48 Toxic and nutritional optic neuropathies

Background

It has been known for a long time that the optic nerve may be damaged by exposure to toxic substances or through nutritional deprivation. The clinical picture is similar regardless of aetiology, patients typically presenting with painless symmetrical caeco-central scotomata, often with rapid onset. The visual loss is associated in some cases with sensorineural hearing loss or a small fibre sensory peripheral neuropathy. The differential diagnosis includes the hereditary, compressive or inflammatory optic neuropathies, maculopathies and malingering. The clinical challenge is diagnostic (exclude all other causes and identify the toxin or nutritional defect) rather than therapeutic, but in individual cases it is often not possible to ascribe the visual loss to a single toxin or nutrient and the diagnosis remains presumptive.

Question

What is the evidence that exposure to or deficiency of any given substance causes an optic neuropathy?

The evidence

The first level of evidence is to prove that there has been exposure to or deficiency of the substance. In the literature on toxic optic neuropathies, exposure to a putative toxin has most commonly been established from the history (for example, tobacco smoking1), occasionally from systemic signs of acute intoxication (for example, ethylene glycol2), but rarely from measurement of blood levels (for example, methanol3). In the literature on sporadic cases of nutritional optic neuropathy, only vitamins B12 and folic acid have been routinely measured in the blood.4 Other vitamin levels have rarely been assayed (for example, niacin5), and in most cases malnutrition has been inferred on clinical grounds (history, general examination and stigmata of specific avitaminoses) when multiple deficiencies are likely to have been present.

Two epidemics of optic neuropathy (Allied prisoners-of- war in the 1940s and Cuba in the 1990s) have afforded

epidemiologists the opportunity to assess toxic, dietary and lifestyle risk factors for visual loss at a population level. In the former epidemic gross malnutrition, deficiencies of B vitamins, hard physical labour, male sex and smoking were common to all affected individuals,6–8 but no case-control studies were performed nor were specific toxins or micronutrients measured. In the more recent epidemic, the Cuba Neuropathy Field Investigation Team conducted a matched-pair case-control study (n = 123) comparing diet, toxin exposure and serum concentrations of vitamin A and carotenoids.9 Factors identified with an increased risk of visual loss included smoking (consumption of four or more cigars a day was associated with an odds ratio of 22·8) and high cassava intake. Factors associated with a reduced risk of visual loss included high dietary intakes of vitamins B2, B12, niacin and methionine, and high serum levels of the anti-oxidant carotenoids found in red fruits. In another casecontrol study mitochondrial DNA analysis showed no genetic predisposition for visual loss in affected cases.10

The second level of evidence is to demonstrate a relationship between the substance and the visual loss. Dose-dependence has been demonstrated for some toxins (for example, ethambutol,11 halogenated hydroxyquinolines12 and tobacco9) but not for any specific nutrients (in man). Improvement in visual function after removing a putative toxin or replacing a specific nutrient has been reported both in individual case reports1,13–15 and in epidemiological studies16 but does not occur in all cases.17 In many studies the reported visual recovery or prevention of visual loss followed much more general measures of nutritional supplementation or toxin avoidance.18 Visual deterioration on re-challenge with the toxin or nutrient deficiency would be unethical in man, and no reports exist in the literature when this has occurred inadvertently.

Tobacco and alcohol have long been implicated as epigenetic triggers for visual loss in patients harbouring pathogenic mutations for Leber’s hereditary optic neuropathy (LHON). Affected patients often smoke or drink excessively19–21 and mitochondrial DNA analysis occasionally reveals primary LHON mutations in singleton cases diagnosed clinically as tobacco–alcohol amblyopia.22 Three case-control studies have examined this association, with differing results (see Table 48.1). The first study23

found weak associations between tobacco and alcohol consumption and visual loss for patients with the 14484 or

3460 mutations, but since half of their unaffected “controls” were unrelated (and presumably did not have LHON mutations) it is hard to interpret these data. The second study24 suggested smoking was a risk factor in one large pedigree with the 11778 mutation. The third and largest study25 considered only exposure prior to visual loss and found no evidence of risk from smoking and, if anything, a protective role for alcohol consumption.

The third level of evidence is to demonstrate histological damage to optic nerve fibres in patients exposed to or deficient in the substance. There are several postmortem studies in patients who have died of methanol intoxication showing retrobulbar demyelination,26 central necrosis27 or atrophy with secondary astrocytic hyperplasia28 of the distal optic nerves; however most other putative toxins are not fatal and postmortem material has not been available to study. There are a few anecdotal reports of lesions in the optic nerves of patients with pernicious anaemia29 and in malnourished Allied prisoners-of-war,30 but patients with specific micronutrient deficiencies usually survive, so autopsy material is rarely available.

The final level of evidence is the establishment of an experimental model proving a causal relationship between the toxin or nutrient and optic neuropathy. Despite the obvious ethical objections there were a number of attempts prior to the second world war to observe the effects of imposing vitamin deficiency on human volunteers31–33: systemic disturbances such as anorexia, nausea/vomiting, fatigue and depression were observed at levels known to be found in patients with beriberi or pellagra, but in no case was vision affected. Good animal models have been established for some toxic (methanol34,35 and ethambutol36–38) and nutritional (B1239,40) optic neuropathies, but other substances have failed to produce optic nerve damage in animal experiments (for example, cyanide41 and vitamin B142).

Discussion

Obtaining evidence to prove a substance caused an optic neuropathy is confounded by the rarity of these cases, the lack of laboratory tests to confirm exposure or deficiency, and the complicated medical backgrounds of this group of patients. There are only a few cases where optic nerve damage can confidently be ascribed to a toxin (methanol, ethambutol) or micronutrient deficiency (vitamin B12); in most cases the association is anecdotal and presumptive. Multiple risk factors usually coexist in these patients, including genetic predisposition, sex, complex nutritional requirements and exposure to toxins many of which have not yet been identified, and it is possible that their combined effect is of more relevance than any individual substance. Despite these diverse risk factors the clinical presentation is impressively stereotyped. This raises the intriguing possibility that in all of these patients there is a final common pathway for damage to optic nerve fibres, perhaps through impairment of mitochondrial ATP production.

Implications for research

Accuracy and specificity when diagnosing toxic or nutritional optic neuropathy needs to be improved by the development of comprehensive, generally available laboratory blood tests to measure exposure or deficiency of different substances. These would enable detailed casecontrol studies to be conducted examining the role of different toxins and nutrients. Animal models are then important because they allow the investigator to study the pathogenetic mechanisms of damage: discovery of a final common pathway might lead to a range of possible therapeutic interventions that are independent of the underlying aetiology.

References

1.Rizzo JF, Lessell S. Tobacco amblyopia. Am J Ophthalmol 1993;116:84–7.

2.Friedman EA, Greenberg JB, Merrill JP et al. Consequences of ethylene glycol poisoning. Am J Med 1962;32:891–902.

3.McMartin KE, Amber JJ, Tephly TR. Methanol poisoning in human subjects: role for formic acid accumulation in the metabolic acidosis. Am J Med 1980;68:414–18.

4.Montgomery RD, Cruickshank EK, Robertson WB et al. Clinical and pathological observations on Jamaican neuropathy. Brain 1964;87:425–62.

5.Knox DL, Chen MF, Guilarte TR et al. Nutritional amblyopia. Retina 1982;2:288–93.

6.Beam AD. Amblyopia due to dietary deficiency: report of eight cases.

Arch Ophthalmol 1946;36:113–19.

7.Bloom SM, Merz EH, Taylor WW. Nutritional amblyopia in American prisoners of war liberated from the Japanese. Am J Ophthalmol 1946;29:1248–57.

8.Dekking HM: Tropical nutritional amblyopia (“camp eyes”).

Ophthalmologica 1947;113:65–92.

9.Cuba Neuropathy Field Investigation Team. Epidemic optic neuropathy in Cuba: clinical characterization and risk factors. N Eng J Med 1995;333:1176–82.

10.Newman NJ, Torroni A, Brown MD et al. Epidemic neuropathy in Cuba not associated with mitochondrial DNA mutations found in Leber’s hereditary optic neuropathy patients. Am J Ophthalmol 1994;118:158–68.

11.Liebold JE. The ocular toxicity of ethambutol and its relation to dose.

Ann NY Acad Sci 1966;135:904–9.

12.Oakley GP. The neurotoxicity of the halogenated hydroxyquinolines. JAMA 1973;225:395–7.

13.Greiner JV, Pillai S, Limaye SR et al. Sterno-induced methanol toxicity and visual recovery after prompt dialysis. Arch Ophthalmol 1989;107:643.

14.Golnik KC, Schaible ER. Folate-responsive optic neuropathy. J Clin Neuro-ophthalmol 1994;14:163–9.

15.Sadun AA, Martone JF, Muci-Mendoza R et al. Epidemic optic neuropathy in Cuba: eye findings. Arch Ophthalmol 1994;112:691–9.

16.Nakae K, Yamamoto S, Shigematsu K et al. Relation between subacute myelo-optic neuropathy (SMON) and clioquinol: nationwide survey. Lancet 1973;1:171–3.

17.Kumar A, Sandramouli S, Verma L et al. Ocular ethambutol toxicity: is it reversible? J Clin Neuro-ophthalmol 1993;13:15–17.

18.Centers for disease control: epidemic neuropathy – Cuba, 1991–1994. MMWR 1994;43:183–92.

19.Wilson J. Leber’s hereditary optic atrophy: some clinical and aetiological considerations. Brain 1963;86:347–62.

20.Adams JH, Blackwood W, Wilson J. Further clinical and pathological observations on Leber’s optic atrophy. Brain 1966;89:15–26.

21.Riordan-Eva P, Sanders MD, Govan GG et al. The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 1995;118:319–37.

22.Cullom ME, Heher KL, Miller NR et al. Leber’s hereditary optic neuropathy masquerading as tobacco–alcohol amblyopia. Arch Ophthalmol 1993;111:1482–5.

23.Chalmers RM, Harding AE. A case-control study of Leber’s hereditary optic neuropathy. Brain 1996;119:1481–6.

24.Tsao K, Aitken PA, Johns DR. Smoking as an aetiological factor in a pedigree with Leber’s hereditary optic neuropathy. Br J Ophthalmol 1999;83:577–81.

25.Kerrison JB, Miller NR, Hsu FC et al. A case-control study of tobacco and alcohol consumption in Leber hereditary optic neuropathy. Am J Ophthalmol 2000;130:803–12.

26.Sharpe JA, Hostovsky M, Bilbao JM et al. Methanol optic neuropathy: a histopathological study. Neurology 1982;32:1093–100.

27.Naeser P. Optic nerve involvement in a case of methanol poisoning.

Br J Ophthalmol 1988;72:778–81.

28.McLean DR, Jacobs H, Mielke BW. Methanol poisoning: a clinical and pathological study. Ann Neurol 1980;8:161–7.

29.Adams RD, Kubik CS. Subacute combined degeneration of the brain in pernicious anaemia. N Engl J Med 1944;231:1–9.

30.Fisher CM. Residual neuropathological changes in Canadians held prisoners of war by the Japanese (Strachan’s disease). Can Serv Med J 1955;11:157–99.

31.Elsom KO. Experimental study of vitamin B deficiency. J Clin Invest 1940;14:40–51.

32.Williams RD, Nason HL, Wilder RM et al. Observations on induced thiamine deficiency in man. Arch Intern Med 1940;66:785–99.

33.Williams RD, Nason HL, Power MH et al. Induced thiamine (vitamin B1) deficiency in man. Arch Intern Med 1943;71:38–53.

34.Baumbach GL, Cancilla PA, Martin-Amat G et al. Methyl alcohol poisoning: IV. Alterations of the morphological findings of the retina and optic nerve. Arch Ophthalmol 1977;95:1859–65.

35.Hayreh MS, Hayreh SS, Baumbach GL et al. Methyl alcohol poisoning: III. Ocular toxicity. Arch Ophthalmol 1977;95:1851–8.

36.Schmidt IG, Schmidt LH. Studies of the neurotoxicity of ethambutol and its racemate for the rhesus monkey. J Neuropath Exp Neurol 1966;25:40–67.

37.Matsuoka Y, Mukyama M, Sobue I. Histopathological study of experimental ethambutol neuropathy. Clin Neurol 1972;12: 453–9.

38.Lessell S. Histopathology of experimental ethambutol intoxication.

Invest Ophthalmol 1976;15:765–9.

39.Hind VMD. Degeneration in the peripheral visual pathway of vitamin B12-deficient monkeys. Trans Ophthalmol Soc UK 1970; 90:839–46.

40.Agamanolis DP, Chester EM, Victor M et al. Neuropathology of experimental vitamin B12 deficiency in monkeys. Neurology 1976; 26:905–14.

41.Foulds WS, Pettigrew AR. Tobacco–alcohol amblyopia. In: Brockhurst RJ, Boruchoff SA, Hutchinson BT et al., eds. Controversy in Ophthalmology. Philadelphia: WB Saunders, 1977, pp. 851–65.

42.Cogan DG, Witt ED, Goldman-Rakic PS. Ocular signs in thiaminedeficient monkeys and in Wernicke’s disease in humans. Arch Ophthalmol 1985;103:1212–20.