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Show Journal of Nnim- Ophlluilmology 18( 2): 106- 111, 1998. © 1998 Lippincoll- Ravcn Publishers, Philadelphia Nutritional Amblyopia Simmons Lessell, M. D. A review was conducted to examine the characteristics and pathogenesis of nutritional amblyopia. Published cases of amblyopia among malnourished allied prisoners of the Japanese during World War II and among Cubans malnourished during the recent economic embargo were analyzed. The picture of nutritional amblyopia derived from these publications is somewhat at variance with the conventional image of the disease. Surprising features include premonitory keratopathy, rapid onset of visual loss, a high incidence of hearing loss, and the presence of peripapillary retinopathy in some cases. No single causative factor can be identified. Genetic susceptibility rarely, if ever, plays a role. Vitamin deficiency may not be important. Protein deficiency, antioxidant deficiency, physical labor, and tobacco smoking are likely to contribute to the occurrence of amblyopia. Key Words: Optic neuropathy- Nutritional deficiency. This is a review of the clinical features of nutritional amblyopia and a discussion of some aspects of etiology, pathology and pathophysiology that, despite centuries of experience with the disease, remain controversial. CLINICAL FEATURES Information about nutritional amblyopia has come from endemic cases, sporadic cases, and epidemic cases. In 1897, Strachan ( 1) published a clinical study of patients who had what is sometimes cited as an endemic form of the disease. Strachan had encountered hundreds of cases while serving as a medical officer in Kingston, Jamaica, and inferred that the disorder had been prevalent on the island for many years. Patients complained of initial symptoms of " numbness and cramps in his hands and feet, dimness of sight, and a tightness round the waist." In a more advanced stage, hearing loss was noted. Although Strachan commented that the deafness may begin suddenly, he did not indicate the tempo of the visual loss. Except in the most advanced stages, the patients retained a good prospect for recovery. Several features of Strachan's cases are suffi- Manuscript received March 17, 1997; accepted January 14, 1998. From the Department of Ophthalmology, Harvard Medical School, and the Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, U. S. A. Address correspondence and reprint requests to Dr. Lessell, 243 Charles Street, Boston, MA 02173, U. S. A. ciently different from those encountered in sporadic and epidemic cases of nutritional amblyopia ( see later description) that it is likely that he was describing another entity or a heterogenous group of disorders. Pain was so severe, especially at night, that hospitalized patients would lie awake moaning. Muscle atrophy developed and progressed to " claw" deformities of the hands and feet. Even when visual loss was profound, it appears that Strachan did not find optic atrophy. Dermatologic changes were prominent and apparently universal. Facial paralysis and even ophthalmoplegia were encountered in a few of the cases. Furthermore, Strachan offered no evidence that his patients were malnourished. The most effective treatment consisted of bed rest, nourishing food, quinine, strychnine, and potassium iodide. Transfer to cooler areas of the island was also helpful. Strachan speculated about etiologic factors, particularly malaria, but he did not even include malnutrition among the possible causes. The Jamaican disorder was reinvestigated in the 1960s ( 2). Most of Strachan's findings were confirmed with the important exception that optic atrophy was prevalent. The patients were divided into a group that had ataxia and a group that exhibited spasticity. The investigators directly explored the issue of nutrition. In the former group in which amblyopia was more common, there was a history of poor dietary intake. In the latter group in which amblyopia was present but less prevalent, there was ". . no clear pattern of undernutrition." The investigators doubted that the cause of the endemic amblyopia occurring in various tropical regions was nutritional. It seems inappropriate that some authorities have endowed nutritional amblyopia with the eponym " Strachan's syndrome" ( 3,4). Most cases of nutritional amblyopia encountered in the United States and Canada are truly sporadic. Even physicians with a special interest in the disorder see few cases. Most patients are abusers of alcohol and are poor historians who do not seek medical care until late in the course of the disease. Therefore, the study of these patients has not taught very much about the early stages of nutritional amblyopia. Our picture of the disorder is further clouded by patients' unreliability. Many of the patients are noncompliant, failing to keep appointments and failing to comply with treatment. In any case, these sporadic cases are said to be characterized by slowly 106 NUTRITIONAL AMBLYOPIA 107 progressive, bilateral, painless visual loss with central or centrocecal scotomata. The fundi are usually normal in the early stages. The most informative picture of nutritional amblyopia, especially of its early stages and natural history, comes from observations of the allied soldiers who were prisoners of the Japanese during World War II ( 5- 13). Early in the war, the Japanese army captured large numbers of allied soldiers. Some of them were already undernourished at the time of their capture, and most were starved in captivity. There were ophthalmologists in some of the prison camps who observed and recorded the findings in prisoners with amblyopia. Ulcerative superficial keratopathy with pain, lacrima-tion, and photophobia was highly prevalent among the prisoners. The keratopathy developed before the optic neuropathy and responded to local treatment. Malnourished American prisoners in the Korean War exhibited apparently identical keratopathy, which could be cured by adding cod liver oil to the diet ( 14). However, nutritional amblyopia, with and without keratopathy, supervened in prisoners. Sensory loss or pain in the legs often accompanied the loss of vision. There was usually a 4 to 12- month delay before prisoners began to lose vision. In keeping with the putative nutritional cause, prisoners who were poorly nourished at the time of their capture had visual symptoms sooner than those who were well nourished at the time of their capture. The two eyes were affected more or less symmetrically, as in sporadic cases, but in the earliest stage of the disease, only one eye might be involved. Immediate dietary supplementation could also cure the first eye before the second eye became symptomatic. In notable contrast to the impression of nutritional amblyopia gained from evaluating sporadic cases in civilian practice is the sizable proportion of prisoner- of-war cases in which vision was lost suddenly or rapidly. In 11% to 25% of cases of nutritional amblyopia, the deficit was maximum within 24 hours. Vision plateaued within 4 weeks in most of the remaining cases. There is even evidence of virtually instantaneous loss of vision ( 6). How a chronic deficiency state would cause acute visual loss is not easily explained. However, a similar situation occurs in Wernicke's encephalopathy, a result of prolonged thiamine depletion, in which the signs of brain stem dysfunction typically appear abruptly. Other unusual clinical features included a high incidence of bilateral nerve deafness and a 1.5% incidence of papillary and peripapillary hemorrhages ( 7). Residual sensorineural deafness was present in 13 of 898 former allied prisoners of the Japanese, 23 to 36 years after release from captivity ( 15). Hearing loss has also been noted in some patients in tropical endemic cases of ( presumed) nutritional optic and peripheral neuropathy ( 1,2,16- 18). In Nigerian patients, tinnitus usually preceded and accompanied the hearing loss, which proved to be sensorineural ( 16). The 1.5% incidence of papillary and peripapillary hemorrhages must be considered a low estimate, in that some of the ophthalmologists only had access to ophthalmoscopes late in the war, and the fundus hemorrhages tended to appear early in the course of the disorder. Otherwise, the disorder in war prisoners closely resembled that in the sporadic cases seen in peacetime. Total blindness never occurred, and profound visual loss in the hand motions- to- light perception range was unusual. Night blindness was so rarely mentioned that it must not have been a feature ( 13). Central and centrocecal scotomata were the predominant visual field defects. Peripheral field constriction was not a feature. The optic discs often remained normal until late in the course when optic atrophy supervened. Because only one investigator described the occurrence of optic disc cupping, it must have been exceptional ( 19). If the patient's diet was supplemented early in the illness, vision recovered, but delay in treatment was associated with a poor outcome. Among 898 allied cx-prisoners who were examined between 23 and 36 years after release, 19 still had reduced visual acuity and optic atrophy ( 15). PATHOLOGIC FEATURES Information on the neuropathologic features of nutritional amblyopia is scarce. Dr. C. Miller Fisher described the results of postmortem examinations on 1 1 allied prisoners of war who died after repatriation from Japanese camps ( 3). His neuropathologic studies showed atrophy of the papillomacular bundle of the optic nerve in 4. Degeneration in the fasciculus gracilis adjacent to the midline of the posterior columns of the spinal cord was the most consistent finding. These lesions were probably responsible for the sensory symptoms that were prevalent in the prisoners. Smiddy and Green ( 20) studied cases of bilateral papillomacular bundle atrophy in the optic nerves recognized in postmortem specimens during a 10- year period in a civilian hospital. Malnutrition, usually associated with alcoholism, was the common theme in these cases. Nutritional amblyopia is generally assumed to be a retrobulbar optic neuropathy. However, there is no reason to doubt that nutritional amblyopia could in some or all instances be a disorder primarily of the inner retinal layers. The peripapillary retinopathy ( 21,22) sometimes seen in the early stages of nutritional amblyopia is compatible with that localization. Centrocecal scotomas, so often demonstrated in patients with nutritional amblyopia, could result from lesions primarily of the inner retina or of the retrobulbar optic nerve ( 23). There certainly is atrophy in the retrobulbar segment of the optic nerve in patients with nutritional amblyopia, but this could result from lesions that originated in the ganglion cells or in the nerve fiber layer of the retina. In one study of a single case, Victor et al. concluded that the pattern of gliosis that they observed in the optic nerves supported primary retrobulbar neuropathy ( 24). ETIOLOGY In considering the etiology of a nutritional disorder, several facts must be acknowledged. First, identifying a ./ Ni'iiw- Ophllmlnml, Vol. 18, No. 2, I99H 108 S. LESSELL deficiency does not mean that the deficiency that has been identified causes the disorder. It merely makes that deficiency a valid etiological candidate. Second, in practice there are few instances in which patients are deficient in only one nutrient. Finally, if the patient recovers when the nutrient is resupplied, it does not necessarily mean that the nutrient was responsible for the recovery. Thiamin deficiency is a case in point. Physicians have known for more than 300 years that patients with beriberi may have loss of vision, and nutritional amblyopia is often attributed to thiamin deficiency. Biochemical evidence of thiamin deficiency has been demonstrated in alcoholic patients with nutritional amblyopia ( 25). Although the evidence is conflicting, thiamin deficiency has damaged the optic nerves and retinal ganglion cells in laboratory experiments ( 26- 28). However, one of the first symptoms of thiamin deficiency is anorexia, which causes patients to reduce their consumption of all foods. With thiamin treatment, appetite improves and more foods of all kinds are consumed. Therefore when a patient with thiamin deficiency loses vision, the thiamin deficiency cannot necessarily be blamed, because the patient's intake of all nutrients is likely to have decreased. Beriberi was almost as prevalent in prisoners of war who had no amblyopia as it was in those who did. In one camp, amblyopia appeared just as the incidence of beriberi was declining ( 13). At a civilian prison camp in Hong Kong during World War II in which physicians could obtain synthetic thiamin, nutritional amblyopia could not be reversed using only thiamin, and patients developed nutritional amblyopia while undergoing treatment with thiamin for beriberi ( 29). Finally, when chronic thiamin deficiency was produced in civilian volunteers, vision was not affected ( 30). However, there is one observation that supports thiamin deficiency as a possible causative factor. Nutritional amblyopia was not prevalent among the most emaciated prisoners of war. In one civilian camp, the incidence appeared to decline when the rice ration was halved ( 7). This evidence favors thiamin deficiency, because reduction in food intake decreases the demand for the vitamin. Further evidence against thiamin deficiency in the causation of optic neuropathy comes from studies of Wernicke's encephalopathy, a disorder of the central nervous system which can confidently be attributed to thiamin deficiency. Optic neuropathy is only exceptionally encountered in such patients. The evidence, poor as it is, is better for thiamin deficiency than it is for any other vitamin deficiencies in the etiology of amblyopia. Because the dermatitis, glossitis, and diarrhea that are features of pellagra were prevalent among malnourished prisoners of war, niacin deficiency ( or dietary deficiency of the precursor amino acid tryptophan) has also been proposed as causative in some cases. There is histopathologic evidence of damage to the motor cortex, basal ganglia, and spinal cord in pellagra, but not to the anterior visual pathway. When human subjects were fed diets deficient in niacin and tryptophan, they exhibited only the cutaneous, gastrointestinal, and neurasthenic symptoms and signs of pellagra ( 31). The other central and peripheral nervous system manifestations failed to appear. There is even doubt about whether the neuropathies ascribed to pellagra might actually be from thiamin or pyridoxine deficiency ( 32). However, it should be noted that there are no convincing published cases of nutritional amblyopia consequent to a dietary deficiency of pyridoxine. Riboflavin deficiency may contribute to the keratopathy that is present in some patients who also have amblyopia, but there is no evidence that deficiency of riboflavin can cause lesions of the retina or optic nerve. Folate deficiency is prevalent among patients with nutritional amblyopia, evidenced by low levels in red blood cells and serum ( 33). Although dietary folate deficiency has never been proved to cause amblyopia, the issue remains alive ( 34). It seems pertinent to note that optic atrophy is not a feature of the several recognized and characterized disorders resulting from inborn errors of folate metabolism and absorption. Vitamin B, 2 deficiency stands as the only vitamin deficiency proved to cause optic neuropathy in man or animals. Dietary vitamin B, 2 deficiency causes optic neuropathy in animals ( cage paralysis) ( 35- 37), and optic neuropathy occurs in pernicious anemia ( 38- 43). However, human optic neuropathy caused by vitamin B] 2 dietary deficiency is a rare disorder seen only in strict vegans. B12 levels are normal in sporadic cases of nutritional amblyopia. Altered B12 metabolism may nevertheless be a factor in certain cases among smokers ( see later discussion). It is exceedingly important to identify cases of optic neuropathy from pernicious anemia, because it will not respond to dietary treatment and requires treatment with injections of vitamin B12. The vitamin deficiency hypothesis must remain just that. In practice, patients in the sporadic cases of nutritional amblyopia generally are given vitamin supplements that include the entire vitamin B complex, together with an improved diet and, as did the prisoners of war, they improve if treated early in the course of their disease. Protein deficiency is an alternative to the vitamin deficiency hypothesis. It is prevalent among the malnourished. Low serum protein concentrations account for much of the " famine edema" observed in such people. The condition was often confused with the edema of beriberi. Severely malnourished people are probably deficient in certain essential amino acids, and this deficiency could secondarily affect neurotransmitters. Levels of neurotransmitters in the central nervous system are affected rapidly by alterations in diet ( 44- 46). In some diseases, a particular causative agent is necessary but is insufficient to cause symptoms and signs. This would seem to be true of nutritional amblyopia. Only a minority of people subjected to dietary deprivation are affected. In one Japanese prisoner- of- war camp, only 200 of approximately 3000 men were affected, a disparity for which there is no obvious nutritional explanation. Furthermore, nutritional amblyopia was far less J Neitm- Ophlhalmot, Vol. 18, No. 2, 1998 NUTRITIONAL AMBLYOPIA 109 prevalent among allied prisoners in Europe than it was among the allied prisoners in the Far East. One explanation might be the difference in the amount of work demanded of the prisoners. The Japanese required many of their prisoners to perform arduous labor, whereas the prisoners of the Germans generally led a more sedentary life. Also, one group of investigators noted that in one Japanese prisoner- of- war camp, amputees who could not work or exercise escaped the various deficiency disorders ( 50). Whatever the cause of nutritional amblyopia, interaction with other constitutional or environmental factors must be necessary to make the visual loss manifest. Most cases of nutritional amblyopia probably have multifactorial causes. In the 19th and early 20th centuries, tobacco smoking was blamed for many cases of amblyopia ( 51). Although all would agree that there has been a remarkable decrease in the incidence of tobacco amblyopia, cases that are judged valid even by skeptical physicians continue to appear ( 52). It is of note that nutritional deficiency has also been postulated in many cases ascribed to smoking, and the visual symptoms and signs of tobacco amblyopia and nutritional amblyopia are essentially identical. Smoking may also impair the intestinal absorption of vitamin B! 2 ( 53). Dr. Charles Schepens reviewed his experience with tobacco amblyopia among Belgian civilians during the Nazi occupation and concluded that tobacco amblyopia was a deficiency disease in which smoking precipitated the visual loss ( 54). He had rarely encountered tobacco amblyopia before World War II but the number of cases rose precipitously during the war, coincident with food shortages. However, Dr. Schepens did not find a single case among nonsmokers. It is of interest ( see earlier discussion) that Dr. Schepens also noted a high incidence of hearing loss among his patients. The data from allied prisoners of war are controversial and inconclusive on the subject of smoking as a contributing factor in amblyopia. Leber's hereditary optic neuropathy is another disorder in which one factor is requisite but not sufficient to cause the disease. The requisite factor is a mitochondrial DNA mutation. Investigators have yet to identify the additional factors necessary to make genetically susceptible people lose their vision. However, it can easily be imagined that nutritional deficiency could precipitate visual loss in patients rendered metabolically vulnerable because they harbor one of these mitochondrial mutations. Although mitochondrial disorders could not account for many cases of nutritional amblyopia, it is important to consider the possibility in selected patients. A report has been published in which 2 of 12 patients with " tobacco- alcohol amblyopia" harbored mitochondrial DNA mutations that have been associated with Leber's hereditary optic neuropathy ( 55). Damage from free radicals has been postulated as the mechanism of cell injury in many disorders ( 56). One group of investigators observed, " It is difficult these days to open a medical journal without seeing some paper on the role of ' reactive oxygen species' or ' free radicals' in human disease." ( 57) Nutritional amblyopia is a disorder in which a role for free radicals deserves consideration. Free radicals ( molecules with an odd number of electrons capable of existing independently) are highly reactive transients that are generated in the course of normal metabolism. Free radicals have been cited as a possible factor in causing tobacco amblyopia, because both substances may damage nervous tissue ( 55). Many cell components are susceptible to attack by free radicals. Organisms dependent on aerobic energy metabolism have evolved mechanisms to protect them from endogenous and exogenous free radicals, and some of the protection comes from the diet. Ascorbic acid, vitamin E, and beta- carotene are protective antioxidants that are supplied in the diet and are probably deficient in many malnourished people. In the face of oxidative stress, cellular damage might occur to the ganglion cells or their axons of malnourished people who are deficient in diet-derived antioxidants. THE CUBA EPIDEMIC The recent epidemic of optic neuropathy in Cuba, which allegedly affected more than 50,000 people, has rekindled interest in nutritional amblyopia. There has been a profusion of publications describing the clinical, laboratory, and epidemiologic features ( 58- 63). Between November 1991 and 1993, coincident with a period of economic stress, numerous cases of optic neuropathy and peripheral neuropathy appeared in Cuba. The incidence was calculated at 461.4 per 100,000 ( 55). Men and women were affected almost equally, but the predominantly optic form was more common in men and the peripheral form in women. People between the ages of 25 and 65 appeared at greatest risk. Weight loss usually preceded the onset of visual, auditory, or neurological symptoms ( 58). At the time of initial examination, approximately one third of the patients had cutaneous or mucosal lesions compatible with the effects of undernutrition, but most did not appear otherwise malnourished. The onset of visual loss was subacute and was accompanied by photophobia in many cases. A minority complained of tearing and retrobulbar pain. In some patients, the visual nadir was reached in as few as 3 days; in most, vision stabilized within 30 days. The peripheral neuropathy was signalled by painful dysesthesia in the feet and sometimes in the hands. There also was numbness and paresthesia. Hearing loss occurred in patients with optic or peripheral neuropathy and was usually accompanied by tinnitus. High-frequency hearing loss was noted on pure- tone testing. Audiometry also detected hearing loss in some patients who had no hearing complaints. Abnormal brain stem auditory- evoked responses were documented in 35% of the subjects with abnormal audiogram findings ( 62 cited by Roman[ 58]). There were no fatal cases, and nearly all patients exhibited substantial recovery of vision and neurologic function ( with the exception of hearing loss) when they ./ Neum- Ophthuimol, Vol. IX. No. 2, 1998 110 S. LESSELL were renourished. Implementation of a multiple vitamin regimen for the general population appeared to halt the epidemic. A controlled study of risk factors was conducted in 1993 in five municipalities of Pinar del Rio, the province of Cuba that had the highest disease rate ( 64). This investigation, limited to patients with the optic form, used 123 case- control pairs matched for age, gender, and location. Increased risk was associated with tobacco use ( cigar smoking) and with cassava consumption. Decreased risk was associated with high serum levels of antioxidant carotenoids and ingestion of animal products and B vitamins. There are striking similarities between the features of the Cuban epidemic cases and the World War II prisoner- of- war cases. Analysis of the risk factors in the Cubans leads to the same general conclusion that had been drawn previously. Nutritional factors are key, but a single specific nutritional deficiency cannot be identified as responsible. The disorder appears to have a multifactorial etiology. In contrast to the prisoner- of- war cases in which the evidence is inadequate to allow definitive conclusions, there is good evidence that tobacco smoking played an important role in the Cuban cases. SUMMARY Although nutritional deficiency amblyopia has been recognized for centuries, the only specific deficiency proved to cause optic neuropathy is vitamin Bl 2 deficiency, and that disorder rarely results from a deficient diet. With that exception, it is concluded that no single deficiency is responsible for the cases of nutritional amblyopia that occur epidemically in times of war or famine or for those that occur sporadically in civilian practice. Different deficiencies may be responsible for different cases, and a multifactorial etiology involving environmental factors is likely. 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