The Development and Progression of Subacute Combined Degeneration of the Spinal Cord in Patients With Pernicious Anemia Treated With Synthetic Pteroylglutamic (Folic) Acid

Abstract

1. Twenty-one patients with pernicious anemia were maintained on synthetic folic acid (pteroylglutamic acid) therapy alone for periods ranging from eight to seventeen months. Satisfactory blood levels were maintained in all cases receiving daily oral doses of 1.25 to 15.0 mg. Severe hematologic relapse occurred within six months in a case treated with monthly injections of 30 mg. 2. Synthetic folic acid in oral doses of 15 mg. daily induced satisfactory hematopoietic responses in 3 patients with pernicious anemia in severe relapse, but only slight hematopoietic response in a fourth patient with mild pernicious anemia but severe subacute combined degeneration of the spinal cord. 3. Ten patients showed a significant improvement in blood values for a few months after substitution of folic acid for liver extract. With one exception these subsided after six or more months to pre-folic acid levels comparable with those previously maintained with liver extract alone. 4. These observations suggest that a combination of orally administered folic acid and parenterally injected liver extract may maintain a better hematologic status than either substance alone. 5. A previously untreated patient with severe subacute combined degeneration of the spinal cord failed to show improvement in neural disease during twentyeight days of folic acid therapy. 6. Eleven patients developed, or showed progression of, subacute combined degeneration of the spinal cord during folic acid treatment. Neurologic disease developed in most of these patients when the peripheral blood was normal. 7. One patient showed an extremely explosive onset and rapid progression of neural disease. The progression of the disease was rapid in 3 other cases. 8. The institution of liver extract therapy in adddition to folic acid in 5 patients who developed subacute combined degeneration during folic acid maintenance therapy failed to prevent progression of the disease in 4 cases, and only partially arrested the disease in the fifth, in which improvement occurred more rapidly when folic acid was discontinued. 9. Subacute combined degeneration occurred with greater frequency in patients on large daily doses of folic acid than it did in patients with small or intermittent doses. 10. The possibility is discussed that folic acid in large daily doses may actually precipitate or aggravate neurologic disease. 11. It is suggested that folic acid may interfere with the metabolism of 1(+) glutamic acid in the central nervous system and possibly disturb the formation or function of acetylcholine.

Optic atrophy in experimental vitamin B12 deficiency in monkeys

“…9-11) developed optic atrophy and visual changes approximately 1 year sooner than the other B12 deficient monkeys. This rapid progression of visual deficit in the monkeys supports the observation in humans that folic acid therapy hastens the development of the neurologic manifestations of pernicious anemia (Heinle & Welch 1947, Meyer 1947, Ross et al 1948, Israels & Wilkinson 1949, Schwartz et al 1950, Stambolian & Behrens 1977.…”

Proposed Recommended Nutrient Densities for Moderately Malnourished Children

“…Persons who are marginal in vitamin B 12 and are given large folic acid supplements will first present with severe and irreversible neurological disease rather than the normal presentation of anemia [367][368][369], although the evidence comes mainly from the older literature; the levels of folate intake recommended have not been shown to precipitate B 12 -deficient neurological disease [370], although it remains a theoretical possibility [371]. In the presence of vitamin B 12 deficiency, folate is not recycled in the body, as it becomes "trapped" in its methyl form so that the person becomes dependent upon the daily intake of "fresh" folate.…”

A High Prevalence of Biochemical Evidence of Vitamin B12 or Folate Deficiency does not Translate into a Comparable Prevalence of Anemia

“…Excess folate intake may mask the changes in vitamin B 12 deficiency. This concern is predicated on the observation that large doses of folic acid administered to patients with pernicious anemia may induce hematological remission of the disease [4,5]. This has become increasingly relevant in recent years following the introduction of folic acid fortification of food in many parts of the world.…”