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Year : 2000  |  Volume : 48  |  Issue : 4  |  Page : 302-4

B12 and folate deficiency : incidence and clinical features.

How to cite this article:
Wadia R S, Bandishti S, Kharche M. B12 and folate deficiency : incidence and clinical features. Neurol India 2000;48:302

How to cite this URL:
Wadia R S, Bandishti S, Kharche M. B12 and folate deficiency : incidence and clinical features. Neurol India [serial online] 2000 [cited 2022 Dec 10];48:302. Available from: https://www.neurologyindia.com/text.asp?2000/48/4/302/1512

The incidence of B12 and folate deficiency in India is unknown but recent evidence suggests that it is commoner than we thought. Some years ago Dastur et al[1] reported 5 cases with neurological manifestation of B12 deficiency, over several years in Bombay. Jeejeebhoy et al[2] found 8 cases and showed that they were due mostly to malabsorption syndrome. Wadia et al[3] randomly studied every 10th admission to the medical general wards. Among 450 cases, B12 deficiency (level below 200 pg/ml) was detected in 0.88%, folic acid deficiency (level below 3 ng/ml) in 1.1% and deficiency of both in 2.4% of patients. 3.8% of cases had levels near the lower limit of normal. The deficiency was more frequent in pure vegetarians than in non vegetarians. Non vegetarians with a meat intake of less than 5 times a month had more frequent deficiency than those with more frequent meat intake. All the cases described by Dastur et al and Jeejeebhoy et al were vegetarians.[1],[2]
Low B12 and folate serum levels are not final evidence of deficiency. A concept has grown that true B12 tissue deficiency is present if serum methylmalonic acid (MMA) is high, as B12 is mandatory in its metabolism.[4] Thus, the deficiency is not true in case B12 levels are low and serum MMA is normal. However, if MMA is high and serum B12 is within normal limits, it suggests deficiency of B12. Similarly cases with true tissue folic acid deficiency have raised homocysteine levels. However, B12 deficiency also causes rise of serum homocysteine. Thus, B12 deficiency produces elevated levels of both, but folate deficiency is associated with only raised homocysteine levels. It is now accepted that levels of B12 between 200-300 pg/ml and folate between 3-4 ng/ml indicate deficiency. Yao et al,[5] while studying older cases, found that 33% of such cases with borderline levels, were truly deficient.
The groups in which deficiency is more common include the elderly, those after gastric surgery, those on anticonvulsants and depressed and demented patients. We found deficiency common in alcoholic patients in Pune but this was not noted by Dastur et al.[1] Another recently described aetiologic factor is surgery under nitrous oxide (NO). NO apparently binds B12. Just after surgery, patients with suboptimal tissue levels of B12 may develop a neurologic deficit. We have seen such finding after cervical laminectomy and initially felt that the posterior and lateral column signs were due to surgical complication, even though the repeat MRI showed no compression.
It may be mentioned that even in the developed world it is realized that B12 deficiency is quite common. Some studies mention an incidence of 1-2% in the younger population and 10-15% in the elderly over 65 years of age.[6] In these cases the serum level may still be normal and, the diagnosis comes only from MMA and homocysteine levels. As a result, there is much discussion in USA on folate fortification of breakfast cereals.

Manifestation of B12 and folate deficiency
The brunt of the damage in deficiency of B12 and folate falls on the skin and mucous membrane, haematologic and nervous systems. The skin manifestations include hyperpigmentation of knuckles, glossitis, stomatitis and brittle hair etc. The haematologic manifestations are well known viz. anaemia, macrocytosis (MCV>95), hypersegmented polymorphs, and megaloblastic bone marrow. These, however, may be absent. In cases of low levels of B12 and folate, Wadia et al[3] found Hb of > 11 gm% in 25%, macrocytosis (MCV > 95) due to B12 deficiency in 43% and due to folate deficiency in 62%, hypersegmented polymorphs in 25% and megaloblastic or dimorphic bone marrow changes in 22.6% of those deficient in both B12 and folate. This implies that if serum B12, folate, MMA or homocysteine levels are not done, the haematologic parameters alone are likely to miss nearly 50-70% of deficient cases. Savage et al found absent macrocytosis in 17% and normal haematocrit in 28% of cases.[7] Carmel et al found hypersegmented polymorphs in only 1 out of 34 cases with demonstrated B12 or folate deficieny.[8] Olgiati and Mombelli[9] studied 30 cases of B12 and folate deficiency and found thrombocytopaenia (platelets levels < 100,000/cmm) in 18 and both thrombocytopaenia and leucopaenia in 11 cases.
The neurologic manifestations of B12 and folate deficiency are varied. In 3 years, the authors have collected 99 cases of true deficiency (serum B12 < 200 pg/ml and folate < 3ng/ml) and 68 cases of borderline deficiency (B12 : 200-300 pg/ml and folate : 3-4 ng/ml). In these 167 cases, neuropathy was detected in 42 cases. Half of these had only sensory neuropathy. Evidence of spinal cord involvement was found in 12 (7.2%), and 7 of these had evidence of involvement of peripheral nerves, posterior columns and pyramidal tracts. Cognitive and behavioural signs were present in 10.3%. Shorvon et al[10] described neuropsychiatric manifestation of B12 and folate deficiency. They found more frequent neuropathy in B12 deficiency, as compared to folate deficiency (40%-18%). The cognitive defect was seen in 25% of both the groups. Depression was frequent in folate deficiency but rarer in B12 deficiency.
Our experience with dementia and cognitive defect is interesting. We found that 17 cases with B12 folate deficiency had cognitive defect but only showed improvement on replacement of the vitamins. Out of 16 cases with MMSE of < 21, 6 improved markedly and 4 partially. This implies that in dementia due to other causes, a secondary B12 and folate deficiency may occur due to nutritional factors (and this may aggravate the higher function abnormality). B12 deficiency in Alzheimer's disease has been described and is not uncommon. 36 out of 42 cases of neuropathy improved with replacement. However, only 6 of 12 patients of cord involvement showed convincing benefit. Of course, failure of cord signs and dementia to improve may be due to long standing deficiency and irreversible damage to the spinal cord. Developmental delay may be noted in children born to and breast fed by under-nourished women (B12 deficient). MRI scan shows cerebellar and cerebral atrophy and defect in myelination. The atrophy seen on MRI may regress with B12 treatment but the developmental delay may persist.[11],[12] In India, the infantile tremor syndrome was described in 1950's. This syndrome was first thought to be due to B12 deficiency by Jadhav et al[13] based on 6 cases with megaloblastic anaemia and improvement with B12. These finding were reproduced by Garewal et al[14] who found megaloblastic anaemia in 20 and low B12 levels (below 100 pg/ml) in 88% of cases. However, several others failed to find megaloblastic anaemia and failed to get improvement with B12.[15],[16] This may imply that B12 deficiency is a cause in a subset of these cases. In adults, orthostatic tremor i.e. tremor seen on standing and disappearing on walking or sitting, has been described due to B12 deficiency (Shaky leg syndrome).[17] Lhermitte's phenomenon may also be seen in B12 deficiency. Severe megaloblastic anaemia can cause retinal haemorrhage and blindness.
Folate deficiency predisposes to neural tube defects and the folate fortification of food is the most useful way to reduce this congenital anomaly.[18] An epileptic patient on treatment should receive folate supplements (4 mg/day) in preconception period, to reduce the risk of this anomaly; and there is a possibility that other congenital defects may also be reduced.
Folate deficiency and B12 deficiency produces hyperhomocysteinaemia. This increases the chances of ischaemic lesions in brain and elsewhere.[20] In most parts of the world, folate is used to lower homocysteine but there is a suspicion that in our country, with its vegetarian population, B12 deficiency may be the more important cause. World over, B12, folate and to a lesser extent, pyridoxine deficiency are the most important causes of hyperhomocysteinaemia, which may be a more important risk factor for arterial occlusion than hypercholesterolaemia.

MRI finding in B12 and folate deficiency
Recently it has been realized that the demyelination produced by B12 deficiency can be recognised on MRI, especially in the cervical and dorsal region, and it looks much like the demyelination of multiple sclerosis. The lesion can be shown to be posteriorly located on the axial scans (posterior colunms). Weeks et al[20] described an inverted V of demyelination to involve the column of Burdach bilaterally. In more severe cases, the lesions may be seen in the brain stem and cerebellum as well.[21] As mentioned before, cases with deficiency in neonatal period will show cortical and cerebellar atrophy and defective myelination which is reported to regress with treatment.[13],[14]
B12 and folate deficiency in India is much more common and it may be present without any haematologic abnormality. Thus, blood levels of B12, folate and homocysteine should be sought frequently. The common cause of B12 and folate deficiency in our country is nutritional (especially for B12), malabsorption and gastric surgery. Drug induced deficiency produced by anticonvulsants, nitrous oxide and antifolic agents is also not uncommon.

The bulwark of treatment is injectable B12 while folate may be given orally. In neurologic cases, B12 is best given parentally at 1000 µ gm per day to start with, then on alternate days, and maintenance of 1000 µ gm once a month. Recently it has been shown that oral use of large doses upto 1000 µ gm can also be used in most cases, even with B12 deficiency. The patient will improve gradually.

  »   References Top

1.Dastur DK, Quaddros EV, Wadia NH et al : Effect of vegetarianism and smoking on vitamin B12, thiocyanate, and folate levels in the blood of normal subjects. BMJ 1972; 3 : 260-264.   Back to cited text no. 1    
2.Jeejeebhoy KN, Wadia NH, Desai HG et al : Role of vitamin B12 deficiency in tropical nutritional neuromyelopathy. J Neurol Neurosurg Psychiatry1967; 30 : 7.   Back to cited text no. 2    
3.Wadia RS, Kharche M, Udar M et al : Vitamin B12 and folate deficiency in a hospital population. Annals of Indian Academy of Neurology (in press) 2000.   Back to cited text no. 3    
4.Allen RH, Stabler SP, Savage DG et al : Diagnosis of cobalamin deficiency, usefulness of serum methylmalonic acid and total homocysteine concentrations. Am J Haemat 1990; 34 : 90.   Back to cited text no. 4    
5.Yao Y, Yao SL, Yao SS et al : Prevalence of vitamin B12 deficiency among geriatrial out patients. J Fam Pract1992; 35 : 524-528.   Back to cited text no. 5    
6.Sumner AE, Chin MM, Abraham JL et al : Elevated methylmalonic acid and total homocysteine levels show high prevalence of vitamin B12 deficiency after gastric surgery. Ann Intern Med 1996; 124 : 469-476.   Back to cited text no. 6    
7.Savage DG, Lindenbaum J, Stabler SP et al : Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med 1994; 96 : 239-246.   Back to cited text no. 7    
8.Carmel R, Green R, Jacobsen DW et al : Neutrophil nuclear segmentation in mild cobalamin deficiency : Relation to metabolic tests of cobalamin status and observations on ethnic differences in neutrophil segmentation. Ann J Clin Pathol 1996; 106 : 57-63.   Back to cited text no. 8    
9.Olgiati ML, Mombelli G : Megaloblastic anemia : 30 cases in district hospital. Schweiz Med Wochenschr 1995; 125 : 113-119.   Back to cited text no. 9    
10.Shorvon SD, Carney MWP, Chanarin I et al : The neuropsychiatry of megaloblastic anaemia. BMJ 1980; 281 : 1036-1038.   Back to cited text no. 10    
11.Lovblad K, Ramelli G, Remonda L et al : Retardation of myelination due to dietary vitamin B12 deficiency : cranial MRI findings. Pediatr Radiol 1997; 27 : 155-158.   Back to cited text no. 11    
12.Von Scheuck U, Bender Gotze C, Koletsko B et al : Persistence of neurologic damage induced by dietary vitamin B12 deficiency in infancy. Arch Dis Child 1997; 77 : 137-139.   Back to cited text no. 12    
13.Jadhav M, Webb JKG, Vaishnava S et al : Vitamin B12 deficiency in Indian infants. A clinical syndrome. Lancet 1962; 2 : 903-906.   Back to cited text no. 13    
14.Garewal G, Narang A, Das KC : Infantile tremor syndrome : A vitamin B12 deficiency in infants. J Trop Pediat 1988; 34 : 174-178.   Back to cited text no. 14    
15.Agarwal SP, Katiyar G : Infantile tremor syndrome. Pediat Clin India 1972; 7 : 203-208.   Back to cited text no. 15    
16.Bajpai BC, Misra PK, Tandon et al : Serum vitamin B12 in infantile tremor syndrome. Indian J Med Res1968; 56 : 1398-1405.   Back to cited text no. 16    
17.Benito Leon J, Porta Etessam J : Shaky leg syndrome in vitamin B12 deficiency. N Engl J Med 2000; 342 : 981.   Back to cited text no. 17    
18.Berry RJ, Zhu Li, Erickson D et al : Prevention of neural tube defects with folic acid in China. N Engl J Med 1999; 341 : 1485-1490.   Back to cited text no. 18    
19.Lefsum H, Ueland PM, Nygard O et al : Homocysteine and cardiovascular disease. Ann Red Med1998; 49 : 31-62.   Back to cited text no. 19    
20.Weeks RA, Valentine A, Savy L et al : Mild tactile disturbance and a Lhermitte phenomenon in a middle aged man. Arch Neurol 1999; 56 : 1515-1516.   Back to cited text no. 20    
21.Katsaros K, Glocker FX, Hemmer B et al : MRI of spinal cord and brain lesions in subacute combined degeneration. 1998; 40 : 716-719.   Back to cited text no. 21    

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