Abstract
This chapter summarizes the application of electroretinogram, electrooculogram, and visual evoked potential in retinal toxicities caused by vigabatrin, hydroxychloroquine (Plaquenil), chloroquine, antipsychotics, cis-platinum, deferoxamine, digoxin, ethambutol, indomethacin, isotretinoin, ocular siderosis, phosphodiesterase type 5 Inhibitor, and quinine.
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Keywords
- Electroretinogram
- Electrooculogram
- Visual evoked potential
- Retinal toxicity
- Vigabatrin
- Hydroxychloroquine (Plaquenil)
- Chloroquine
- Antipsychotics
- Cis-platinum
- Deferoxamine
- Digoxin
- Ethambutol
- Indomethacin
- Isotretinoin
- Ocular siderosis
- Phosphodiesterase type 5 inhibitor
- Quinine
Vigabatrin
Vigabatrin (VGB) , sold under the brand name Sabril, is an anticonvulsant medication inhibiting gamma-aminobutyric acid (GABA) degradation for the treatment of epilepsy. It is an irreversible inhibitor of GABA transaminase. By irreversibly binding to GABA-transaminase, thus metabolism of GABA is hurdled. The accumulation of GABA then damages the neurons in the eye and brain. It can reduce visual acuity, contrast sensitivity, retinal thickness, the a-wave and b-wave of scotopic and photic electroretinography (ERG), oscillatory potential (OP) amplitudes, 30-Hz flicker ERG amplitude, multifocal electroretinography (mfERG) amplitudes, electrooculography (EOG) Arden ratio, and the VEP amplitude from central or peripheral visual field and increase the latencies of ERG a-wave and b-wave [1,2,3,4,5,6,7,8,9,10,11]. Reduction in b-wave amplitudes and 30 Hz flicker amplitudes are usually the first signs of toxicity. There is also evidence that light exposure in mice administered VGB produces the taurine deficiency, causing the retinal degeneration [2, 12]. Dysregulated expression of transcripts in the mTOR pathway, GABA/glutamate transporters GABAA/B receptors, and metabotropic glutamate receptors 1/6 in the eye are associated with the reduction of VEP amplitude after VGB administration [13].
Complex full-field electroretinography (ffERG) changes can be found in children placed on vigabatrin for intractable epilepsy (Fig. 9.1). However, importantly, some ffERG changes can precede exposure to vigabatrin, underscoring that these patients may have preexisting changes in their retinal function related to their underlying condition. Thus, to correctly assess vigabatrin-mediated toxicity, obtaining baseline ffERGs is essential. With this caveat in mind, toxic effects during exposure to vigabatrin onto retinal function can affect both receptoral and post-receptoral responses and can vary from patient to patient (Fig. 9.1).
Hydroxychloroquine (Plaquenil) and Chloroquine
Hydroxychloroquine (HCQ) and chloroquine (CQ) are antimalarial agents commonly used in the treatment of lupus erythematosus, Sjogren’s disease, rheumatoid arthritis, and dermatological inflammations. HCQ is also used in the treatment of uncomplicated malaria caused by chloroquine-sensitive strains of Plasmodium species or in the prophylaxis in regions with chloroquine-resistant strains. HCQ inhibits movements of neutrophils and eosinophils and also impairs complement-dependent antigen–antibody reactions. Its antirheumatic properties are proposed to result from their interference with “antigen processing” in macrophages and other antigen-presenting cells [14].
Both HCQ and CQ belong to the quinolone family and have similar clinical indications and side effects, including retinal toxicity. Hobbs et al. first described the CQ-induced retinal toxicity in 1959 [15], and Shearer et al. first described the HCQ toxicity to retina in 1967 [16]. HCQ has much less retinal side effect so that CQ has almost been replaced by HCQ for the treatment of inflammatory diseases. The retinal damage induced by these medications is usually irreversible. In a portion of patients with long-term HCQ/CQ treatment, HCQ-/CQ-induced toxicity can be found in cornea and macula, possibly related to the factors of cumulated dosage, duration of use, age, concomitant use of certain medications (e.g., tamoxifen), and health status (e.g., renal disease). In the retina, it may cause bilateral Bull’s eye pattern of maculopathy (Fig. 9.2a), parafoveal damage of retina in early stage, and extramacular damage of retina in later stage. It affects ganglion cell layer, photoreceptors, and retinal pigment epithelium (RPE) by the inhibition of protein synthesis [17, 18] and peroxidation of lipid [19]. The risk of HCQ-/CQ-induced maculopathy is associated to the daily dose and the duration of HCQ/CQ administration [20, 21]. More damage may occur after the initial damage with continued use of HCQ/CQ [22]. Therefore, early screening of HCQ/CQ toxicity in these patients is necessary.
In mfERG test, HCQ-/CQ-induced maculopathy shows paracentral decrease of mfERG amplitude and prolongation of latency (Fig. 9.2b) [21, 23,24,25,26,27,28,29,30]. The ffERGs can be abnormal in some patients [31]. In the late stages of HCQ-induced retinopathy, ffERGs and other tests can be used together for the differential diagnosis [32]. For early detection of HCQ/CQ toxicity, mfERG, spectral domain optical coherence tomography (SD-OCT) (Fig. 9.2c), and fundus autofluorescence (FAF) (Fig. 9.2d) may have higher sensitivity than perimetry [24, 28, 33,34,35,36,37] and are part of the standard Plaquenil patient workup. In addition, mfERG can provide objective data of the retinal function across visual field [20].
Antipsychotics
Chlorpromazine (CPZ) and thioridazine are members of the first-generation antipsychotic class, also known as typical antipsychotics. Their mechanism of action depends on the blockage of postsynaptic D2 receptors in the mesolimbic and mesocortical pathways. Typical antipsychotics may also block muscarinic, alpha 1-adrenergic, histamine, and 5-HT2 receptors.
CPZ administration can cause latency prolongation of the ffERG mixed response and cone response, decrease of rod and cone b-wave amplitude, and latency prolongation of the oscillatory potentials (OPs). However, CPZ is not known to change parameters of the fVEP, pERG, and the retinocortical times calculated from the difference of pERG and pVEP latencies [38].
Thioridazine (also known as Mellaril) is a dopaminergic antagonist (similar to CPZ) first used as antipsychotic with indication for the management of schizophrenic patients who fail to respond adequately to the treatment with other first-line antipsychotic drugs.
Because of its serious retinal and cardiac side effects (thioridazine may increase the risk of potentially fatal ventricular arrhythmias), its use is presently recommended only for selected cases. Probably due to an idiosyncratic response, retinal toxicity has also been reported for short-term and low-dose administrations [39]. However, long-term thioridazine treatments are usually associated with the highest risk of retinopathy.
The earliest signs of thioridazine retinal toxicity is RPE mottling of the macula and perimacular regions. Full-blown retinopathy is characterized by nummular (coin shaped) patches of RPE loss in both posterior pole and periphery, with a RP-like appearance [40, 41] (Fig. 9.3). Decreased visual acuity, night blindness, paracentral scotomas, and loss of peripheral vision can all occur in thioridazine retinopathy. In more advanced stages of the disease, there is definite electrophysiological (ffERG, EOG, and mfERG) evidence of diffuse retinal compromise (Figs. 9.4 and 9.5).
The mechanism of retinal damage is still unclear, but it is thought to be similar to chlorpromazine, accumulating mainly in pigmented cells including the uveal level [42]. This presumed mechanism may explain the extensive choriocapillaris loss and RPE dysfunction and damage co-contributing to the retinal damage. Direct dopaminergic mechanisms have also been suspected, but not proven.
Thioridazine discontinuation is the only treatment available. Regression has been described, but only in early-diagnosed cases, and further progression of retinal damage over several years after discontinuation can (more commonly) occur [43].
Cis-Platinum
Cis-platinum is a medicine used for the chemotherapy of bladder, testicular, ovarian, small and non-small cell lung, esophageal, breast, prostate, stomach, and cervical cancers. It is also used to treat mesothelioma, sarcomas, melanoma, multiple myeloma, neuroblastoma, and Hodgkin’s and non-Hodgkin’s lymphomas. Cis-platinum is an alkylating agent active during resting phase of the cell. Therefore, this drug is cell cycle nonspecific. The manifestation of electrophysiology of cis-platinum side effect includes reduction of ERG dark-adapted and light-adapted b-wave amplitudes, amplitude of OPs, amplitude of 30 Hz flicker ERG, and dark-adapted a-wave amplitude (Fig. 9.6) [44,45,46].
Deferoxamine
Deferoxamine (DFO) is an IV detoxification agent used in both acute iron intoxication and chronic iron overload. It is also used for the detoxification of aluminum intoxication. DFO chelates iron from ferritin and hemosiderin and enhances its elimination. Both ocular and auditory disturbances have been reported with this agent, suggesting pigmentary retinopathy and optic neuropathy can be caused by DFO. The ocular symptoms of its side effects include vision loss, dyschromatopsia, nyctalopia, and scotomas that can be partially recovered after the cessation of DFO administration. Electrophysiology can be used to monitor this side effect seen in the reduction of ERG responses of rod and cone pathways (Fig. 9.7), EOG Arden ratio, mfERG amplitude in central field, and the prolongation of VEP latency [47,48,49,50,51]. The visual function may be recovered after the cessation of the DFO administration.
Digoxin
Digoxin is a drug in the cardiac glycoside family of medications for the treatment of some cardiac disorders, including heart failure, atrial fibrillation and atrial flutter. Its side effects include abnormal vision, irregular heartbeat, nausea, loss of appetite, confusion, and breast enlargement. The symptoms of the visual disorder include blurry vision, central scotomas, photopsia, abnormal color vision, and xanthopsia [52,53,54,55]. Studies show ERG or mfERG in the central field in some patients treated with digoxin is abnormal [56,57,58,59]. Some studies with animals also confirmed the side effect of digoxin on retinal cone and rod photoreceptors displayed as abnormal ERG results and other tests of visual function and morphology [60,61,62,63].
Ethambutol
Ethambutol (EMB) is mainly used to treat tuberculosis. Its side effects include ethambutol-induced optic neuropathy and retinopathy. For early detection of ethambutol-induced retinopathy, mfERG can show the decrease of P1 amplitudes and/or prolonged P1 latencies in the central, bitemporal, peripheral, nasal, or the whole tested field even before the visual symptoms occur [64,65,66,67,68,69]. These papers suggest mfERG is probably suitable for early diagnosis of ethambutol-induced retinopathy.
Indomethacin
Indomethacin is a nonsteroidal, anti-inflammatory drug that can be used to treat fever, pain, and inflammation. Indomethacin is a reversible inhibitor of cyclooxygenase 1 and 2, leading to decreased production of prostaglandins. Indomethacin can cause retinopathy reflected in significant reduction of rod and cone responses of ERG and the Arden ratio of EOG [70].
Isotretinoin
Isotretinoin is a medication primarily used to treat severe acne unresponsive to conventional therapy and occasionally used in the treatment and prevention of cancer. Isotrentinoin’s exact mechanism of action is unknown. However, isotretinoin may induce apoptosis. Due to its high teratogenicity, isotretinoin is distributed under a risk evaluation and mitigation strategy (REMS) program called iPledge, intended to prevent fetal exposure to the drug. The ocular side effect of isotretinoin can be manifested by the reduction of scotopic ERG amplitudes and Arden ratio of EOG [71,72,73].
Ocular Siderosis
Ocular siderosis (OS) is caused by retained iron-containing intraocular foreign body after a penetrating ocular injury (Fig. 9.8a) that can cause significant vision loss. Pigmentary retinopathy and cataract are common in OS. The degree of retinal damage and recovery is affected by many factors, such as location and size of the foreign body, which can be monitored by the decrease and improvement of ffERG amplitudes (Fig. 9.8b) [74,75,76,77,78,79], mfERG latency [80], the relationship of a-wave and b-wave amplitudes [81], or the Arden ratio of EOG [82].
Phosphodiesterase (PDE) Type 5 Inhibitors (Erectile Dysfunction Medication)
Phosphodiesterase (PDE) type 5 inhibitors , such as sildenafil, tadalafil, vardenafil, udenafil, and avanafil, are commonly used in erectile dysfunction and pulmonary hypertension. PDE5 inhibition leads to decreased degradation of cGMP leading to vasodilation. Sexual stimulation leads to a physiological release of nitric oxide activating guanylate cyclase and production of cGMP. Increased levels of cGMP from the medication leads to smooth muscle relaxation and increased blood flow to the penis. However, these drugs may cause transient retinal disorders or optic neuropathy [83, 84].
The side effect in patients includes abnormal color vision, blurred vision, photophobia, ocular pain, and conjunctival hyperemia [85]. Decrease of amplitude and prolongation of latency in ffERG and mfERG were observed in some subjects or animals without preexisting ocular disorders after sildenafil administration [86,87,88,89,90,91]. Decrease of response in retinal ganglion cells in rat after sildenafil administration was also observed [92]. However, sildenafil increased the a-wave and b-wave amplitude in a rat model of neonatal hypoxia-ischemia [93] and the b-wave amplitude in a mouse carrier of retinitis pigmentosa [88]. In addition, both sildenafil and tadalafil may cause central serous chorioretinopathy [94, 95] and damage photoreceptors [96]. Sildenafil, tadalafil, and udenafil may cause optic neuropathy [91, 97,98,99,100,101,102,103,104,105,106,107,108]. Therefore, it is complicated to explain the electrophysiologic results of the users of PDE5 inhibitor for the diagnosis of other ocular disorders.
Quinine
Quinine is used in the treatment of uncomplicated malaria where resistance to chloroquine has been documented. Quinine is also used in the prevention of nocturnal leg cramps. The exact mechanism of antimalarial activity is not known. However, it is thought quinine can inhibit nucleic acid synthesis, protein synthesis, and glycolysis. The amplitudes of ffERG, mfERG, VEP, and EOG can be reduced after the administration of quinine [109,110,111,112,113,114].
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Yu, M., Senatore, A., Iannaccone, A., Kheir, W.J., Creel, D. (2019). Characteristics of Visual Electrophysiology in Retinal Toxicities. In: Yu, M., Creel, D., Iannaccone, A. (eds) Handbook of Clinical Electrophysiology of Vision. Springer, Cham. https://doi.org/10.1007/978-3-030-30417-1_9
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