologic effect of vigabatrin or early toxic effect of vigabatrin or both (93,94). Only careful follow-up with serial visual fields and full-field ERG will determine whether further progression occurs supporting a toxic effect (Fig. 15.5).

Several authors have reported a greater cone than rod full-field ERG impairment in vigabatrin-treated patients with the b-wave amplitude of the photopic cone flicker response being the strongest correlate of the degree of visual field constriction (85,89,95,96). For instance, in most children treated with vigabatrin, the cone flicker amplitude declines between 6 months and 1 year of treatment (97). Although photopic b- wave reduction is the most frequent full-field ERG finding in vigabatrin-treated patients, reduced scotopic b-wave amplitudes and impaired oscillatory potentials can also occur (87,98,99). Taken together, these findings indicate a more selective dysfunction of the inner retina.

Focal and multifocal ERG may be reduced centrally as well as peripherally in vigabatrin-treated patients (86,100– 102). Reduced light-peak to dark-trough EOG amplitude ratio is noted often in vigabatrin-treated patients (103). However, EOG abnormality is not significantly associated with the degree of vigabatrin-induced visual field loss (95,104).

Impairment of conventional VEP is common in vigaba- trin-treated patients and does not necessarily correlate with severity of ERG changes (89). A specialized VEP called ‘‘special VEP H-Stimulus’’ has been developed by Harding et al. (105,106) to assess the effect of vigabatrin. The technique elicits pattern VEP response from the central 5 radius and from

Figure 15.5. Full-field ERG responses of a 28-year-old man treated with vigabatrin for seizure disorder for 1 year. Note the reduced cone single-flash and 30-Hz responses as well as the impaired oscillatory potentials. Despite the ERG impairment, the patient has been visually asymptomatic with stable visual fields and ERG responses after 4 years of follow-up. Therefore, the non-progressive impaired ERG responses in this patient are likely related to the non-toxic pharmacological effect of vigabatrin.

a peripheral outer rim between 30 and 60 radius. The technique has a sensitivity of 75% and a specificity of 87.5% in identifying visual field defect and may be used in young children older than 3 years, who are unable to perform reliable visual fields.

With discontinuation of vigabatrin, visual field defects and electrophysiologic abnormalities may persist (91,101,107). In patients with minimal or no visual field loss, visual

impairment as well as ERG amplitude loss are more likely to be reversible (91). In patients with vigabatrin-associated visual field constrictions, the ERG and the EOG may demonstrate recovery after discontinuation of the medication without corresponding improvement of visual field (108).

SILDENAFIL (VIAGRA )

Sildenafil (Viagra ) is a medication for penile erectile dysfunction and acts by potentiating the vascular dilation effect of sexual stimulation on the corpus cavernosum of the penis. Cyclic guanosine monophsophate (cGMP) is a potent vascular smooth muscle relaxant of the corpus cavernosum and is inactivated by phosphodiesterase 5. Sildenafil limits the inactivation of cGMP by directly inhibiting phosphodiesterase 5. However, sildenafil also has about a 10% cross inhibitory effect on phosphodiesterase 6 which is involved in the process of phototransduction in retinal photoreceptor cells.

Incidence of visual symptoms is dose-related ranging from about 3% after ingesting sildenafil 50 mg to near 50% after ingesting 200 mg (109). Visual disturbance is likely to occur 1 hr after ingesting sildenafil and resolves over 3–4 hr. The transient visual symptoms from sildenafil include bluish vision, increased light sensitivity, and diminished color perception. Transient mild visual field and ERG alterations may occur (109,110). Vobig et al. (111) found reduced a-wave and b-wave of the scotopic combined rod–cone full-field ERG response to 63% and 77% of baseline, respectively, 1 hr after ingesting sildenafil 100 mg in five healthy subjects. Other parameters of the full-field ERG showed only small insignificant reductions, and the implicit times remained unaffected. The ERG changes correlated well with peak sildenafil plasma concentration and resolved 6 hr after ingestion. In contrast, Gabrieli et al. (112) noted higher full-field ERG scotopic rod response and greater rod sensitivity as determined by vari- able-intensity stimuli in a patient with visual halos 2 hr after sildenafil administration. This result was confirmed by the same research group in a subsequent study of 12 subjects (113).

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In a study with both full-field and multifocal ERG, Luu et al. (114) found slightly depressed cone function in the macula and the peripheral retina for at least 5 hr after dildenafil 200 mg in 14 healthy persons, but the ERG parameters still remained within normal limits. In the same study, the authors also noted a slightly increased scotopic combined rod–cone full-field ERG response; similar to the findings of Gabrieli but unlike those of Vobig. In a randomized, dou- ble-blind, placebo-controlled clinical trial of 20 men, Jagle et al. (115) performed full-field ERG responses 65 min after ingestion of 100 mg of sidenafil or placebo and found significant prolongations in the implicit times of scotopic a-wave (combined rod–cone response) and photopic b-wave (cone single-flash and flicker responses) after sidenafil ingestion. The ERG responses returned to normal after 24 hr.

Although the visual symptoms and ERG alterations of sildenafil appear to be transient, the effect of chronic sildenafil use in affected persons and asymptomatic carriers of retinal dystrophy is unknown. Because of this, caution regarding sildenafil use in affected persons and known carriers of retinal dystrophy has been advocated by some investigators. In a study of mice, heterozygous for a recessive mutation causing absence of g subunit of rod phosphodiesterase 6, Behn and Potter (116) reported a significant reversible dose-dependent decrease in ERG a-wave and b-wave after intraperitoneal injection of sildenafil in these heterozygous carriers as compared to normal mice. However, whether sildenafil is likely to produce a greater transient ERG effect in asymptomatic human carriers of retinal dystrophy is unknown and whether these transient retinal effects would cause permanent dysfunction has not been demonstrated.

GENTAMICIN

Retinal toxicity from intravitreal or subconjunctival gentamicin, an aminoglycoside antibiotic, is well recognized. D’Amico et al. (117,118) using a rabbit model found that gentamicin was the most toxic aminoglycoside compared to netilmicin,

tobramycin, amikacin, and kanamycin, and an intravitreal dose of 200 mg or greater of gentamicin resulted in electron microscopic damage to the photoreceptors and retinal pigment epithelium as well as reduced ERG. The risk of toxicity decreased markedly with a gentamicin dosage of 100 mg or less (119–121). Further, subconjunctival gentamicin injection adjacent to thinned sclera may lead to localized retinal toxicity (122). Moreover, inadvertent intraocular injection during subconjunctival injection of gentamicin produces retinal whitening with a macular cherry-like spot, diffuse retinal necrosis, and a rapid extinction of ERG (123). Clinically, this may mimic a central retinal artery occlusion or a combined central retinal artery and vein occlusion. In such cases, full-field ERG is helpful, because in retinal vascular occlusions, the ERG is usually not completely extinguished but demonstrates detectable a-waves.

ETHAMBUTOL

Ethambutol is a medication used in the treatment of tuberculosis and may produce optic nerve toxicity resulting in impaired visual acuity and visual field defects such as central scotoma, arcuate scotoma, and enlarged blind spot. Visual impairment is generally, at least partially, reversible if the drug is discontinued promptly but may be irreversible in some cases. The severity of the optic neuropathy does not necessarily correlate with the total cumulative intake of ethambutol. Several studies have documented reduced and prolonged VEP in ethambutol optic neuropathy (124–126). In addition, impaired VEP may occur in asymptomatic patients indicating subclinical optic neuropathy. With prompt drug cessation, visual acuity improves over months but recovery may not be complete, and in about one-third of the patients, prolonged VEP persists (127,128). Full-field ERG and EOG responses are usually normal although one study reported reduced EOG light-peak to dark-trough amplitude ratio in 26% of eyes with ethambutol optic neuropathy (129).

CISPLATIN

Cisplatin is an antineoplastic agent used in the treatment of several types of carcinoma. Visual impairment is reported rarely as a consequence of cisplatin neurotoxicity that may produce cortical blindness, optic neuritis, and retinopathy. Wilding et al. (130) examined 13 cisplatin-treated patients with ocular symptoms of blurred vision or altered color vision and found reduced cone full-field ERG response and considerably less affected rod ERG responses in 11 patients who underwent ERG testing. Loss of color discrimination and saturation, particularly on the blue–yellow axis, was common, and the retinal appearance was usually normal with irregular macular pigmentation in six (46%) of the patients. Hilliard et al. (131) reported two children, aged 4 and 7, treated with high-dose cisplatin and etoposide, who suffered visual loss to 20=600 with granular pigmentary retinopathy, optic nerve head pallor, and non-detectable full-field ERG. The authors proposed that the retinal toxicity was related to decreased renal clearance of cisplatin due to previous nephrotoxic drugs and perhaps also to cisplatin-induced nephrotoxicity. Of interest, Marmor (132) studied a 68-year-old woman with decreased vision after inadvertent overdosage with cisplatin. Both scotopic and photopic full-field ERG responses were marked reduced with a relative selective decrease in b-wave amplitude that was large enough to produce a negative ERG pattern with b-wave to a-wave amplitude ratios of less than 1 on scotopic bright-flash combined rod–cone response and photopic cone flash response. Oscillatory potentials were also notably decreased, and long-duration flash ERG demonstrated marked reduced photopic on-responses with near normal off-responses. Katz et al. reported a 55-year-old man who received four times the intended dose of intravenous cisplatin as part of therapy for non-Hodgkin lymphoma. Vision decreased to 20=300 in each eye immediately and never improved. Full-field ERG was non-detectable except for scotopic bright-flash rod–cone response where a reduced a-wave was visible with no b-wave. At autopsy 8 months later, photoreceptors appeared normal, and splitting of the outer

plexiform layer of the retina was present (133). Because cisplatin may also produce optic neuritis, and cortical blindness, impaired VEP responses may also occur and may be more likely in those receiving intra-arterial cisplatin (134).

INDOMETHACIN

Indomethacin is a frequently used non-steroidal antiinflammatory analgesic medication that very rarely produces a pigmentary retinopathy associated with reduced visual acuity, visual field defects, impaired scotopic full-field ERG responses, and reduced EOG light-peak to dark-trough amplitude ratio (135,136). Improvement of visual function usually occurs with discontinuation of the medication. Burns (136) reported ocular findings of 34 patients treated with indomethacin, most of the whom had rheumatoid arthritis and were seen for ocular symptoms. Six (18%) of the 34 patients were found to have indomethacin-induced corneal deposits and 10 (29%) had macular pigmentary disturbance. Abnormal full-field ERG responses were also noted in some of the patients. Henkes et al. (135) documented reduced EOG light-peak to dark-trough amplitude ratio and impaired scotopic full-field ERG responses, obtained after 15 min of dark adaptation, with no impairment of photopic responses in a 58-year-old man with rheumatoid arthritis and treated with indomethacin. After discontinuation of indomethacin, visual function, EOG, and ERG improved after several months.

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