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Autonomic dysfunction and orthostatic hypotention caused by vitamin B12 deficiency
  1. Department of Neurology, Tokyo Medical and Dental University, Tokyo, Japan
  2. Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo Japan
  1. Dr T Yokota, Department of Neurology, Tokyo Medical and Dental University, 1-5-45 Yoshima, Bunkyo-Ku, Tokyo 113-8519, Japan. Fax 0081-3-5803-0169.
  1. Department of Neurology, Tokyo Medical and Dental University, Tokyo, Japan
  2. Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo Japan
  1. Dr T Yokota, Department of Neurology, Tokyo Medical and Dental University, 1-5-45 Yoshima, Bunkyo-Ku, Tokyo 113-8519, Japan. Fax 0081-3-5803-0169.

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Orthostatic hypotension sometimes is a reversible neurological complication of vitamin B12 deficiency.1 2 Eisenhofer detected deficient sympathetic catecholamine release in insulin tolerance testing,2 but the mechanism of orthostatic hypotension in vitamin B12 deficiency remains unclear. We report a patient with vitamin B12 deficiency and reversible orthostatic hypotension, and discuss the mechanism of this symptom.

A 77 year old man admitted to our hospital had had unstable gait and urinary urgency for 6 months, clumsiness of the hands and tingling sensations in the legs for 3 months, and, for a month, occasional dizziness on standing. The dizziness was mild without any attack of syncope. He had no other symptoms or signs of autonomic dysfunction but impotence and erectile failure were noted 10 years before the onset of neurological symptoms. He had not taken any medicine which would affect the autonomic nervous system. He did not have a habit of drinking.

Physical examination on admission detected no signs of anaemia, heart failure, or dehydration. Neurological examination showed dysaesthesia and decreased sensation of all modalities in distal parts of all the limbs. Deep tendon reflex was absent in the lower limbs, and Babinski’s sign was positive bilaterally. Mild limb ataxia was seen in the four limbs, and Romberg’s test was positive.

Haematological studies disclosed mild macrocytic hyperchromic anaemia (haemoglobin 14.0 g/dl, mean corpuscular volume 104 fl, mean corpuscular haemoglobin concentration 35.2 pg), with a few (3%) hypersegmented polymorphonuclear cells. His serum vitamin B12 concentration was markedly decreased (38 pg/ml; normal 249–938 pg/ml). Intrinsic factor and parietal cell antibodies were positive in the serum. Echo cardiography showed no evidence of heart failure. In a study of peripheral nerve conduction, amplitudes of sensory nerve action potentials were slightly decreased in the lower limbs. The somatosensory evoked potential on median nerve stimulation showed a moderately prolonged central conduction time. Urodynamic studies disclosed uninhibited neurogenic bladder with detrusor sphincter dyssynergia.

Results of the autonomic nervous system tests before and 6 months after treatment are given in the table. When the patient was tilted up to 60 degrees, he experienced dizziness and a significant fall in systolic blood pressure over 30 mm Hg with normal heart rate response. His serum noradrenalin concentration was reduced at rest, and its increase after tilting up was minimal. Sudomotor function was evaluated by sympathetic skin response (SSR)3 and local sweat response to acetylcholine (Ach).4

Before treatment, the SSR amplitude was decreased, and the number and area of sweat droplets were decreased in responses to intradermal ACh injection.

The myelinated fibre density of biopsied sural nerve was 5927/mm2. Some thin myelinated fibres were present, as were a few myelin ovoids. Examination of the teased fibres showed evidence of demyelination (about 20%) and axonal degeneration (about 10%). Electron microscopy showed a normal unmyelinated fibre density (30 945 /mm2). Collagen pockets (15 000 /mm2), and denervated Schwann cell subunits (12 000 /mm2) were present, but their densities were within the normal range for his age.5

A highly sensitive acetylcholinesterase (AChE) histochemical test (modified Tago’s method)6 of the sural nerve detected a slightly reduced density of sudomotor sympathetic unmyelinated fibres (3500 /mm2; normal 3700–6500 /mm2).

Daily intramuscularly administered 1 mg vitamin B12 for a week then 1 mg once a month increased its serum concentration rapidly to normal, resulting in the gradual amelioration of orthostatic dizziness, and his neurological symptoms except for erectile failure, after a month.

The abnormalities seen in the autonomic nervous system tests also disappeared when vitamin B12 was given for 6 months (table). The lesion of the baroreflex responsible for his orthostatic hypotension is considered to be in the efferent pathway because of the preserved heart rate response in head up tilt test. The low serum noradrenalin concentration in particular can be explained by disturbance of the sympathetic postganglionic fibres. These findings are supported by the decreased SSR amplitude and the reduced local sweat response to ACh. By contrast, the density of the unmyelinated fibres and AchE positive fibres were relatively well preserved when his age was considered. Furthermore, there was the rapid recovery of serum noradrenalin concentraton, the SSR size, and the sweat response to ACh after giving the vitamin B12 supplement. These results suggest dysfunction of the sympathetic postganglionic fibres without marked morphological change, although we cannot exclude the possibility that sympathetic neurons in the brainstem or spinal cord induce the dysfunction of postganglionic fibres by a trans-synaptic effect.7 8 Vitamin B12 is related to the methylation reaction regulated by S-adenosylhomocystine and S-adenosylmethionine.9 This reaction has a crucial role in the myelin formation associated with neurological deficits in patients with vitamin B12 deficiency. Dysfunction in unmyelinated sympathetic neurons, however, has not been shown. Our findings suggest that vitamin B12 is required for the physiological function of sympathetic postganglionic fibres.

Results of autonomic nervous system tests before and after vitamin B12 treatment