93
Journal of the neurological Sciences, 1975, 25:93-98 ~' Elsevier Scientific Publishing Company, Amsterdam
Printed in The Netherlands
Reversible Central Nervous System Dysfunction in Folate Deficiency E LDAD MELAMED, AVINOAM RECHES, AND CHAIM HERSHKO
Departments of Neurology and Haematolooy, Hadassah UniversityHospitaland Hebrew University- Hadassah Medical School, Jerusalem (Israel) (Received 5 November, 1974)
INTRODUCTION
The megaloblastic anemia of folic acid deficiency is indistinguishable from that caused by lack of vitamin B~2. However, in contrast to the well-established neurological disorders produced by vitamin B12 deficiency such as subacute combined degeneration of the spinal cord, dementia and peripheral neuropathy, it was generally accepted (DeGruchy 1970) that folic acid deficiency does not affect the nervous system. This view has been challenged by several recent reports (Brain 1969) relating various neurological syndromes to folic acid deficiency. The establishment of such an aetiological relationship necessitates the demonstration of low serum folic acid levels in the presence of normal vitamin B~2 absorption and serum values, and the reversibility of the neurological manifestations following folic acid administration. However, when surveying the literature it becomes evident that the association of folic acid deficiency and neurological disorders has been more often suggestive than clearly proven. The paucity of such clear-cut cases prompted the report on the following patient, in whom all of these criteria were fulfilled. CASE HISTORY In March 1974, a 75-year-old woman was admitted to the Department of Neurology of the Hadassah University Hospital with a history of chronic epilepsy treated with anticonvulsant drugs, progressive mental deterioration for the last 2-3 months, gait disturbances for the last 3~, weeks, incontinence, and anaemia. The patient was known to suffer from generalized epileptic fits since 1948. She has been hospitalized several times elsewhere, most recently in 1964, and underwent repeated neurological examinations which were within normal limits. Laboratory tests including skull X-ray, electroencephalograms, cerebral angiograms, and pneumoencephalogram were non-revealing. There was no evidence of anaemia. For many years, she was treated with a combination of diphenylhydantoin 200 mg/day and phenobarbital 100 rag/day, despite which she still had recurrent generalized fits, 1-3 times monthly. A few years ago, she developed personality changes with paranoid traits and negativism which necessitated hospitalization in an old people's home for patients with chronic diseases. A year prior to the present admission, primidone 500 rag/day was substituted for the diphenylhydantoin, however, with no effect on the frequency of the
94
Z. MELAMEI). A. RECHES, C. HERSHKO
epileptic attacks. Nevertheless, treatment with primidone at the above dosage and phenobarbital 100 rag/day was continued throughout the last year up to the present hospitalization. During tile last 2 3 months, her son noticed that she had forgotten the names of her grandsons, did not always recognize visiting family members, and neglected her appearance. The mental deterioration was rapidly progressive, and in the last weeks, there was almost no communication with the patient who appeared to be confused and mumbling to herself most of the time. During the last 4 weeks, gait disturbances developed, with unsteady walk. occasional falling, and within the last few days, she became bedridden and incontinent There was no history of alcoholism, diabetes, hypertension, abdominal operations, chronic diarrhea or g:~rointestmal bleeding. On admission, physical examination disclosed an undernourished female patient with marked pallor and mild atrophic glossitis. The liver was palpated 2 cm below the right costal margin. Blood pressure was 100/50 turn Hg and the pulse was regular at a rate of 92/min. On neurological examination she was found to be severely demented. Communication was almost impossible, but when established, disclosed disorientation as to place, time, and person. Though being repeatedly told, she could not relate where she was, the date, her address, or place of birth. Only occasionally did she give her name correctly. She could not recognize her family members and was mumbling incoherently most of the day. The muscle tone was increased in both upper and lower extremities. There were no signs of segmental muscular wasting or fascieulations. Tendon reflexes were remarkably hyperactive in the upper limbs and knees and diminished in both ankles. Bilateral plantar extensor responses and positive Tremner and Hoffman signs were elicited. The patient could neither walk nor stand. With the aid of the examiner, she could make a few staggering, broad-based steps with marked trunk ataxia. Position sense, vibration and superficial sensation could not be examined properly, though withdrawal of all limbs occurred when lightly pricked by a needle Nystagmus was not observed. There was urinary and occasionally fecal incontinence. Laboratory examinations on admission were as follows: E.S.R. 37 mm in 1 hour; haemoglobin ¢~.8g/100 ml, erythrocytes 2.6 millions/ram3, hematocrit 21 ~o, mean corpuscular haemoglobin 25 ~tpg, mean corpuscular volume 81 Ftp3, mean corpuscular haemoglobin concentration 32~F,,. Reticulocytes 0.4"0, platelet count 125,000/mm 3. Leucocytes 3400/ram ~, with 60 "i, neutrophils (many with polysegmented nuclei) and 40 ~o lymphocytes, on differential count. A peripheral blood smear showed the red blood cells to be slightly hypochromic with marked anisocytosis and poikilocytosis. Analysis of the urine was negative. Routine blood biochemistry tests, including B.U.N., glucose, electrolytes, cholesterol, bilirubin, calcium, phosphorus, transaminases and total glycerides were within normal limits. Total protein was 6.9, albumin 3.2 and globulin 3.7 g/100 ml. The cerebrospinal fluid (CSF) was normal. Tests for syphilis in the serum and CSF were negative. Tests for fecal occult blood were consistently negative. An electrocardiogram showed incomplete right bundle branch block. An electroencephalogram (EEG) was grossly abnormal with generalized 4-6 c/s theta activity. An electromyogram (EMG) and motor nerve conduction velocity tests failed to show evidence of peripheral nerve involvement. Plasma anticonvulsant levels were not measured. Vitamin B~2 in the serum was normal, ranging from 500 to 560 pg/ml on repeated examinations. The Schilling test was normal: 16.5 ~. However, the blood folate levels were remarkably low, 36 and 33 ng/mt in repeated whole blood measurements. Normal values exceed 100 ng/ml (Grossowich. MandelbaumShavit, Davidoffand Aronovitch 1962). Folates were extremely low in the serum, 1.3-2.4 ng/m] on repeated examinations (normal values exceed 7 ng/ml). Free acid was found in gastric aspirates. The D-xyluse tolerance and faecal fat excretion tests were within normal limits. Absorption tests following intake of "TABLE I RESULTSOF FOLATliABSORPTIONSTUDIES PG A ~ Time (hr)
0 1
2 3
.
.
serum (ng/ml)
2.6 4.3 4.2
.
.
.
Lit;er ~'
.
.
.
.
.
.
.
.
.
.
.
Broccol?
.
.
.
.
.
.
.
whole blood (n•/ml)
serum (ng/ml )
whole blood (ng/ml)
serum (ng/rnl)
127
1.3 3.9 6.5 5.2
110 90 95 108
2. t 2.0 4.8 5.0
.
.
.
.
.
l~hole blood ( ng/ml )
120 100
150 145
" PGA = pteroylglutamic acid (100 Itg); Liver meal equivalent to 100 Itg of reduced polyglytamates; Broccoli meal equivalent to 100/~g of non-reduced polyglutamates.
REVERSIBLE CNS DYSFUNCTION IN FOLATE DEFICIENCY
95
pteroylglutamic acid (unconjugated), liver meal (reduced polyglutamates) and broccoli meal (non-reduced polyglutamates) were within normal limits, as shown in Table 1. These studies performed with the simultaneous continued administration of primidone, excluded reduced absorption of folates as the cause of the anaemia. The first examination of the bone marrow disclosed marked erythroid hyperplasia with many pronormoblasts and basophilic normoblasts. Giant band forms and metamyelocytes were also found. Only occasional megaloblasts and nacronormoblasts were detected. The absence of distinct megaloblastic changes in the face of severe folate deficiency, suggested a mixed type of nutritional anaemia with coexistent iron deficiency and indeed the serum iron was found to be low: 34 #g/100 ml. A repeated bone marrow examination following a parenteral course of iron (Jectofer) for 5 days to a total dose of 500 mg disclosed a clear-cut megaloblastic picture. A mild reticulocyte response was noticed a few days after hospitalization with no special treatment. probably due to normalization of folate intake on regular hospital diet. It increased following the folate absorption tests, the iron treatment, and later the daily administration of 100/~g pteroylglutamic acid orally, reaching a maximal value of 5 % Haemoglobin levels increased progressively to 10.1 g/100 ml in 3 weeks, the erythrocytes rose to 4.2 million/mm3, the hematocrit to 35 % and the leucocytes to 5800/mm 3. Serum iron increased to 127/~g/100 ml and the folic acid in whole blood to 190 ng/ml. However, the most striking improvement occurred in the neurological features. Gradually the patient became coherent and oriented. She could identify her family members and medical personnel, could tell the date, and knew her whereabouts. Eventually, the signs and symptoms of dementia cleared up almost completely and the patient was able to converse and to communicate freely. She becane her old self with querulous behaviour, negativism and paranoid traits. There was a progressive improvement in her gait. Gradually she could get out of bed, stand alone, perform some unsteady, widebased steps and later could walk freely, unaided. She regained complete urinary and faecal control. The bilateral extensor responses and Tremner and Hoffman signs disappeared. Tendon reflexes remained mildly hyperactive. Vibration and position sense, examined when the patient was more cooperative, were found to be normal. A repeat EEG showed marked improvement, with only occasional 6-7 c/s theta activity in the occipito-temporal areas, bilaterally. The neurological and hematological improvement occurred within a period of 3 weeks. The patient was later discharged receiving oral folic acid 15 mg/day, supplemented by ferrous sulfate. Diphenylhydantoin 300 mg/day was prescribed instead of the primidone. There were no neurological findings, except for mildly hyperactive knee jerks, on repeated follow-up examinations for 3 months. DISCUSSION
The neurological manifestations in our patient were those of progressive dementia, bilateral pyramidal tract signs, incontinence and ataxia (probably due to cerebellar dysfunction), combined with a mixed type of anaemia. Serum folate levels were extremely low in the presence of normal serum levels and absorption of vitamin B 1z. The neurological abnormalities and the anaemia abated following administration of folic acid. These data strongly indicate a cause and effect relationship between folic acid deficiency and the neurological syndrome. Some reported cases provide only partial evidence in support of such a relationship. Thus, Ungar and Cowling (1960) described a chronic epileptic patient on diphenylhydantoin treatment who developed a megaloblastic anaemia and subacute combined degeneration of the spinal cord. Though the serum vitamin B 12 values were low, the condition responded only to folic acid therapy. Hansen, Nordquist and Sourander (1964) reported an epileptic patient treated by diphenylhydantoin with megaloblastic anemia and peripheral neuropathy, low serum folates and normal vitamin B 12 levels. Only the anaemia responded to folic acid treatment. At autopsy, lesions were found in the cerebellar vermis, spinal cord and root pouches and were ascribed by the authors to folic acid deficiency. Another epileptic patient treated by anticonvulsant drugs who developed dementia, subacute combined degeneration of the spinal cord and megaloblastic anaemia was reported by Aanand (1964). Though there is no mention
96
E. MELAMED, A. RECHES, C. ltERSHKO
of the serum levels of both vitamins, improvement occurred following folic acid administration only. Robertson, Dinsdale and Campbell (1971) described a case with subacute combined degeneration of the cord proven at autopsy, with normal serum values of vitamin B12. Though the serum level of folic acid was not determined, the neurological phenomena were believed to be due to folic acid deficiency. Read. Gough. Paradoe and Nicholas (1965) described an old patient with megaloblastic anaemia, dementia, incontinence and low serum folate due to nutritional deficiency who responded to folic acid treatment. A clear-cut association between folate deficiency and neurological abnormalities as described in our patient has been reported only rarely. Thus, Strachan and Henderson (1967) reported 2 undernourished patients with dementia, macrocytic anaemia and low serum folate levels. The dementia slowly cleared after folic acid therapy. Ahmed's (1972) patient with subacute combined degeneration of the spinal cord and low serum folate, partially responded to folic acid administration. Pincus, Rynolds and Glaser (1972) reported a case with subacute combined degeneration of the spinal cord, dementia, sensory neuropathy, megaloblastic anaemia and low serum folate levels. All these abnormalities cleared after treatment with folic acid. Fehling, Jagersad, Lindstrand and Elmquist (1974) described a latent polyneuropathy in a patient with folate deficiency resulting from intestinal disease, which improved following folic acid therapy. It is worthwhile to mention that Herbert (1962), in his study of experimental folate deficiency, stated that neurological changes more severe than sleeplessness, forgetfulness and irritability did not develop after 4½ months of folate deprivation. However, even these minor symptoms indicate central nervous system involvement. Further support of the association between neurological disorders and folate deficiency was lent by the observation of Grant, Hoffbrand and Wells (1965) that 7 out of 10 patients with undiagnosed myelopathy and/or peripheral neuropathy with megaloblastic changes in the bone marrow, were found to be folate deficient. Likewise, Reynolds. Rothfeld and Pincus (1973) found a significant increase in organic brain syndrome and pyramidal tract damage in folate-deficient patients as compared with a control group of patients with normal serum folates. The correction of the severe anaemia may have contributed to the neurological improvement. However, in agreement with Strachan and Henderson (1967) it seems unlikely that the anaemia, per se, was a major factor in the development of the nervous system dysfunction encountered in our patient. The association of folate-deficient megaloblastic anaemia with anticonvulsant drug therapy is well known, but the underlying mechanism is still uncertain (Beck 1972). The normal folate absorption studies performed in our patient with the simultaneous. continued administration of primidone and phenobarbital, rule out reduced absorption of folates due to competition of the anticonvulsants as previously reported (Druskin, Wallen and Bonagura 1962). The lack of signs of malabsorption, the mixed (iron and folate) nature of the deficiency anaemia and the combination of psychosis, epilepsy and residence in an old people's home, prompted us to believe that the folate deficiency in our patient was due to reduced dietary intake as suggested by Jensen and Olesen (1970) and was probably of long duration. A dietary survey performed in her institute (to be reported) disclosed a low average daily folate intake of 75/~g.
REVERSIBLE CNS DYSFUNCTION IN FOLATE DEFICIENCY
97
It was also found that over 60 ~ of 80 patients examined in this institute had serum folate values of 3 ng/ml or less. While nutritional folic acid deficiency is common (Read et al. 1965) the neurological manifestations, unlike the haematological ones, are quite rare in this condition. One must, therefore, assume that the nervous system is more resistant to folate deprivation than the haematopoetic tissues, and that either an individual susceptibility or certain precipitating factors operate in their development. It is possible that the severity of folate deficiency and its duration are also important. It should be noted that the whole blood folate level of 30 ng/ml found in our patient was the lowest among the several thousand examinations performed within the last 10 years in this hospital. Girdwood and Lenman (1956) pointed out a structural similarity between anticonvulsant drugs and folic acid, and suggested that they may act as competitive inhibitors of an enzyme normally involving folic acid as a co-factor. It may be that the introduction of primidone in this already folate-deficient patient thus precipitated the development of the neurological abnormalities. The pathogenic mechanism by which folate deficiency induces nervous system disease has not yet been established. There is, however, experimental evidence that severe folate deficiency may directly interfere with neuronal RNA synthesis (Haltia 1970). Though uncommon, it seems that the association of folic acid deficiency and neurological abnormalities such as dementia, myelopathy, cerebellar dysfunction, and peripheral neuropathy, is by now well-established. Thus, in the search for treatable neurological disorders, folate deficiency should be looked for, particularly in conditions which may lead to its development such as malnutrition, malabsorption, and chronic anticonvulsant drug therapy. SUMMARY
An epileptic patient on chronic anticonvulsant drug therapy is described, in whom anaemia and neurological abnormalities including progressive dementia, bilateral pyramidal tract signs, incontinence and ataxia developed. Vitamin B12 serum levels and absorption were normal, but serum folic acid levels were low. Both the neurologic~tl disturbances and anaemia resolved following oral folic acid administration. This sequ~.~cc of events in our patient suggests a cause and effect relationship between the folate deficiency and the coexistent, transient neurological syndrome.
REFERENCES AHMED, A. (1972) Neurological disease and folate deficiency, Brit. med. J., 1 : 181. ANAND, M. P. (1964) Iatrogenic megaloblastic anemia with neurological complications, Scot. med. J., 9:388 390. BECK, W. S. (1972) Folic acid deficiency. In: J. W. WILLIAMS,E. BEUTLER,A. J. ERSLEVAND R. W. RUNDLZS (Eds.), Haernatology, McGraw-Hill, New York, N.Y., pp. 218-297. BRAIN, M. (1969) Recent Advances in Neurology and Neuropsychiatry, edited by M. Brain and M. Wilkinson, Churchill, London. DEGRUCHY, G. C. (1970) Clinical Haematology in Medical Practice, 3rd edition, Blackwell, Edinburgh, p. 138.
98
E. MELAMED, A. RECHES, C. HERSHKO
DRUSKIN,M. S., M. H. WALLENAND L. BONAGURA(1962) Anticonvulsant associated megaloblastic anemia - Response to 25 micrograms of folic acid administered by mouth daily, New Eng/. J. Med., 267 : 483-485. FEHLING, C., M. JAGERSAD,K. LINDSTRANDAND D. ELMQUIST(1974) Folate deficiency and neurological disease, Arch. Neurol. (Chic.), 30: 263-265. GIRDWOOD, R. H. AND J. A. R. LENMAN(1956) Megaloblastic anemia occurring alter primidone therapy, Brit. reed. J., l: 14(~147. GRANT, H. C., A. V. HOFFBRANDAND D. G. WELLS (1965) Folate deficiency and neurological disease, Lancet, 2: 763--767. GROSSOW|CH, N., F. MANDELBAUN-SI-IAVIT,R. DAVIDOEE AND J. ARONOVITCH (1962) Microbiologic determination of folic acid derivatives in blood, Blood, 20:609 616. HALTIA, M. (1970) The effect of folate deficiency on neuronal RNA content, Brit. J. ca~,. Patho/.. 51: 191-196. HANSEN,H. A., P. NOgDQUISTANDP. SOURANDER(1964) Megaloblastic anemia and neurologic disturbances combined with folic acid deficiency, Acta reed. scan&, 176: 243-250. HERBERT,V. (I 962) Experimental nutritional folate deficiencyin man, Trans. Ass. Amer. Ph):~s.,75 : 307 320. JENSEN, O. N. AND O. V. OLESEN (1970) Subnormal serum folate due to anticonvulsive therapy, Arch. Neurol. (Chic.), 22: 181-182. PIycus, J. H., E. H. REYNOLDSAND G. H. GLASER {1972) Subacute combined system degeneration with folate deficiency, J. Amer. reed. Ass., 221 : 496-497. READ, A. E., K. P. GOUGH, J. L. PARADOEAND A. NICHOLAS (1965) Nutritional studies on the entrants to an old people's home with particular reference to folic acid deficiency, Brit. reed. J.. 2: 843-845. ROSERTSON, D. M., H. B. DINSDALEAND R. J. CAuJ'l~rIL (1971) Subacute combined degeneration of the spinal cord No association with vitamin B~2 deficiency, Arch. Neurol. (Chic.), 24, 203-209. REYNOt.I) . E. n., P. ROTHFELD AND J. H. PINCUS (1~)73) Neurological disease associated with folate deficiency, Brit. reed. J., 2: 398-400. STRAt ~tAN,R. W. ANDJ. G. HENDERSON(1967)Dementia and folate deficiency, Quart. J. Med., 36: 18%204. UNGAR, B, AND D. C. COWLING(1960) Megaloblastic anemia associated with anticonvulsant drug therapy, Med. J. Aust., 2: 461-462.
Journal of the neurological Sciences, 1975, 25:93-98 ~' Elsevier Scientific Publishing Company, Amsterdam
Printed in The Netherlands
Reversible Central Nervous System Dysfunction in Folate Deficiency E LDAD MELAMED, AVINOAM RECHES, AND CHAIM HERSHKO
Departments of Neurology and Haematolooy, Hadassah UniversityHospitaland Hebrew University- Hadassah Medical School, Jerusalem (Israel) (Received 5 November, 1974)
INTRODUCTION
The megaloblastic anemia of folic acid deficiency is indistinguishable from that caused by lack of vitamin B~2. However, in contrast to the well-established neurological disorders produced by vitamin B12 deficiency such as subacute combined degeneration of the spinal cord, dementia and peripheral neuropathy, it was generally accepted (DeGruchy 1970) that folic acid deficiency does not affect the nervous system. This view has been challenged by several recent reports (Brain 1969) relating various neurological syndromes to folic acid deficiency. The establishment of such an aetiological relationship necessitates the demonstration of low serum folic acid levels in the presence of normal vitamin B~2 absorption and serum values, and the reversibility of the neurological manifestations following folic acid administration. However, when surveying the literature it becomes evident that the association of folic acid deficiency and neurological disorders has been more often suggestive than clearly proven. The paucity of such clear-cut cases prompted the report on the following patient, in whom all of these criteria were fulfilled. CASE HISTORY In March 1974, a 75-year-old woman was admitted to the Department of Neurology of the Hadassah University Hospital with a history of chronic epilepsy treated with anticonvulsant drugs, progressive mental deterioration for the last 2-3 months, gait disturbances for the last 3~, weeks, incontinence, and anaemia. The patient was known to suffer from generalized epileptic fits since 1948. She has been hospitalized several times elsewhere, most recently in 1964, and underwent repeated neurological examinations which were within normal limits. Laboratory tests including skull X-ray, electroencephalograms, cerebral angiograms, and pneumoencephalogram were non-revealing. There was no evidence of anaemia. For many years, she was treated with a combination of diphenylhydantoin 200 mg/day and phenobarbital 100 rag/day, despite which she still had recurrent generalized fits, 1-3 times monthly. A few years ago, she developed personality changes with paranoid traits and negativism which necessitated hospitalization in an old people's home for patients with chronic diseases. A year prior to the present admission, primidone 500 rag/day was substituted for the diphenylhydantoin, however, with no effect on the frequency of the
94
Z. MELAMEI). A. RECHES, C. HERSHKO
epileptic attacks. Nevertheless, treatment with primidone at the above dosage and phenobarbital 100 rag/day was continued throughout the last year up to the present hospitalization. During tile last 2 3 months, her son noticed that she had forgotten the names of her grandsons, did not always recognize visiting family members, and neglected her appearance. The mental deterioration was rapidly progressive, and in the last weeks, there was almost no communication with the patient who appeared to be confused and mumbling to herself most of the time. During the last 4 weeks, gait disturbances developed, with unsteady walk. occasional falling, and within the last few days, she became bedridden and incontinent There was no history of alcoholism, diabetes, hypertension, abdominal operations, chronic diarrhea or g:~rointestmal bleeding. On admission, physical examination disclosed an undernourished female patient with marked pallor and mild atrophic glossitis. The liver was palpated 2 cm below the right costal margin. Blood pressure was 100/50 turn Hg and the pulse was regular at a rate of 92/min. On neurological examination she was found to be severely demented. Communication was almost impossible, but when established, disclosed disorientation as to place, time, and person. Though being repeatedly told, she could not relate where she was, the date, her address, or place of birth. Only occasionally did she give her name correctly. She could not recognize her family members and was mumbling incoherently most of the day. The muscle tone was increased in both upper and lower extremities. There were no signs of segmental muscular wasting or fascieulations. Tendon reflexes were remarkably hyperactive in the upper limbs and knees and diminished in both ankles. Bilateral plantar extensor responses and positive Tremner and Hoffman signs were elicited. The patient could neither walk nor stand. With the aid of the examiner, she could make a few staggering, broad-based steps with marked trunk ataxia. Position sense, vibration and superficial sensation could not be examined properly, though withdrawal of all limbs occurred when lightly pricked by a needle Nystagmus was not observed. There was urinary and occasionally fecal incontinence. Laboratory examinations on admission were as follows: E.S.R. 37 mm in 1 hour; haemoglobin ¢~.8g/100 ml, erythrocytes 2.6 millions/ram3, hematocrit 21 ~o, mean corpuscular haemoglobin 25 ~tpg, mean corpuscular volume 81 Ftp3, mean corpuscular haemoglobin concentration 32~F,,. Reticulocytes 0.4"0, platelet count 125,000/mm 3. Leucocytes 3400/ram ~, with 60 "i, neutrophils (many with polysegmented nuclei) and 40 ~o lymphocytes, on differential count. A peripheral blood smear showed the red blood cells to be slightly hypochromic with marked anisocytosis and poikilocytosis. Analysis of the urine was negative. Routine blood biochemistry tests, including B.U.N., glucose, electrolytes, cholesterol, bilirubin, calcium, phosphorus, transaminases and total glycerides were within normal limits. Total protein was 6.9, albumin 3.2 and globulin 3.7 g/100 ml. The cerebrospinal fluid (CSF) was normal. Tests for syphilis in the serum and CSF were negative. Tests for fecal occult blood were consistently negative. An electrocardiogram showed incomplete right bundle branch block. An electroencephalogram (EEG) was grossly abnormal with generalized 4-6 c/s theta activity. An electromyogram (EMG) and motor nerve conduction velocity tests failed to show evidence of peripheral nerve involvement. Plasma anticonvulsant levels were not measured. Vitamin B~2 in the serum was normal, ranging from 500 to 560 pg/ml on repeated examinations. The Schilling test was normal: 16.5 ~. However, the blood folate levels were remarkably low, 36 and 33 ng/mt in repeated whole blood measurements. Normal values exceed 100 ng/ml (Grossowich. MandelbaumShavit, Davidoffand Aronovitch 1962). Folates were extremely low in the serum, 1.3-2.4 ng/m] on repeated examinations (normal values exceed 7 ng/ml). Free acid was found in gastric aspirates. The D-xyluse tolerance and faecal fat excretion tests were within normal limits. Absorption tests following intake of "TABLE I RESULTSOF FOLATliABSORPTIONSTUDIES PG A ~ Time (hr)
0 1
2 3
.
.
serum (ng/ml)
2.6 4.3 4.2
.
.
.
Lit;er ~'
.
.
.
.
.
.
.
.
.
.
.
Broccol?
.
.
.
.
.
.
.
whole blood (n•/ml)
serum (ng/ml )
whole blood (ng/ml)
serum (ng/rnl)
127
1.3 3.9 6.5 5.2
110 90 95 108
2. t 2.0 4.8 5.0
.
.
.
.
.
l~hole blood ( ng/ml )
120 100
150 145
" PGA = pteroylglutamic acid (100 Itg); Liver meal equivalent to 100 Itg of reduced polyglytamates; Broccoli meal equivalent to 100/~g of non-reduced polyglutamates.
REVERSIBLE CNS DYSFUNCTION IN FOLATE DEFICIENCY
95
pteroylglutamic acid (unconjugated), liver meal (reduced polyglutamates) and broccoli meal (non-reduced polyglutamates) were within normal limits, as shown in Table 1. These studies performed with the simultaneous continued administration of primidone, excluded reduced absorption of folates as the cause of the anaemia. The first examination of the bone marrow disclosed marked erythroid hyperplasia with many pronormoblasts and basophilic normoblasts. Giant band forms and metamyelocytes were also found. Only occasional megaloblasts and nacronormoblasts were detected. The absence of distinct megaloblastic changes in the face of severe folate deficiency, suggested a mixed type of nutritional anaemia with coexistent iron deficiency and indeed the serum iron was found to be low: 34 #g/100 ml. A repeated bone marrow examination following a parenteral course of iron (Jectofer) for 5 days to a total dose of 500 mg disclosed a clear-cut megaloblastic picture. A mild reticulocyte response was noticed a few days after hospitalization with no special treatment. probably due to normalization of folate intake on regular hospital diet. It increased following the folate absorption tests, the iron treatment, and later the daily administration of 100/~g pteroylglutamic acid orally, reaching a maximal value of 5 % Haemoglobin levels increased progressively to 10.1 g/100 ml in 3 weeks, the erythrocytes rose to 4.2 million/mm3, the hematocrit to 35 % and the leucocytes to 5800/mm 3. Serum iron increased to 127/~g/100 ml and the folic acid in whole blood to 190 ng/ml. However, the most striking improvement occurred in the neurological features. Gradually the patient became coherent and oriented. She could identify her family members and medical personnel, could tell the date, and knew her whereabouts. Eventually, the signs and symptoms of dementia cleared up almost completely and the patient was able to converse and to communicate freely. She becane her old self with querulous behaviour, negativism and paranoid traits. There was a progressive improvement in her gait. Gradually she could get out of bed, stand alone, perform some unsteady, widebased steps and later could walk freely, unaided. She regained complete urinary and faecal control. The bilateral extensor responses and Tremner and Hoffman signs disappeared. Tendon reflexes remained mildly hyperactive. Vibration and position sense, examined when the patient was more cooperative, were found to be normal. A repeat EEG showed marked improvement, with only occasional 6-7 c/s theta activity in the occipito-temporal areas, bilaterally. The neurological and hematological improvement occurred within a period of 3 weeks. The patient was later discharged receiving oral folic acid 15 mg/day, supplemented by ferrous sulfate. Diphenylhydantoin 300 mg/day was prescribed instead of the primidone. There were no neurological findings, except for mildly hyperactive knee jerks, on repeated follow-up examinations for 3 months. DISCUSSION
The neurological manifestations in our patient were those of progressive dementia, bilateral pyramidal tract signs, incontinence and ataxia (probably due to cerebellar dysfunction), combined with a mixed type of anaemia. Serum folate levels were extremely low in the presence of normal serum levels and absorption of vitamin B 1z. The neurological abnormalities and the anaemia abated following administration of folic acid. These data strongly indicate a cause and effect relationship between folic acid deficiency and the neurological syndrome. Some reported cases provide only partial evidence in support of such a relationship. Thus, Ungar and Cowling (1960) described a chronic epileptic patient on diphenylhydantoin treatment who developed a megaloblastic anaemia and subacute combined degeneration of the spinal cord. Though the serum vitamin B 12 values were low, the condition responded only to folic acid therapy. Hansen, Nordquist and Sourander (1964) reported an epileptic patient treated by diphenylhydantoin with megaloblastic anemia and peripheral neuropathy, low serum folates and normal vitamin B 12 levels. Only the anaemia responded to folic acid treatment. At autopsy, lesions were found in the cerebellar vermis, spinal cord and root pouches and were ascribed by the authors to folic acid deficiency. Another epileptic patient treated by anticonvulsant drugs who developed dementia, subacute combined degeneration of the spinal cord and megaloblastic anaemia was reported by Aanand (1964). Though there is no mention
96
E. MELAMED, A. RECHES, C. ltERSHKO
of the serum levels of both vitamins, improvement occurred following folic acid administration only. Robertson, Dinsdale and Campbell (1971) described a case with subacute combined degeneration of the cord proven at autopsy, with normal serum values of vitamin B12. Though the serum level of folic acid was not determined, the neurological phenomena were believed to be due to folic acid deficiency. Read. Gough. Paradoe and Nicholas (1965) described an old patient with megaloblastic anaemia, dementia, incontinence and low serum folate due to nutritional deficiency who responded to folic acid treatment. A clear-cut association between folate deficiency and neurological abnormalities as described in our patient has been reported only rarely. Thus, Strachan and Henderson (1967) reported 2 undernourished patients with dementia, macrocytic anaemia and low serum folate levels. The dementia slowly cleared after folic acid therapy. Ahmed's (1972) patient with subacute combined degeneration of the spinal cord and low serum folate, partially responded to folic acid administration. Pincus, Rynolds and Glaser (1972) reported a case with subacute combined degeneration of the spinal cord, dementia, sensory neuropathy, megaloblastic anaemia and low serum folate levels. All these abnormalities cleared after treatment with folic acid. Fehling, Jagersad, Lindstrand and Elmquist (1974) described a latent polyneuropathy in a patient with folate deficiency resulting from intestinal disease, which improved following folic acid therapy. It is worthwhile to mention that Herbert (1962), in his study of experimental folate deficiency, stated that neurological changes more severe than sleeplessness, forgetfulness and irritability did not develop after 4½ months of folate deprivation. However, even these minor symptoms indicate central nervous system involvement. Further support of the association between neurological disorders and folate deficiency was lent by the observation of Grant, Hoffbrand and Wells (1965) that 7 out of 10 patients with undiagnosed myelopathy and/or peripheral neuropathy with megaloblastic changes in the bone marrow, were found to be folate deficient. Likewise, Reynolds. Rothfeld and Pincus (1973) found a significant increase in organic brain syndrome and pyramidal tract damage in folate-deficient patients as compared with a control group of patients with normal serum folates. The correction of the severe anaemia may have contributed to the neurological improvement. However, in agreement with Strachan and Henderson (1967) it seems unlikely that the anaemia, per se, was a major factor in the development of the nervous system dysfunction encountered in our patient. The association of folate-deficient megaloblastic anaemia with anticonvulsant drug therapy is well known, but the underlying mechanism is still uncertain (Beck 1972). The normal folate absorption studies performed in our patient with the simultaneous. continued administration of primidone and phenobarbital, rule out reduced absorption of folates due to competition of the anticonvulsants as previously reported (Druskin, Wallen and Bonagura 1962). The lack of signs of malabsorption, the mixed (iron and folate) nature of the deficiency anaemia and the combination of psychosis, epilepsy and residence in an old people's home, prompted us to believe that the folate deficiency in our patient was due to reduced dietary intake as suggested by Jensen and Olesen (1970) and was probably of long duration. A dietary survey performed in her institute (to be reported) disclosed a low average daily folate intake of 75/~g.
REVERSIBLE CNS DYSFUNCTION IN FOLATE DEFICIENCY
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It was also found that over 60 ~ of 80 patients examined in this institute had serum folate values of 3 ng/ml or less. While nutritional folic acid deficiency is common (Read et al. 1965) the neurological manifestations, unlike the haematological ones, are quite rare in this condition. One must, therefore, assume that the nervous system is more resistant to folate deprivation than the haematopoetic tissues, and that either an individual susceptibility or certain precipitating factors operate in their development. It is possible that the severity of folate deficiency and its duration are also important. It should be noted that the whole blood folate level of 30 ng/ml found in our patient was the lowest among the several thousand examinations performed within the last 10 years in this hospital. Girdwood and Lenman (1956) pointed out a structural similarity between anticonvulsant drugs and folic acid, and suggested that they may act as competitive inhibitors of an enzyme normally involving folic acid as a co-factor. It may be that the introduction of primidone in this already folate-deficient patient thus precipitated the development of the neurological abnormalities. The pathogenic mechanism by which folate deficiency induces nervous system disease has not yet been established. There is, however, experimental evidence that severe folate deficiency may directly interfere with neuronal RNA synthesis (Haltia 1970). Though uncommon, it seems that the association of folic acid deficiency and neurological abnormalities such as dementia, myelopathy, cerebellar dysfunction, and peripheral neuropathy, is by now well-established. Thus, in the search for treatable neurological disorders, folate deficiency should be looked for, particularly in conditions which may lead to its development such as malnutrition, malabsorption, and chronic anticonvulsant drug therapy. SUMMARY
An epileptic patient on chronic anticonvulsant drug therapy is described, in whom anaemia and neurological abnormalities including progressive dementia, bilateral pyramidal tract signs, incontinence and ataxia developed. Vitamin B12 serum levels and absorption were normal, but serum folic acid levels were low. Both the neurologic~tl disturbances and anaemia resolved following oral folic acid administration. This sequ~.~cc of events in our patient suggests a cause and effect relationship between the folate deficiency and the coexistent, transient neurological syndrome.
REFERENCES AHMED, A. (1972) Neurological disease and folate deficiency, Brit. med. J., 1 : 181. ANAND, M. P. (1964) Iatrogenic megaloblastic anemia with neurological complications, Scot. med. J., 9:388 390. BECK, W. S. (1972) Folic acid deficiency. In: J. W. WILLIAMS,E. BEUTLER,A. J. ERSLEVAND R. W. RUNDLZS (Eds.), Haernatology, McGraw-Hill, New York, N.Y., pp. 218-297. BRAIN, M. (1969) Recent Advances in Neurology and Neuropsychiatry, edited by M. Brain and M. Wilkinson, Churchill, London. DEGRUCHY, G. C. (1970) Clinical Haematology in Medical Practice, 3rd edition, Blackwell, Edinburgh, p. 138.
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DRUSKIN,M. S., M. H. WALLENAND L. BONAGURA(1962) Anticonvulsant associated megaloblastic anemia - Response to 25 micrograms of folic acid administered by mouth daily, New Eng/. J. Med., 267 : 483-485. FEHLING, C., M. JAGERSAD,K. LINDSTRANDAND D. ELMQUIST(1974) Folate deficiency and neurological disease, Arch. Neurol. (Chic.), 30: 263-265. GIRDWOOD, R. H. AND J. A. R. LENMAN(1956) Megaloblastic anemia occurring alter primidone therapy, Brit. reed. J., l: 14(~147. GRANT, H. C., A. V. HOFFBRANDAND D. G. WELLS (1965) Folate deficiency and neurological disease, Lancet, 2: 763--767. GROSSOW|CH, N., F. MANDELBAUN-SI-IAVIT,R. DAVIDOEE AND J. ARONOVITCH (1962) Microbiologic determination of folic acid derivatives in blood, Blood, 20:609 616. HALTIA, M. (1970) The effect of folate deficiency on neuronal RNA content, Brit. J. ca~,. Patho/.. 51: 191-196. HANSEN,H. A., P. NOgDQUISTANDP. SOURANDER(1964) Megaloblastic anemia and neurologic disturbances combined with folic acid deficiency, Acta reed. scan&, 176: 243-250. HERBERT,V. (I 962) Experimental nutritional folate deficiencyin man, Trans. Ass. Amer. Ph):~s.,75 : 307 320. JENSEN, O. N. AND O. V. OLESEN (1970) Subnormal serum folate due to anticonvulsive therapy, Arch. Neurol. (Chic.), 22: 181-182. PIycus, J. H., E. H. REYNOLDSAND G. H. GLASER {1972) Subacute combined system degeneration with folate deficiency, J. Amer. reed. Ass., 221 : 496-497. READ, A. E., K. P. GOUGH, J. L. PARADOEAND A. NICHOLAS (1965) Nutritional studies on the entrants to an old people's home with particular reference to folic acid deficiency, Brit. reed. J.. 2: 843-845. ROSERTSON, D. M., H. B. DINSDALEAND R. J. CAuJ'l~rIL (1971) Subacute combined degeneration of the spinal cord No association with vitamin B~2 deficiency, Arch. Neurol. (Chic.), 24, 203-209. REYNOt.I) . E. n., P. ROTHFELD AND J. H. PINCUS (1~)73) Neurological disease associated with folate deficiency, Brit. reed. J., 2: 398-400. STRAt ~tAN,R. W. ANDJ. G. HENDERSON(1967)Dementia and folate deficiency, Quart. J. Med., 36: 18%204. UNGAR, B, AND D. C. COWLING(1960) Megaloblastic anemia associated with anticonvulsant drug therapy, Med. J. Aust., 2: 461-462.
