Epidemic optic and peripheral neuropathy in Cuba: A unique geopolitical public health problem

SURVEY OF OPHTHALMOLOGY

VOLUME

41.

NUMBER

4 *JANUARY-FEBRUARY

1997

ELSEVIER

PUBLIC HEALTH AND THE EYE JOHANNA

SEDDON

Epidemic A Unique

AND DONALD

FONG, EDITORS

Optic and Peripheral Neuropathy in Cuba: Geopolitical Public Health Problem

THOMAS R. HEDGES III, MD,’ MICHIO HIRANO, AND BENJAMIN CABALLERO, MD, PHD4

MD,2 KATHERINE

TUCKER,

PHD,3

‘Departments of Ophthalmology and Neurology, New England Eye Centq New England Medical Cente Tufts University, Boston, Massachusetts, USA, 2Department of Neurology, College of Physicians and Surgeons, Columbia University, New Ymk, New York, USA,3 Tufts University School of Nutrition, Boston, Massachusetts, USA, and 4Center for Human Nutrition and Department of International Health, The Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland, USA

During 1992 and 1993 an epidemic of optic and peripheral neuropathy affected over Abstract. 50,000 Cubans. This occurred in the unique setting of a communist country which had a widespread health care network and wherein sudden changes in the economy affected most of the population. Although nutritional factors appeared to play a key role in the pathogenesis of the epidemic neuropathy, viral, toxic, and genetic factors were investigated by Cuban and North American scientists. The authors, representing different disciplines and different groups that visited Cuba during the epidemic, review and reflect on the clinical and laboratory findings which became available through their own experience and through reviewing the literature. The recent Cuban epidemic is compared to similar outbreaks of optic and peripheral neuropathy which have occurred in the past. (Surv Ophthalmol41:341-353, 1997. 0 1997 by Elsevier Science Inc. All rights reserved.) Key words. Cuba epidemic tobacco/alcohol amblyopia l

neuropathy

l

optic neuropathy

In the spring of 1993 news of epidemic blindness and peripheral neuropathy sweeping Cuba began to appear in the United States media. In May of 1993 the first visitors from the United States brought back specific information regarding the epidemic,2s and others were soon invited.35,41,42,51 From January 1, 1992, through January 14, 1994, the Ministry of Public Health in Cuba identified more than 50,000 cases of optic and peripheral neuropathy among a population of 10.8 million.5 The setting of the Cuban neuropathy epidemic was unique. This public health problem occurred at a time when the Cuban health system boasted an in-

0 1997 by Elsevier All rights reserved.

Science

Inc.

l

peripheral

neuropathy

l

nutrition

l

fant mortality rate of 10.2/1,000 births (8.5 in the USA), a life expectancy of 75.7 years (75.9 in the USA) and a dramatic decline in mortality from infectious disease (Cuban Ministry of Health, personal communication). The Cuban government had developed an extensive network of health care workers, which was overseen by a centralized bureaucracy and complemented by well equipped specialists in clinical aswell as laboratory medicine. The excellent health care system enabled Cuban epidemiologists and physicians to gather data rapidly about the epidemic and to respond quickly. Unfortunately, the isolation of Cuban physicians

0039-6257/97/$17.00

PI1 SOO39-6257(96)00008-2

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ET AL

TABLE 1 Cuban Epidemic of Optic Neuropathy: Ophthalmic Findings

Report

Visual Acuity

Lincoff et alZs Sadunet a14’ Johnset alZ3 Santiestebanet a143 CNFIT’

0.67-countingfingers ave. 0.043 1.0-0.08 0.6770.20 1.0-0.5

and scientists from their North American and Western European counterparts reduced the flow of expertise and information that might have contributed to a deeper understanding of the precise contribution of nutritional, environmental, toxicmetabolic, genetic and infectious factors involved in the epidemic. Much of the information obtained by those who visited Cuba has been anecdotal. Only a few publications by Cuban scientists have been published, and only two case-control studies, which were completed late in the epidemic and after treatment measures were instituted, have been published. 7,35These and other factors added to the uniqueness of the epidemic and the experience of those who became involved. For those of us who participated, the investigation of the epidemic transcended political and ideological differences and allowed us to exchange knowledge and to promote collegiality. The following is an account of the Cuban epidemic from the point of view of representatives from different clinical and scientific backgrounds and different groups from the United States who investigated the epidemic.

The

Clinical

Syndromes

In early 1992 ophthalmologists from the western Cuban providence of Pinar de1 Rio began to see young men with bilateral visual loss. Of the 50,862 cases reported by January of 1994, 26,446 (52%) were found to have the optic form. The rest had peripheral neurologic complaints alone or a combination of optic and peripheral neuropathy which has been referred to as the “mixed form.“43 A clear case definition of the disease was somewhat difficult to determine, because some patients had the optic form, some had only the peripheral form, and some were mixed. The optic form was easiest to define.42

Optic Nerve Abnormalities (Nerve Fiber Layer Drop-out)

Central Scotomas

Visual Evoked Potential Abnormalities

55% 60% 100% 69% -

90% 100% 87.5% 79% 76%

NA NA 100%n = 6 86% n = 100 -

OPTIC

NEUROPATHY

The symptoms of visual loss were characterized by progressive, bilateral, and usually symmetric loss of central visual function. Visual acuity, color vision, and central visual fields were primarily affected. Individuals often noted difficulty reading, many were unable to perform their work, and others complained of difficulty in recognizing faces. Some described photophobia and superficial ocular irritation or burning. Many noted visual function to be worse at dawn and at dusk, and some experienced positive visual phenomena, including multicolored points of light or bright lines. The visual symptoms tended to progress over a period of weeks to months. Rarely, loss of vision was acute. Neuro-ophthalmic evaluations (Table 1) showed best corrected Snellen visual acuities ranging from 20/20 to counting fingers. Most patients had visual acuities in the range of 20/200. Color vision deficits were prominent, especially for red and green. Visual field testing showed central or centrocecal scotomas in the vast majority of individuals who were tested (Fig. 1). Peripheral visual field losswas rare among individuals whose eye problems could truly be attributed to the epidemic, and many who had constricted visual fields were diagnosed as hysteric or malingering.42 Ophthalmic examinations were generally normal except for the appearance of the optic nerves. There was palor of the optic nerves in many patients and dropout of retinal nerve fibers in the maculo-papillary bundle in the majority (Fig. 2). On rare occasions there was mild swelling in the nerve fiber layer surrounding the Contrast sensitivity testing was aboptic disk.-“8,42,43 normal in most patients studied.42,43Visual evoked potential recordings were done in a large number of individuals, and were abnormal in almost all who were tested and identified to be affected by the epidemic.*3a43Electroretinograms showed mild diminution of the amplitude of the A-wave.43 One

EPIDEMIC

NEUROPATHY

343

IN CUBA

Fig. 1. Tangent screen visual fields from a patient central scotomas.

with Cuban

observer noted cogwheel pursuit on eye movement testing in three cases.42 Some patients improved spontaneously. By May of 1993 all patients identified as having epidemic neuropathy were given multivitamin therapy and, by the late spring of 1993, when most of the groups from the United States were visiting Cuba, the epidemic appeared to be subsiding. Nevertheless, most of the visiting physicians and scientists were able to observe new cases. Although there may have been some overlap, most of the cases seen by the groups of USA physicians listed in Tables 1 and

epidemic

optic neuropathy

showing

bilateral

ceco-

2 were from separate groups of patients seen at different hospitals. Many of the cases seen by North Americans are probably included in a series prepared by Cuban authors also listed in Tables 1 and 2.43 PERIPHERAL

NEUROPATHY

Of the 50,862 epidemic neuropathy patients identified by the Cuban Ministry of Public Health, about half (48%) had peripheral neuropathy with or without optic neuropathy. The peripheral neuropathy mainly affected distal limb sensory nerves;

Fig. 2. Left: Red-free nerve fiber layer photograph showing normal fibers from a patient with Cuban epidemic optic neuropathy.

nerve fibers. Right: Dropout

of maculopapillary

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TABLE 2 Cuban Epidemic

of Optic Neuropathy:

# Patients with Ophthalmic Date of Sump- Male: Evaluation toms Female

Age (Years)

Lincoff et a12*

5193

17

9:8

19-63

Sadunet aP2* Johnset a123

5 & 9193 6193

15 9

4:l 712

16-52 23-60 15-60 ave 41 20-69

Santiesteban et a143 3-7193

604

1.4:l.O

CNFIT7

150

2.8: 1

9193

Historical

Weight Loss (‘3 kg) 73% ave 7.9 kg ave 7.2 kg 75% ave 12.2 kg 71% -

Findings

Excess Alcoho1 Consump- Tobacco Other tion ConsumpNeuro>l tion >5 Other logic Liter/ Ciga- Medical SympWeek rettes/DaySymptoms toms 35%

76%

46% 22%

92% 77.8%

66.7% 77.8%

67%

80%

30%

83%

-

-

81% 100% 33% 30% -

* Data are combinedfor evaluationsperformedin 5/93 (7 patients)and 9/93 (8 patients)

however, in some patients, motor nerves, spinal cord posterior and lateral columns, and auditory nerves were affected. The clinical sensory symptoms of patients were striking. Patients frequently reported positive sensations in the distal extremities, such as burning, electrical sensations, paresthesia, gritty sensations reminiscent of sand on the skin, numbness and dysesthesia.28j44 Some individuals reported altered temperature sensation; for example, one woman vividly described the sense that water always felt cold regardless of the actual temperature of the water.28 Gait imbalance, with proprioceptive loss, was noted in some patients. Cranial nerves, other than the optic nerve, were sometimes affected and manifested by hearing loss, hoarseness, and dysphagia. Symptoms of dysautonomia reported by patients included urinary frequency, urinary urgency, and excessive perspiration. On physical examination, stocking-glove sensory loss was the most common finding.zs Impaired temperature and pain sensations implicated small diameter sensory fiber loss in many patients. Impaired proprioception and vibration suggested that large diameter sensory fibers, dorsal columns, or both, were affected in some individuals. Gait instability, especially prominent with tandem gait, was usually present when proprioception was abnormal; thus, the ataxic gait was due to sensory defects rather than to cerebellar dysfunction. Santos-Anzorandia and colleagues performed sensory and motor conduction studies in 99 Cuban neuropathy patients and diagnosed optic neuropathy in 36, peripheral neuropathy in 36, and mixed form in 27 patients.44 Sixty-eight of 99 pa-

tients had sensory nerve conduction abnormalities which were predominantly decreased sensory nerve action potentials (62 patients), either with or without decreased nerve conduction velocities. Motor nerve conductions were abnormal in only nine patients. Electromyography was not performed. Although electromyography might have identified patients with features of denervation, these nerve conduction results are consistent with an axonal neuropathy affecting sensory more than motor nerve fibers. Interestingly, Santos-Anzorandia and colleagues found that the nerve conduction abnormalities did not correlate with the presence or severity of the clinical symptoms.44 There is one published report which describes sural nerve histology of 34 patients; 7 with sensory neuropathy, 5 with “dorsolateral myeloneuropathy,” and 22 with optic and peripheral neuropathy.2 All of the nerves demonstrated morphological evidence of axonal neuropathy which predominantly affected large-diameter myelinated fibers. They noted a few mononuclear cells in 17 patients and no viral particles in the nerves, findings that are contrary to those one might expect in inflammatory or infectious neuropathies. Borrajero and colleagues concluded that the nerve biopsy morphology was consistent with nutritional, toxic, or metabolic defects. In some of the Cuban neuropathy patients, clinical features suggested central nervous system involvement. Dorsal column myelopathy seemed evident in individuals afflicted with proprioception and vibration sensation loss. In the setting of a peripheral neuropathy, it is difficult to define the degree of posterior column function loss due to the

EPIDEMIC

NEUROPATHY

contribution of the neuropathy, as compared to the role of the myelopathy. Nevertheless, in some individuals, loss of joint position sense and vibration out of proportion to the peripheral neuropathy implicated posterior column pathway patholog-y.28Some Cuban patients complained of memory problems, suggesting cerebral involvement. Cubero and colleagues studied 120 Cuban epidemic neuropathy patients (peripheral, mixed, and optic neuropathy) using the Brown and Peterson paradigm of trigram recall.8 Patients were shown three letters (e.g., KTH) for one second and were then asked to recall the letters at intervals from O-45 seconds. They found that the patients with peripheral neuropathy and, to a lesser extent, those with mixed neuropathy, had worse declines in the trigram recall with time than control and individuals with optic neuropathy. Although these data are preliminary, they do suggest cognitive impairment in some patients. MIXED

FORM

Although patients were categorized as having either optic or peripheral neuropathy by the Cuban Ministry of Health epidemiological survey, the experience of four independent groups of medical investigators demonstrated that many affected Cubans had features of both forms of neuropathy.Ys~z8~~z~~~? Perhaps because patients tended to be more incapacitated by their optic neuropathy than by their peripheral neuropathy, the peak incidence of the optic neuropathy appeared to occur earlier than the peak of the peripheral form. The neurophysiological data of Santos and colleagues support the concept that the mixed form of neuropathy was common. +I In their patients with optic neuropathy, they found the same incidence of sensory peripheral nerve conduction abnormalities as the patients with the diagnosis of mixed or peripheral neuropathy. Thus, patients with optic neuropathy were likely to have subclinical, but electrophysiologically detectable peripheral neuropathy. In a case control study performed by the Cuba Neuropathy Field Investigation Team, in which the most severe cases in the province of Pinar de1 Rio were selected, peripheral neuropathies were detected in a majority of cases.’ Perhaps with more sensitive neurophysiological studies of the optic and peripheral nerve functions, many more patients would have been diagnosed with the mixed form of Cuban epidemic neuropathy.

Pathophysiologic

345

IN CUBA

Considerations

The clinical and electrophysiologic findings in patients with visual loss indicated that epidemic Cuban optic neuropathy was due to selective, yet

symmetrical, involvement of maculopapillary axons, ganglion cells, or both. The process spared the peripheral retinal nerve fibers and was, for the most part, reversible. There was some evidence of mild, transient injury to the ocular surface, and subclinical damage to the outer retina in some patients. The type of optic neuropathy seen in Cuba was similar to that seen in patients with tobaccoalcohol or nutritional optic neuropathy, certain toxic optic neuropathies, such as that seen from ethambutol, and Leber’s hereditary optic neuropathy. The underlying pathophysiology of all these conditions may be dysfunction of oxidative phosphorylation within mitochondria.2Jz4.d0.4z The medical histories, clinical symptoms and signs, nerve conduction studies and nerve biopsy studies of patients with the peripheral form of the Cuban epidemic neuropathy indicate that it was predominantly a sensory axonal neuropathy. Also, large-diameter myelinated nerve fibers seemed to be most affected in the small sample set described by Borrajero and colleagues; these findings are consistent with the clinical features of sensory ataxia, proprioceptive loss, and vibration sensation deficits in many of the affected Cubans.’ However, small peripheral nerve fiber functions may have been affected clinically in the Cuban patients who complained of altered temperature sensation and features of dysautonomia.‘,“” These findings can be due to nutritional deficiencies, metabolic disorders, toxins, or a combination of these factors. EPIDEMIOLOGY

Etiologic investigation of the population characteristics associated with the problem proved elusive, despite concerted efforts by Cuban scientists and health officials to investigate the epidemic (Table 2). The majority of persons affected were adults between the ages of 25 and 64 years. As of June 1993, only 57 children aged four years through 14 had been diagnosed with the disease, and no children less than age four years had developed it. There was speculation that the preferential rationing system of food for children was protective. 27A case control study of these children found few significant correlates, with only parental smoking identified as a risk factor (Cuban Ministry of Health, 1993, personal communication). Initial case control studies conducted by the Cuban Ministry of Health revealed larger weight lossesamong patients compared with control subjects (the average per person weight loss in the general population over the year preceding the epidemic was reported to be lo-20 pounds). There was also more smoking and/or alcohol consumption among patients vs. controls (the correlation

346

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TABLE 3 Cuban Neuropathy: EpidemiologicalRisk Factors OddsRatio (ConfidenceInterval) Risk Factor Smoking Missing meals Weight loss High sugarconsumption Heavy drinking Cassavause

CMH* 4.9 4.7 2.8 2.7 2.3

(2.5-9.3) (2.5-8.9) (2.2-3.6) (2.0-3.7) (1.0-5.4)

NA

CNF’IT** 6.6 (3.2-13.9) 5.9 (1.8-15)

NA NA NA 0.3 (0.1-0.5)

* CMH: Cuban Ministry of Health personalcommunication50 ** CNFIT: CubaNeuropathyField InvestigationTeam7

was particularly strong for smoking among those with the optic form). Males were more likely to have the optic form, while the peripheral form was more frequent in women. In a compilation of results published by Mas Bermejo and colleagues in 1993, odds ratios were reported for smoking, 4.9 (Confidence Interval 2.5-9.3); missing meals, 4.7 (2.5-8.8), weight loss, 2.8 (2.2-3.6); high sugar consumption, 2.7 (2.0-3.7); and heavy drinking, 2.3 (1.0-5.4) (Table 3) .31Scientists in Pinar de1Rio initially reported seeing glossitis, cheilitis and cheilosis in many patients, and noted that patients reported lower milk, fish, and soy hamburger consumption and higher rice, beans and cabbage consumption than did controls (Cuban Ministry of Health, personal communication). The Cuban economy had declined rapidly and food availability dwindled soon after loss of trade with the Eastern Block countries, compounding the negative effects on trade caused by the continuing USA trade embargo. As a consequence, the diet of the general population changed dramatically in the years just preceding the epidemic. Meats and dairy products, previously a prominent part of the Cuban diet, were no longer generally available. Milk was rationed only for children and pregnant women, soy “hamburger” was rationed at one serving per person once or twice per month, and bread rolls were also rationed (one roll per person per day). Other flour-based products were not generally available, and the variety and quantity of fruits and vegetables were limited and rationed. Unenriched rice, black or red beans and sugar made up the majority of foods that supply energy through protein. There was, therefore, a fairly sudden shift in diet composition toward lower intake of protein, fat, vitamins and minerals, as well as higher intake of carbohydrate.51 Due to the severity of the food shortages, vitamin deficiencies were recognized as a likely important

HEDGES

ET AL

factor in the causation of the epidemic. Because of this, it was decided early in the epidemic that any patients with severe symptoms would be hospitalized and treated with intravenous B vitamins (including vitamin B12, folate, thiamin, riboflavin and niacin) along with vitamins A and E. Furthermore, as both a generalized treatment and prevention effort, oral vitamin supplements, including 2.5 mg tbiamin, 1.6 mg riboflavin, 20 mg niacin, 2 mg vitamin B6, 6 ug vitamin B12, 250 ug folate, and 2500 IU retinol were provided to the entire population, with half dosages for children (Cuban Ministry of Health, personal communication). After widespread supplementation was implemented, incident cases dropped off sharply. The provision of vitamins to the population was considered a necessary humanitarian action, although it was recognized that it would not then be possible to study nutritional differences in the population for specific etiologic analyses. The apparent treatment effect of the vitamins, however, has convinced many that they played a central role in the epidemic. Still, the symptoms of the epidemic did not present as classic vitamin deficiencies, and there was a concerted attempt to identify toxic substances which may have interacted with the low vitamin status. Cyanide was immediately suspected, and several potential sources were investigated, including increased use of cassava and other cyanide containing foods and heavy smoking. A national study of cassavaconsumption in 1993 revealed that, even in this time of food stress, cassavawas apparently not consumed in levels sufficient to cause this problem. Fewer than 10% of the sample of patients reported eating cassava more than twice a week, and more than 50% of patients reported that they never ate cassava (Cuban Ministry of Health, 1993, personal communication). However, a subsequent report from The Cuba Neuropathy Field Investigation Team suggested that cassava consumption in the face of low energy intake may have been significant.’ It is unclear if this is a contributing factor, possibly one among multiple sources of cyanide, or a non-causal covariate of food stress. Imported legumes, particularly Vicia sativa or common vetch, have been mentioned as another potential cyanide source which may have entered the food supply in the “soy hamburger” or ground as flour in the bread rolls (Daniel Puttnam, personal communication). Biochemical analyses of blood cyanide and thiocyanate testing reportedly showed higher levels in smokers, but no significant difference between patients and controls. Patients were seen to have lower levels of sulfbydryl groups. Chronic methanol poisoning from homemade alcohol was also considered.42 Because the initial out-

EPIDEMIC

NEUROPATHY

347

IN CUBA

break of the illness occurred in a tobacc+growing region, pesticide effects were tested, but no differences were seen between cases and controls in blood levels of pesticides or heavy metals (Cuban Ministry of Health, 1993, personal communication) . Another line of testing revolved around the theory that the epidemic was caused by an enterovirus, which was isolated in fecal samples and spinal fluid of some patients. However, no greater risk for family members of patients or for contacts in boarding schools was apparent, and no differences between patients and controls were seen in immunologic and biochemical indicators which might suggest infection; thus, a viral etiology was considered unlikely. The conclusion of Cuban scientists and multiple investigation teams remains that the condition was caused by the combination of fairly sudden changes in nutritional status, weight loss and B vitamin deficiencies, in combination with some yet to be established toxic exposure (Cuban Ministry of Health, 1993, personal communication). In 1993 a case-control study was started by the Cuba Neuropathy Field Investigation Team, a collaboration of The Cuban Ministry of Health, The Pan American Health Organization, The Centers for Disease Control and Emory University.7 They matched control subjects by age, sex, and municipality to cases, defined as such only when two neuro-ophthalmologists diagnosed deterioration of the optic nerve. Questionaires were administered to determine exposure to a variety of toxins and to assessdietary intake retrospectively prior to onset of the illness. Blood analyses were conducted to determine levels of vitamin A, carotenoids, and selenium. Urinary cotinine was also measured as a marker for tobacco intake. The results of this carefully conducted study were similar to earlier observations and led to similar conclusions. Cases had significantly lower incomes and education levels. Illness was associated with tobacco, particularly cigar use (those smoking four or more cigars per day had an odds ratio (OR) for risk of optic neuropathy of 22.8), low frequency of meal consumption (the OR for risk of going whole days without food was 5.9), and cassavaintake (OR was 3.0 for highest vs lowest quartile, after control for total energy intake). Dietary intake measures which appeared to be protective included intake of total energy (OR = 0.2 for highest vs lowest quartile) and energy adjusted measures for methionine (OR = 0.3), and B vitamins (B1?OR = 0.2, riboflavin OR = 0.3, pyridoxine OR = 0.4, thiamin, niacin and folate OR = 0.5). Blood measures suggested strong protective effects of antioxidant nutrients, partic-

ularly lycopene (OR = 0.05 for highest vs. lowest quartile), OLand p carotene ( OR = 0.2) and selenium (OR = 0.3).7 The interrelationship of nutrient intakes makes it difficult to specify one nutrient as most causally related. However, a nutrient deficient diet clearly appears to have been a central factor in Cuban epidemic neuropathy.

Discussion The precise etiology of Cuban epidemic neuropathy remains unclear; however, this epidemic may not be entirely unique. Since the late I9th century, there have been several outbreaks of neuropathy or myeloneuropathies in tropical environments.41 In fact, a strikingly similar epidemic was described in Havana at the end of the last century during a blockade of the island by the USA Navy as part of the war against Spain. 38In most accounts of such epidemics, the pathophysiology was not clearly determined. The differential diagnosis of optic and peripheral neuropathies is long (Table 4). The general categories of suspected etiologies include nutritional deficiencies, toxic-metabolic, and infectious agents. Genetic susceptibility factors might have played a contributing role. PATHOPHYSIOLOGIC

CONSIDERATIONS

Numerous infectious agents have been associated with optic and peripheral neuropathy, and most of those agents cause neuritis by direct invasion or by a para-infectious autoimmune phenomenon. The Cuban neuropathy lacked clinical features of inflammation; specifically, the patients with optic neuropathy had bilaterally symmetric involvement, generally did not complain of pain with eye movement, and did not demonstrate papillitis on funduscopic examination. Cerebrospinal fluid did not reveal elevated protein levels, and sural nerve biopsies failed to shdw inflammatory cell infiltrates that one would expect in an inflammatory peripheral neuropathy. HTLV-I retrovirus is a cause of tropical spastic paraparesis and has also been associated with a neuritis;41 however, the clinical features of the Cuban patients were atypical for that retrovirus. Specifically, spastic paraparesis was not prominent in the epidemic. The Inoue-Melnick virus was implicated in the subacute myelo-optic neuropathy (SMON) outbreak that a& flitted approximately 10,000 individuals in Japan between 1956 and 1992, but the pathogenic role of that agent is uncertain. *OThe epidemiological data argues against an infectious etiology of the Cuban neuropathy. There were no household or work place clusterings of cases.Children and the elderly were rarely affected. Toxins have been responsible for outbreaks of

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199’7 TABLE

HEDGES

ET AL

4

Cuban Neuropathy: Differential Diagnosis NutritionaNToxic-Metabolic Strachan disease Tobacco-alcohol amblyopia Beri-beri (thiamin deficiency) Subacute combined degeneration (B 12 deficiency) Cassava (chronic cyanide poisoning) Clioquinol Methanol Heavy metals Ethambutol Streptomycin Isoniazid Chlorpropamide Digitalis Chloroquine Placidyl Antabuse Chloromycetin

InfectiouslInJlammatoryprocesses Viral infections of childhood (e.g. measles, mumps, chicken pox) Para-infectious, or post-infectious syndromes (e.g. Guillain-Barrt syndrome) Herpes zoster Granulomatous inflammations (syphilis, tuberculosis, cryptococcosis, sarcoidosis) Systemic lupus erythematosis Infectious mononucleosis HIV and HIV-related syndromes HTLV-I infection Lyme disease Coxsackie virus Inoue-Melnick virus

Geneticfactors Mitochondrial

DNA polymorphisms?

syndromes similar to the Cuban neuropathy. Iodochlorhydroxyquin or clioquinol, originally an oral intestinal amebicide, is another candidate toxin. Many individuals think that it was the cause of 10,000 cases of subacute myelo-optic neuropathy in Japan between 1956 and 1971,46 but that medication is not widely available in Cuba and is, therefore, an unlikely cause. Methanol toxicity was considered by Sadun and collegues who analyzed samples of homemade rum. A concentration of 1% was found, less than enough to cause acute optic neuropathy, but enough, perhaps, to cause a subacute problem, especially in the face of folate deficienthat neurotoxic substances, perCY*48 It is possible haps resulting from pesticide residues or other toxins stored in adipose tissue, were released into the blood under conditions of rapid weight loss, but this is very speculative (William Graham, personal communication). Cassava, also known as yuca, is the tuber of the maniac shrub and has been blamed for chronic cyanide poisoning, a condition characterized by peripheral neuropathy, optic neuropathy, and spas-

tic paraparesis. 39,52 The upper motor neuron syndrome causing the spastic paraparesis has been called konzo in East African epidemics.52 In one outbreak of purported cyanide poisoning in Nigeria, the patients generally demonstrated progressive concentric constriction of the visual fields. Less than 5% of the Nigerian patients had central scotomas similar to the Cuban patients.39 Besides the clinical dissimilarities between the syndromes, few of the Cuban patients who we examined admitted consuming cassava in large amounts. The Cuba Neuropathy Field Investigation Team did not see differences in absolute intake of cassava between cases and controls when examined as a proportion of total energy intake, but they did see a higher risk among those consuming more cassava proportionally.7 However, as mentioned above, it is not clear if cassava use was coincidental. Nutritional deficiencies in Cuba appear to have had a major pathogenic role in the neuropathy epidemic. The collapse of the former Soviet Union with subsequent loss of trade and economic aid

EPIDEMIC

NEUROPATH-Y

IN CUBA

from that country to Cuba, led to severe food rationing late in 1992. The foods which were generally available (rice, beans, sugar and some vegetables) are limited in B vitamins. Early in the epidemic, thiamin deficiency was proposed as a possible factor.’ Thiamin deficiency, in its severe form, presents as a peripheral neuropathy with numbness in the legs and irritability (dry beriberi) or as a cardiomyopathy and peripheral edema (wet beriberi). It remains a problem in less developed countries among individuals consuming diets high in polished rice and low in animal products. Eye involvement with beriberi was documented in the early 1900s by Elliot, who described a retrobulbar optic neuropathy with central scotoma, disturbed color vision and photophobia.” More common in Western countries is Wernicke-Korsakoff syndrome, which occurs in alcoholics and is characterized by confusion and ocular Milder thiamin deficiency motility disturbances. may also cause neurologic symptoms including impaired gait and hand-eye coordination. Riboflavin deficiency is not uncommon when diets are limited in dairy and other animal products. It is associated with cheilosis and glossitis, symptoms which were reported among some patients in Pinar de1 Rio. Severe niacin deficiency causes pellagra, a severe condition with characteristic dermatitis, dementia and diarrhea. A few cases of pellagra were reported in Cienfuegos Cuba in 1993.“’ With respect to the possible role of tobacco use during the Cuban epidemic, riboflavin is also important for maintainence of levels of reduced glutathione, an antioxidant associated with protection from tobacco toxins.“.’ Vitamin B6, or pyridoxine, is a coenzyme required for numerous biochemical reactions, including those involved in the formation of DNA and certain neurotransmitters. Mild deficiency has been associated with weakness, irritability, depression and difficulty walking. Folate also functions as a coenzyme in reactions involved in the formation of proteins and DNA. Folate deficiency interferes with cell replication, particularly apparent in red blood cells, resulting in macrocytic anemia. Defyciency in folate is common among low income populations where diets are limited in variety. Golnik et al described patients with so-called tobaccoalcohol amblyopia who had low blood levels of folate which, when restored to normal, led to improvement in optic nerve function. The authors proposed that folate deficiency could lead to accumulation of formic acid which may be toxic to cytochrome c oxidase. ” Sadun proposed that folate deficiency, in combination with “toxins related to cyanide or methanol” with resulting insult to

349 the mitochondria, may be responsible for the neuropathy in Cuba.42 Like folate, vitamin B12 is also important for DNA synthesis and cell replication, and deficiency also results in megaloblastic anemia. Vitamin B12 is also required for the synthesis of myelin, and deficiency results in demyelination of nerve fibers with a variety of associated neurologic symptoms. Recent studies suggest that neurologic problems, including sensory losses and dementia, may occur at blood levels previously thought to be norrnal.*‘j, zg Vitamin B12 is found almost exclusively in animal products, which were rarely available in Cuba during the epidemic. The Cuba Neuropathy Field Investigation Team case control study also identified significant associations of disease occurrence with blood antioxidant levels, particularly with lycoprene, a carotenoid with strong antioxidant properties, but also with (Y and p carotene, crytoxanthin and selenium.’ Antioxidants protect against a wide variety of degenerative conditions by decreasing oxidative damage to DNA and other macromolecules. Exposure to substances like cigarette smoke cause increased oxidation rates and deplete levels of antioxidants. Although not specifically linked to a disorder like the Cuban epidemic, it has been hypothesized that neurodegenerative disease could arise from increased oxidative stress in the face of decreased antioxidant levels or from increased exposure to reactive oxygen species.“” The poor overall quality of the diets of patients with Cuban neuropathy makes it difficult to define the importance of any single nutrient. However, the combination of the high risk level presented by heavy cigar smoking and the apparent strong protective effect of lycoprene intake seen by the Cuba Neuropathy Field Investigation Team is intriguing. No single vitamin deficiency describes the set of ophthalmologic symptoms seen in the Cuban epidemic, although the neurologic involvement of each of these vitamins makes them candidates as causal factors in combination with other factors. Of known conditions, the symptoms of the epidemic most closely resemble tobacco-alcohol amblyopia, which may result from toxic compounds like cyanide in tobacco smoke combined with low B vitamin intake (B12 in particular) from poor diet.9s2”,53 One study showed that, in the presence of smoking tobacco, optic neuropathy occurred well before the anemia seen with severe B12 deficiency.‘” Nutritional deficiencies may potentiate the effects of environmental toxins by limiting the rate of clearance of these substances through specific pathways. Fig. 3 summarizes some relevant nutrient-toxin interactions. For example, cyanide excretion requires

Surv Ophthalmol,41

(4) January-February

1997

HEDGES

ET AL

Cyanocobalamine

Oxidative

NADHttComplex

IttCo

Phosphorylation

Q ++Complex

III++Cyt

c tf Complex

IV & V+OZ

B-thiocyanoalanine

‘OH

Free Radicals

‘OH

11778 14484 3460

0

Q

Leber

Mutations

0

Fig. 3. Inter-relationships between some vitamins and detoxification processes, particularly between vitamin B12, folic acid, cyanide and oxidative phosphorylation. Primary mitochondrial DNA point mutations are listed below the oxidative nhosnhorvlation process. THF indicates tetrahvdrofolate, ATP, adenosine triphosphate, NADH, nicotinamide adenine dinucleotide, SAM, S-adenosylmethionine. I

I

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an adequate supply of cysteine, which originates from a complex series of reactions involving folic acid and vitamins B12 and B6. Other toxins are cleared by methylation reactions, with amino acid metbionine acting as a methyl donor, also involving folate and B12 as cofactors of methyl transfer reactions. Some of the changes described in the Cuban diet, such as increased use of soy protein (which is deficient in methionine) and decreased intake of folic acid, as well as vitamins B12 and B6, may have impaired the ability to eliminate toxins, triggering the appearance of clinical signs of disease. Fig. 3 shows how a combination of vitamin deficiencies, particularly vitamin B12 and folate, along with excess cyanide and free radicals might impair oxidative phosphorylation, thereby reducing production of adenosine triphosphate (ATP) . HISTORICAL

CONSIDERATIONS

The clinical features of the Cuban patients also closely resemble the symptoms and signs of a “multiple peripheral neuritis” among Jamaicans, first

identified in 1888 by Strachan, a British medical officer stationed in that country.32 In the original report, Strachan observed 510 patients in the Kingston Public Hospital with the following clinical features: “ (1) dimness of vision; (2) impaired hearing; (3) numbness and cramps in the extremities; (4) girdle pain; (5) joint pains and other abnormal symptoms or sensations. Certain objective symptoms or signs were further discussed: (1) trophic changes; (2) monoplegias; (3) altered gait; (4) conditions of pateliar reflex; (5) conditions of cutaneous reflexes; (6) conditions of sensations; (7) soreness of mucocutaneous lines of junctions; (8) wasting of muscles.“4g The patients at the Public Hospital were treated with bed rest, “nourishing food,” quinine, strychnine, and often potassium iodine.+g Strachan noted that, among the patients, death was unusual, and “recovery, more or less complete, [was] the rule.“32 He attributed the Jamaican neuritis to malaria, although he did not have any direct evidence for his hypothesis. Strathan’s original reports were largely ignored, until

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Fisher described pathological findings of Canadian prisoners during World War II who were afflicted with the disorder that Fisher entitled “Strachan’s disease.“12 Surprisingly, one year after Strachan’s report, Madun of Havana described 80 casesof optic neuropathy which occurred in the small town of Matanzas, Cuba.3RAs in the recent Cuban epidemic, during the 1897 epidemic, there also was a blockade by the USA, isolating Cuba as part of the war against Spain. Although “alcoholic amblyopia” was suspected as a cause, Madun apparently questioned this and suggested nutritional deficiency as an important factor.38 Several other reports of neuropathy outbreaks, in a variety of settings, are reminiscent of Strathan’s disease, including outbreaks in Jamaica during the early 19OOs,in Madrid during the Spanish Civil War, and among World War II prisoners.10,1’.‘4.4.5,47.~* In all of these settings, hundreds of individuals were afflicted with optic neuropathy, sensory peripheral neuropathy, or both. All of these reports described the poor nutritional status of affected individuals, clinical similarities to known nutritional deficiency syndromes, and the likely pathogenic role of vitamin deficiencies. Despite the speculations about the pathogenesis, data to support their conclusions were circumstantial. Many reports of the World War II prisoners meticulously described the dietary intake of affected individuals, but there were no data regarding serum or tissue vitamin levels in those people. MICROBIOLOGIC

CONSIDERATIONS

Another factor which was considered possibly to account for why a small proportion of the Cuban population developed the disorder despite relatively uniform dietary food rations was genetic susceptibility that became manifest because of changes in diet before 1993. Several groups of investigators from the United States considered the possibility that mitochondrial DNA mutations associated with Leber hereditary optic neuropathy (LHON) might have contributed to the optic neuropathy in some of the Cuban patients or that changing environmental factors in Cuba may have precipitated the phenotypic expression of underlying abnormalities in genetically predisposed individuals.‘6,‘7.23,?*,““,3j LHON is a disorder that typically affects young men. It causesacute or subacute optic neuropathy, usually in one eye, and often affects the other eye weeks to months later.37 The disease is maternally inherited; however, men are affected more frequently than women, perhaps due to an X-linked recessive trait.96 More than 12 mitochondrial DNA (mtDNA) polymorphisms have been associated

351 with LHON.‘R~21,36.54 At least three of the mtDNA alterations seem to be individually pathogenic1R,19,zzs54 and are called primary mutations. The other mtDNA polymorphisms are considered secondary and occur in combination with the primary mutations or with each other; they may play pathogenically synergistic roles. There were clinical similarities between the Cuban optic neuropathy and LHON. Smoking tobacco and drinking alcohol have been postulated to be risk factors for LHON.*l,?? These habits were thought to be risk factors for the young men that developed the Cuban optic neuropathy early in the epidemic and were diagnosed with tobacco-alcohol amblyopia.5 There may be an overlap, at least at the phenotypic level, between LHON and tobaccoalcohol amblyopia. g Rizzo recently hypothesized that mitochondrial adenosine triphosphate (ATP) synthesis defects might be the common pathophysiological mechanism in these two diseases.40 An underlying, mitochondrial genetic deficiency in oxidative phosphorylation should render the system more vulnerable to agents which are toxic to oxidative phosphorylation (Fig. 3). Four groups of investigators screened Cuban optic neuropathy patients for LHON-associated mtDNA mutations.17*Z3,‘4,35 The majority of the Cuban optic neuropathy patients did not have LHONassociated mtDNA alterations. Hirano found that of 11 patients, two probands had pathogenic LHON mutations one at nucleotide (nt) 11778 and the other at nt 3460.” Johns and colleagues found two out of nine patients with a mtDNA polymorphism at nt 9438 with a novel change at nt 9738. The nt 9438 polymorphism was thought to be pathogenic.23 However, another study of 12 Cuban optic neuropathy patients showed no mutations, although one individual, not considered to be part of the epidemic, was found to have the LHON mutation at nt 11778.‘4 Newman”” and TorronijO found a high frequency of mtDNA polymorphisms, including the nt 9438 polymorphism in patients from Pinar de1 Rio, but in approximately equal proportions among Cuban optic neuropathy patients and controls.35,50 DNA samples from Pinar de1 Rio were screened for 22 mitochondrial polymorphic haplotypes in order to characterize the ethnic origin of the Cubans and to discern whether different mtDNA haplotypes were present in the patients compared to unaffected Cubans. They found alterations in 14 out of 87 individuals tested, but failed to find a significant difference between cases and controls. They inferred that underlying mtDNA backgrounds were unlikely to have a role in the epidemic neuropathy.35,91Unfortunately, epigenetic differences, especially dietary intake and

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(4) January-February 199’7

toxic exposure, between patients with optic neuropathy and control caseswith abnormal mtDNA were not reported. Although the combined results of the mtDNA screening demonstrate that LHON-associated mtDNA polymorphisms do not play a major pathogenic role in the Cuban neuropathy, the finding of at least two probands with primary LHON mutations is intriguing. These patients might have been coincidentally symptomatic during the Cuban epidemic. Alternatively, there might have been an interaction between environmental factors that caused the Cuban optic neuropathy and the effects of the mtDNA mutations.

Conclusion The cause or causative factors responsible for epidemic optic and peripheral neuropathy in Cuba remain elusive. Several problems limited investigation of the Cuban epidemic. One was the initial lack of a specific case definition early in the epidemic which could be used for carefully constructed case-control studies. It was not until after the initiation of measures to treat the population of Cuba with vitamins that case control studies were initiated. The ability to correctly or confidently diagnose the problem was limited by lack of a specific diagnostic test, and much of the diagnosis of neuropathy similar to that seen in Cuba depended on subjective data supplied by patients. The diagnosis of toxic and nutritional amblyopia is difficult to make even under the best of circumstances, and functional visual loss can easily be mistaken for optic neuropathy from a variety of causes. The primary problem in Cuba may have been multifactoral. One aspect of the epidemic, which has not been addressed is the abruptness of the environmental changes that took place in Cuba at the outset of the epidemic. Unlike other areas of the world where chronic, nutritional deficiency is compounded by loss of nutrients to the point of starvation, Cuban health and nutrition were good before the epidemic began. This was followed by sudden changes in nutrition status, as well as sudden increases in physical activity. Significant rapid weight loss in Cubans was common across the country. This phenomenon is consistent with reports of other outbreaks of similar illnesses during periods of sudden change in food intake level, as in the caseof prisoners of war. Although not clearly documented, World War II prisoners suffering from optic neuropathy presumably were relatively well-nourished before they were incarcerated and then underwent rapid change in their eating habits and body weight. It is of some interest that a similar epidemic has

HEDGES

ET AL

been recently described in Tanzania.25 Some of the lessons learned in Cuba can be applied to studies which are currently being undertaken in that part of Africa and to similar epidemics which may occur in the future. It is critical that a clear case definition is established and that carefully designed casecontrol studies are initiated asearly as possible during an epidemic of this kind. Another issue which affected investigation of the epidemic involved politics. The Cubans spent considerable time explaining to those who visited Cuba that they felt that the epidemic and the socalled “Special Period in Time of Peace” were directly related. With loss of trade with Russia and tightening restrictions by the USA on the 30-yearold embargo came widespread food shortages and dietary restrictions. This political issue unfortunately clouded objective scientific investigation as well as dialogue. However, the epidemic has at least initiated interactions between scientists and physicians from the United States and Cuba. This scientific and cultural exchange is long overdue, and it is hoped that the relationships established will continue and flourish when relations between the USA and Cuba are normalized.

References 1. Altman LK: Mysterious Cuban epidemic seems to subside. The New York Times 1993, Sept 30;A6 2. Borrajero I, Perez JL, Dominguez C, et al: Epidemic neuropathy in Cuba: morphological characterization of peripheral nerve lesions in sural nerve biopsies. J Neural Sci 127: 68-76, 1994 3. Carroll FD: Nutritional amblyopia. Arch Ophthalmol 76: 406411, 1966 4. Costagliola C, Cotticelli L, Menzione M, et al: Red cell reduced glutathione and tobacco smoke-induced optic neuropathy. Metab Pediatr Syst Ophthalmol 13:96-98. 1990 5. Center for Disease Control: Epidemic Neuropathy-Cuba, 1991-1994. Morb Mortal Wkly Rep 43:183,189-192, 1994 6. Crus SJ: Bilateral amblyopia in West Indians. Trans Ophthalmol Sot UK 83:653-667, 1963 7. Cuba Neuropathy Field Investigation Team: Epidemic optic neuropathy in Cuba-clinical characterization and risk factors. N Engl J Med 333:117-2, 1995 8. Cuber0 Rego L, Mayor Rios J, Valdes-Sosa M, Almirall Hernandez P: Trastornos de la memoria en la neuropathia epidemica. in Neuropatia Epidemica en Cuba: 1992-1994, Havana, 1995 9. Cullom ME, Heher KL, Miller NR, et al: Leber’s hereditary optic neuropathy masquerading as tobacco-alcohol amblyonia. Arch Ouhthalmol 111:1482-1485, 1993 10. Denny-Brown D: Neurological conditions resulting from prolonged and severe dietary restriction. Medicine 26:41113, 1947 Tropical Ophthalmology. London, Frow11. Elliott RH Henry: de-Hodder and Stoughton, pp 405-415, 1920 changes in Canadians 12. Fisher CM: Residual neuropathologic held prisoners of war by the Japanese (Strachan’s disease). Can Serv Med J. 11:157-199, 1955 13. Golnik KC, Schaible ER: Folate-responsive optic neuropathy. J Neuro-ophthalmol 14:163-169, 1994 C, Peraita M: Avitaminosis y Sistema Nervioso. Mi14. Grande guel Servet, Madrid,1941 15. Heaton JM, McCormick AJA, Freeman AG: Tobacco ambly-

EPIDEMIC

16.

17.

18.

19.

20. 21.

22.

23.

NEUROPATHY

353

IN CUBA

opia. A clinical manifestation of vitamin B12 deficiency. Lancet 2:286-289, 1958 Hiram M, Cleat-y JM, Stewart AM, et al: Mitochondrial DNA mutations in an outbreak of optic neuropathy in Cuba. Neurology 44:843-845, 1994 Hirdno M, Lincoff NS, Mojon D, Ode1 JG: LHON mutations in an outbreak of optic neuropathy in Cuba. Clin Neurosci 2:173-178, 1994 Howell N, Kubackd I, Xu M, McCullough DA: Leber hereditary optic neuropathy: involvement of the mitochondrial ND1 gene and evidence for intragenic suppressor gene. Am J Hum Genet 48:935-942, 1991 Huoponen K, Vilkki J, Auia P, et al: A new ntDNA mutation associated with Leber hereditary optic neuroretinopathy. Am J Hum &net 481147-1153, 1991 Inoue LIK: Melinick virus and associated diseases in man: recent advances. Prog Med Virol 38:167-179, 1991 Johns DR. Neufeld MJ, Park RD: A ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem Biophys Res Commun 187:1551-1557, lQY2 Johns DR, Heher KL, Miller NR, Smith KH: Leber’s hereditary optic neuropathy. Clinical manifestations of the 14484 mutation. Arch Ophthdlmol 111:495-499, 1993 Johns DR. Neufeld MJ, Hedges TR: Mitochondrial DNA mutations in Cuban optic and peripheral neuronathv. I Neuroophthalmol 14:135’-140, 1964 ‘ Johns DR, Sadun AA: Cuban epidemic optic neuropathy. Mitochondrial DNA analysis. J Neuro-ophthalmol. 14:130134, 1994 Johnson GJ, Mtanda AT, Negrel AD: Macular degeneration of unknown origin in Tanzania. The Lancet 3383827-828, 1991 Knox DL, Chen MF, Guilaite TR, et al: Nutritional amblyopia: folic acid, vitamin B12 and other vitamins. Retina 2: 288-292.1982 Kunt7 D: The politics of suffering: the impact of the U.S. embargo on the health of the Cuban people. Report of a fdct-finding trip to Cuba, June 611. 1993. InternatJ Health Serv 24:161-179, 1YY4 Lincoff NS, Ode1 JG, Hirdno M: ‘Outbreak’ of optic and peripheral neuropathy in Cuba? JAMA. 270:511-518, 1993 Lindenbaum J, Healton EB, Savage DC, et al: Neuropyschiatric disorders caused by Cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 318:17201728, 1988 Llanos G, Ahser D, Brown P, et al: Epidemic neuropathy in Cuba. Epidemiol Bull 14:1-4, 1993 Mas Bermejo P, Rodriquez R, Barcelo C. et al: Neuropatia epidemica en Cuba: un analisis epidemiologico. La Habana. Ministerio de Salud Publica, pp 1-14, 1993 Mills CK, Lloyd JH: Peripheral nervous diseases and general neurosis. Sajon’s Annual of the Universal Medical Sciences 1:112-183, 1888 Mojon DS, Kaufmann P, Baker H, et al: Vitamin status and mitochondrial mutations in patients with incomplete recovery from an epidemic neuropathy in Cuba. Neuro-ophthalmology. in press Muller DPR: Vitamin E and other antioxidants in neurological function and disease, in Frei B (ed): Natural Antioxidants in Health and Disease. San Diego, Academic Press, 1994, pp 535-566 Newman NJ, Torroni A, Brown MD, et al: Epidemic neuropathv in Cuba not associated with mitochondrial DNA I

24.

25.

26.

27.

28. 29.

30. 31.

32.

33.

34.

35.

I

36. 37.

38.

39.

40. 41.

42.

43.

.a

44

45 46

47

48 49 50

51

52

53

54

mutations found in Leber’s hereditary optic neuropathy patients. Am J Ophthalmol 118:158-168, 1994 Newman NJ: Leber’s hereditary epic neuropathy. New genetic considerations. Arch Ophtalmol 50:540-548, 1993 Nikoskelainan EK, Savontaus N-J, Wanne OP, et a!: Leber’s hereditary neuroretinopathy, a maternally inherited disease. A geneologic study in four pedigrees. Arch Ophthalmol 105:665-671, 1987 Ordunez-Garcia PO, Nieto FJ, Espinosa-Brito AD, Caballero B: Cuban epidemic optic neuropathy, 1991-1994: History repeats itself a century after the “Amblyopia of the Blockade.” Am J Public Health 86:738-743, 1996 Ostuntoken VO: An ataxic neuropathy in Nigeria: a clinical, biochemical and electrophysiological study. Brain 91:215248, 1968 Rizzo JF: Adenosine triphosphate deficiency: a genre of optic neuropdthy. Neurology 45:Il-16, 1995 Roman GC: Epidemic neuropathy in Cuba: a plea to end the United States economic embargo on a humanitarian basis. Neurology. 44:1784-1786, 1994 Sadun AA, Martone JF, Muci-Mendoza R, et al: Epidemic optic neuropathy in Cuba: eye findings. Arch Opthalmol 112:691-699, 1994 Santiesteban R, Luis S, Marquez M, et al: Aspectos neuro oftalmologicos de la neuropatia epidemica en Cuba: Estudio de 602 pacientes. La Habana, Instituto de Neurologia y Neurocirugia, 1993, pp 1-22 Santos-Anzorandia CM, Viera C, Alonso-Gonzalez N, Gutierrez J: Peripheral nerve conduction abnormalities in the epidemic axonal neuropathy in Cuba. Electromyogr Neurophys Clin, in press Scott H: An investigation into an acute outbreak of “central neuritis.” Ann Trop Med Parasitol. 12:109-196, 1918 Schaumburg HH, Spencer PS: Clioquinol, in Spencer PS, Schaumburg HH (eds): Experimental and Clinical Neurotoxicology. Baltimore Maryland, Williams and Wilkins, 1980, pp 395-406 Smith I-IV. Spalding JNK Outbreak of paralysis in Morocco due to ortho-cresyl phosphate poisoning. Lancet 2:10191020, 1959 Spillane J: Nutritional Disorders of the Nervous System. Edinburgh, E ik S Livingstone, 1947 Strachan H: On a form of multiple neuritis prevalent in the West Indies. Practitioner 59:477-484, 1897 Torroni A, Brown MD, Lott MT, et al: African, Native American and European mitochondrial DNAs in Cubans from Pinar de1 Rio province and implications for the recent epidemic neuropathy in Cuba. Hum Mutat 5:310-317, 1995 Tucker K, Hedges TR: Food shortages and an epidemic of optic and peripheral neuropathy in Cuba. Nun-it Rev 51: 349-357, 1993 Tylleskar T, Howlett WP, Rwiza HT, et al: Konzo: a distinct disease entity with selective motor neuron damage. J Neural Neurosurg Psychiatr 56:638-643. 1993 Victor M: Tobacco amblyopia, cyanide poisoning in Vitamin B-12 deficiency: a critique of current concepts, in Smith JA (ed): Neuro-ophthalmology; Symposium of the University of Miami and Bascom Palmer Eye Institute, Vol 5. Hallandale, Florida, Huffman Publishing Company, 1970, pp 3.3-48 Wallace DC, Singh G, Lott MT, et al: Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 242:1427-I 430, 1988

Reprint address: Thomas Eye Center, 750 Washington

R. Hedges III, MD, New England St., Box 351, Boston, MA 02111.