1. Folic acid, when administered alone, did not prevent the development or progression of subacute combined degeneration in 12 of 22 patients receiving this agent for from twelve to twenty-five months.

2. One patient with total gastrectomy and a macrocytic anemia developed subacute combined degeneration after five months of folic acid therapy.

3. Neurologic disease did not develop in 6 pernicious anemia patients treated with folic acid and liver extract for three and one-half to thirty-nine months.

4. In 10 pernicious anemia patients with good nutrition, neurologic relapses did not progress when liver extract or vitamin B12 therapy was instituted, even though folic acid therapy was continued. In 2 patients with abnormal nutrition and complicating organic abnormalities, nervous system disease progressed after institution of liver extract therapy.

5. Our observations are best explained by the theory that the hematologic and neurologic manifestations of pernicious anemia and other macrocytic anemias associated with gastro-intestinal tract pathology and inadequate nutrition are due to a deficiency of more than one substance. The administration of folic acid may improve the hematologic status but induce a deficiency of another substance or substances, e.g., vitamin B12, which are essential for the maintenance of a normal blood picture and the integrity of the central nervous system. This deficiency will eventually result in the development of a suboptimal blood picture or subacute combined degeneration of the spinal cord, or both.

6. The hematologic status of patients with pernicious anemia is not maintained in a more satisfactory state by supplementation of liver extract or vitamin B12 therapy with folic acid.

7. Folic acid therapy did not produce neurologic disease in patients with iron deficiency anemia who had free gastric hydrochloric acid in their gastric secretions and presumably sufficient intrinsic factor. It did not influence response to ferrous sulfate therapy.

8. Patients with sprue, nutritional macrocytic anemia and other macrocytic anemias associated with gastro-intestinal tract pathology who are treated with folic acid should also be given supplemental liver extract or vitamin B12 to insure against the development of nervous system disease.

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