Patrick D. Williams,
David Callanan
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Key Features: |
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BOX 176.2
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Screening for hydroxychloroquine toxicity |
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INTRODUCTION
Medications that are toxic to the retina can produce variable presentations and clinical courses. The retinal changes can be subtle or dramatic, and the damage can be benign or devastating. The retina can demonstrate toxicity in numerous ways, including cystoid macular edema, damage to the retinal pigment epithelium (RPE), damage directly to the retina, and accumulation of the substance in tissue. Knowledge of the known toxicities can help the practitioner to decipher the sometimes unusual clinical presentations and treat patients accordingly.
PHENOTHIAZINES
The phenothiazine class of compounds is used to treat psychiatric conditions such as acute psychosis. Chlorpromazine (Thorazine) and thioridazine (Mellaril) are known to cause retinopathy with the high doses sometimes used to treat acutely psychotic patients. Chlorpromazine is used to treat intractable hiccoughs as well as psychiatric diseases.
THIORIDAZINE
GENERAL INFORMATION
Thioridazine has been used for acute psychosis since the 1950s. A dose of greater than 800 mg/day of thioridazine is more likely to produce toxicity, and 2 weeks of high-dose therapy is commonly required for retinopathy.[1] A high daily dosage is considered to be a greater risk factor than cumulative dosage. Although toxicity has been reported with chronic use at doses less than 800 mg/day, the incidence is extremely low.[2]
BOX 176.1
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Systemic medications that cause retinal toxicity |
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CLINICAL FEATURES
Patients typically complain of blurred vision, dyschromatopsia (brownish or reddish vision), and nyctalopia with acute thioridazine toxicity.[3-5] The visual symptoms can be variable, and acute toxicity may present with a normal retina or a granular stippling of the RPE with or without pigment clumping. More chronic disease can cause patients to develop geographic 'nummular' areas of atrophy of the RPE and retina (Fig. 176.1).[1] Early cessation of the medication may allow for some return of visual acuity.[6] The retina and RPE changes usually progress, suggesting atrophy of previously damaged cells.[1,6]
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FIGURE 176.1 Right eye of patient that used Mellaril (thioridazine) for many years with nummular areas of hypopigmented RPE. |
ANCILLARY TESTING
Ancillary testing can confirm thioridazine toxicity, although it is unclear if it can reveal preclinical disease. The fluorescein angiogram shows irregularity of the RPE initially, with severe atrophy of the RPE and choriocapillaris in the late stages of toxicity.[1] Fluoroscein angiogram changes can be more striking than clinical findings. Visual fields, electroretinogram, and electrooculogram are variably affected. Visual fields can have varying ring or paracentral scotomata or constriction.[4] Electroretinography can be normal or can have photopic and scotopic amplitude reductions.[6,7] Electroretinography changes, like visual symptoms, are reversible with quick cessation of medication.
PATHOPHYSIOLOGY
The toxicity of thioridazine may be due to its piperidyl side chain. The only other phenothiazine with a piperidyl side chain was NP-207, a drug never marketed. Severe retinopathies, similar to thioridazine toxicity, were found in early clinical trials.[8] Pathology specimens of eyes with thioridazine toxicity show initial atrophy and disorganization of the photoreceptors followed by loss of the choriocapillaris and RPE.[9] Both thioridazine and chlorpromazine bind to melanin and show accumulation in the melanin granules of pigmented tissues.[10-12] Phenothiazine toxicity may involve dopamine metabolism in the eye.[13] Dopamine regulates melatonin, which is involved in retinal physiology and prevents light toxicity.
CHLORPROMAZINE
CLINICAL FEATURES
Chlorpromazine causes hyperpigmentation of tissues, including sun-exposed skin and conjunctiva.[14-16] Corneal deposits and a characteristic cataract can develop. Retinopathy associated with chlorpromazine is rare. When it occurs, it presents as a diffuse hyperpigmentation of the RPE. The changes are fier and more diffuse than those of thioridazine toxicity. Patients may have arteriolar attenuation and optic nerve pallor. Alternatively, chlorpromazine toxicity may present with more well-defied patches of depigmentation.[17] Very large doses (~1-2 g/day) are required for retinopathy.[14-16]
QUINOLINES
GENERAL INFORMATION
The quinoline derivative antimalarials include both chloroquine and hydroxychloroquine (Plaquenil). Chloroquine was first used to treat malaria in the mid-twentieth century. It was first discovered in Germany in 1934, but was not used extensively until after World War II. The toxic side effects of chloroquine and hydroxychloroquine became apparent with the increasing use for rheumatoid diseases, as these diseases required higher doses and chronic treatment. The first reported case of chloroquine retinopathy was a case report of pigmentary retinopathy of unknown origin associated with systemic lupus erythematosus.[18]
CHLOROQUINE
Chloroquine can cause retinal damage with long-term daily use. Daily doses exceeding 250 mg and cumulative doses between 100 and 300 g are typically required to affect the posterior segment.[19] The daily dose may be more important than the cumulative dose. Doses at or below 3-3.5 mg kg?1 day?1 appear to prevent toxicity.[20,21] Maintaining a low daily dose appears to control the risk of toxicity, even with very high cumulative doses.[22]
HYDROXYCHLOROQUINE
Hydroxychloroquine has largely supplanted chloroquine for the treatment of rheumatoid diseases, in no small part due to its improved safety profile. Although hydroxychloroquine toxicity has been well documented, the incidence of hydroxychloroquine retinal toxicity is much lower than that of chloroquine.[23-25] The accepted safe dose is regarded as 6.5 mg kg?1 day?1. Below this threshold, the incidence of retinopathy is rare, but it has been reported.[26] At doses below 6.5 mg kg?1 day?1, 6 years of treatment is typically required before any retinopathy is appreciated. The most recent estimate of the incidence of toxicity at normal doses for greater than 6 years duration was 0.5%.[27] Patients using low-dose hydroxychloroquine therapy with massive cumulative doses can still avoid retinopathy.[28]
CLINICAL FEATURES
The most common early symptoms of toxicity are paracentral scotomata. As toxicity progresses, patients can also report a loss of acuity, nyctalopia, and photophobia. Dyschromatopsia can occur as well.[29]Toxicity is not limited to the retina. Poliosis, subepithelial corneal deposits, decreased corneal sensitivity, and even sixth cranial nerve palsies may develop.[29] These findings were much more common with chloroquine than what is reported now with hydroxychloroquine.
Early disease may not reveal retinal changes on biomicroscopy. The earliest signs include loss of the foveal reflex and nonspecific changes in the macular RPE.[30] In the later stages, there is granularity of the RPE in the classic bull's-eye pattern.[31] Bull's-eye maculopathy consists of a circular area of RPE hyperpigmentation centered on the fovea. An oval area of RPE hypopigmentation around the circle creates the appearance of a bull's eye (Fig. 176.2). Subsequent arteriolar narrowing, optic disk pallor, and peripheral RPE degeneration develop as well, giving an appearance similar to retinitis pigmentosa (Fig. 176.3).
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FIGURE 176.2 Classic bull's-eye pattern of retinopathy due to chloroquine toxicity. |
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FIGURE 176.3 Advanced chloroquine toxicity mimicking retinitis pigmentosa with bone spicules and arteriolar narrowing. |
There is no treatment besides drug cessation. Unfortunately, the toxicity can often progress even after the drug is stopped. It will eventually stabilize, but the central acuity can be significantly affected. In some cases of early toxicity, visual acuity has improved after stopping therapy.
ANCILLARY TESTING
There is still controversy about whom and how to monitor these patients for early signs of toxicity. As stated above, hydroxychloroquine toxicity is exceedingly rare in doses under 6.5 mg kg?1 day?1 and less than 5 years duration. Other factors, however, can influence the risk of toxicity. In 2002, the American Academy of Ophthalmology (AAO) published a guideline for hydroxychloroquine screening.[32] Not only do dose and duration of therapy affect toxicity risk, but liver or renal disease, obesity, concomitant retinal disease, and age over 60 may play a role. Liver or renal disease can affect chloroquine and hydroxychloroquine levels because these drugs are cleared by both organs. Obesity is a risk factor because neither drug is stored in fat cells. People in which fat contributes a large percentage of total body weight must be placed on relatively lower doses.
The clinical examination is the basis of all ophthalmologic testing for chloroquine and hydroxychloroquine toxicity.[32] The AAO recommends a baseline examination, although the efficacy has not been proven. Routine examinations should be maintained based on risk stratification. Unfortunately, early toxicity may be missed by only relying on clinical examination. Considering the rare incidence of hydroxychloroquine toxicity, there has been much debate over the costs and benefits of extensive ancillary screening.
Color Vision
There are no changes in color vision specific to chloroquine or hydroxychloroquine retinopathy, but nonspecific changes may occur with disease.[33] In general, Ishihara color plates and the Farnsworth D-15 panel have poor sensitivity for early toxicity.[34,35] The standard Pseudoisochromatic Plates part 2 and the AO HRR tests are more reliable predictors of retinal toxicity.[35] A baseline color vision examination may be beneficial in males to later differentiate inherited color deficiencies from equivocal cases of toxicity. Also, color vision testing can be useful in elderly patients, in which accurate perimetry is difficult.
Amsler Grid
The Amsler grid is widely used for evaluation of early hydroxychloroquine toxicity, and is recommended by the AAO.[32] It is inexpensive and easy to administer, making it ideal for clinic and home use. The scotomata produced on Amsler grid correlate well with those found on perimetry.[36] In patients with normal perimetry, the Amsler grid can sometimes reveal relative scotomata.[37]
Modifications in the Amsler grid may improve its sensitivity. Red Amsler grid testing yields a higher incidence of scotomata, but the sensitivity is questionable due to a lack of confirmation of many positive tests.[38,39] These may be early toxic changes or may be false-positive results. Recently, the threshold Amsler grid has been proposed as a test more sensitive than even the red Amsler grid.[38] The patient looks through cross-polarizing filters at a standard Amsler grid, thereby reducing contrast sensitivity and eliciting milder relative scotomata. The sensitivity of threshold Amsler grid testing is much higher than that of either the standard Amsler grid or the red Amsler grid.[38] As with the red Amsler grid, the true specificity is difficult to ascertain.
Perimetry
Perimetry has become commonplace in the evaluation of hydroxychloroquine patients. Both kinetic (Goldmann) and static (Humphrey) perimetry have been used to evaluate hydroxychloroquine and chloroquine toxicity. Humphrey 10-2 visual fields allow focused examination of macular function.[40] The sensitivity and specificity of Humphrey static perimetry has been evaluated and is accepted as reasonable for decisions whether to continue or withdraw medication.[41] Red target perimetry appears to be more sensitive than white target perimetry (91.3% and 78%, respectively), but the specificity of red target perimetry is worse (57.8% and 84%, respectively). The AAO currently recommends either Amsler grid testing or Humphrey 10-2 perimetry to monitor patients taking hydroxychloroquine.[32]
Fluoroscein Angiogram
Fluoroscein angiography can highlight the changes seen on ophthalmologic exam (Fig. 176.4). It is not mandatory for routine evaluation, but can help differentiate toxicity from other maculopathies.[32]
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FIGURE 176.4 Fluoroscein angiogram highlighting bull's eye retinopathy due to chloroquine toxicity. |
Electrooculogram
Early reports suggested that the electrooculogram (EOG) may be a useful tool in chloroquine toxicity screening.[42,43] An Arden ratio of less than 1.85 appeared to signify toxicity. EOG has a poor specificity, however, and active episodes of rheumatologic disease can also alter the EOG.[44] The most recent review of EOG findings suggested a sensitivity of 50% and a specificity of 54%.[45]
Multifocal Electroretinogram
Multifocal electroretinogram (mfERG) is a newer screening modality for hydroxychloroquine toxicity. Decrease in mfERG amplitudes have been demonstrated in documented hydroxychloroquine toxicity, consistent with the decline in visual acuity.[46] More interestingly, changes in mfERG have been noted in patients with no other evidence of toxicity.[47-49] The significance of these changes is unknown, as there is no comparison to known parameters. Abnormalities were noted in patients with less than 5 years of hydroxychloroquine use, suggesting an early subclinical toxicity that was reversible with discontinuation of the medication. Normal mfERG examinations have also been found in patients taking the medication for over 10 years, however.[49] Therefore, there are likely some individual differences in mfERG responses, just as there are individual differences in frank toxicity. Multifocal ERG may become standard in hydroxychloroquine screening, but more information is needed to interpret abnormal results when no other abnormalities are found.
PATHOPHYSIOLOGY
The pathophysiology of chloroquine and hydroxychloroquine toxicity is, for the most part, unknown.[50] Chloroquine is concentrated in the RPE and uvea and is bound by melanin. Due to the fact that the toxicity appears to be concentrated in the macula, some have hypothesized a direct effect on cone cells. Chloroquine toxicity affects lysosomal metabolism in the neurosensory retina and RPE.[51] In a rat model, lysosomal pH rises with in vivo administration of chloroquine. Numerous membranous cytoplasmic bodies can be seen in retinal neurons, including cone cells but not rod cells. RPE metabolism is affected, with increase in lysosomal associated organelles and lysosomal accumulation of rod outer segments. The difference in toxicity between chloroquine and hydroxylchloroquine may be due to the difference in effect on lysosomal metabolism.[52] In vitro administration of chloroquine to RPE cells causes greater accumulation of lipofuscin than does administration of hydroxychloroquine. Lipofuscin accumulation is increased by elevated lysosomal pH and oxidative breakdown of phagocytosed material.
Changes in lipid metabolism are also present in the neurosensory retina.[53,54] An accumulation of lipids, which can cause direct neuronal damage, has been documented with chloroquine toxicity. Based on comparisons to electroretinographic findings in a rat model, lipidosis is not likely the direct cause of toxicity.
CRYSTALLINE RETINOPATHIES
Several chemicals can cause deposition of crystals in the retina. These include talc, tamoxifen, canthaxanthin, and methoxyflurane. In the majority of these cases, the patient is unaware of the presence of these crystals and they are found on a routine dilated retinal exam.
TALC
General Information
Talc is the common name for hydrous magnesium silicate. It is an inert filler used in oral medication such as methylphenidate (Ritalin) and can cause crystalline retinopathy in intravenous drug abusers.[55-57]With intravenous injection, crystals smaller than 7 ?m can pass through the lungs. The large talc crystals are trapped in the lungs, but pulmonary shunt vessels develop with repeated injections.[57] The crystals can then enter the arteriolar system and embolize to the eye. This likely explains why chronic intravenous drug abuse is usually required before retinopathy develops.
Clinical Features
Patients can be asymptomatic with talc crystalline retinopathy.[56] The crystals appear reflective and migrate to the end arterioles (Fig. 176.5). With persistent crystal deposition, an ischemic retinopathy develops.[56,58,59] Ischemia is confied to areas with capillary nonperfusion due to emboli. Other sequelae of ischemia, such as microaneurysms, cotton wool spots, and collateral vessels may also be present. Neovascularization of the disk or elsewhere can develop, leading to vitreous hemorrhage and retinal detachment.[58] Vision loss can also occur due to macular fibrosis.[60] Animal model of talc retinopathy suggests that the ischemic response is similar to other vascular diseases such as diabetes and sickle cell retinopathy.[61-63] Retinal photocoagulation to the ischemic retina can prevent complications of proliferative disease, just as in other vascular retinopathies.[64]
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FIGURE 176.5 Talc crystals in the right eye of a patient with chronic intravenous drug use. The patient had developed severe hypertension and suffered an intracranial hemorrhage as well. |
TAMOXIFEN
General Information
Tamoxifen is an estrogen receptor antagonist typically used in treating estrogen-receptor positive breast cancer. The number of cases with tamoxifen retinopathy has greatly declined since the daily dose was lowered to 10-20 mg/day, but retinopathy is still possible.[65-67] The classic descriptions of tamoxifen retinopathy were associated with doses of 180 mg/day in the treatment of metastatic disease.[68,69] While tamoxifen retinopathy can happen at standard doses, it is rare. There is no evidence to support routine screening of patients taking tamoxifen at standard doses.[70,71] Even if patients develop retinal crystals, there is typically little change in retinal function.
Clinical Features
Patients develop white, glistening crystals in the inner plexiform layer and nerve fiber layer. Varying degrees of pigmentary changes may also be present. With high doses, patients may lose vision due to direct retinal toxicity as well as macular edema and optic neuropathy.[72] Patients can have improvement in vision with termination of tamoxifen therapy.[73]
Ancillary Testing
Electroretinography demonstrates a decrease in the photopic and scotopic a- and b-wave amplitudes.[73] Fluoroscein angiography can highlight the cystoid macular edema. Optical coherence tomography also demonstrates the cystoid spaces as well as photoreceptor disruption.[74]
Pathophysiology
Small intracellular lesions (3-10 ?m in diameter) in the macula and larger extracellular crystals in the paramacular region (30-35 ?m in diameter) have been described by electron microscopy.[69] These lesions were assumed to be the clinically apparent crystals and seemed to represent the products of axonal degeneration.
CANTHAXANTHINE
General Information
Canthaxanthine has been used as an oral tanning agent, but its use seems to have diminished since the reports of deposits in the retina. It is a naturally occurring carotenoid also used to treat vitiligo and disorders involving photosensitivity. It also can be found in common foods and has been suggested to be toxic with large dietary ingestion.[75] The first reports of retinopathy were in the European literature.[76-79] In cumulative doses greater than 60 g, a majority of patients have clinically apparent retinopathy.[79,80]
Clinical Features
In high doses for chronic use, canthaxanthine produces a characteristic crystalline retinopathy with an annular distribution of glistening crystals.[76-78,80,81] The ring of crystals is localized in the macula and is centered on the fovea (Fig. 176.6). Most patients with clinically apparent crystals are asymptomatic. Patients can, however, develop metamorphopsia or decreased vision. The retinopathy is reversible, with slow resolution of the crystals over years.[82]
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FIGURE 176.6 Right eye of a patient that used canthaxanthin for several months. There are numerous tiny crystals that are extremely reflective around the fovea. |
Ancillary Testing
Ten-degree static perimetry can show reduced sensitivity in patients with retinopathy, but patients taking canthaxanthine without clinical toxicity have normal visual fields.[83] Electrophysiology studies have not been consistent across studies, but some alterations have occurred clinically and in animal models.[84-87]
Pathophysiology
Based on histopathology, the crystals settle in the nerve fiber layer and can be found throughout the retina, even though clinically they are only apparent in the macula.[88] The crystals are actually canthaxanthine-lipoprotein complexes in which only the central portion can be appreciated clinically.
METHOXYFLURANE
Methoxyflurane is an inhalational anesthetic that metabolizes into oxalate crystals. With extended use, renal failure ensues due to the oxalate deposition in the kidney. A flecked retinal appearance with copious small yellow-white punctate lesions in the posterior pole and mid-periphery has been described (Fig. 176.7).[89] Toxicity due to chronic illicit abuse of methoxyflurane has also been reported.[90] Cotton wool spots, large retinal crystals in a periarteriolar pattern, and crystals in the RPE were clinically apparent. Histopathology has demonstrated oxalate crystals in the inner retina and RPE, as well as throughout the body.[91]
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FIGURE 176.7 Left eye of a patient with retinal oxalosis due to methoxyflurane anesthesia. |
The relationship between retinal changes in methoxyflurane toxicity and primary oxaluria is unknown. Both flecked retina and crystalline retinopathy have been reported in primary disease.[92-95] Unlike methoxyflurane toxicity, pigmented patches in the RPE have been described in primary oxaluria.
CISPLATIN
Cisplatin has been used for the treatment of malignant nervous system tumors as well as metastatic breast cancer and is commonly used in concert with other chemotherapeutic agents. It binds directly to DNA to inhibit normal DNA functioning. Nephrotoxicity, ototoxicity, and peripheral neuropathy are all common. Transient blurred vision is also common in high-dose intravenous infusion.[96]
The platinum in cisplatin is believed to cause direct retinal toxicity when administered directly into the carotid artery.[97-99] It has also been documented in an inadvertently high dose given intravenously.[100]These patients can develop a pigmentary retinopathy with severe vision loss in the eye ipsilateral to the carotid infusion.[97,98] The a-wave is attenuated and the b-wave is lost on electrophysiology. Histopathology reveals normal photoreceptors, but a splitting of the outer plexiform layer, which may explain the loss of the b-wave on ERG.[100]
Another form of retinopathy associated with cisplatin use involves an ischemic maculopathy and optic neuropathy.[97,99] Patients can present with arteriolar attenuation, cotton wool spots, retinal hemorrhages, and macular exudates. Optic nerve head edema may be present, and these patients can have significant visual loss. Permanent vision loss may be due to the optic nerve disease, as patients with only retinopathy had improvement in both symptoms and signs.[99] BCNU (carmustine) may account for some of the toxicity, as it can produce a similar retinopathy without concomitant cisplatin treatment.[97,101]
INTERFERON
GENERAL INFORMATION
Interferon alpha is a common adjuvant in the treatment of malignant melanoma as well as renal cell carcinoma, lymphoma, and leukemia. Alone or in combination with ribavirin, interferon is now the standard of care for treatment of hepatitis C. An ischemic retinopathy can develop in patients taking interferon, in some cases causing serious visual decline. Many of the descriptions of interferon retinopathy are in the Japanese language literature.[102]
CLINICAL FINDINGS
The earliest reports of interferon retinopathy in the English literature were in cancer patients receiving combination chemotherapy.[103] Patients developed common sequelae of retinal ischemia, including capillary nonperfusion, cotton wool spots, retinal hemorrhages, and occlusive disease (Fig. 176.8). Subsequently, corroborating reports have described ischemic retinopathy in both cancer treatment and hepatitis C treatment.[104-107] A similar retinopathy develops in patients undergoing treatment for hepatitis C, suggesting that the pathophysiology is similar regardless of the underlying disease.[104,106]Retinopathy begins within the first few months of therapy and the retinal signs fade with cessation of interferon.[103-110] Cystoid macular edema has been reported and severe, permanent vision loss can occur due to arteriolar occlusion.[108,109] Retinal changes commonly occur in asymptomatic patients, suggesting the need for ophthalmologic screening concurrent with therapy.[106,110]
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FIGURE 176.8 Left eye of a patient treated with interferon for hepatitis C. Cotton wool spots are apparent. |
PATHOLOGY
Based on analysis of intravitreal interferon in the rabbit eye, interferon retinopathy appears to have an immune-mediated etiology.[111] Complement pathway activation and immune complex deposition may be the underlying cause.
DIDANOSINE
The 2',3' dideoxyinosine (didanosine) is an antiretroviral medication used in the treatment of HIV. Pancreatitis and peripheral neuropathy are well described complications.[112] It can cause peripheral RPE atrophy in children without changes in central visual acuity.[113-115] The toxicity appears to be dose dependent and is common in the pediatric population (7.0%).[113] Didanosine is also associated with visual field deficits in adults.[116] In a report of two cases, an annular scotoma occurred in one patient and a mild increase in the physiologic blind spot occurred in the other. Both patients had abnormal EOG (Arden ratio < 1.6 in both eyes of both patients), suggesting diffuse RPE dysfunction.
Histopathologic examination has revealed loss of the RPE with surrounding hypertrophy or hypopigmentation.[114] Partial loss of the choriocapillaris and neurosensory retina were present in the areas of RPE loss. Electron microscopy demonstrated lamellar inclusion and cytoplasmic bodies in the RPE, suggesting that the primary toxicity is at the level of the RPE.
NIACIN
GENERAL INFORMATION
Nicotinic acid (Niacin) is both a vitamin and a medication that reduces cholesterol levels when ingested orally in large doses.[117] It causes spectrum alterations in both lipid and cholesterol metabolism and is relatively inexpensive. Common side effects, such as flushing, rise in uric acid levels, and gastritis have curtailed its use in exchange for other cholesterol reducing medications.[118] An extended-release formulation of nicotinic acid (Niaspan) has been introduced as an alternative for lowering of cholesterol levels.[119] The side effect profile is improved in comparison to Niacin, and no reports of macular edema have been published.
CLINICAL FEATURES
Cystoid macular edema is a rare but well known complication of high-dose niacin use and can be associated with blurred vision.[112-123] Most reports have documented CME associated a dosage of 3 g/day, but CME has been reported with as little as 1.5 g/day.[124] The clinical appearance of CME is similar to the edema caused by numerous other etiologies, however no other retinal changes are typically found with niacin maculopathy. The edema rapidly improves after discontinuation of niacin with resolution and improvement in vision commonly within 2 weeks.[120-123]
ANCILLARY TESTING
Fluoroscein angiography does not reveal any leakage.[120-123] Thus, nicotinic acid maculopathy fits with retinitis pigmentosa and Goldman-Favre disease as causes of 'angiographically negative' cystoid macular edema. Optical coherence tomography does, however, demonstrate cystoid spaces in the outer plexiform layer.[125] The author postulated that this fiding confirms the cystic nature of the toxicity and makes other possible etiologies, such as muller cell engorgement, less likely. Minor disruptions in the blood-ocular barrier may cause leakage too slow for fluoroscein angiography, but still result in edema.
CLOFAZIMINE
GENERAL INFORMATION
Clofazimine is one of a class of drugs known as riminophenazines.[126] This type of drug was developed for treatment of Mycobacterium tuberculosis. They have since been tried in other mycobacterial diseases, including Mycobacterium leprae and Mycobacterium avium complex (MAC).[127,128] Clofazimine has been approved by the World Health Organization for the treatment of leprosy and in particular dapsone-resistant cases. It is currently under increased study for use in multidrug resistant tuberculosis as well as systemic or discoid lupus erythematosus.[129,130]
CLINICAL FEATURES
The most common side-effect is a brownish discoloration of the skin that occurs in 75-100% of patients after a few weeks of treatment. It also causes brownish discoloration of the conjunctiva, tears, and thin superficial lines in the cornea.[131,132] There are only a few brief reports of pigmentary retinal changes in patients with leprosy treated with clofazimine.[132-134] There are three reports of a bull's eye type of retinopathy in patients treated with clofazimine.[135-137] All of these occurred in HIV positive individuals. At least one eye in these patients had evidence of an infectious retinitis. All of the patients died within months of the detection of the retinopathy and there was no pathologic specimen obtained. Patients that are HIV positive and treated with clofazimine may have an increased risk for retinal toxicity and should be monitored. There are other riminophenazines being studied now as possible new agents for use in leprosy and tuberculosis.[126]
ANCILLARY TESTING
The angiogram in the above mentioned HIV patients shows an annular area of RPE depigmentation in the macula. Electroretinography shows a decrease in the amplitude of the b-wave under both scotopic and photopic conditions. There is also a delay in the implicit time.[135,136]
PATHOPHYSIOLOGY
Riminophenazines accumulate in the intracellular space of mononuclear phagocytic cells and also in adipose tissue. The mechanism of injury to the RPE or retina is unknown. In two of the well documented cases, the patients received more than 40 g total of clofazimine. The dosage used was 200 mg/day in one patient and 300 mg/day in the other.[135,136]
DEFEROXAMINE
GENERAL INFORMATION
This drug is most commonly used for treatment of hemosiderosis. Excessive levels of iron can lead to cardiac failure; so the treatment is often life-saving. The most common predisposing factor is repetitive blood transfusions in patients with thalassemia or aplastic anemia.[138-141] The drug chelates or binds copper, iron, aluminum, and zinc. The iron present in normal hemoglobin is not chelated. Patients with renal failure and high aluminum levels are also sometimes treated with deferoxamine.[142,143] Deferoxamine can be given subcutaneously, intramuscularly, or sometimes intravenously.
CLINICAL FEATURES
Patients present with an acute onset of decreased vision, nyctalopia, ring scotoma, or color vision abnormalities as early as 7-10 days after treatment.[144-148] Patients can also develop symptoms after several months of treatment. The fundus may appear normal initially, but later develops a salt and pepper-like RPE abnormality (Fig. 176.9). Haimovici et al and Gass have reported a loss of transparency or opacification of the outer retina and RPE in the early stages of toxicity.[144,149] This is accompanied by late hyperfluorescent staining in the macula. This then progresses to RPE hypopigmentation and mottling on the angiogram and a decrease in the late hyperfluorescence. Haimovici also reported patients with peripapillary, papillomacular, and paramacular changes similar to those described above. Gonzalez and co-workers reported two patients treated with deferoxamine who presented with vitelliform lesions.[150] It is not known whether the vitelliform lesions were present prior to treatment with deferoxamine. Both patients were 70 years old so a preexisting condition can not be ruled out. Neither patient improved after discontinuation of deferoxamine. One of the patients had an abnormal ERG and showed more typical RPE mottling 1 year after the drug was stopped. Patients can also develop a high-frequency sensorineural hearing loss.[146,147] The visual symptoms and hearing loss often diminish when the drug is stopped, but not all patients fully recover. Optic neuropathy has been reported as well.[144,145,147,151]
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FIGURE 176.9 Right eye of patient with aplastic anemia. After receiving multiple transfusions, the patient developed hemosiderosis treated with deferoxamine. Mottling of the RPE is shown. |
ANCILLARY TESTING
The ERG is often abnormal with increased implicit times and a- and b-wave diminution under either scotopic or photopic conditions.[144,152,153] The EOG shows a reduced light peak to dark trough or Arden ratio. The EOG may serve as an early detector of toxicity or monitoring test.[153] An audiogram often shows high-frequency loss.[146,147] The ERG and EOG changes can also improve following discontinuation of deferoxamine.
PATHOPHYSIOLOGY
Light and electron microscopy evaluation of the eyes from a patient with deferoxamine toxicity showed RPE degeneration.[154] The patient had decreased vision and a subnormal EOG. The changes in the RPE included loss of microvilli from the apical surface, patchy depigmentation, vacuolation of the cytoplasm, and swelling with calcification of mitochondria. Bruch's membrane overlying these degenerated RPE cells was abnormally thickened with accumulation of elastic fibers and collagen. At least two teams of investigators have suggested that deferoxamine may increase the transport of copper, out of cells and raise the extracellular concentration of copper.[151,155] Measurements of copper levels in the cerebrospinal fluid of a few patients are compatible with this hypothesis. A model of deferoxamine toxicity in the albino rat demonstrated increased toxicity with light and oxygen exposure.[156] This was postulated to be related to increased free radical production. There is no further evidence to support this hypothesis. The exact cause of the RPE toxicity from deferoxamine remains unknown. It may be a direct effect of the drug or a secondary effect from chelation of divalent metal ions. One study in albino rats showed a reduction in toxicity as measured by electrophysiology when it was conjugated with hydroxyethyl starch.[157] There are at least two new agents, deferiprone and deferasirox, under study as replacements for deferoxamine or as combination therapy.[138,139] The use of these chelating agents is necessary to prevent the dire consequences of iron overload. It is hoped that their side effects can be minimized. Any patient treated with deferoxamine should be carefully monitored for visual changes.
METHANOL
GENERAL INFORMATION
Methanol toxicity is commonly due to accidental poisoning in alcoholics. Improper distillation allows for methanol formation as well as ethanol. Inhalation and skin contact can also induce methanol toxicity. When methanol is ingested, an anion gap metabolic acidosis occurs with acute renal failure. Fomepizole is a competitive alcohol dehydrogenase inhibitor with demonstrated efficacy in methanol poisoning.[158] Electophysiologic testing suggests that it benefits retinal toxicity as well as systemic toxicity.[159]
CLINICAL FEATURES
Patients develop blurred vision and scotomata within hours of ingestion.[160,161] Optic nerve hyperemia and posterior retinal edema are present. If the toxicity is not reversed, permanent vision loss and optic atrophy ensue.
PATHOPHYSIOLOGY
Methanol metabolizes into formic acid, which is the cause of the neurotoxicity.[162,163] It is a mitochondrial toxin that causes direct damage to the ganglion cells and optic nerve. Electrophysiologic and histopathologic examinations have suggested a direct effect to the RPE as well as the neurosensory retina.
QUININE
Quinine is an antimalarial now used in the treatment of muscle cramps and restless leg syndrome. It is the active ingredient in tonic water, which was used by sailors as a malaria prophylactic. Toxicity can be both acute and chronic.[164-167]
The syndrome of acute toxicity is known as cinchonism, from the natural source of quinine - the cinchona bark. Cinchonism consists of headache, dizziness, hearing loss, nausea, and tremor.[168] The pupils can be poorly responsive during unconsciousness, and vermiform movements of the pupils have been described.[166] Patients can lose consciousness and, if they survive, awake blind. While vision may return, patients may be left with permanent, severe visual field constriction. During the acute phase, the retinal arterioles can be normal with mild venous distention. Within weeks to months, the arterioles become severely constricted and the optic nerve becomes atrophic.
There has been some debate regarding the mechanism of retinal toxicity. The classic theory included ischemia due to vascular constriction.[165-167] More recent studies have suggested a direct retinal toxicity, however.[165-169] Electrophysiology, including ERG, EOG, and VEP, can be abnormal in the acute phase of toxicity, and ERG and histopathology are suggestive of diffuse damage to neurosensory retina. Even without signs of quinine toxicity, ERG demonstrates a transient decrease in photoreceptor function at therapeutic doses.[170]
Despite the evidence of direct retinal toxicity, recent reports have proposed the treatment of blindness due to cinchonism with vasodilating agents.[171] The results have not been tested in comparative trials.
ANTIEPILEPTICS
VIGABATRIN
Vigabatrin is an irreversible inhibitor of GABA transaminase used in the treatment of pediatric and adult seizures.[172,173] It is known to cause visual field defects at therapeutic doses.[174-176] The peripheral retina can be atrophic and the optic disk can exhibit nasal or diffuse pallor.[177,178] The visual loss can be transient or permanent. Toxicity can occur within the first few years of therapy. Although a dose dependent toxicity was found in one study, no dose response or risk factors for retinopathy were found in another.[179,180]
Visual field changes can be asymptomatic, and, in children, accurate peripheral visual testing can be dfficult.[181] ERG, EOG, and VEP changes correlate with the visual field changes, however, and can be used for routine evaluation.[182-184] Reductions in the cone b-wave and oscillatory potentials are well documented.
LAMOTRIGINE
Lamotrigine is another antileptic with documented changes in electrophysiology.[185] No clear cases of toxicity have been identified, but one patient on high-dose lamotrigine therapy had transient visual field changes.
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