This article includes discussion of ulnar neuropathies, Guyon canal neuropathy, ulnar neuropathy at the wrist, and flexor carpi ulnaris exit compression.
Jun. 07, 2021
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This article includes discussion of toxic and nutritional deficiency optic neuropathies, Cuban epidemic optic neuropathy, drug-induced toxic optic neuropathies, nutritional deficiency optic neuropathies, tobacco-alcohol amblyopia, toxic optic neuropathies, and tropical amblyopia. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Toxic and deficiency optic neuropathies are fairly uncommon in the United States. They are usually the result of drug toxicity. Due to the effects of these conditions on mitochondria and cellular energy production, these entities share many signs and symptoms. Awareness of the hallmark findings of these entities as well as an increased index of suspicion in patients with chronic disease will assist the clinician with diagnosis.
• Toxic or nutritional optic neuropathy is classically characterized by gradual painless progressive vision loss, bilateral central or cecocentral scotomas, marked dyschromatopsia, loss of high spatial frequency contrast sensitivity, temporal pallor, and loss of papillomacular bundle.
• Many toxic and nutritional optic neuropathies selectively affect the papillomacular bundle due to a common underlying mitochondrial pathway.
• A thorough history of medication use, toxic exposure, substance abuse, dietary deficiency, past surgeries, family history, and peripheral neurologic symptoms should be documented.
• The workup for toxic and nutritional optic neuropathies includes visual field testing, optic coherence tomography, and ancillary laboratory testing tailored to the medical history and examination findings. Magnetic resonance imaging of the brain may be necessary to rule out compressive lesions.
• Early recognition, removal of toxic agents, and supplementation of nutritional deficiencies may lead to protracted visual recovery.
Toxic and nutritional optic neuropathies are uncommon in the United States. However, in some times and places these types of optic neuropathies have been far more common; they took on epidemic proportions in Cuba in the early 1990s (63). This family of diseases tends to be relegated to the background until such events as famine, new application of pharmaceuticals, or changes in the workplace health and living conditions lead to nutritional deficiencies or toxic exposures.
Ordinarily, these entities are divided into nutritional (deficiency states) and toxic neuropathies. But many are multi-factorial, a clear etiology cannot be established, and the terms are often used presumptively. There is no doubt, however, that as the number of new drugs and chemicals increases, more toxic-metabolic optic neuropathies will be identified. One example that illustrates that these multi-factorial conditions have been considered either toxic or nutritional deficiencies is "tobacco-alcohol amblyopia." This entity was first well described by Traquair, who emphasized the slowly progressive time course of the bilateral visual field loss (75). The etiologic factors in tobacco-alcohol amblyopia are now better appreciated, even as there has been a marked decrease in the prevalence of the condition in the United States (58). The term "tobacco-alcohol amblyopia" suggests the relative roles of cyanide (from tobacco) and low levels of vitamin B12 due to poor nutrition and poor absorption associated with alcohol consumption. Deficiencies of B12, other B vitamins, and folic acid are known causes of a similar clinical picture (18). Indeed, it is one of the fundamental curiosities of these disorders that these nutritional deficiency optic neuropathies, as well as a myriad of toxic optic neuropathies, can have similar clinical manifestations (49).
In most cases, patients with toxic or nutritional optic neuropathy present with slowly progressive bilateral loss of visual acuity, often described as a central haze or cloud. The patients may describe an inability to read, to see traffic signs, or to see details in the faces of acquaintances. Patients do not complain of pain or positive visual phenomena such as photopsias. Sometimes paresthesias, ataxia, or hearing loss are associated; however, such neurologic symptoms are more characteristic of general nutritional deficiencies sometimes found in clusters in equatorial countries and termed "tropical amblyopias." They are not usually described in single-vitamin deficiency (42).
Patients generally have bilateral reduction in visual acuity that varies from minimal losses (20/25) to finger counting. The visual acuity loss in the two eyes is usually symmetrical. Visual acuity rarely falls below 20/400. Loss of color vision is constant and usually more profound than the loss of visual acuity. Patients with minimal dysfunction may present with isolated color vision deficiencies. The hallmark of toxic and nutritional optic neuropathies is the cecocentral scotoma that begins nasal to the blind spot and extends to involve fixation on both sides of the vertical meridian. An area of relative scotoma forms a bridge between the two islands of absolute scotoma at fixation and the blind spot. Complete loss of the perception of red is common, and red perimetry will demonstrate a much larger elliptical cecocentral scotoma than is found with white light stimuli. Bilateral cecocentral scotomas can look like bitemporal hemianopic scotomas on automated perimetry and can lead to the incorrect presumptive diagnosis of a chiasmal lesion. However, diminished foveal thresholds on automated visual field testing are more common in toxic and nutritional optic neuropathy than in chiasmal lesions. Because of the binocular symmetry of toxic and nutritional optic neuropathy, tests of optic nerve function that depend on asymmetry (relative afferent pupillary defect and brightness sense) will be normal.
The optic fundus may initially appear normal. However, a careful examination may reveal nerve fiber layer loss in the papillomacular bundle sometimes associated with swelling of the nerve fiber layer in the arcuate bundles above and below the denuded area between the fovea and optic nerve head (63; 64). Later in the course of the disease, the temporal optic disc appears mildly pale. The mismatch between relatively mild temporal disc pallor and severe depression of visual acuity, visual field, and color vision may lead to the misconception that the patient is malingering.
If the cause of the toxic or deficiency optic neuropathy can be found and treated early (for example, cessation of smoking and the administration of vitamins in tobacco-alcohol amblyopia), vision may return to near normal over several months' time. However, visual loss is often permanent in cases of long-standing toxic or nutritional optic neuropathy.
Ethambutol, an antimicrobial agent frequently used against pulmonary tuberculosis, is a frequent cause of toxic optic neuropathy. In the past, when the recommended dose was 50 mg/kg per day, toxic optic neuropathy was common (04; 37).The incidence of ethambutol toxic optic neuropathy has declined as a consequence of a downscaling of dosing guidelines to 25 mg/kg per day for the first six weeks with a further reduction to 15 mg/kg per day thereafter (37). Nonetheless, even with this dosage guideline, the incidence of toxic optic neuropathy among patients on ethambutol has been reported as high as 5% to 6% at 25 mg/kg per day and 0.7% to 1% when at least 15 mg/kg per day is prescribed (67; 81). Patients with renal failure are at particular risk, owing to reduced excretion of the drug (14). A meta-analysis suggested that renal function be tested in all patients on ethambutol in order to screen for even mild renal dysfunction (74). Patients on dialysis may be at particular risk, as ethambutol is not well dialyzed (68), and therefore, should be prescribed at lower doses. The slowly progressive bilateral loss of visual acuity is first noted a few months after intake of the agent. Together with severe dyschromatopsia, central or cecocentral scotomas are noted on visual field testing. The fundus findings of slight temporal pallor and nerve fiber layer dropout in the papillomacular bundle are subtle and often overlooked. Once the ethambutol is discontinued, visual recovery may begin within six weeks, but recovery may be delayed as long as six months (36). In some cases, there is no recovery. A small study of 16 subjects reported a 50% likelihood of visual improvement at six months after discontinuation. Improvement was noted in the group receiving a daily dose of less than 15 mg/kg (09). The window of reversibility is mostly due to the fact that mitochondrial impairment does not result in immediate neuronal death (66). The mechanism of ethambutol-induced optic neuropathy may be chelation of copper, thereby precluding normal cytochrome c oxidase activity and mitochondrial metabolism in the optic nerve (31). Appropriate dose adjustments should be made in the most vulnerable populations: the underweight, the elderly, and those with renal insufficiency. All patients treated with ethambutol should have a baseline ophthalmological examination, including Humphrey visual field testing, and be monitored on a regular basis. Optical coherence tomography (OCT) has also been utilized by some to detect decreased retinal nerve fiber layer thickness (08).
Disulfiram, another chelating agent, may produce a toxic optic neuropathy with a picture similar to that of ethambutol, but the prognosis is generally better once the drug is discontinued (16). Complete recovery of disulfiram-induced optic neuropathy usually occurs within two months of its discontinuation. However, irreversible toxicity has been reported (32).
Linezolid, an oxazolidinone antimicrobial active against gram-positive infections, has been reported by several authors to cause a reversible optic neuropathy (41; 59; 23). Although linezolid is probably safe for short courses of therapy, it may be toxic if used in a prolonged course of therapy for osteomyelitis and other chronic infections (73). Linezolid inhibits translation of bacterial DNA by binding to bacterial ribosomal RNA subunits (the binding sites differ from those of the macrolides). Therefore, its prolonged use may also inhibit mitochondrial protein synthesis. A study identified a probable linezolid-associated optic neuropathy that presented with abnormal color vision, characteristic optic nerve changes, and central scotomas attributed to toxic damage to mitochondria (76). In most cases, optic neuropathy has only developed after three months or more of continuous use.
Chloramphenicol, used to treat infection resistant to common antibiotics, may cause toxic optic neuropathy by inhibiting mitochondrial protein synthesis. The incidence and severity of optic neuropathy is dose-dependent. Prompt cessation of the drug and treatment with vitamin B complex usually leads to substantial recovery of visual function. Optic discs appear hyperemic with blurred margins and swelling of the papillomacular bundle, and visual field testing displays central or cecocentral scotomas (Godel et al 1980; Wong et al 2013).
Isoniazid, another antimicrobial frequently used to treat tuberculosis, is also toxic to the optic nerves but much less so than ethambutol. Optic neuropathies from isoniazid use are associated with severe bilateral optic disc swelling (28; 70) and with peripheral neuropathy (34). Others have suggested that the visual field defects in isoniazid optic neuropathy may have the appearance of bitemporal hemianopic scotomas (27).
Tacrolimus, a cytotoxic t-cell suppressor used in transplant medicine, has been reported to cause bilateral or unilateral optic neuropathy (21). In one reported case (03), the optic neuropathy was of rapid onset and with features resembling ischemic optic neuropathy, calling into question the etiology. The onset of vision loss was much more insidious in the other two reported cases (35; 29). In one of these cases (29), there was reversal of vision loss after discontinuation of the tacrolimus. Vasoconstriction and tissue ischemia has been hypothesized as the underlying mechanism (83). Given the extremely low number of reported cases, clinicians should remain vigilant but not deterred in the use of this agent.
Amiodarone, a medication used to treat ventricular arrhythmias, has been implicated in cases of toxic optic neuropathy. Its presentation is said to be similar to that of isoniazid and that it follows a much more rapid course than ethambutol-induced optic neuropathy. It is characterized by disc swelling and profound visual field defects. It often results in permanent vision loss (48). Ultrastructural changes have also been reported in the optic nerves of patients on long-term amiodarone therapy (39). The incidence rate was 0.3% in a large retrospective study. Male gender was associated with a nearly 3-fold increased risk of optic neuropathy. Increased cumulative incidence was observed with treatment duration of more than 41 days (10). On the other hand, Mindel reported an annual incidence of 1.6 per 100,000 patients using the IMS and FDA data from 2008 through 2012 (44). Because anterior ischemic optic neuropathy also displays many of these clinical features, and is common in the setting of arteriosclerosis, a common feature in patients treated with amiodarone, the cause-and-effect relationship between amiodarone and optic neuropathy remains uncertain.
Phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil), employed in the treatment of erectile dysfunction and pulmonary hypertension, have also been reported to cause optic neuropathy (02). The clinical picture appears similar to that of nonarteritic anterior ischemic optic neuropathy (NAION), in that the etiology appears to be vascular and not a direct or indirect toxic effect of the medication on the optic nerve. In many of the cases, the dose and frequency of medication use or time between ingestion of medication and onset of vision loss is not fully documented (55), making it difficult to establish a direct causal relationship (47). Because the use of these medications is widespread and the number of patients experiencing visual loss relatively small (fewer than 50 reported cases), it is considered an infrequent cause of optic neuropathy. However, in patients who have experienced NAION in one eye, or who have adequate vision in only one eye, it is prudent to discourage use of these medications (24).
Methanol and ethylene glycol are implicated in toxic optic neuropathy. Methanol is found in poorly distilled alcoholic beverages (“home brews”). Its ingestion produces a metabolic acidosis as a consequence of the accumulation of formate, one of its toxic metabolites. Methanol produces vision loss within hours of exposure and can lead to complete blindness (84). The optic disc is often hyperemic and swollen. Lack of pupillary reactivity to light usually indicates a poor prognosis (19). Ethylene glycol, the main ingredient in antifreeze, may also produce blindness with a time course similar to that of methanol.
An epidemic of nutritional deficiency optic neuropathy affected thousands of severely malnourished patients in Cuba between 1992 and 1993 (64; 62). This epidemic provided an opportunity for the careful analysis of affected patients before and after treatment with vitamin B12 and folic acid (63). The patients had reported a marked weight loss associated with severe deficiencies of protein and vitamin intake. In particular, laboratory testing demonstrated marked deficiencies of B12 and folate. Twenty Cuban patients with this optic neuropathy were carefully examined just before and three months after the administration of cyanocobalamin (3 mg) and folate (250 mg) each day. Their average visual acuity improved from 20/400 to 20/50 and their average color vision from a correct score of 25% to 87% on the American Optical Color test plates. The arcuate nerve fiber axon bundles were swollen before treatment but recovered afterward. The optic disc, which looked normal initially in most cases, went on to show temporal pallor (63). The clearest objective finding was marked thinning of the nerve fiber layer in the region of the papillomacular bundle forming a wedge defect bordered by swollen nerve fiber layers above and below. This finding was the most important aspect of the case definition, which required five signs: (1) bilateral progressive loss of visual acuity, (2) bilateral cecocentral scotomas, (3) bilateral dyschromatopsia, (4) bilateral losses of high spatial frequency contrast sensitivity, and (5) saccadic pursuit eye movements.
In addition to the visual symptoms, over one third of the patients in the Cuban epidemic had neurologic symptoms, consisting mostly of peripheral neuropathy, ataxia, and hearing loss. Malnourished prisoners of war have also been described to have an optic neuropathy that is associated with a peripheral neuropathy (17). The visual symptoms are accompanied by dysesthesias, particularly in the legs, together with ataxia and hearing loss (51). In these cases, the vitamin deficiencies associated with poor diet may have been compounded by the ingestion of cassava, which may have led to elevated levels of cyanide (52).
Immune checkpoint inhibitors have become an important class of cancer immunotherapy for various malignancies such as metastatic malignant melanoma and non-small cell lung cancer. Inhibition of immune checkpoint molecules can lead to unsuppressed immune response in various organ systems, which manifest as autoimmune-like side effects known as immune-related adverse events (irAEs). Ocular immune-related adverse events are rare, occurring in less than 1% of patients and are predominantly uveitis (33). The presentation is usually delayed and prolonged.
Ipilimumab, a human monoclonal antibody, works by blocking the cytotoxic T lymphocyte-antigen-4 (CTLA-4), which normally downregulates activation of T cells and allows tolerance to self-antigens. Ipilimumab thereby stimulates the immune response against tumor cells. Cases of thyroiditis and inflammatory orbitopathy have been reported (43; 40; 54; 71). Bilateral optic neuropathy was reported in one patient who presented with concurrent uveitis six weeks after the third ipilimumab infusion (82). A case of bilateral optic neuritis was reported five months after initiation of ipilimumab concurrent with steroid treatment (79). Pembrolizumab and nivolumab regulate T cell activation by blocking the protein programmed death 1 (PD-1). Bilateral optic neuritis and neuromyelitis optica spectrum disorder have been reported as rare immune-related adverse events of nivolumab (Kartal and Atas 2018; 46).
Early recognition of immune-related adverse events is important for effective management, which may include discontinuation of the toxin, or initiation of immunosuppressive therapy, or both. Immune-related adverse events generally respond to steroids. Cases that are refractory to steroid treatment may require plasmapheresis, IVIG, mycophenylate, or infliximab. A study was conducted to evaluate the effect of systemic immunosuppression on survival and time to treatment failure in patients with melanoma receiving ipilimumab. The study found no association between the use of corticosteroids and overall survival or treatment failure (25). Therefore, the authors concluded that immune-related adverse events requiring systemic immunosuppression should not compromise the therapeutic benefit.
A rapid diagnosis is crucial because the reversibility of visual loss is largely determined by how quickly the toxin can be removed or the deficient vitamin can be replenished. Surprisingly, vision may recover following the discontinuation of a toxin as long as six to 12 months after exposure (especially in the case of ethambutol toxicity). Despite severe losses of the nerve fiber layer and optic disc temporal pallor, patients may show dramatic degrees of visual recovery (63).
Case 1. A 68-year-old 50 kg woman presented with a complaint of progressive loss of vision in both eyes over several months. The past medical history was significant for the diagnosis of pulmonary tuberculosis made eight months earlier and the intake of isoniazid (300 mg per day) and ethambutol (120 mg per day, reduced after six weeks to 80 mg per day).
Best-corrected visual acuities were 20/400 in both eyes. There was a complete lack of color vision in both eyes. The pupils were slightly sluggish, but there was no relative afferent pupillary defect and no optic disc pallor. Tangent visual field testing demonstrated large bilateral cecocentral scotomas.
There was an elevated creatinine level of 1.9. Two months after stopping ethambutol, visual acuity had improved to 20/100 right eye and 20/200 left eye, but the rest of the examination remained unchanged.
This is a case of ethambutol-induced toxic optic neuropathy. Although the patient was also using isoniazid, which is known to produce optic neuropathy, the diagnosis of isoniazid optic neuropathy is unlikely. There have been far fewer reports of isoniazid-induced optic neuropathy, and the other clinical features are unlike those associated with isoniazid toxicity.
Case 2. A 62-year-old woman with a history of Crohn disease and multiple ileostomies presented with a chief complaint of progressive bilateral vision loss. She described the vision as dim and reported that colors appeared less bright and that red objects appeared brown. She had undergone a resection of the distal ileum approximately 13 months prior to presentation. She was on oral multivitamin supplementation.
On examination, best-corrected visual acuities were 20/400 in both eyes. She was able to identify only two of 15 American Optical color plates. Pupils were sluggishly reactive to light, but no relative afferent pupillary defect was noted. Humphrey visual field testing revealed bilateral central scotomas. Fundus examination revealed bilateral temporal pallor with loss of the papillomacular bundle. The patient was also found to have mild ataxia and decreased sensation on the feet. A macrocytic anemia was present.
This is a case of B12 deficiency seen in a patient following ileal resection. The distal ileum is the site of absorption of the vitamin after binding to intrinsic factor produced by the parietal cells of the gastric mucosa. The patient’s visual acuity eventually improved to 20/80 in both eyes after six weeks of intramuscular injection of cyanocobalamin.
The toxins most clearly established as producing an optic neuropathy include ethambutol, disulfiram, linezolid, chloramphenicol, isoniazid, methanol, ethylene glycol, arsacetin, carbon monoxide, clioquinol, cyanide, hexachlorophene, lead, plasmocid, and triethyl tin (72). Less clearly established as toxic to the optic nerve are amiodarone, tacrolimus, nucleoside analogue reverse transcriptase inhibitor, phosphodiesterase-5 inhibitors, carbon disulfide, pheniprazine, quinine, and thallium. Other toxins suspected but unproven as causes of optic neuropathy include carbon tetrachloride, dapsone, and suramin (72).
In regard to vitamins, deficiencies of the following are associated with optic neuropathy: vitamin B12 (cobalamin), vitamin B1 (thiamine), vitamin B2 (riboflavin), folic acid, and copper (56). Proteins, in particular those containing the sulfur amino acids, probably are also crucial for efficient oxidative phosphorylation. Reduced vitamin E and vitamin B1 levels have been suggested to play a role in the development of ethambutol optic neuropathy (57). Optic neuropathies due solely to nutritional deficiencies remain rare in the United States except in the setting of heavy tobacco and alcohol consumption. Severe eating disorders and gastric bypass surgery are risk factors for multiple nutritional deficiencies.
The clinical picture is relatively uniform. The common features are dyschromatopsia, cecocentral scotomas, and the selective loss of the papillomacular bundle. Combined deficiencies of several B vitamins are common.
The fact that so many nutritional deficiencies and toxic optic neuropathies produce similar clinical pictures relates to shared metabolic pathways (78). Oxidative phosphorylation within the mitochondria involves electron transfer to oxygen near the beginning of the cycle and the production of adenosine triphosphate (ATP) at the end. Vitamins such as B12 and folic acid are crucial to this process, and their deficiency would lead to reductions of ATP. Similarly, agents such as cyanide or formate (a metabolic product of methanol) block this electron transport. The final common product of these deficiencies and toxins is decreased ATP production by mitochondria within all of the cells of the body. Selective involvement of the optic nerve and most particularly of the papillomacular bundle may owe to reduced compensatory mechanisms. Muscle cells, for example, can deal with decreased mitochondrial deficiency by producing more mitochondria (61). However, neurons, particularly those with long or thin axons, are at a great disadvantage. All neuronal mitochondria are made in the cell body and must be transported via axoplasmic flow down the axon. Axonal transport is highly energy dependent. Furthermore, mitochondria have a relatively limited lifespan and their transport must be rapid and efficient or the terminal end of the axon will suffer ATP insufficiency and degenerate. Hence, such impairments are first seen in the longest axons (leading to a peripheral neuropathy) and the smallest axons (papillomacular bundle) (65). These dynamics involving mitochondrial insufficiency and mitochondrial axonal transport have been explored in an animal model in which rats are maintained on a folate-deficient diet and exposed to methanol such that formate levels rose and led to blocked electron transport (60). Patients in the Cuban epidemic optic neuropathy were found to have increased serum and cerebrospinal fluid concentrations of formate (15).
Preexisting dysfunction in mitochondrial metabolism from genetic causes such as Leber hereditary optic neuropathy and autosomal dominant optic atrophy likely renders patients more vulnerable to drug-induced mitochondrial optic neuropathy.
The nucleoside analog azidothymidine (AZT), also known as zidovudine, is an important component of highly active antiretroviral therapy (HAART) in the treatment of human immunodeficiency virus. It belongs to a class of drugs known as nucleoside reverse transcriptase inhibitors that function by interfering with viral DNA replication. This class of drugs is utilized not only by retroviral reverse transcriptase, but also by the mitochondrial DNA polymerase gamma. Therefore, all nucleoside analogue reverse transcriptase inhibitors may induce mitochondrial toxicity by inhibiting mitochondrial polymerase gamma and mitochondrial DNA (mtDNA) replication.
Case reports of profound visual loss and color deficiencies in Leber hereditary optic neuropathy patients harboring either the 11778 or 14484 mutations after initiation of highly active antiretroviral therapy have been reported, suggesting that antiretroviral therapy may be associated with increased risk in genetically predisposed patients (38). Ethambutol has also been suggested to trigger Leber hereditary optic neuropathy (69). Similarly, ethambutol has been linked to visual loss in a patient with autosomal dominant optic atrophy with an OPA1 mutation (20). If possible, these drugs should be avoided in patients harboring genetic mitochondrial defects.
Concurrent use of ethambutol and nucleoside analogue reverse transcriptase inhibitors may similarly further increase the risk of mitochondrial toxicity (45).
The reviews on nutritional deficiency optic neuropathies by Carroll (05; 06; 07) and Rizzo and Lessell (58) are landmark articles. However, the epidemic of optic neuropathy involving tens of thousands of Cubans in 1993 reminds us of two important epidemiological points. The first is that changing politics and social structures may lead to large-scale and devastating new problems in terms of nutritional deficiencies and toxic exposures, even in a sophisticated, modern world. Secondly, in Cuba there existed an excellent medical infrastructure with which to document this optic neuropathy (62). The concurrence of a sophisticated medical system with economic hardship and malnutrition revealed what may be a surprisingly widespread problem worldwide where smaller-scale similar epidemics are frequently missed for lack of medical and scientific sophistication.
The optic disc changes seen in association with toxic and nutritional deficiency optic neuropathies may be subtle; hence, there is a great need to rely on the patient's history, not only to gain a suspicion that there is a metabolic optic neuropathy, but also for possibilities of toxic exposure and nutritional deficiency. Patients who describe slow, progressive bilateral visual loss and in whom dyschromatopsia and cecocentral scotomas are found must be carefully investigated. Many such patients are initially given the diagnosis of psychogenic visual loss and later turn out to have tobacco-alcohol amblyopia or another toxic or nutritional deficiency. In the case of ethambutol, the best screening tests are those that measure papillomacular bundle function, such as visual acuity, color vision, contrast sensitivity testing, red Amsler grid testing, foveal thresholds, and other perimetric static thresholds (especially with use of the Humphrey 10-2 protocol, which is rarely used otherwise in neurodiagnosis) (66).
The differential diagnosis for toxic and nutritional optic neuropathies includes disorders that cause acute and subacute symmetrical visual acuity and color vision loss.
Leber hereditary optic neuropathy is due to point mutations in the DNA and, as such, is inherited through the maternal line. Probably because of the common pathology involving oxidative phosphorylation, the disease can look like toxic and nutritional deficiency optic neuropathies (53). Generally, patients develop acute or subacute loss of vision in one eye followed by the other eye in days, weeks, or months. Leber hereditary optic neuropathy most often presents in men in their late teens or early 20s. It can be distinguished from toxic and nutritional optic neuropathies by the presence of a family history, the occasional presence of telangiectatic vessels around the optic nerve head of the uninvolved eye during the acute phase, consecutive rather than simultaneous involvement of the two eyes, and laboratory study of the point mitochondrial DNA mutation.
Kjer autosomal dominant optic atrophy is less often confused with toxic and nutritional optic neuropathies. This type of optic neuropathy occurs much more slowly and progressively in late childhood and follows an autosomal dominant inheritance pattern. Isolation of the gene for this condition shows that it codes for a mitochondrial regulatory protein (12). Although less commonly confused with toxic and nutritional optic neuropathies, chiasmal lesions must also be ruled out. Pituitary adenomas or other lesions that compress the optic chiasm generally present with bitemporal visual field loss. However, in the early stages, bitemporal field losses may look like cecocentral scotomas. Chiasmal lesions are generally masses that are readily discovered on standard imaging studies.
Optic neuritis can occur in both eyes simultaneously. Almost any type of visual field defect can be encountered, including central scotomas that resemble the cecocentral defects of toxic and nutritional optic neuropathies. If the patient has multiple sclerosis, scattered high signal abnormalities may be detected on T2-weighted MRI. Fortunately, patients with optic neuritis usually show dramatic recovery of visual acuity over the ensuing two months.
Finally, psychogenic visual loss must be considered in the differential diagnosis given that objective abnormalities may be subtle or absent in toxic and deficiency optic neuropathies. Visual evoked potentials may be useful to document the increased signal latency that should be present in any organic cause of bilateral optic neuropathy but not in psychogenic visual loss.
A good history of exposure is a far more effective means of establishing the diagnosis than any laboratory test. However, suspected toxicities can be confirmed through serum and urine analysis. In particular, a 24-hour urine collection for heavy metal screening may yield unexpectedly positive results. In addition to serum vitamin levels for B1, B2, B12, and folic acid, red blood cell folate is a useful measure of folate levels over the past 100 days. Methylmalonic acid levels and homocysteine are markedly elevated in the majority of cases of B12 deficiency, but can have high false positive rates in the elderly. The usefulness of serum pyruvate remains to be determined, but it has been shown to be elevated in some cases of Wernicke encephalopathy (13).
Optical coherence tomography can be useful as a means of charting progressive retinal nerve fiber layer loss in patients with established diagnoses (01). However, in early phases of nutritional and toxic disease, the OCT macular thickness analysis may lag behind by a period of several months and, therefore, will not reliably diagnose disease or predict visual outcomes (85; 11). Thinning of the perifoveal ganglion cell-inner plexiform layer thickness at the onset of visual symptoms may be an early diagnostic marker (22; 77).
Humphrey visual field is an important diagnostic test. Visual field defects in toxic and nutritional optic neuropathies are usually symmetric central or cecocentral scotomas. Bitemporal hemianopia has been reported, with or without overlapping cecocentral scotomas, which may mimic chiasmal compression (30).
In toxic and nutritional optic neuropathies, magnetic resonance imaging (MRI) may demonstrate increased T2 signals within in the optic chiasm without evidence of restricted diffusion, suggesting toxicity at the level of optic chiasm (50). Bitemporal hemianopic visual field defects may be seen in those cases.
The only forms of effective management are those that entail removing the toxins or supplementing the deficient vitamin. In terms of prevention, the most important role of the physician is to have an appropriately high index of suspicion and a sufficient knowledge of pharmacokinetics to identify patients at high risk. In the case of ethambutol, those with high serum levels of ethambutol have the greatest risk of developing permanent visual loss (66). For example, patients with renal impairments are far more likely to develop ethambutol-induced toxic optic neuropathy because of reduced excretion and probably should be maintained at lower doses than specified in the usual guidelines.
Once a deficiency has been identified, rapid supplementation is important. The following table lists common nutrients often implicated in metabolic optic neuropathy, the USDA recommended daily allowance (RDA) for adults, and the dosages commonly given for repletion.
Mild deficiency: 10 mg by mouth daily for a week followed by 3 to 5 mg by mouth for at least 6 weeks
30 mg by mouth daily
1000 mcg intramuscularly once per week until deficiency is corrected, then once per month. Alternatively, 2000 mcg by mouth daily followed by 1000 mcg by mouth daily as long as malabsorption exists
1 mg po daily
3 mg po daily
In addition, vitamin and mineral supplementation in the setting of any toxic and metabolic optic neuropathy may be beneficial (64). For example, in the case of the Cuban optic neuropathy, despite only mild deficiencies in folate and B12, supplementation of these vitamins helped reverse the effects of the neuropathy.
Little or no information is available regarding the role of pregnancy in these disorders.
Michelle Y Wang MD
Dr. Wang of the Southern California Permanente Medical Group and Department of Ophthalmology has no relevant financial relationships to disclose.See Profile
Jonathan D Trobe MD
Dr. Trobe of the University of Michigan has no relevant financial relationships to disclose.See Profile
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