Optic Neuropathy Associated with Vitamin B12Deficiency

OPTIC NEUROPATHY ASSOCIATED WITH VITAMIN B

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D W I G H T STAMBOLIAN, M . D . , AND M Y L E S BEHRENS, M . D .

New York, New York described as a big eater although he was always small. In April 1974, he complained of fatigue, and infectious mononucleosis was diagnosed. Macrocytic anemia was noted (hemoglobin level, 11.4 g/100 ml) and he was treated with 1 mg of folic acid daily, until late June, after his visual symptoms had begun. "Monospot" test was negative at that time. He had a weight loss of 3.2 kg (7 lb) during this period. He had no history of exposure to tobacco, alcohol, or other obvious toxins. There was no family history of visual loss. Physical examination—The patient appeared younger than his age. He weighed 37.2 kg (82 lb) and was 160 cm (5 ft 3 inches) tall. There was minimal axillary and pubic hair. The abdomen was normal except for an old midline surgical scar. There was no hepatomegaly, splenomegaly, or O p t i c neuropathy has also been associlymphadenopathy, and the general physical examiated with vitamin B deficiency o f other nation was otherwise unremarkable. origins, for example, fish tapeworm infesNeurologic and ophthalmic examinations—He was alert and cooperative but with a peculiar affect tation and v e g a n i s m . W e report a case that prompted us to consider a nonorganic basis for that occurred after resection of the ileum, his complaint. Neurologic examination was othera recognized basis for the malabsorption wise unremarkable including cranial nerves, pain and vibration sense, motor examination, coordinaof vitamin B . In our patient the visual tion, and reflexes with 1 + knee and ankle jerks and symptoms developed during folic acid flexor plantar responses. Screening evaluation of the therapy. higher cerebral functions revealed no specific deficit. Corrected visual acuity was 6/60 (20/200) in both CASE REPORT eyes with centrocecal scotomas in both eyes to a On July 12, 1974, a 17-year-old boy had had 10/1000 red object, variably to a 3/1000 white, that progressive "difficulty in reading" for three weeks expanded appropriately on testing at 2 meters (Figand in seeing approaching cars. New glasses did not ure). Results of an external ocular examination and help. He had no headache or eye pain. No neurologmotility were normal with convergence to 40 mm ic symptoms were present. and intact optokinetic nystagmus. The pupils were equal and reacted to light well without afferent At 4 weeks of age, his whole distal small bowel defect. Of the six H-R-R color test plates, only Nos. from the midportion of the jejunum through the 1, 3, half of 4, and 5 were perceived slowly using ileocecal valve, including part of the cecum, had both eyes. The fundi appeared normal. been resected because of gangrene caused by volvulus. An ascending colon-midjejunal anastomosis was Laboratory studies—Hemoglobin level was 13.2 performed with preservation of approximately 18 g/100 ml; erythrocyte count, 3,650,000/mm ; mean cm of proximal small bowel. During the next year he corpuscular volume, 109 u, ; mean corpuscular required repeated hospital admissions for dehydrahemogloblin level, 35.8 u,g; and mean corpuscular tion and malnutrition. In 1966, the last barium study hemoglobin concentration, 33%. There was some demonstrated a redundant dilated colon and normal macrocytosis and anisocytosis. The leukocyte count upper gastrointestinal tract with an atonic dilated was 3,600/mm with a normal differential cell count. small bowel segment. Nevertheless, he maintained Platelets were considered adequate. The chest x-ray a regular diet without chronic diarrhea. He was film was normal. X-ray films of the skull with views of the optic foramina demonstrated no abnormalities. Serum folate level was 50 ng/ml (normal, 4-20 ng/ml); and vitamin B i , 190 \¡.\¡.%lm\ (normal, greater than 200 u,u.g/ml). A Schilling test with From the Department of Ophthalmology, College intrinsic factor revealed only 0.28% of radioactive of Physicians and Surgeons of Columbia University, vitamin B in the urine in 24 hours (normal, greater New York, New York. Reprint requests to Myles Behrens, M.D., 635 W. than 7.5%). Serum carotene level was 9.0 u.g/100 ml (normal, 40-180 ug/100 ml); vitamin A, 15.9 u.g/100 165th St., New York, NY 10032. Optic neuropathy occurs only occasionally in patients with vitamin B defic i e n c y . Numerous cases o f patients with pernicious anemia and optic atrophy have been d o c u m e n t e d since B a s t i a n e l l i ' s report in 1 8 9 7 . C o h e n first pointed out that visual loss may precede the hematologic and neurologic signs. T u r n e r emphasized the frequency of bilateral centrocecal scotomas with well-documented cases. T h e s e a u t h o r s emphasized the reversibility o f the visual loss by adequate treatment at an early stage. 1 2

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ml (normal, 30-80 u.g/100 ml); and 72-hour fecal fat result was 98.2 g/day (normal, 6 g/day), on a diet containing 100 g of fat, documenting his malabsorption. Heterophile agglutinin titer was within normal limits. We administered prednisone, 30 mg daily, and vitamin B complex (Lederplex), four times daily, and 1,000 ng of cyanocobalamin intramuscularly. Two weeks later he was unchanged. Prednisone was tapered to none over the next two weeks and he received another intramuscular injection of 1,000 u,g of cyanocobalamin. Vitamin B complex was continued. Four weeks after initiation of treatment, he thought his vision had improved but it was essentially unchanged on examination; hemoglobin level was 13.3 g/100 ml; erythrocyte count, 4,470,000/m ; morphology was normal; mean corpuscular volume, 97 u, ; reticulocyte count, 1.3%; and leukocyte count, 5,200/mm. At this time vitamin B complex was decreased to one capsule daily. During the sixth week of treatment, we injected 1,000 u.g of hydroxocobalamin, with repeated injections at four-week intervals thereafter. After ten weeks visual acuity was R.E.: 6/7.5 (20/25), and L.E.: 6/12 (20/40), with only a trace of residual centrocecal scotomas. His affect had improved and he had gained 5.9 kg (13 lb). After 23 weeks visual acuity was 6/6 (20/20) in both eyes with normal visual fields and fundi. 3

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Optic neuropathy associated with centrocecal scotomas in a patient with vitamin Bia deficiency during folic acid thera-

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py prompts consideration of the optic neuropathy o f vitamin B deficiency as well as the possible role of folic acid in its development. T h e role of vitamin B deficiency in our patient's optic neuropathy is suggested by: (1) the similarity o f his clinical picture to previously reported c a s e s ; (2) the low serum vitamin B level, abnormal Schilling test, the history o f small bowel resection, and his undernourished and underdeveloped state; (3) its occurrence during folic acid therapy for mild macrocytic anemia; (4) the reversal of his visual defect while receiving intramuscular vitamin B ; and (5) the lack o f another likely explanation. Although infectious mononucleosis occasionally causes optic n e u r o p a t h y , its documented resolution before his visual complaints militates against this explanation. Optic neuritis caused by multiple sclerosis cannot be ruled out although bilateral centrocecal scotomas developed and resolved without other s y m p t o m s . T h e appearance of the optic disks and recovery rule out Leber's optic a t r o p h y . T h e r e was no history o f 1 2

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exposure to toxic substances, including those most c o m m o n l y associated with this kind of optic neuropathy; tobacco and alcohol. W e added hydroxocobalamin to his therapeutic regimen b e c a u s e studies indicated it may b e preferable to cyanocobalamin ' in the treatment of so-called tobacco amblyopia, and because tobacco amblyopia and the optic neuropathy caused by vitamin J3i deficiency may b e causally r e l a t e d (with hydroxocobalamin playing a role in the detoxification of c y a n i d e ) . However, others, including F . D . Carroll (personal communication, 1976), strongly doubt this relationship and patients with both disorders have recovered without the use of hydroxocobalamin. 1 4

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In conclusion, the presence of optic neuropathy with bilateral centrocecal scotomas should prompt consideration of vitamin B , deficiency as an alternative to the more c o m m o n l y responsible nutritional deficiency responsive to vitamin B complex, even in the a b s e n c e o f other neurologic symptoms and occasionally even of hematologic manifestations. Pa2

tients with vitamin B deficiency should not b e treated with folic acid alone because o f the possible exacerbation of neurologic symptoms reported. 1 2

SUMMARY

A 17-year-old boy with vitamin B deficiency that occurred after a small bowel resection developed bilateral centrocecal scotomas during folic acid therapy and improved on therapy including vitamin B complex. 1 2

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T h e possible role of folic acid in the development o f optic neuropathy in vitamin Bi2 deficiency, as in our patient, remains unresolved. Although the administration of folic acid alone produces hematologic remission in vitamin B deficient macrocytic anemia, neurologic lesions may progress or d e v e l o p . Folic acid may play an active although indirect role in producing these l e s i o n s , perhaps, as C h a n a r i n suggested, by mobilizing the remaining vitamin B stores, thereby exacerbating the deficiency. Will and a s s o c i a t e s found, in contrast, that folic acid does not increase the vitamin B , requirement in pernicious anemia or have a direct effect on vitamin B metabolism. Herbert and T i s m a n considered the neurologic impairment in vitamin B deficiency to proceed similarly, whether or not folic acid was being given.

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REFERENCES

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ogy of retrobulbar neuritis in Addisonian pernicious anaemia. Lancet 1:908, 1961. 17. Heaton, J . M., McCormick, A. J . A., and Freeman, A. G.: Tobacco amblyopia: A clinical manifestation of vitamin B deficiency. Lancet 2: 286, 1958. 18. Smith, A. D. M.: Retrobulbar neuritis in Addisonian pernicious anaemia. Lancet 1:1001, 1961. 19. Foulds, W. S., Chisholm, I. A., and Pettigrew, A. R.: The toxic optic neuropathies. Br. J. Ophthalmol. 58:386, 1974. 20. Lesseil, S.: Toxic and deficiency optic neuropathies. In Smith, J. L., and Glaser, J . S. (eds.): Neuro-Ophthalmology Symposium of the University of Miami and the Bascom Palmer Eye Institute. St. Louis, C. V. Mosby Co., 1973, vol. 7, p. 21. 21. Victor, M.: Tobacco amblyopia, cyanide poisoning and vitamin B deficiency. A critique of current concepts. In Smith, J. L. (ed.): NeuroOphthalmology. Hallandale, Florida, Huffman Publishing Co., 1970, vol. 5, p. 33. 22. Meyer, L. M.: Folic acid in the treatment of pernicious anemia. Blood 2:50, 1947. 23. Vilter, C. F., Vilter, R. W., and Spies, T. D.: The treatment of pernicious and related anemias with synthetic folic acid. J. Lab. Clin. Med. 32:262, 1 2

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1947. 24. Hall, B. E . , and Watkins, C. H.: Experience with pteroylglutamic (synthetic folic) acid in the treatment of pernicious anemia. J . Lab. Clin. Med. 32:622, 1947. 25. Heinle, R. W., and Welch, A. D.: Folic acid in pernicious anemia. J.A.M.A. 133:739, 1947. 26. Ross, J. F., Beiding, H., and Paegel, B. L.: The development and progression of subacute combined degeneration of the spinal cord in patients with pernicious anemia treated with synthetic pteroylglutamic (folic) acid. Blood 3:68, 1948. 27. Nieweg, H. O., Faber, J. G., deVries, J. A., and Stenfertkroese, W. F.: The relationship of vitamin B and folic acid in megaloblastic anemias. J. Lab. Clin. Med. 44:118, 1954. 28. Editorial: A warning regarding the use of folic acid. N. Engl. J. Med. 237:713, 1947. 29. Chanarin, I.: The Megaloblastic Anaemias. Philadelphia, F . A. Davis Co., 1969, p. 588. 30. Will, J. J„ Mueller, J. R., Brodine, C , Kiely, C. E . , Friedman, B., Hawkins, V. R., Dutra, J., and Vilter, R. W.: Folic acid and vitamin B , in pernicious anemia. J. Lab. Clin. Med. 53:22, 1959. 31. Herbert, V., and Tisman, G.: Pinpointing nutritional anemias. Consultant 12:117, 1972. 12

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