Journal of
J. Neurol. 214, 183--193 (1977)
Neurology © by Springer-Verlag 1977
Peripheral Neuropathy with Vitamin B12 Deficiency M. C. Kayser-Gatchalian and B. NeundSrfer Neurological Hospital of the Universityof Heidelberg, KlinikumMannheim (Director: Prof. Dr. O. Hallen), Theodor-Kutzer-Ufer, D-6800 Mannheim, Federal Republic of Germany
Summary. Seven patients with neuropathy associated with vitamin BI2 deficiency are reported. Four of them had other signs of malabsorption aside from the abnormal Schilling test. The neuropathy was diagnosed on the basis of the whole clinical picture and the neurophysiological findings. The pathogenesis of the peripheral nerve disease is discussed in the light of the evidence in the literature. Key words: Neuropathy - Vitamin B12 - Vitamin deficiency - Malabsorption. Zusammenfassung. Es wird tiber 7 Patienten mit einer Neuropathie bei gesicherter Vitamin B]2 Resorptionsst6rung berichtet. Bei 4 Patienten wurden andere Anzeichen einer Malabsorption neben dem pathologischen Schilling Test festgestellt. Die Neuropathie wird aus dem gesamten klinischen Bild und den neurophysiologischen Befunden diagnostiziert. Die Pathogenese der peripheren Nervensch~idigung wird anhand der Literatur diskutiert.
The components of the vitamin B complex are generally considered to be "neurotropic" vitamins so that it has become an injudicious habit to prescribe the vitamin B complex for all possible disorders of the peripheral nervous system. In reality only a small number of neuropathies have been demonstrated to be due to a deficiency of a vitamin B fraction or of the whole B complex. Hence, by insufficient nutritional intake vitamin B~ deficiency, Beriberi, gives rise to polyneuropathy with symmetrical sensorimotor symptoms (Dumont, 1958; Schretzenmayer, 1938, 1941). Deficiency of several fractions of the vitamin B complex is the cause of the so-called "burning-feet" disease which was often observed in Madrid during the famine of the Spanish Civil War (Peraita, 1941, 1946) and in the internment camps in the Far East during World War II (Clarke and Sneddon, 1946; Clarke and Sircus, 1952; Cruickshank, 1946; Denny-Brown, 1947; Miller-Fisher, 1955; Simpson, 1946; Smith et al., 1951). This was a polyneuropathy mainly of the symmetrical sensory type with extremely tormenting burning pains in the feet with
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M.C. Kayser-Gatchalian and B. Neundtirfer
n o c t u r n a l exacerbations. The patients suffered f r o m paraesthesias as well as hypersensitivity to touch and pain in the distal parts of the lower extremities. Vitamin B 6 deficiency is supposed to play a decisive role in the occurrence of a p o l y n e u r o p a t h y during I N H therapy which is initially symmetrical sensory and in its later course becoming sensorimotor. This is attributed to an interference by I N H in the pyridoxine metabolism (Klinghardt, 1961). A l t h o u g h earlier authors had referred to the occurrence of p o l y n e u r o p a t h y with vitamin B l2 deficiency (Bielschowski, 1901; Dynes and Norcross, 1943; Greenfield and Carmichael, 1953; H a m i l t o n and Nixon, 1921; Henneberg, 1899, 1904; McAlpine, 1929)relatively few studies concerning this problem have been reported in recent years (Aita, 1972; Bischoff et al., 1975; E r b s l r h and Abel, 1970; Mayer, 1965; Pallis and Lewis, 1974; Spatz et al., 1976; Werner and Mortillaro, 1972). W h e n special methods of investigation such as E M G and E N G are not employed, the affection of the peripheral nerves is overlooked because its s y m p t o m s are disguised by the frequently c o n c o m i t a n t funicular myelosis. We t h o u g h t it worthwhile to report seven cases to draw attention to this disorder, although we do not intend go as far as Pallis and Lewis (1974), w h o maintain that the n e u r o p a t h y is the c o m m o n e s t complication of vitamin BI2 deficiency.
Material
Seven patients (3 females and 4 males) with vitamin B~2 deficiency, who showed pathological results in the Schilling test, are described. Some of them have further evidence of malabsorption in the Xylose test and in the gastroduodenai biopsy data. The results of the electromyographic and conduction velocity studies in each patient are reported.
Case t. S.D., Female, 62 Years Three months prior to admission the patient suffered from loss of appetite, easy fatigability and loss of weight and for 14 days there was increasing inability to walk. On neurological examination the deep reflexes of the upper and lower extremities were absent, vibration sense was impaired. The superficial sensation was intact. The pyramidal tract signs were negative. Blood count: RBC= 1.09 mill/ram 3, WBC = 2600/mm 3, Reticulocytes = 180/00,Hemoglobin = 4.7 g%, Hematocrit = 14%, MCH = 41 pg, MCV = 128 g.3. Schillitig test: pathological. Schilling test with intrinsic factor: normal. Gastroscopy: distinct signs of mucosal atrophy and moderate gastritis. Histology: chronic atrophic gastritis. Gastric analysis: achlorhydia. Sternal puncture: megaloblastic anaemia. EMG: no denervation activity. Conduction velocity (motor): fibular nerve: 38 m/s; posterior tibial nerve: 40 m/s.
Case 2. R.H., Female, 30 Years Six weeks prior to admission numbness and tingling sensations in the toes were noticed by the patient. She developed pains in the legs and progressive weakness of the lower extremities. There was atrophy of the calf muscles.
Peripheral Neuropathy with Vitamin B~2 Deficiency
185
On neurological examination we found atrophy of the foot and lower leg muscles, distally accentuated paresis of the lower extremities, absent deep reflexes in the legs although the tendon reflexes of the arms were very active. The pyramidal signs were negative. Vibration sense was severely impaired at the tibial tuberosity, as well as the position sense in the toes. Blood count: RBC = 3.89 m i l l / m m 3, WBC = 5~600/mm 3, Reticulocytes = 30o/00;Hematocrit = 42%, M C H = 35 pg, M C V = 108 tt 3. Schilling test: pathological. Schilling test with intrinsic factor: normal. Xylose test: normal. Gastric analysis: not performed. EMG: fibrillations and positive sharp waves in more than two places in the m. extensor digitorum brevis and m. flexor hallucis brevis of the right side. Conduction velocity (motor): fibular nerve: 55 m/s; posterior tibial nerve: 42 m/s.
Case 3. R.H., Female, 65 Years Pernicious anaemia was diagnosed in 1945. Since that time the patient could not walk straight at night. She had weakness of the legs and pins and needles sensations in the fingers and toes. Since J a n u a r y 1970 she could no longer walk up the stairs and she had tingling sensations in the fingers up to the lower arms as well as in the feet. The neurological examination revealed increased muscular tonus of the upper and lower extremities, mild, distally accentuated paresis of the legs, very active deep tendon reflexes, hypaesthesia and hypalgesia in the lower legs with stocking distribution and severe disturbance of deep sensation in the legs. Blood count: RBC = 3.66 mill/mm3, WBC = 3800/mm 3, Reticulocytes = 80/00, Hemoglobin = 12.3g%, HbE = 33 ~7. Schilling test: not performed. Xylose test: not performed. Sternal puncture in 1964: pernicious anaemia. Gastric analysis: anacidity. EMG: no denervation activity. Conduction velocity (motor): fibular nerve: 38 m/s; posterior tibial nerve: 36 m/s.
Case 4. H.F., Male, 61 Years For one year prior to admission the patient had been having burning paraesthesias in the buttocks and the posterior part of the thighs on sitting. He also felt burning sensations in the soles of the feet and in the toes. A few months before admission he noticed a feeling of weakness of the lower extremities. On neurological examination, we found slight weakness of the legs with distal accentuation, increased deep reflexes in both arms and legs, negative pyramidal tract signs, hypaesthesia and hypalgesia in the lower legs of stocking distribution, impaired vibration sense at the tibial tuberosity. Blood count: RBC = 4.72 mill/mm 3, WBC = 6200/mm 3, Hemoglobin = 15.6 g %, M C H = 33 pg, M C V = 95 V~3, Hematokrit = 45%. Schilling test: pathological. Schilling test with intrinsic factor: normal. Xylose test: slightly pathological. Gastric analysis: not performed. Gastroduodenoscopy: patchy atrophic gastritis. EMG: massive fibrillations and positive sharp waves as well as mixed pattern on maximal innervation in the m. extensor digitorum brevis and m. flexor hallucis brevis. Conduction velocity (motor): fibular nerve: 52 m/s; posterior tibial nerve: 42 m/s. Conduction velocity (sensory): sural nerve: 57 m/s.
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M.C. Kayser-Gatchalian and B. Neund6rfer
Table 1, Clinical and laboratory data of the 7 patients
Case 1
Case 2
Case 3
Case 4
65 yrs
61 yrs
Age
62 yrs
30 yrs
Symptoms
progressive walking difficulty
numbness and tingling weakness of the legs sensations in the toes, paraesthesia in toes, weakness and pains in fingers, feet and arms the legs
Findings
absent deep re- distally accentuated flexes, impaired paresis and atrophy of vibration sense legs, deep reflexes of legs absent, impaired deep sensation
Xylose test Schilling test
pathological
Schilling test normal with intrinsic factor
hyperactive reflexes impaired superficial and deep sensation
normal
slightly pathological
pathological
pathological
normal
normal
Gastric analysis achlorhydia Gastroscopy
distally accentuated leg paresis, hyperactive deep reflexes, impaired superficial and deep sensation
burning sensations in buttocks and thighs, burning feet,weakness of the legs
anacidity patchy atrophic gastritis
chronic atrophic gastritis
Sternal puncture megaloblastic anaemia
pernicious anaemia
Case 5. P. K., Male, 69 Years In 1956 the patient underwent a Billroth II resection. One year prior to admission he developed unsteadiness of gait and a few months later there was marked weakness of the legs. He often had muscular cramps ha the calf and thighs. The neurological examination revealed a generalized but distally accentuated muscular atrophy of the extremities. There was slight paresis. The deep reflexes were moderately active in the arms and hyperactive in the legs. The pyramidal signs were negative. The superficial sensation was intact while the deep sensation was severely impaired with loss of vibration sense in the lower extremities up to the anterior iliac spine. Position sense in the toes was lost. Blood count: RBC =3.27 mill/mm3, W B C = 3 2 0 0 / m m 3, Hemoglobin= 11.5 g%, Hematokrit = 31%, MCH = 35pg, MCV = 94 ~t3. Schilling test: pathological. Schilling test with intrinsic factor: pathological. Gastric analysis: pentagastrin refractory anacidity. Xylose test: pathological. EMG: fibrillations in the m. flexor hallucis brevis in more than two places; no pathological spontaneous activity in the m. extensor digitorum brevis. Conduction velocity (motor): fibular nerve: 36 m/s; posterior tibial nerve: 42 m/s.
Case 6. A. S., Male, 57 Years In 1951 the patient underwent a Billroth II resection. In 1975 he had iron deficiency anaemia. Ten days before admission he had increasing weakness in the legs so that he could not walk unaided at the time of admission. He had a feeling of numbness in both legs.
Peripheral Neuropathy with Vitamin B~2 Deficiency
187
Table 1 (continued) Case 5
Case 6
Case 7
Age
69 yrs
57 yrs
65 yrs
Symptoms
unsteadiness of gait, weak- progressive weakness of the paraesthesias in the toes, feet ness of the legs, cramps legs, numbness in both legs and fingers, progressive weakness of the toes and feet
Findings
distally accentuated muscle atrophy, hyperactive reflexes, impaired deep sensation
paresis of legs, atrophy of distally accentuated paresis of distal muscles, weak ankle legs, absent ankle reflex, imreflex, impaired vibration paired superficial and deep sense, from Th12--Li down- sensation wards hypalgesia/ hypaesthesia
Xylose test
pathological
pathological
pathological
Schilling test
pathological
pathological
pathological
Schilling test pathological with intrinsic factor
pathological
normal
Gastric analysis anacidity
Gastroscopy
normal basal secretion, on maximal stimulation with pentagastrin abnormal values chronic atrophic gastritis, atrophic gastritis nonspecific jejunitis, Billroth II resected stomach
Sternal puncture
The neurological examination revealed marked paresis of the lower extremities, atrophy of the distal muscles of the legs, hyperactive patellar reflexes, very weak ankle jerks, negative Babinski but positive Strumpell sign. From the level of the twelfth dorsal-first lumbar dermatome downwards there was hypalgesia and hypaesthesia. Vibration sense was totally lost in the lower extremities. Blood count: RBC = 3.4 mill/mm 3, WBC = 8200/mm 3, Hemoglobin = 11.9 g% Hematokrit = 38%, MCH = 35 pg, MCV = 112~. 3. Schilling test: pathological. Schilling test with intrinsic factor: pathological. Xylose test: pathological. Gastroscopy: BII resected stomach. Chronic atrophic corpus gastritis. Nonspecific jejunitis. EMG: fibrillations in the distal muscles of both feet and single oscillations on maximal innervation. Conduction velocity (motor): fibular nerve: 34.6 m/s; posterior tibial nerve: 36 m/s.
Case 7. A. M., Male, 65 Years For 3 years prior to admission paraesthesia~"as if the wind passes between the toes"--was felt. Later he had numbness of the feet and one year before admission progressive weakness of the big toes and the feet and unsteadiness of gait developed. On neurological examination we found severe paresis of the toe extensors and flexors as well as the foot extensors and flexors, moderately active deep reflexes but absent Achilles reflex.
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M. C. Kayser-Gatchalian and B. Neund6rfer
Table 2. Electrophysiological findings
Case no.
Denervation Motor CV activity fibular nerve
1
O
2 3 4 5 6 7
÷ O + ÷ ÷ +
38 m/s 55 m/s 38m/s 52m/s 36m/s 34.6 m/s no action potential
Motor CV posterior tibial nerve
Sensory CV sural nerve
40 m/s 42 m/s 36m/s 42 m/s 57 m/s 42m/s 36 m/s no action potential 18.3 m/s
There was hypalgesia and hypaesthesia of stocking distribution up to just above the ankles. Vibration sense and appreciation of passive toe movements were strongly impaired. Blood count: RBC =4.45 mill/mm 3, WBC= 7900 mm/3, Hemoglobin= 14.7 g%, Hematokrit = 46%, MCH = 33 pg, MCV = 103 ~t3. Schilling test: pathological. Schilling test with intrinsic factor: normal. Xylose test: pathological. Gastroscopy: chronic gastritis with beginning atrophy of the glandular bodies. Hyperlipidaemia Type IV Frederikson. Glucose tolerance test: non-diabetic curve. Gastric analysis: normal basal secretion and normacidity. On maximal stimulation with pentagastrin the values were way below normal. EMG: frequent fibrillations in almost all places in the distal muscles of both legs and single oscillations on maximal innervation. Conduction velocity (motor): on stimulating the fibular and the posterior tibial nerve, no action potential could be evoked. Conduction velocity (sensory): sural nerve, left: 18.3 m/s.
Discussion
It has l o n g been the subject o f c o n t r o v e r s y w h e t h e r the n e u r o l o g i c a l s y m p t o m s o f v i t a m i n B j2 deficiency a r e p u r e l y m y e l o p a t h i c o r p a r t l y n e u r o p a t h i c . W e find it a p t to review the evidence in o u r cases a n d in the literature available. Five o f o u r p a t i e n t s h a d paraesthesias. Collier (1925) w a r n e d against i n t e r p r e t i n g p e r i p h e r a l subjective sensations in a n a e m i c p a t i e n t s as being caused always by n e u r o l o g i c a l c h a n g e s since tingling a n d n u m b n e s s a r e c o m m o n in every variety o f a n a e m i a . G r i n k e r (1926) s h a r e d this o p i n i o n by e m p h a s i z i n g t h a t severe i r o n deficiency a n a e m i a m i g h t be a s s o c i a t e d with distal p a r a e s t h e s i a s t h a t s u b s i d e d as the a n a e m i a was corrected. O n the o t h e r hand, it is well k n o w n t h a t sensory s y m p t o m s can p r e c e d e the objective signs in n e u r o p a t h y . T o have s o m e c e r t a i n t y in the d i a g n o s i s f r o m the clinical s y m p t o m a t o l o g y , we c o n s i d e r e d for this r e p o r t only those p a t i e n t s with subjective c o m p l a i n t s a n d p h y s i c a l signs. A l l seven p a t i e n t s h a d bilateral, progressive w e a k n e s s o f the lower extremities. O n e x a m i n a t i o n t h e r e was d i s t a l l y a c c e n t u a t e d paresis o f the legs with loss o f deep
Peripheral Neuropathy with Vitamin B~2Deficiency
189
reflexes or of the ankle jerk except in three patients in whom the tendon reflexes were increased. Atrophy of the foot and leg muscles was found only distally or distally accentuated. The impaired superficial sensation in the periphery of the limbs was of stocking type. The patients with the hyperactive deep reflexes had this sensory disturbance. All patients had disturbance of vibration sense with or without other signs of impairment of deep sensation. In one patient there was hypaesthesia and hypalgesia from the level of Th~2--L~, which was thought to be due to an associated myelopathic involvement. The clinical picture in each patient, taken in its entirety, leads necessarily to the assumption of a neuropathy. In a review of 24 cases of pernicious anaemia McAlpine 0929) stated that two varieties of sensory loss might occur: a) diminution or loss of vibration sense, either alone or occasionally accompanied by impaired postural sensibility in the fingers and toes, other forms of sensation being unaffected; b) impairment of all forms of sensation in the periphery of the limbs of glove and stocking distribution. The deep reflexes were absent in over half of the cases. McAlpine stressed that pathological evidence did not support the occurrence of lesions in the posterior roots or posterior root entry zones, which might have explained the areflexia, and concluded that the interruption of the reflex arc does not take place in the cord or posterior root but in the peripheral nerve. Dynes and Norcross (1943) using strict clinical criteria found peripheral neuropathy in 23% of 92 patients with pernicious anaemia. In the study of the clinical symptomatology of 38 patients with pernicious anaemia van der Scheer and Koek (1951) maintained that the occurrence of lesions of the peripheral nerves must be assumed, not as an exception but as a rule. They based their conclusion on the frequency of the following symtoms: a) superficial sensory impairment of distal distribution, in addition to the more "classical" impairment of postural sense and of vibration sense; b) burning and painful dysaesthesia, occasionally with hyperalgesia; c) a topographical distribution of sensory signs more in keeping with neuropathy than with either radiculopathy or myelopathy; d) tender peripheral nerves; e) early impairment or loss of ankle jerks; f) distal weakness out of proportion to any pyramidal deficit. The neurophysiological findings in our patients confirm the presence of a peripheral nerve lesion. All patients had pathological spontaneous activity a n d / o r slight slowing of motor conduction velocity of one or two nerves. In Case 7 the motor conduction velocity could not be measured because of the muscle atrophy and the sensory conduction velocity of the sural nerve was considerably slowed. Mayer (1965) found in his Group 3 patients (32 patients with existing symptoms and signs secondary to central or peripheral nerve dysfunction) a significant reduction of the mean velocities in the distal sensory fibers in the median and ulnar nerves. The shape and the amplitude of the potentials were normal. The velocities in the proximal parts of these nerves were normal. The conduction velocity in the posterior tibial and deep peroneal nerves (ankle-knee) were normal. The distal segments of these nerves could not be measured with their technique. The mean latency of the H reflex was prolonged. In some patients, the conduction defect returned to normal over a period of 6 to 12 months during vitamin B~Etreatment. Lockner et al. (1969) found the nerve action potential of the median nerve in 27 patients with pernicious anaemia to be significantly reduced, taken as a group compared with that of controls. In 33% the amplitude was outside the normal
190
M.C. Kayser-Gatchalianand B. NeundSrfer
limits, although only 7% had upper limb symptoms. The authors emphasized that electrophysiological findings indicating neuropathy were found in early cases of pernicious anaemia suggesting that neuropathy is not exceptional in pernicious anaemia. Gilliatt et al. ( 1961) reported 3 cases of vitamin B 12deficiency presenting a picture of mainly peripheral nerve involvement with flexor plantar responses and a superficial sensory loss of stocking distribution. In studying the lateral popliteal nerve, they were not able to record a nerve action potential at the fibula on stimulation at the ankle in one case while there was a reduction of the sensory potential amplitude in two cases. Werner and Mortillaro (1972) found in 9 of 20 patients with disturbance of vitamin BI2 resorption electromyographic signs indicating neurogenic damage: denervation potentials, loss of motor units, increased polyphasia. Seven of these patients showed slowing of the motor conduction velocity of the ulnar a n d / o r the peroneal nerve. Pathological evidence of peripheral nerve changes with pernicious anaemia was reported as early as 1900 by Russell et al. who considered them to be a late manifestation of the disease and to be of minor significance in the clinical picture. Since then other studies have been reported (Hamilton and Nixon, 1921; van Bogaert, 1927; Greenfield and Carmichael, 1953, van der Scheer and Koek, 1951; Foster, 1945; Bischoff et al., 1975). Foster found a reduction in the number of myelin sheaths and axis cylinders, degeneration of myelin and increase in Schwann cells and endoneural connective tissue. Axonal reaction changes in the posterior root ganglia and degenerative changes in the intramedullary course of the afferent posterior root fibres were present, suggesting a "dying back" or axonal process. Van der Scheer and Koek (1951) examined 4 cases of pernicious anaemia with Weigert-Pal staining and found a very great reduction in the amount of myelin. They assumed that the deficiency of myelin begins peripherally and decreases proximally. In one case there were no changes in the proximal part of the obturator nerve, but evidences of distinct degeneration in the lateral cutaneous femoral nerve. Pant et al. (1968), in a review of the neuropathological data of 40 cases of myelopathy complicating pernicious anaemia, were able to study portions of the peripheral nerves in I1 cases, of which only 8 were systematically sampled. They found only in one case a form of fibre loss. In two there was denervation atrophy of the leg muscles examined without recognizable changes in the available nerves. They did not take their observations as evidence for or against the existence of significant peripheral nerve involvement. Bischoff et al. (1975) found in the sural nerve of a patient with vitamin B~2 deficiency a remarkable loss of the myelinated nerve fibres with marked reduction of the fibres of bigger diameter to about 30% of normal. Because of their electronmicroscopic findings they concluded that the underlying process is a primary axon degeneration. Demyelinating lesions in the nervous system with vitamin B i2 deficiency states in chicks, rats and calves were described by Alexander (1956). Oxnard and Smith (1966) observed paralysis in five of 15 rhesus monkeys who were kept for prolonged periods on a strict vegetarian diet. These monkeys showed spongiform demyelination of the posterior and lateral columns of the spinal cord without significant gliosis; three of them had patchy demyelination of the peripheral nerves. Later studies (Oxnard et al., 1969, 1970; Torres et al., 1971), including elegant
Peripheral Neuropathy with Vitamin Bl2 Deficiency
191
methods of staining and quantitative investigations of individual nerve fibres, showed that segmental demyelination was the main lesion with evidences of remyelination. In the severest cases there was axonal degeneration. A selective distal involvement of axons ("dying back") was not observed. Lehoczky et all (1967) induced vitamin B n deficiency in rats by putting them on a B~2free diet. The animals gradually became ataxic and paraphlegic. After 13 weeks 18 animals were sacrificed. While they found considerable to mild foci of demyelination and lacunar fields in the spinal cord, there was no demyelination of the peripheral nerves, but some slight axonal degeneration in 2 cases. Whereas the question of whether vitamin B~2 deficiency produces peripheral neuropathy in man is still controversial, the above animal experiments undoubtably have shown that this is the case in primates. While Bodechtel (1974) denies the occurrence of polyneuropathy in pernicious anaemia, ErbslSh and Abel (1970) believe in the possibility of a latent neuropathy with funicular myelosis, which they, as other authors (Spatz et al., 1976; Werner and Mortillaro, 1972), propose to be due to the presence of other deficiency conditions within the context of "malabsorption" or "maldigestion" or of toxic disorders like alcoholism. In an extensive study of the neurological symptomatology in 161 patients with insufficient vitamin BI2 resorption, Spatz et al. (1976) were able to show roentgenological and histological changes in the gastrointestinal tract, as well as signs of maldigestion in the stool analysis. Our Cases 4, 5, 6, and 7 also show indications of associated malabsorption in the pathological results of the Xylose test and the histological findings in the gastroduodenal biopsy specimen. On the other hand, other authors (Aita, 1972; Bischoff et al., 1975; Dynes and Norcross, 1943; Mayer, 1965; Pallis and Lewis, 1974; Werner and Mortillaro, 1972) believe that the peripheral nerve dysfunction is directly caused by the vitamin B~2 deficiency. This assumption is supported by the results of animal experiments and by the reported favorable results of vitamin BI2 substitution. Mayer (1965) reported the return to normal of the conduction velocities in the distal sensory fibres of the median and ulnar nerves after vitamin Bi2 therapy. There are also undoubtably patients with funicular myelosis and neuropathy, or with peripheral neuropathy alone, such as our Cases 1, 2, 3 and Case 1 of Bischoff et al. (1975), in whom aetiological factors other than vitamin B~2 deficiency are not probable. Bischoff et al. (1975) proposed a pathogenetic mechanism for the primary axonal degeneration which they were able to demonstrate. In vitamin Bl2 deficiency there is an impaired break-down of methyl-malonyl-COA which exercises an inhibitory effect on the malonyl-COA catalyzed enzyme reactions necessary for fatty acid synthesis (Dayan and Ramsey, 1974). This disturbance of fatty acid synthesis leads to the appearance of abnormal saturated fatty acids. The incorporation of these irregular fatty acids in the lipids of the axon membrane leads to defects which underly the dysfunction in the neuropathy.
References
Aita, J. A.: Neurological manifestations of general diseases. Springfield, I11.:Thomas 1972 Alexander, W. F.: Pathomorphology of the nervous systemin vitamin B12deficiency.In: Vitamin B12 and intrinsic factor (ed. H. D. Heinrich), pp. 372. Stuttgart: Enke 1956
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M.C. Kayser-Gatchalian and B. Neund6rfer
Bielschowsky, M.: Myelitis und Sehnervenentztindung. Berlin: Karger 1901 Bischoff, A., LtRschg, I., Meier, CI.: Polyneuropathie bei Vitamin-B,2- und Fols~iuremangel. Klinisch-histologische Studie mit elektronenmikroskopischer Analyse des Nervus suralis. MUnch. med. Wschr. 117, 1593 (1975) Bodechtel, G.: Erkrankungen des peripheren Nervensystems. In: Differentialdiagnose neurologischer Krankheitsbilder. Stuttgart: Thieme 1974 van Bogaert, L.: La polyn6vrite an6mique. Annales de m6dicine 321 (1927) Clarke, C. A., Sircus, W.: Nutritional neuropathy in prisoners-of-war repatriated from HongKong. A follow up. Lancet 1952 II, 113 Clarke, C. A., Sneddon, J. B.: Nutritional neuropathy in prisoners-of-war and internees from Hong-Kong. Lancet 1946 I, 734 Collier, J.: Discussion on the aetiology and treatment of subacute combined degeneration of the spinal cord. Proc. Roy. Soc. Med. lg, 21 (1925) Cruickshank, E. K.: Painful feet in prisoners-of-war in the far east. Review of 500 cases. Lancet 1946 II, 369 Dayan, A. D., Ramsey, R. B.: An inborn error of vitamin B~2 metabolism associated with cellular deficiency of coenzyme forms of the vitamin. J. neurol. Sci. 23, 117 (1974) Denny-Brown, D.: Neurological conditions resulting from prolonged and severe dietary restriction (case reports in prisoners-of-war and general review). Medicine (Baltimore) 26, 41 (1947) Dumont, F., Denny-Brown, D.: Nutritional disease. Fed. Proc. 17, Suppl. 2, 35 (1958) Dynes, J. B., Norcross, J. W.: Peripheral neuritis as a complication of pernicious anemia. JAMA. 122, 586 (1943) Erbsl6h, F., Abel, M.: Deficiency neuropathies. In: Handbook Clin. Neurol. (eds. P. J. Vinken, G. W. Bruyn), Vol. 7. Amsterdam: North-Holland 1970 Foster, D. B.: Degeneration of peripheral nerves in pernicious anaemia. Arch. Neurol. Psychiat. 54, 102 (1945) Gilliatt, R. W., Goodman, H. V., Willison, R. E.: The recording of lateral popliteal nerve action potentials in man. J. Neurol. Neurosurg. Psychiat. 24, 305 (1961) Greenfield, J. G., Carmichael, E. A.: The peripheral nerves in cases of subacute combined degeneration of the cord. Brain 58, 483 (1953) Grinker, R. R.: Pernicious anaemia, achylia gastrica and combined degeneration and their relationship. Arch. Int. Med. 38, 292 (1926) Hamilton, A. S., Nixon, C. F.: Sensory changes in the subacute combined degeneration of pernicious anemia. Arch. Neurol. Psychiat. 6, 1 (1921) Henneberg, H.: tiber "funicul~ire Myelitis" (kombinierte Strangdegeneration). Arch. Psychiat. Nervenkr. 40, 222 (1905) Henneberg, R.: Beitrlige zur Kenntnis der kombinierten Strangdegeneration. Arch. Psychiat. Nervenkr. 32, 555 (1899) Henneberg, R.: ~ber kombinierte Strangdegeneration. Klin. Wschr. 1904, 124 (1904) Klinghardt, G. W.: Experimentelle degenerative Nervensch~idigungen durch Verbindungen des Hydrazins und Hydroscylamins. Naturwiss. 48, 381 (1961) Lehoczky, T., Sos, J., Halasy, M.: Alt6rations neuropathologiques au cours d'exp6rimentations d'avitaminose B12 chez le rat. Acta neurol, belg. 67, 116 (1967) Lockner, D., Reizenstein, P., Wennberg, A., Wid6n, L.: Peripheral nerve function in pernicious anemia before and after treatment. Acta haemat. 41, 257 (1969) Mayer, R. F.: Peripheral nerve function in vitamin Bi2 deficiency. Arch. Neurol. (Chic.) 13, 355 (1965) McAlpine, D.: A review of nervous and mental aspects of pernicious anemia. Lancet 192911, 643 Miller-Fisher, B. A.: Residual neuropathological changes in Canadians held prisoners-of-war by the Japanese (Strachans disease). Canad. Serv. med. J. 11, 157 (1955) Oxnard, C. E., Smith, W. T.: Neurological degeneration and reduced serum vitamin B12 levels in captive monkeys. Nature 210, 507 (1966) Oxnard, C. E., Smith, W. T., Torres, I.: Peripheral neuropathy and hypovitaminosis Bt2 in captive monkeys. In: Proceedings of the 2nd International Congress Primatology, Vol. 3, pp. 162. Basel-New York: Karger 1969
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Oxnard, C. E., Smith, W. T., Torres, I.: Vitamin Bl2 deficiency in captive monkeys and its effect on the nervous system and the blood. Lab. Animals 4, 1 (1970) Patlis, Ch. A., Lewis, P. D.: The neurology of gastrointestinal disease. London-PhiladelphiaToronto: Saunders 1974 Pant, S. H., Asbury, A. K., Richardson, E. P.: The myelopathy of pernicious anaemia. A neuropathological reappraisal. Acta neurol, scand. 44, Suppl. 35 (1968) Peraita, M.: Neuropathie infolge mangelhafter Ern~ihrung. Arch. Psychiat. Nervenkr. 114, 611 (1941) Peraita, M.: Deficiency neuropathies observed in Madrid during the civic war. Brit. med. J. 1946, 784 (1946) Russell, J. S. R., Batten, F. E., Colliev, J.: Subacute combined degeneration of the spinal cord. Brain 23, 39 (1900) van der Scheer, W. M., Koek, H. C.: Peripheral nerve lesions in cases of pernicious anemia. Blood 6, 61 (1951) Schretzenmayer, A.: Beobachtungen an 1200 Beri-Beri-Patienten. Med. Welt (Stuttg.) 12, 454 (1938) Schretzenmayer, A.: VI. Die Beriberi des Menschen. Ergeb. inn. Med. Kinderheilk. 60, 314 (1941) Simpson, I.: . Burning feet' in British prisoners-of-war in the far east, Lancet 1946 I, 959 Smith, D. A., Woodruft, M. F. A., Bennet, L.: Deficiency diseases in Japanese prison camps. Spec. Rep. Ser. med. Res. Count. (London) 1951, 274 Spatz, R., Thimm, R., Heinze, H. G., Ross, A., K6nig, M.: Zum klinischen Gestaltwandel der Vitamin Bl2-Mangelerkrankungen. Nervenarzt 47, 169 (1976) Torres, I., Smith, W. T., Oxnard, C. E.: Peripheral neuropathy associated with vitamin B~2 deficiency in captive monkeys. J. Pathol. 105, 125 (1971) Werner, W., Mortillaro, M.: Zur Frage der peripheren NervenRision bei neurologischen Bl2 Mangelsyndromen. Nervenarzt 47, 458 (1972)
Received July 16, 1976
J. Neurol. 214, 183--193 (1977)
Neurology © by Springer-Verlag 1977
Peripheral Neuropathy with Vitamin B12 Deficiency M. C. Kayser-Gatchalian and B. NeundSrfer Neurological Hospital of the Universityof Heidelberg, KlinikumMannheim (Director: Prof. Dr. O. Hallen), Theodor-Kutzer-Ufer, D-6800 Mannheim, Federal Republic of Germany
Summary. Seven patients with neuropathy associated with vitamin BI2 deficiency are reported. Four of them had other signs of malabsorption aside from the abnormal Schilling test. The neuropathy was diagnosed on the basis of the whole clinical picture and the neurophysiological findings. The pathogenesis of the peripheral nerve disease is discussed in the light of the evidence in the literature. Key words: Neuropathy - Vitamin B12 - Vitamin deficiency - Malabsorption. Zusammenfassung. Es wird tiber 7 Patienten mit einer Neuropathie bei gesicherter Vitamin B]2 Resorptionsst6rung berichtet. Bei 4 Patienten wurden andere Anzeichen einer Malabsorption neben dem pathologischen Schilling Test festgestellt. Die Neuropathie wird aus dem gesamten klinischen Bild und den neurophysiologischen Befunden diagnostiziert. Die Pathogenese der peripheren Nervensch~idigung wird anhand der Literatur diskutiert.
The components of the vitamin B complex are generally considered to be "neurotropic" vitamins so that it has become an injudicious habit to prescribe the vitamin B complex for all possible disorders of the peripheral nervous system. In reality only a small number of neuropathies have been demonstrated to be due to a deficiency of a vitamin B fraction or of the whole B complex. Hence, by insufficient nutritional intake vitamin B~ deficiency, Beriberi, gives rise to polyneuropathy with symmetrical sensorimotor symptoms (Dumont, 1958; Schretzenmayer, 1938, 1941). Deficiency of several fractions of the vitamin B complex is the cause of the so-called "burning-feet" disease which was often observed in Madrid during the famine of the Spanish Civil War (Peraita, 1941, 1946) and in the internment camps in the Far East during World War II (Clarke and Sneddon, 1946; Clarke and Sircus, 1952; Cruickshank, 1946; Denny-Brown, 1947; Miller-Fisher, 1955; Simpson, 1946; Smith et al., 1951). This was a polyneuropathy mainly of the symmetrical sensory type with extremely tormenting burning pains in the feet with
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M.C. Kayser-Gatchalian and B. Neundtirfer
n o c t u r n a l exacerbations. The patients suffered f r o m paraesthesias as well as hypersensitivity to touch and pain in the distal parts of the lower extremities. Vitamin B 6 deficiency is supposed to play a decisive role in the occurrence of a p o l y n e u r o p a t h y during I N H therapy which is initially symmetrical sensory and in its later course becoming sensorimotor. This is attributed to an interference by I N H in the pyridoxine metabolism (Klinghardt, 1961). A l t h o u g h earlier authors had referred to the occurrence of p o l y n e u r o p a t h y with vitamin B l2 deficiency (Bielschowski, 1901; Dynes and Norcross, 1943; Greenfield and Carmichael, 1953; H a m i l t o n and Nixon, 1921; Henneberg, 1899, 1904; McAlpine, 1929)relatively few studies concerning this problem have been reported in recent years (Aita, 1972; Bischoff et al., 1975; E r b s l r h and Abel, 1970; Mayer, 1965; Pallis and Lewis, 1974; Spatz et al., 1976; Werner and Mortillaro, 1972). W h e n special methods of investigation such as E M G and E N G are not employed, the affection of the peripheral nerves is overlooked because its s y m p t o m s are disguised by the frequently c o n c o m i t a n t funicular myelosis. We t h o u g h t it worthwhile to report seven cases to draw attention to this disorder, although we do not intend go as far as Pallis and Lewis (1974), w h o maintain that the n e u r o p a t h y is the c o m m o n e s t complication of vitamin BI2 deficiency.
Material
Seven patients (3 females and 4 males) with vitamin B~2 deficiency, who showed pathological results in the Schilling test, are described. Some of them have further evidence of malabsorption in the Xylose test and in the gastroduodenai biopsy data. The results of the electromyographic and conduction velocity studies in each patient are reported.
Case t. S.D., Female, 62 Years Three months prior to admission the patient suffered from loss of appetite, easy fatigability and loss of weight and for 14 days there was increasing inability to walk. On neurological examination the deep reflexes of the upper and lower extremities were absent, vibration sense was impaired. The superficial sensation was intact. The pyramidal tract signs were negative. Blood count: RBC= 1.09 mill/ram 3, WBC = 2600/mm 3, Reticulocytes = 180/00,Hemoglobin = 4.7 g%, Hematocrit = 14%, MCH = 41 pg, MCV = 128 g.3. Schillitig test: pathological. Schilling test with intrinsic factor: normal. Gastroscopy: distinct signs of mucosal atrophy and moderate gastritis. Histology: chronic atrophic gastritis. Gastric analysis: achlorhydia. Sternal puncture: megaloblastic anaemia. EMG: no denervation activity. Conduction velocity (motor): fibular nerve: 38 m/s; posterior tibial nerve: 40 m/s.
Case 2. R.H., Female, 30 Years Six weeks prior to admission numbness and tingling sensations in the toes were noticed by the patient. She developed pains in the legs and progressive weakness of the lower extremities. There was atrophy of the calf muscles.
Peripheral Neuropathy with Vitamin B~2 Deficiency
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On neurological examination we found atrophy of the foot and lower leg muscles, distally accentuated paresis of the lower extremities, absent deep reflexes in the legs although the tendon reflexes of the arms were very active. The pyramidal signs were negative. Vibration sense was severely impaired at the tibial tuberosity, as well as the position sense in the toes. Blood count: RBC = 3.89 m i l l / m m 3, WBC = 5~600/mm 3, Reticulocytes = 30o/00;Hematocrit = 42%, M C H = 35 pg, M C V = 108 tt 3. Schilling test: pathological. Schilling test with intrinsic factor: normal. Xylose test: normal. Gastric analysis: not performed. EMG: fibrillations and positive sharp waves in more than two places in the m. extensor digitorum brevis and m. flexor hallucis brevis of the right side. Conduction velocity (motor): fibular nerve: 55 m/s; posterior tibial nerve: 42 m/s.
Case 3. R.H., Female, 65 Years Pernicious anaemia was diagnosed in 1945. Since that time the patient could not walk straight at night. She had weakness of the legs and pins and needles sensations in the fingers and toes. Since J a n u a r y 1970 she could no longer walk up the stairs and she had tingling sensations in the fingers up to the lower arms as well as in the feet. The neurological examination revealed increased muscular tonus of the upper and lower extremities, mild, distally accentuated paresis of the legs, very active deep tendon reflexes, hypaesthesia and hypalgesia in the lower legs with stocking distribution and severe disturbance of deep sensation in the legs. Blood count: RBC = 3.66 mill/mm3, WBC = 3800/mm 3, Reticulocytes = 80/00, Hemoglobin = 12.3g%, HbE = 33 ~7. Schilling test: not performed. Xylose test: not performed. Sternal puncture in 1964: pernicious anaemia. Gastric analysis: anacidity. EMG: no denervation activity. Conduction velocity (motor): fibular nerve: 38 m/s; posterior tibial nerve: 36 m/s.
Case 4. H.F., Male, 61 Years For one year prior to admission the patient had been having burning paraesthesias in the buttocks and the posterior part of the thighs on sitting. He also felt burning sensations in the soles of the feet and in the toes. A few months before admission he noticed a feeling of weakness of the lower extremities. On neurological examination, we found slight weakness of the legs with distal accentuation, increased deep reflexes in both arms and legs, negative pyramidal tract signs, hypaesthesia and hypalgesia in the lower legs of stocking distribution, impaired vibration sense at the tibial tuberosity. Blood count: RBC = 4.72 mill/mm 3, WBC = 6200/mm 3, Hemoglobin = 15.6 g %, M C H = 33 pg, M C V = 95 V~3, Hematokrit = 45%. Schilling test: pathological. Schilling test with intrinsic factor: normal. Xylose test: slightly pathological. Gastric analysis: not performed. Gastroduodenoscopy: patchy atrophic gastritis. EMG: massive fibrillations and positive sharp waves as well as mixed pattern on maximal innervation in the m. extensor digitorum brevis and m. flexor hallucis brevis. Conduction velocity (motor): fibular nerve: 52 m/s; posterior tibial nerve: 42 m/s. Conduction velocity (sensory): sural nerve: 57 m/s.
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Table 1, Clinical and laboratory data of the 7 patients
Case 1
Case 2
Case 3
Case 4
65 yrs
61 yrs
Age
62 yrs
30 yrs
Symptoms
progressive walking difficulty
numbness and tingling weakness of the legs sensations in the toes, paraesthesia in toes, weakness and pains in fingers, feet and arms the legs
Findings
absent deep re- distally accentuated flexes, impaired paresis and atrophy of vibration sense legs, deep reflexes of legs absent, impaired deep sensation
Xylose test Schilling test
pathological
Schilling test normal with intrinsic factor
hyperactive reflexes impaired superficial and deep sensation
normal
slightly pathological
pathological
pathological
normal
normal
Gastric analysis achlorhydia Gastroscopy
distally accentuated leg paresis, hyperactive deep reflexes, impaired superficial and deep sensation
burning sensations in buttocks and thighs, burning feet,weakness of the legs
anacidity patchy atrophic gastritis
chronic atrophic gastritis
Sternal puncture megaloblastic anaemia
pernicious anaemia
Case 5. P. K., Male, 69 Years In 1956 the patient underwent a Billroth II resection. One year prior to admission he developed unsteadiness of gait and a few months later there was marked weakness of the legs. He often had muscular cramps ha the calf and thighs. The neurological examination revealed a generalized but distally accentuated muscular atrophy of the extremities. There was slight paresis. The deep reflexes were moderately active in the arms and hyperactive in the legs. The pyramidal signs were negative. The superficial sensation was intact while the deep sensation was severely impaired with loss of vibration sense in the lower extremities up to the anterior iliac spine. Position sense in the toes was lost. Blood count: RBC =3.27 mill/mm3, W B C = 3 2 0 0 / m m 3, Hemoglobin= 11.5 g%, Hematokrit = 31%, MCH = 35pg, MCV = 94 ~t3. Schilling test: pathological. Schilling test with intrinsic factor: pathological. Gastric analysis: pentagastrin refractory anacidity. Xylose test: pathological. EMG: fibrillations in the m. flexor hallucis brevis in more than two places; no pathological spontaneous activity in the m. extensor digitorum brevis. Conduction velocity (motor): fibular nerve: 36 m/s; posterior tibial nerve: 42 m/s.
Case 6. A. S., Male, 57 Years In 1951 the patient underwent a Billroth II resection. In 1975 he had iron deficiency anaemia. Ten days before admission he had increasing weakness in the legs so that he could not walk unaided at the time of admission. He had a feeling of numbness in both legs.
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187
Table 1 (continued) Case 5
Case 6
Case 7
Age
69 yrs
57 yrs
65 yrs
Symptoms
unsteadiness of gait, weak- progressive weakness of the paraesthesias in the toes, feet ness of the legs, cramps legs, numbness in both legs and fingers, progressive weakness of the toes and feet
Findings
distally accentuated muscle atrophy, hyperactive reflexes, impaired deep sensation
paresis of legs, atrophy of distally accentuated paresis of distal muscles, weak ankle legs, absent ankle reflex, imreflex, impaired vibration paired superficial and deep sense, from Th12--Li down- sensation wards hypalgesia/ hypaesthesia
Xylose test
pathological
pathological
pathological
Schilling test
pathological
pathological
pathological
Schilling test pathological with intrinsic factor
pathological
normal
Gastric analysis anacidity
Gastroscopy
normal basal secretion, on maximal stimulation with pentagastrin abnormal values chronic atrophic gastritis, atrophic gastritis nonspecific jejunitis, Billroth II resected stomach
Sternal puncture
The neurological examination revealed marked paresis of the lower extremities, atrophy of the distal muscles of the legs, hyperactive patellar reflexes, very weak ankle jerks, negative Babinski but positive Strumpell sign. From the level of the twelfth dorsal-first lumbar dermatome downwards there was hypalgesia and hypaesthesia. Vibration sense was totally lost in the lower extremities. Blood count: RBC = 3.4 mill/mm 3, WBC = 8200/mm 3, Hemoglobin = 11.9 g% Hematokrit = 38%, MCH = 35 pg, MCV = 112~. 3. Schilling test: pathological. Schilling test with intrinsic factor: pathological. Xylose test: pathological. Gastroscopy: BII resected stomach. Chronic atrophic corpus gastritis. Nonspecific jejunitis. EMG: fibrillations in the distal muscles of both feet and single oscillations on maximal innervation. Conduction velocity (motor): fibular nerve: 34.6 m/s; posterior tibial nerve: 36 m/s.
Case 7. A. M., Male, 65 Years For 3 years prior to admission paraesthesia~"as if the wind passes between the toes"--was felt. Later he had numbness of the feet and one year before admission progressive weakness of the big toes and the feet and unsteadiness of gait developed. On neurological examination we found severe paresis of the toe extensors and flexors as well as the foot extensors and flexors, moderately active deep reflexes but absent Achilles reflex.
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Table 2. Electrophysiological findings
Case no.
Denervation Motor CV activity fibular nerve
1
O
2 3 4 5 6 7
÷ O + ÷ ÷ +
38 m/s 55 m/s 38m/s 52m/s 36m/s 34.6 m/s no action potential
Motor CV posterior tibial nerve
Sensory CV sural nerve
40 m/s 42 m/s 36m/s 42 m/s 57 m/s 42m/s 36 m/s no action potential 18.3 m/s
There was hypalgesia and hypaesthesia of stocking distribution up to just above the ankles. Vibration sense and appreciation of passive toe movements were strongly impaired. Blood count: RBC =4.45 mill/mm 3, WBC= 7900 mm/3, Hemoglobin= 14.7 g%, Hematokrit = 46%, MCH = 33 pg, MCV = 103 ~t3. Schilling test: pathological. Schilling test with intrinsic factor: normal. Xylose test: pathological. Gastroscopy: chronic gastritis with beginning atrophy of the glandular bodies. Hyperlipidaemia Type IV Frederikson. Glucose tolerance test: non-diabetic curve. Gastric analysis: normal basal secretion and normacidity. On maximal stimulation with pentagastrin the values were way below normal. EMG: frequent fibrillations in almost all places in the distal muscles of both legs and single oscillations on maximal innervation. Conduction velocity (motor): on stimulating the fibular and the posterior tibial nerve, no action potential could be evoked. Conduction velocity (sensory): sural nerve, left: 18.3 m/s.
Discussion
It has l o n g been the subject o f c o n t r o v e r s y w h e t h e r the n e u r o l o g i c a l s y m p t o m s o f v i t a m i n B j2 deficiency a r e p u r e l y m y e l o p a t h i c o r p a r t l y n e u r o p a t h i c . W e find it a p t to review the evidence in o u r cases a n d in the literature available. Five o f o u r p a t i e n t s h a d paraesthesias. Collier (1925) w a r n e d against i n t e r p r e t i n g p e r i p h e r a l subjective sensations in a n a e m i c p a t i e n t s as being caused always by n e u r o l o g i c a l c h a n g e s since tingling a n d n u m b n e s s a r e c o m m o n in every variety o f a n a e m i a . G r i n k e r (1926) s h a r e d this o p i n i o n by e m p h a s i z i n g t h a t severe i r o n deficiency a n a e m i a m i g h t be a s s o c i a t e d with distal p a r a e s t h e s i a s t h a t s u b s i d e d as the a n a e m i a was corrected. O n the o t h e r hand, it is well k n o w n t h a t sensory s y m p t o m s can p r e c e d e the objective signs in n e u r o p a t h y . T o have s o m e c e r t a i n t y in the d i a g n o s i s f r o m the clinical s y m p t o m a t o l o g y , we c o n s i d e r e d for this r e p o r t only those p a t i e n t s with subjective c o m p l a i n t s a n d p h y s i c a l signs. A l l seven p a t i e n t s h a d bilateral, progressive w e a k n e s s o f the lower extremities. O n e x a m i n a t i o n t h e r e was d i s t a l l y a c c e n t u a t e d paresis o f the legs with loss o f deep
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reflexes or of the ankle jerk except in three patients in whom the tendon reflexes were increased. Atrophy of the foot and leg muscles was found only distally or distally accentuated. The impaired superficial sensation in the periphery of the limbs was of stocking type. The patients with the hyperactive deep reflexes had this sensory disturbance. All patients had disturbance of vibration sense with or without other signs of impairment of deep sensation. In one patient there was hypaesthesia and hypalgesia from the level of Th~2--L~, which was thought to be due to an associated myelopathic involvement. The clinical picture in each patient, taken in its entirety, leads necessarily to the assumption of a neuropathy. In a review of 24 cases of pernicious anaemia McAlpine 0929) stated that two varieties of sensory loss might occur: a) diminution or loss of vibration sense, either alone or occasionally accompanied by impaired postural sensibility in the fingers and toes, other forms of sensation being unaffected; b) impairment of all forms of sensation in the periphery of the limbs of glove and stocking distribution. The deep reflexes were absent in over half of the cases. McAlpine stressed that pathological evidence did not support the occurrence of lesions in the posterior roots or posterior root entry zones, which might have explained the areflexia, and concluded that the interruption of the reflex arc does not take place in the cord or posterior root but in the peripheral nerve. Dynes and Norcross (1943) using strict clinical criteria found peripheral neuropathy in 23% of 92 patients with pernicious anaemia. In the study of the clinical symptomatology of 38 patients with pernicious anaemia van der Scheer and Koek (1951) maintained that the occurrence of lesions of the peripheral nerves must be assumed, not as an exception but as a rule. They based their conclusion on the frequency of the following symtoms: a) superficial sensory impairment of distal distribution, in addition to the more "classical" impairment of postural sense and of vibration sense; b) burning and painful dysaesthesia, occasionally with hyperalgesia; c) a topographical distribution of sensory signs more in keeping with neuropathy than with either radiculopathy or myelopathy; d) tender peripheral nerves; e) early impairment or loss of ankle jerks; f) distal weakness out of proportion to any pyramidal deficit. The neurophysiological findings in our patients confirm the presence of a peripheral nerve lesion. All patients had pathological spontaneous activity a n d / o r slight slowing of motor conduction velocity of one or two nerves. In Case 7 the motor conduction velocity could not be measured because of the muscle atrophy and the sensory conduction velocity of the sural nerve was considerably slowed. Mayer (1965) found in his Group 3 patients (32 patients with existing symptoms and signs secondary to central or peripheral nerve dysfunction) a significant reduction of the mean velocities in the distal sensory fibers in the median and ulnar nerves. The shape and the amplitude of the potentials were normal. The velocities in the proximal parts of these nerves were normal. The conduction velocity in the posterior tibial and deep peroneal nerves (ankle-knee) were normal. The distal segments of these nerves could not be measured with their technique. The mean latency of the H reflex was prolonged. In some patients, the conduction defect returned to normal over a period of 6 to 12 months during vitamin B~Etreatment. Lockner et al. (1969) found the nerve action potential of the median nerve in 27 patients with pernicious anaemia to be significantly reduced, taken as a group compared with that of controls. In 33% the amplitude was outside the normal
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M.C. Kayser-Gatchalianand B. NeundSrfer
limits, although only 7% had upper limb symptoms. The authors emphasized that electrophysiological findings indicating neuropathy were found in early cases of pernicious anaemia suggesting that neuropathy is not exceptional in pernicious anaemia. Gilliatt et al. ( 1961) reported 3 cases of vitamin B 12deficiency presenting a picture of mainly peripheral nerve involvement with flexor plantar responses and a superficial sensory loss of stocking distribution. In studying the lateral popliteal nerve, they were not able to record a nerve action potential at the fibula on stimulation at the ankle in one case while there was a reduction of the sensory potential amplitude in two cases. Werner and Mortillaro (1972) found in 9 of 20 patients with disturbance of vitamin BI2 resorption electromyographic signs indicating neurogenic damage: denervation potentials, loss of motor units, increased polyphasia. Seven of these patients showed slowing of the motor conduction velocity of the ulnar a n d / o r the peroneal nerve. Pathological evidence of peripheral nerve changes with pernicious anaemia was reported as early as 1900 by Russell et al. who considered them to be a late manifestation of the disease and to be of minor significance in the clinical picture. Since then other studies have been reported (Hamilton and Nixon, 1921; van Bogaert, 1927; Greenfield and Carmichael, 1953, van der Scheer and Koek, 1951; Foster, 1945; Bischoff et al., 1975). Foster found a reduction in the number of myelin sheaths and axis cylinders, degeneration of myelin and increase in Schwann cells and endoneural connective tissue. Axonal reaction changes in the posterior root ganglia and degenerative changes in the intramedullary course of the afferent posterior root fibres were present, suggesting a "dying back" or axonal process. Van der Scheer and Koek (1951) examined 4 cases of pernicious anaemia with Weigert-Pal staining and found a very great reduction in the amount of myelin. They assumed that the deficiency of myelin begins peripherally and decreases proximally. In one case there were no changes in the proximal part of the obturator nerve, but evidences of distinct degeneration in the lateral cutaneous femoral nerve. Pant et al. (1968), in a review of the neuropathological data of 40 cases of myelopathy complicating pernicious anaemia, were able to study portions of the peripheral nerves in I1 cases, of which only 8 were systematically sampled. They found only in one case a form of fibre loss. In two there was denervation atrophy of the leg muscles examined without recognizable changes in the available nerves. They did not take their observations as evidence for or against the existence of significant peripheral nerve involvement. Bischoff et al. (1975) found in the sural nerve of a patient with vitamin B~2 deficiency a remarkable loss of the myelinated nerve fibres with marked reduction of the fibres of bigger diameter to about 30% of normal. Because of their electronmicroscopic findings they concluded that the underlying process is a primary axon degeneration. Demyelinating lesions in the nervous system with vitamin B i2 deficiency states in chicks, rats and calves were described by Alexander (1956). Oxnard and Smith (1966) observed paralysis in five of 15 rhesus monkeys who were kept for prolonged periods on a strict vegetarian diet. These monkeys showed spongiform demyelination of the posterior and lateral columns of the spinal cord without significant gliosis; three of them had patchy demyelination of the peripheral nerves. Later studies (Oxnard et al., 1969, 1970; Torres et al., 1971), including elegant
Peripheral Neuropathy with Vitamin Bl2 Deficiency
191
methods of staining and quantitative investigations of individual nerve fibres, showed that segmental demyelination was the main lesion with evidences of remyelination. In the severest cases there was axonal degeneration. A selective distal involvement of axons ("dying back") was not observed. Lehoczky et all (1967) induced vitamin B n deficiency in rats by putting them on a B~2free diet. The animals gradually became ataxic and paraphlegic. After 13 weeks 18 animals were sacrificed. While they found considerable to mild foci of demyelination and lacunar fields in the spinal cord, there was no demyelination of the peripheral nerves, but some slight axonal degeneration in 2 cases. Whereas the question of whether vitamin B~2 deficiency produces peripheral neuropathy in man is still controversial, the above animal experiments undoubtably have shown that this is the case in primates. While Bodechtel (1974) denies the occurrence of polyneuropathy in pernicious anaemia, ErbslSh and Abel (1970) believe in the possibility of a latent neuropathy with funicular myelosis, which they, as other authors (Spatz et al., 1976; Werner and Mortillaro, 1972), propose to be due to the presence of other deficiency conditions within the context of "malabsorption" or "maldigestion" or of toxic disorders like alcoholism. In an extensive study of the neurological symptomatology in 161 patients with insufficient vitamin BI2 resorption, Spatz et al. (1976) were able to show roentgenological and histological changes in the gastrointestinal tract, as well as signs of maldigestion in the stool analysis. Our Cases 4, 5, 6, and 7 also show indications of associated malabsorption in the pathological results of the Xylose test and the histological findings in the gastroduodenal biopsy specimen. On the other hand, other authors (Aita, 1972; Bischoff et al., 1975; Dynes and Norcross, 1943; Mayer, 1965; Pallis and Lewis, 1974; Werner and Mortillaro, 1972) believe that the peripheral nerve dysfunction is directly caused by the vitamin B~2 deficiency. This assumption is supported by the results of animal experiments and by the reported favorable results of vitamin BI2 substitution. Mayer (1965) reported the return to normal of the conduction velocities in the distal sensory fibres of the median and ulnar nerves after vitamin Bi2 therapy. There are also undoubtably patients with funicular myelosis and neuropathy, or with peripheral neuropathy alone, such as our Cases 1, 2, 3 and Case 1 of Bischoff et al. (1975), in whom aetiological factors other than vitamin B~2 deficiency are not probable. Bischoff et al. (1975) proposed a pathogenetic mechanism for the primary axonal degeneration which they were able to demonstrate. In vitamin Bl2 deficiency there is an impaired break-down of methyl-malonyl-COA which exercises an inhibitory effect on the malonyl-COA catalyzed enzyme reactions necessary for fatty acid synthesis (Dayan and Ramsey, 1974). This disturbance of fatty acid synthesis leads to the appearance of abnormal saturated fatty acids. The incorporation of these irregular fatty acids in the lipids of the axon membrane leads to defects which underly the dysfunction in the neuropathy.
References
Aita, J. A.: Neurological manifestations of general diseases. Springfield, I11.:Thomas 1972 Alexander, W. F.: Pathomorphology of the nervous systemin vitamin B12deficiency.In: Vitamin B12 and intrinsic factor (ed. H. D. Heinrich), pp. 372. Stuttgart: Enke 1956
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Received July 16, 1976
