NEUROLOGIC SEQUELAE IN MACROCYTIC ANEMIA OF
GASTROINTESTINAL ORIGIN FOLLOWING
FOLIC ACID THERAPY*
LEO M. MEYER, M.D.
From the Department of Medicine, The ATew York Hospital, and the
Cornell University Medical College, Areu> York, A'ew York
The incidence of combined system disease in untreated macrocytic hyperchromic anemia other than addisonian pernicious anemia is extremely rare.
Peripheral neuritis and mental symptoms are noted more frequently when the
general nutrition of the patient is severely impaired. Since the introduction of
folic acid therapy, numerous reports have appeared indicating an absence of
protection of the central nervous system in patients with pernicious anemia
treated with this drug. 3-7, "• 12 Recently, Davidson and Girdwood2 reported
idopathic steatorrhea and mild peripheral neuritis in a patient who was treated
with 10 mg. of folic acid dailjr. The neurologic condition deteriorated during
this treatment even though the folic acid was supplemented by thiamine.
With discontinuance of the folic acid and substitution of liver extract, the
neurologic status improved. A second patient with sprue also developed signs
of peripheral neuritis while being treated with 20 mg. of folic acid per day, and
the neuritis was completely relieved by the administration of liver extract and
other members of the B complex group.
The present report is of interest because of the infrequency of spontaneous
combined system disease in patients with macrocytic anemia due to faults in
intestinal absorption and the failure of folic acid to prevent the development of
this complication.
REPORT OF CASE
In 1926, the patient, a white male, aged 16, was treated at a New York City hospital
because of nausea, vomiting, diarrhea and loss of weight. A diagnosis of ulcerative colitis
was made. He was found to have a macrocytic hyperchromic anemia and was treated with
oral liver extract with clinical and hematologic improvement. In 1928 he developed tuberculous pleural effusion and was treated at a sanatorium. Between 1928 and 1939 the
patient suffered numerous attacks of diarrhea, lost weight and developed a moderately
severe anemia, which was often of the macrocytic hyperchromic type. He responded
moderately well to diet and to oral and parenteral liver therapy. In 1939, at the age of 29,
he developed signs of intestinal obstruction and was admitted to the hospital where the
terminal ileum and ascending colon were resected. Histologic examination revealed regional ileitis. One year following the operation the patient complained of having large,
bulky, soft, yellow stools about 5 times a day and was found to have hyperchromic macrocytic anemia. Injection of liver extract produced an improvement in the blood picture and
a reduction in the number and size of the stools. After six months of liver therapy, the
patient stopped treatment but returned four months later with the same complaints. At
this time liver extract was administered intramuscularly, each injection being followed by
* Read before The Society for the Study of the Blood, New York Academy of Medicine,
New York, May 27, 194S. Received for publication, July 16, 19-1S.
811
812
MEYER
severe urticaria. Occasionally vasomotor collapse occurred. L a m b liver extract produced
similar reactions, a n d oral t h e r a p y with liver, ventriculin and Brewer's yeast induced no remissions. F r o m 1941 t o 1945 t h e patient was maintained with blood transfusions and even
these were given infrequently since the p a t i e n t had severe febrile reactions. In November
1945 t h e red blood cell count was 2.3 million per cu. m m . and the hemoglobin 5.8 Gm. per
100 ml. blood. H e was given 50 mg. of folic acid by m o u t h daily. After four days he reported t h a t his a p p e t i t e reappeared. At the end of one m o n t h the erythrocyte count was
4.5 million, t h e hemoglobin 9.9 Gm., and he had gained 5 pounds in weight. At t h e end of
two months t h e red cell count was 4.9 million and the hemoglobin value 11.6 Gm. The patient had then gained 15 pounds, and t h e stools were b e t t e r formed and the bowel movements
were reduced to two or three per day. At this time the dosage of folic acid was cut to 25 mg.
per day and the general well-being of the p a t i e n t had improved. T h e total gain in weight
was 25 pounds and he was able to r e t u r n t o work. This hematologic and symptomatic
improvement was m a i n t a i n e d until thirteen months after t h e beginning of folic acid
t r e a t m e n t . In December 1946 he complained of paresthesia in his hands, s t a t i n g t h a t his
fingers became cold, bluish red in color, and t h a t the skin was wrinkled.
A neurologic examination revealed no abnormalities a n d t h e p a t i e n t continued t a k i n g
folic acid 25 mg. per day. He was referred to t h e vascular clinic where the disturbance was
believed t o be n u t r i t i o n a l and the p a t i e n t was given calcium l a c t a t e , vitamins A and D ,
wheat germ a n d b u t t e r m i l k , and he was told t o stop smoking. In May 1947 the e r y t h rocyte count was 4.4 million per cu. m m . a n d t h e hemoglobin level 13.3 Gm. per 100 ml. blood.
T h e p a t i e n t had not followed t h e instructions given to him in t h e peripheral vascular clinic.
H e now complained of numbness and tightness in his hands, feet and thighs. Neurologic
examination revealed a slightly ataxic gait and absence of vibrator}' sense in t h e right ankle.
However the knee jerks and Achilles reflexes were present, t h e sense of position of the toes
was normal and there were no Romberg's or Babinski's signs. T h e patient was advised to
take 6 capsules of v i t a m i n B complex and 20 mg. of folic acid per day.
T h e following m o n t h t h e e r y t h r o c y t e count was 3.9 million and t h e hemoglobin 16.0 Gm.
H e complained of numbness of the feet and legs. Ataxia was severe, there was hyperesthesia above t h e knees and hypesthesia in the legs and feet, the sense of position of the toes
was absent, v i b r a t o r y sense was absent a t t h e ankles and present a t t h e knees, t h e sense of
pain was i n t a c t , t h e knee jerks and the Achilles reflexes were slightly.hyperactive, and there
was t r a n s i e n t ankle clonus and Babinski's sign bilaterally. At this time he was a d m i t t e d
t o the hospital. T h e other significant findings were a red, smooth b u t painless tongue,
a n d an a p p a r e n t loss of about 20 pounds in weight. N - r a y examination of t h e gastrointestinal t r a c t showed evidence of regional ileitis. Free hydrochloric acid was present in
t h e gastric juice after histamine.
Skin tests were performed by Dr. Mary Loveless with intraheptol and crude and refined
liver e x t r a c t from various manufacturers. All produced considerable local erythema and
swelling. T h e p a t i e n t was given 50 mg. of Benadryl (diphenhydramine hydrochloride) t.i.d.
and daily injections of increasing doses of liver e x t r a c t until he was receiving 22 units a t one
t i m e . T h e r e were no local or systemic reactions. T h e Benadryl was t h e n given a t increasing intervals until he was receiving it once every four days. Folic acid t h e r a p y was
discontinued in J u l y 1947. During his s t a y in t h e hospital the red blood cell count was 3.9
million and t h e hemoglobin varied between 12 and 13 G m . At t h e time of his discharge from
t h e hospital he was walking with the aid of two canes. T h e patient was t a u g h t to administer the injections of liver extract (22 units every four days) to himself. He was also
given 6 vitamin B capsules by m o u t h daily and was placed on a high caloric, high vitamin
diet.
T h e e r y t h r o c y t e count rose t o 5.0 million a n d the hemoglobin to 14 or 15 Gm. and remained c o n s t a n t a t these levels. In August t h e ataxia was moderate, Romberg's sign was
present, t h e sense of position of the toes was gone, t h e v i b r a t o r y sense was absent a t the
ankles b u t present a t t h e knees, and no paresthesias were present. He required one cane to
walk, b u t in September he discarded t h e cane, and t h e only abnormal neurologic findings
^
*
Fia. 1. Values of Hemoglobin and Erythrocyte Counts Following Folic Acid and Liver Extract Therapy
00
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MEYER
were slight a t a x i a and diminution of vibrator}' sense a t t h e left ankle. H e had now gained
18 pounds. I n November he complained of slight numbness of t h e soles of his feet with
diminution of v i b r a t o r y sense a t t h e left ankle. I n F e b r u a r y 194S, his entire neurologic
s t a t u s was normal. At t h e present time t h e p a t i e n t is t a k i n g liver extract, 22 units every
four days, and 6 vitamin B complex capsules daily.
DISCUSSION
Two explanations have been offered for the development of neurologic sequelae
in patients with pernicious anemia treated with folic acid. Ross7 has suggested
that folic acid, which contains a glutamic acid radical, may interfere with the
normal metabolism of glutamic acid in the nervous system in a competitive
manner similar to the action of para-aminobenzoic acid in inhibiting the activity
of the sulfonamide drugs. Davidson and Gird wood2 suggested that there may
be an antagonism between members of the vitamin B complex groups since
patients showing vitamin deficiency, when treated with one member of the
vitamin B complex, will develop signs of deficiency of another member. The
clinical evidence for the latter view has been demonstrated in pellagra and
riboflavin deficiency.1'8"10
SUMMARY
A patient with macrocytic hyperchromic anemia, attributable to faulty intestinal absorption, was successfully treated with liver extract to which he became sensitive. Treatment with folic acid for thirteen months was followed by
the development of peripheral neuritis and combined system disease. Successful desensitization to liver extract and treatment with this drug resulted in
complete remission of the neurologic disease and return to health.
REFERENCES
1. B I C H E L , J . , AND MEULENCRACHT, E . : Pellagra developing after t r e a t m e n t of PlummerVinson syndrome with riboflavin. Nord. med., 9: 185-190, 1941.
2. DAVIDSON, L. S. P . , AND GIKDWOOD, R . H . : T h e imbalance of vitamins with particular
reference t o folic acid. Lancet, 254: 360-363, 1948.
3. H A L L , B . E . , AND W A T K I N S , C . H . : Experience with pteroylglutamic acid (synthetic folic
acid) in t r e a t m e n t of pernicious anemia. J. Lab. and Clin. Med., 32: 622-634, 1947.
4. H E I N L E , R . W., AND W E L C H , A. D . : Folic acid in pernicious anemia; failure t o prevent
neurologic relapse. J. A. M. A., 133: 739-741, 1947.
5. MEYER, L. M.: Experiences with folic acid in macrocytic anemia. Bull. New York
Acad. Med., 22: 484, 1946.
6. M E Y E R , L. M.: Folic acid in t r e a t m e n t of pernicious anemia. Blood, 2 : 50-62, 1947.
7. R o s s , J . F . , B E L D I N G , H . , AND P A E G E L , B . L . : T h e development a n d progression of subacute combined degeneration of t h e spinal cord in p a t i e n t s with pernicious anemia
t r e a t e d with s y n t h e t i c pteroylglutamic (folic) acid. Blood, 3 : 68-90, 1948.
S. SALVESEN, O . : Pellagra a n d pellagrous cutaneous changes after t r e a t m e n t with vitamin Bi a n d v i t a m i n C. Nord. med., 5: 279-282, 1940.
9. SEBRELL, W. H . , J R . , AND B U T L E R , R . E . : Riboflavin deficiencv in m a n (ariboflavinosis). P u b . H e a l t h R e p . , 54: 2121-2131, 1939.
10. S P I E S , T . D . , V I L T E R , R . W., AND A S H E , W. F . : Pellagra, beriberi and riboflavin deficiency in h u m a n beings; diagnosis a n d t r e a t m e n t . J. A. M. A., 113: 931-937, 1939.
11. VILTER, C. F . , V I L T E R , R . W., AND S P I E S , T . D . : Occurrence of combined system disease in persons with pernicious anemia during t r e a t m e n t with Lacto-bacMus casei
factor (folic a c i d ) . P r o c . Central Soc. Clin. Research, 19: 26-27, 1946.
12. V I L T E R , C. F . , V I L T E R , R . W., AND S P I E S , T . D . : T r e a t m e n t of pernicious a n d related
anemias with s y n t h e t i c folic acid.
J. L a b . and Clin. Med., 32: 262-273, 1947.