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Peripheral nerve involvement in pernicious anaemia
Journal of the Neurological Sciences, 1980, 45:367-371
367
© Elsevier/North-Holland Biomedical Press
P E R I P H E R A L NERVE I N V O L V E M E N T IN PERNICIOUS A N A E M I A
M. COX-KLAZINGA and L. J. ENDTZ Department of Neurology, Municipal Hospitals, The Hague The Netherlands)
(Received 8 October, 1979) (Accepted 30 October, 1979)
SUMMARY Impairment of nervous function and thiamine metabolism were studied in 40 patients suffering from pernicious anaemia, 20 of whom had not been treated and the other 20 were on hydroxocobalamin therapy. Of the untreated patients 13 (65 ~ ) showed signs of peripheral nerve dysfunction with reduced conduction velocities, as compared with only 1 (5 ~ ) of the treated patients. Reduced blood thiamine levels were found in 16 of the untreated patients (80~), 10 (60~) of whom showed biochemical signs of thiamine deficiency. In the treated group, 7 patients (30 ~ ) had reduced blood thiamine levels. Thus, peripheral nerve involvement in pernicious anaemia is much more frequent than would be expected from the literature, and thiamine deficiency was present in the majority of these cases.
INTRODUCTION Subacute combined degeneration of the cord is classically associated with pernicious anaemia (PA) in a number of cases, but peripheral nerve involvement is considered to be rare in PA (Victor and Lear 1956; Victor 1975). The symptoms in these cases vary from paraesthesia to muscle atrophy and impairment of sensibility in a stocking distribution. Hornabrook and Marks (1960), who described 4 cases of peripheral neuropathy in PA, obtained evidence of thiamine depletion with the Friedeman and Haugen technique for pyruvate determination. The pyruvate levels in these patients became normal after thiamine therapy, but the clinical symptoms only improved after supplementation with vitamin BlZ. Since 1960, new techniques for the determination of thiamine depletion have been developed and the disturbance of peripheral nerve function has been assessed by Correspondence to L. J. End tz, M. D., Department of Neurology, Municipal Hospitals of the Hague, Leyweg 275, The Hague, The Netherlands.
368 electrophysiological methods in a number of cases (Mayer 1965). The aim of the present study was to gain information on the occurrence of peripheral nerve involvement in PA and to investigate the role of thiamine depletion in these cases. MATERIAL AND METHODS The investigations were carried out between November, 1974, and April, 1979. Forty patients suffering from PA were studied. Twenty of these patients were seen before they received any treatment, and the other 20 were being treated with hydroxocobalamin. All of them had initially been referred to the departments of hematology and internal medicine of our hospital. Patients with other disease processes known to affect peripheral nerves, such as diabetes mellitus, chronic alcoholism, and a primary nutritional deficiency, were excluded. The patients were subjected to a thorough neurological examination, a vibration test, electrophysiological examination, haematological analysis, and thiamine, transketolase, and pyruvate determinations. The following criteria were applied for the diagnosis of PA: megaloblastic erythropoiesis with a low serum level of vitamin B12 determined in a microbiological assay using Lactobacillus leichmannii (Spray 1955) or a radio immuno assay with a commercial kit (Phadebas B12 test); loss of acid secretion from the gastric mucosa (st;mulation with histamine or pentagastrine); abnormal vitamin B12 absorption assessed by the urinary excretion method (Schilling test) and response to vitamin BI~ therapy; and normal or increased serum folate levels. The perception of vibration on the medial malleoli and on the great toes was tested in two ways: with an ordinary tuning fork and by a vibration test using an electromagnetically operated vibrator (biothesiometer). To measure motor conduction velocity in the peroneal nerve, evoked potentials were obtained from the extensor digiti brevis muscle after stimulation at a proximal and distal site along the nerve. To calculate the conduction velocity, the distance between the stimulating cathodes was divided by the difference between the two latencies. Serum thiamine was measured microbiologically, using Lactobacillus viridescem as test organism (Deibel et al. 1957; Hankin and Squires 1960). Transketolase and thiamine pyrophosphate (TPP) factor were determined enzymatically according to Schouten et al. (1964). A TPP factor of 25 ~ or more was considered abnormal, Pyruvate determination took place with the enzymatic method employing N A D H ~Marbach and Weil 1967). Blood samples were taken under fasting conditions and 60 and 90 min after glucose loading. RESULTS Of the 20 patients investigated before any treatment was started (group A), 14 were male and 6 female, the age ranging from 50 to 82 years. The 20 patients in the treated group (group B) included 11 males and 9 females aged between 50 and 79 years. The relevant neurological symptoms and signs found in the untreated patients
369 ,~...,~
....
~, . . . .
~ ....
rleutop~ c t I ~ naur,opatI'~ E.M.G. th~
r,~
l:V.m~c ac~l a b r ~
GROUPA
,. ~ , , / ~ . . . ?
I~
....
,p . . . .
~, . . . .
2o
and/ot Fig. 1. Occurrence of peripheral nerve involvement and thiamine deficiencyin pernicious anaemia: group A = untreated; group B = hydroxocobalamin therapy.
are shown in Table 1. In general, it may be said that in this group the somatoneurological signs and symptoms were mild. Impaired vibration sense was by far the most common symptom and was seen in all 20 untreated patients (100 ~). In the treated patients (group B) we found on the whole few neurological disturbances. Only in two cases was an impaired vibration sense found. One patient complained of weakness in both legs; this could not be made objective however. Electromyography disclosed signs of peripheral nerve dysfunction in 13 of the 20 patients in group A. Conduction velocities of the peroneal nerves were significantly reduced in these cases. Only one patient in group B showed reduced conduction velocities. Significantly reduced blood thiamine levels were found in 16 patients in group A. In 10 of these patients the depressed thiamine activity was also indicated by either low transketolase activity and high TPP factor or high pyruvate levels after glucose loading. In group B reduced thiamine levels were present in 7 patients, with low transketolase activity and high TPP factor or high pyruvate levels in 3 of them. Figure 1 shows the occurrence of reduced blood thiamine levels and peripheral nerve involvement in both groups.
TABLE 1 CLINICAL NEUROLOGICAL SIGNS AND SYMPTOMS IN 20 UNTREATED PATIENTS SUFFERING FROM PERNICIOUS ANAEMIA (GROUP A) Paraesthesia Hypaesthesia and dysaesthesia Pain Dizziness, unsteady gait Diminished deep reflexes Distal weakness without pyramidal deficit Impaired vibration sense
8 4 2 4 4 2 20
370 DISCUSSION Involvement of the spinal cord is well known in patients with PA and the defect has been clinically related to vitamin Blz deficiency. The existence of a peripheral neuropathy in these patients was first explicitly stated by Van der Scheer and Koek (1938). Unlike the myelopathy in PA, little is known about the peripheral nerve involvement, which is generally thought to be rare (Victor and Lear 1956; Pant et al. 1968; Victor 1975). In contrast with this opinion, Pallis and Lewis stated in 1974 that peripheral neuropathy is common in patients with vitamin BI~ deficiency who exhibit neurological symptoms or signs and supported this statement by clinical, pathological, and electrophysiological evidence. As stated by these authors : "Vitamin Baz deficiency is usually recognized early by haematologists, gastroenterologists, or general physicians. Appropriate therapy is prescribed before neurological complications have had time to occur. When neurological symptoms or signs develop, they are seldom investigated by modern techniques of nerve biopsy or electromyography, bejbre specific therapy is instituted" (author's italics). In the course of their study on lateral popliteal nerve action potentials in man, Gilliatt et al. (11961) found disturbances of peripheral nerve function in 4 patients with pernicious anaemia and Mayer (1965) determined nerve conduction velocities in the peripheral nerves of patients with PA. The present series comprised 40 cases of PA. Twenty of these patients were studied before institution of treatment and 20 were being treated with hydroxocobalamin. The majority of the first group (65 ~ ) showed defective nerve conduction affecting the velocity in the peroneal nerves. In the second group peripheral nerve dysfunction was only found in 5 ~. It must therefore be concluded that peripheral nerve involvement in the initial stage of PA is far more frequent than the literature suggests. Cayer et al. (1946) described a reduction in the levels of thiamine, nicotinic acid, and riboflavin in PA. Although their series was small, the results cannot be ignored. The metabolic mechanisms underlying vitamin Blz deficiency have been discussed by Reynolds (1976) but details of the biochemical role of vitamin B12 and its interaction with other vitamins are still obscure. It is conceivable that the accumulation of pyruvic acid in vitamin Blz deficiency is due to impaired pyruvate-oxidase activity. In our series 80 % of the untreated group showed significantly reduced blood thiamine levels, and 60° k of these patients had elevated blood pyruvate levels or low transketolase activity. Thus, in the majority of these cases of peripheral neuropathy in untreated PA a deficiency of both vitamin B12 and thiamine was present. In contrast, peripheral nerve dysfunction was found in few of the patients receiving hydroxocobalamin treatment, although even in these patients, with or without neuropathy, signs of thiamine deficiency were present in a number of cases. On the basis of these findings, the addition of thiamine to the hydroxocobalamin treatment might be advisable in at least some of the patients. ACKNOWLEDGEMENTS The authors thank Dr. H. Kerkhofs for his assistance in evaluation of the haematological data and Dr. C. Goor for his expert neurophysiological help.
371 REFERENCES Cayer, D., J. M. Rul~n and W. A. Perlzweig (1946) Vitamin levels in pernicious anemia, Amer. J. med. Sci., 212: 179-184. Deibel, R. H., J. B. Evans and C. F. Niven (1957) Microbiological assay for thiamine using Lactobacillus viridescens, J. Bact. (Bait.), 74: 818-821. Gilliat, R. W., H. V. G o o d m a n and R. E. Willison (1961) The recording of lateral popliteal nerve action potentials in man, J. Neurol. Neurosurg. Psychiat., 24: 305-318. Hankin, L. and S. Squires (1960) A n evaluation of the Lactobacillus viridescens assay for thiamine, Appl. Microbiol., 8:209-211. Hornabrook, R. W. and V. Marks (1960) The effect of vitamin B1 therapy on blood pyruvate levels in subacute combined degeneration of the cord, Lancet, 2 : 893-895. Marbach, E. P. and M. H. Weil (1967) Rapid enzymatic measurement of bloodlactate and pyruvate - Use and significance of metaphosphoric acid as a common precipitant, Clin. Chem., 13 : 314-325. Mayer, R. F. (1965) Peripheral nerve function in vitamin B12 deficiency, Arch. Neurol. (Chic.), 13: 355-363. Pallis, C. A. and P. D. Lewis (1974) The Neurology of Gastrointestinal Disease, W. B. Saunders, London. Pant, S. H., A. K. Asbury and E. P. Richardson (1968) The myelopathy of pernicious anemia - - A neuropathological reappraisal, Acta neurol, scand., 44: Suppl. 35. Reynolds, E. H. (1976) The neurology of vitamin B12 deficiency - - Metabolic mechanisms, Lancet, 2: 832-833. Schouten, H., L. W. Statius van Eps and A. M. Struyker Boudier (1964) Transketolase in blood, Clin. chim. Acta, 10: 474476. Spray, G. H. (1955) Improved method for rapid estimation of vitamin B~a in serum, Clin. Sci., 14:661667. Van der Scheer, W. N. and H. C. Koek (1938) Peripheral nerve lesions in cases of pernicious anemia, Acta psychiat, neural., 13: 61-92. Victor, M. (1975) Neuropathy of pernicious anemia (vitamin B12 deficiency). In: P. J. Dyck, P. K. Thomas and E. H. Lambert (Eds.), Peripheral Neuropathy, Vol. 2, W. B. Saunders, Philadelphia, PA, pp. 1054-1056. Victor, M. and A. A. Lear (1956) Subacute combined degeneration of the spinal cord, Amer. J. Med., 20: 896-911.
367
© Elsevier/North-Holland Biomedical Press
P E R I P H E R A L NERVE I N V O L V E M E N T IN PERNICIOUS A N A E M I A
M. COX-KLAZINGA and L. J. ENDTZ Department of Neurology, Municipal Hospitals, The Hague The Netherlands)
(Received 8 October, 1979) (Accepted 30 October, 1979)
SUMMARY Impairment of nervous function and thiamine metabolism were studied in 40 patients suffering from pernicious anaemia, 20 of whom had not been treated and the other 20 were on hydroxocobalamin therapy. Of the untreated patients 13 (65 ~ ) showed signs of peripheral nerve dysfunction with reduced conduction velocities, as compared with only 1 (5 ~ ) of the treated patients. Reduced blood thiamine levels were found in 16 of the untreated patients (80~), 10 (60~) of whom showed biochemical signs of thiamine deficiency. In the treated group, 7 patients (30 ~ ) had reduced blood thiamine levels. Thus, peripheral nerve involvement in pernicious anaemia is much more frequent than would be expected from the literature, and thiamine deficiency was present in the majority of these cases.
INTRODUCTION Subacute combined degeneration of the cord is classically associated with pernicious anaemia (PA) in a number of cases, but peripheral nerve involvement is considered to be rare in PA (Victor and Lear 1956; Victor 1975). The symptoms in these cases vary from paraesthesia to muscle atrophy and impairment of sensibility in a stocking distribution. Hornabrook and Marks (1960), who described 4 cases of peripheral neuropathy in PA, obtained evidence of thiamine depletion with the Friedeman and Haugen technique for pyruvate determination. The pyruvate levels in these patients became normal after thiamine therapy, but the clinical symptoms only improved after supplementation with vitamin BlZ. Since 1960, new techniques for the determination of thiamine depletion have been developed and the disturbance of peripheral nerve function has been assessed by Correspondence to L. J. End tz, M. D., Department of Neurology, Municipal Hospitals of the Hague, Leyweg 275, The Hague, The Netherlands.
368 electrophysiological methods in a number of cases (Mayer 1965). The aim of the present study was to gain information on the occurrence of peripheral nerve involvement in PA and to investigate the role of thiamine depletion in these cases. MATERIAL AND METHODS The investigations were carried out between November, 1974, and April, 1979. Forty patients suffering from PA were studied. Twenty of these patients were seen before they received any treatment, and the other 20 were being treated with hydroxocobalamin. All of them had initially been referred to the departments of hematology and internal medicine of our hospital. Patients with other disease processes known to affect peripheral nerves, such as diabetes mellitus, chronic alcoholism, and a primary nutritional deficiency, were excluded. The patients were subjected to a thorough neurological examination, a vibration test, electrophysiological examination, haematological analysis, and thiamine, transketolase, and pyruvate determinations. The following criteria were applied for the diagnosis of PA: megaloblastic erythropoiesis with a low serum level of vitamin B12 determined in a microbiological assay using Lactobacillus leichmannii (Spray 1955) or a radio immuno assay with a commercial kit (Phadebas B12 test); loss of acid secretion from the gastric mucosa (st;mulation with histamine or pentagastrine); abnormal vitamin B12 absorption assessed by the urinary excretion method (Schilling test) and response to vitamin BI~ therapy; and normal or increased serum folate levels. The perception of vibration on the medial malleoli and on the great toes was tested in two ways: with an ordinary tuning fork and by a vibration test using an electromagnetically operated vibrator (biothesiometer). To measure motor conduction velocity in the peroneal nerve, evoked potentials were obtained from the extensor digiti brevis muscle after stimulation at a proximal and distal site along the nerve. To calculate the conduction velocity, the distance between the stimulating cathodes was divided by the difference between the two latencies. Serum thiamine was measured microbiologically, using Lactobacillus viridescem as test organism (Deibel et al. 1957; Hankin and Squires 1960). Transketolase and thiamine pyrophosphate (TPP) factor were determined enzymatically according to Schouten et al. (1964). A TPP factor of 25 ~ or more was considered abnormal, Pyruvate determination took place with the enzymatic method employing N A D H ~Marbach and Weil 1967). Blood samples were taken under fasting conditions and 60 and 90 min after glucose loading. RESULTS Of the 20 patients investigated before any treatment was started (group A), 14 were male and 6 female, the age ranging from 50 to 82 years. The 20 patients in the treated group (group B) included 11 males and 9 females aged between 50 and 79 years. The relevant neurological symptoms and signs found in the untreated patients
369 ,~...,~
....
~, . . . .
~ ....
rleutop~ c t I ~ naur,opatI'~ E.M.G. th~
r,~
l:V.m~c ac~l a b r ~
GROUPA
,. ~ , , / ~ . . . ?
I~
....
,p . . . .
~, . . . .
2o
and/ot Fig. 1. Occurrence of peripheral nerve involvement and thiamine deficiencyin pernicious anaemia: group A = untreated; group B = hydroxocobalamin therapy.
are shown in Table 1. In general, it may be said that in this group the somatoneurological signs and symptoms were mild. Impaired vibration sense was by far the most common symptom and was seen in all 20 untreated patients (100 ~). In the treated patients (group B) we found on the whole few neurological disturbances. Only in two cases was an impaired vibration sense found. One patient complained of weakness in both legs; this could not be made objective however. Electromyography disclosed signs of peripheral nerve dysfunction in 13 of the 20 patients in group A. Conduction velocities of the peroneal nerves were significantly reduced in these cases. Only one patient in group B showed reduced conduction velocities. Significantly reduced blood thiamine levels were found in 16 patients in group A. In 10 of these patients the depressed thiamine activity was also indicated by either low transketolase activity and high TPP factor or high pyruvate levels after glucose loading. In group B reduced thiamine levels were present in 7 patients, with low transketolase activity and high TPP factor or high pyruvate levels in 3 of them. Figure 1 shows the occurrence of reduced blood thiamine levels and peripheral nerve involvement in both groups.
TABLE 1 CLINICAL NEUROLOGICAL SIGNS AND SYMPTOMS IN 20 UNTREATED PATIENTS SUFFERING FROM PERNICIOUS ANAEMIA (GROUP A) Paraesthesia Hypaesthesia and dysaesthesia Pain Dizziness, unsteady gait Diminished deep reflexes Distal weakness without pyramidal deficit Impaired vibration sense
8 4 2 4 4 2 20
370 DISCUSSION Involvement of the spinal cord is well known in patients with PA and the defect has been clinically related to vitamin Blz deficiency. The existence of a peripheral neuropathy in these patients was first explicitly stated by Van der Scheer and Koek (1938). Unlike the myelopathy in PA, little is known about the peripheral nerve involvement, which is generally thought to be rare (Victor and Lear 1956; Pant et al. 1968; Victor 1975). In contrast with this opinion, Pallis and Lewis stated in 1974 that peripheral neuropathy is common in patients with vitamin BI~ deficiency who exhibit neurological symptoms or signs and supported this statement by clinical, pathological, and electrophysiological evidence. As stated by these authors : "Vitamin Baz deficiency is usually recognized early by haematologists, gastroenterologists, or general physicians. Appropriate therapy is prescribed before neurological complications have had time to occur. When neurological symptoms or signs develop, they are seldom investigated by modern techniques of nerve biopsy or electromyography, bejbre specific therapy is instituted" (author's italics). In the course of their study on lateral popliteal nerve action potentials in man, Gilliatt et al. (11961) found disturbances of peripheral nerve function in 4 patients with pernicious anaemia and Mayer (1965) determined nerve conduction velocities in the peripheral nerves of patients with PA. The present series comprised 40 cases of PA. Twenty of these patients were studied before institution of treatment and 20 were being treated with hydroxocobalamin. The majority of the first group (65 ~ ) showed defective nerve conduction affecting the velocity in the peroneal nerves. In the second group peripheral nerve dysfunction was only found in 5 ~. It must therefore be concluded that peripheral nerve involvement in the initial stage of PA is far more frequent than the literature suggests. Cayer et al. (1946) described a reduction in the levels of thiamine, nicotinic acid, and riboflavin in PA. Although their series was small, the results cannot be ignored. The metabolic mechanisms underlying vitamin Blz deficiency have been discussed by Reynolds (1976) but details of the biochemical role of vitamin B12 and its interaction with other vitamins are still obscure. It is conceivable that the accumulation of pyruvic acid in vitamin Blz deficiency is due to impaired pyruvate-oxidase activity. In our series 80 % of the untreated group showed significantly reduced blood thiamine levels, and 60° k of these patients had elevated blood pyruvate levels or low transketolase activity. Thus, in the majority of these cases of peripheral neuropathy in untreated PA a deficiency of both vitamin B12 and thiamine was present. In contrast, peripheral nerve dysfunction was found in few of the patients receiving hydroxocobalamin treatment, although even in these patients, with or without neuropathy, signs of thiamine deficiency were present in a number of cases. On the basis of these findings, the addition of thiamine to the hydroxocobalamin treatment might be advisable in at least some of the patients. ACKNOWLEDGEMENTS The authors thank Dr. H. Kerkhofs for his assistance in evaluation of the haematological data and Dr. C. Goor for his expert neurophysiological help.
371 REFERENCES Cayer, D., J. M. Rul~n and W. A. Perlzweig (1946) Vitamin levels in pernicious anemia, Amer. J. med. Sci., 212: 179-184. Deibel, R. H., J. B. Evans and C. F. Niven (1957) Microbiological assay for thiamine using Lactobacillus viridescens, J. Bact. (Bait.), 74: 818-821. Gilliat, R. W., H. V. G o o d m a n and R. E. Willison (1961) The recording of lateral popliteal nerve action potentials in man, J. Neurol. Neurosurg. Psychiat., 24: 305-318. Hankin, L. and S. Squires (1960) A n evaluation of the Lactobacillus viridescens assay for thiamine, Appl. Microbiol., 8:209-211. Hornabrook, R. W. and V. Marks (1960) The effect of vitamin B1 therapy on blood pyruvate levels in subacute combined degeneration of the cord, Lancet, 2 : 893-895. Marbach, E. P. and M. H. Weil (1967) Rapid enzymatic measurement of bloodlactate and pyruvate - Use and significance of metaphosphoric acid as a common precipitant, Clin. Chem., 13 : 314-325. Mayer, R. F. (1965) Peripheral nerve function in vitamin B12 deficiency, Arch. Neurol. (Chic.), 13: 355-363. Pallis, C. A. and P. D. Lewis (1974) The Neurology of Gastrointestinal Disease, W. B. Saunders, London. Pant, S. H., A. K. Asbury and E. P. Richardson (1968) The myelopathy of pernicious anemia - - A neuropathological reappraisal, Acta neurol, scand., 44: Suppl. 35. Reynolds, E. H. (1976) The neurology of vitamin B12 deficiency - - Metabolic mechanisms, Lancet, 2: 832-833. Schouten, H., L. W. Statius van Eps and A. M. Struyker Boudier (1964) Transketolase in blood, Clin. chim. Acta, 10: 474476. Spray, G. H. (1955) Improved method for rapid estimation of vitamin B~a in serum, Clin. Sci., 14:661667. Van der Scheer, W. N. and H. C. Koek (1938) Peripheral nerve lesions in cases of pernicious anemia, Acta psychiat, neural., 13: 61-92. Victor, M. (1975) Neuropathy of pernicious anemia (vitamin B12 deficiency). In: P. J. Dyck, P. K. Thomas and E. H. Lambert (Eds.), Peripheral Neuropathy, Vol. 2, W. B. Saunders, Philadelphia, PA, pp. 1054-1056. Victor, M. and A. A. Lear (1956) Subacute combined degeneration of the spinal cord, Amer. J. Med., 20: 896-911.