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The difficulties with vitamin B12
  1. Ruth Dobson1,
  2. Debie Alvares1,2
  1. 1Hurstwood Park Neurosciences Centre, Haywards Heath
  2. 2St Richards Hospital, Chichester, UK
  1. Correspondence to Dr Ruth Dobson, Hurstwood Park Neurosciences Centre, Lewes Road, Haywards Heath, RH16 4EX, UK; ruth.dobson{at}qmul.ac.uk

Abstract

A 22-year-old woman presented with progressive sensory ataxia and optic neuropathy. Previous investigation by her general practitioner had found a low serum vitamin B12, which had been corrected with oral supplementation. Neurological investigations showed raised plasma homocysteine and methylmalonic acid towards the upper limit of normal with a low serum vitamin B12. MRI showed an extensive cord lesion in keeping with subacute combined degeneration of the spinal cord. We treated her with high dose parenteral vitamin B12 and she has made a partial recovery. We discuss the management of patients who present with neurological manifestations of vitamin B12 deficiency; highlighting the fact that parenteral replacement is needed in such cases, even if the serum vitamin B12 level appears to be normal. We also discuss ancillary investigations that should be performed in patients with suspected vitamin B12 deficiency.

  • B12 DEFICIENCY
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Case

A 22-year-old woman presented to the neurology clinic in March 2014. Her neurological symptoms had begun in June 2013, when she developed swelling of her feet, progressing to numbness and pins and needles, which spread up her legs over days to weeks. A few months later, her hands became numb with pins and needles. Her symptoms stabilised in December 2013, with numbness up to her mid-calf and less severe symptoms from mid-calf to chest.

In February 2014, she woke with blurred vision simultaneously in both eyes. This problem peaked at its onset, and did not deteriorate further. There was no pain on eye movement to suggest optic neuritis. In March 2014 she described ongoing blue-yellow colour desaturation and slight visual blurring. An optician measured her visual acuity as 6/36 in the right eye and 6/60 in the left.

She denied significant alcohol intake, use of any over-the-counter supplements, illicit drugs or inhaling any volatile substances. There was no previous eating disorder or restriction in her diet, and she had tended to be overweight. She reported that she ate meat, but did not eat much fresh fruit, dairy or vegetables and almost exclusively ate processed foods and ready meals; her mother corroborated this.

She had a history of depression and anxiety, and first attended psychiatric services when aged 11 years and had taken sertraline for many years. She also took diltiazem for paroxysmal tachycardia. She did not smoke.

On examination on admission, her eye movements were normal with no intranuclear ophthalmoplegia. There was an afferent pupillary defect on the left, with bilateral disc pallor. Her pinhole visual acuity was 6/18 on the right and 6/12 on the left and N6 in near vision bilaterally. She could read all 13 of the Ishihara plates. She had an enlarged blind spot on the left. Schirmer's test showed normal tear production on both sides.

Facial movements were normal and there were no other abnormalities of the cranial nerves. There was pseudoathetosis of the upper limbs with no pronator drift. She had normal tone in both upper limbs and mildly increased tone in her lower limbs. She had mild weakness of elbow extension, wrist extension, knee extension and ankle flexion, more marked on the left at 4+/5. She had brisk reflexes throughout without pathological reflexes, and her plantar responses were mute bilaterally. She had significant sensory loss. Vibration sense was lost to the wrist in both arms and the anterior superior iliac spine in both legs. She had intact pinprick sensation in her hands; in the lower limbs this was reduced to mid-calf. Proprioceptive responses were reduced distally. Her gait was that of a sensory ataxia.

A full blood count on admission showed normal haemoglobin but a mildly raised mean corpuscular volume of 101.6 (76–100). Renal and liver function, thyroid function tests, immunoglobulins, serum copper and ceruloplasmin, serum ACE, antineuronal antibodies and a full autoimmune screen were all normal or negative. Serum antiaquaporin-4 and antimyelin oligodendrocyte glycoprotein antibodies were negative.

Serum vitamin B12 was 166 pcg/mL (normal 197–866 pcg/mL). It had been 78 pcg/mL when measured by her general practitioner (GP) in November 2013, increasing to 218 pcg/mL in March 2014 following oral supplementation. Folate was normal at 5.3 μg/L (4.0–18.7 μg/L). Plasma homocysteine was increased at 21.3 μmol/L (5–15 μmol/L) and serum methylmalonic acid was at the upper end of normal at 0.26 μmol/L (0–0.29 μmol/L). Serum intrinsic factor antibody and antiparietal cell antibodies were negative. Genetic testing for Leber's hereditary optic neuropathy was negative. Endoscopy including gastric biopsy was normal.

Cerebrospinal fluid (CSF) analysis showed 1 white cell and 20 red cells with a raised protein of 719 mg/L. CSF glucose was normal at 3.3 (serum 4.7). CSF oligoclonal bands were negative. MRI of the neuroaxis showed diffuse T2 and fluid-attenuated inversion recovery (FLAIR) hyperintense signal change within the cervical and thoracic spinal cord, appearing to affect dorsal and lateral columns, extending from C2 to T11 (figure 1). There was no enhancement with gadolinium. These appearances were felt to be in keeping with subacute combined degeneration of the spinal cord.

Figure 1

(A) Sagittal T2, (B) short tau inversion recovery (STIR) and (C) axial T2 images of the cervical spinal cord from May 2014 showing diffuse T2 signal change affecting predominantly the dorsal columns. There was no enhancement following gadolinium.

Visual evoked potentials showed delayed latencies consistent with demyelination of both optic nerves. Upper limb somatosensory evoked potentials showed delayed N13 and 20 end peak latencies consistent with bilateral central somatosensory pathway involvement; lower limb somatosensory evoked potentials showed absent cortical responses on both sides. Brainstem auditory evoked potentials were normal bilaterally.

We therefore treated her with 1 mg of vitamin B12 intramuscularly on alternate days until her mean corpuscular volume normalised following advice from the haematologists and in line with National Institute for Health and Care Excellence guidelines, in addition to folate supplementation. We advised her to continue with intramuscular vitamin B12 replacement in the long term. In December 2014 her plasma homocysteine had improved to 13.1 pg/mL and serum methylmalonic acid had fallen to 0.13 μmol/L. The signal change seen in her previous MR scan of spine had improved but had not completely normalised (figure 2).

Figure 2

(A and B) Sagittal T2 and (C) axial T2 images of the cervical spinal cord showing improvement in the T2 signal change seen in May 2014. The interval between the images was 6 weeks, during which time the patient was treated with high dose vitamin B12.

Discussion

Vitamin B12 is an essential cofactor integral to methylation processes. Deficiency leads to disruption of DNA and cell metabolism with potentially serious clinical consequences. Vitamin B12 deficiency is relatively common, affecting up to 6% of those aged under 60 years and around 20% of those over 60 years in the UK and USA.1 Deficiency levels are far higher in Africa and Asia, affecting up to 70%–80% of the population.1 In retrospect, our patient presented with classical symptoms of B12 deficiency, and it could be argued that she should not have been so extensively investigated. However, despite oral B12 replacement given by her GP, which resulted in normalisation of her serum B12 levels and resolution of her macrocytosis, her symptoms continued to progress; there was concern that she may have dual pathology. As we discuss below, neither of these features exclude B12 deficiency as the cause of her neurological syndrome.

The ‘classical’ manifestation of B12 deficiency is megaloblastic anaemia; however, the severity of the anaemia appears to be inversely correlated with the degree of neurological dysfunction.2 The reasons behind this remain unclear. Other non-neurological conditions associated with B12 deficiency include glossitis, depression/mania, infertility and thrombosis, presumably a result of secondary hyperhomocysteinaemia. However, neurological manifestations may be the only clinical evidence of significant B12 deficiency.

Vitamin B12 is necessary for the development and initial myelination of the central nervous system as well as the maintenance of normal function. The neurological manifestations of vitamin B12 deficiency are those associated with demyelination: demyelination of the dorsal and lateral columns of the spinal cord, peripheral demyelination and optic neuropathy. An initially demyelinating polyneuropathy may result in secondary axonal death; a mixed picture on nerve conduction studies does not exclude B12 deficiency as a cause of peripheral demyelination. An estimated 20% of those with neurological manifestations do not manifest anaemia;1 as such a normal full blood count does not exclude a diagnosis of vitamin B12 deficiency.

Vitamin B12 levels are commonly requested in neurological practice, often as part of a ‘neuropathy screen’. While extremely low B12 levels are clinically useful, a normal result should not be taken as fully reassuring in the context of a suggestive clinical history, as in our patient. There may be both false negative and false positive results at a rate of up to 50%.2 Only 20% of total measured vitamin B12 is bound to the cellular delivery protein transcobalamin. New assays measuring B12 saturation of transcobalamin are in development, but these have not yet been clinically validated.

Methylmalonic acid and plasma homocysteine levels can be used as surrogate measures for vitamin B12 deficiency; both are significantly elevated in clinical B12 deficiency. Levels of both fall following vitamin B12 replacement, which can be used as a surrogate marker for adequate replacement. Methylmalonic acid is a more specific marker for vitamin B12 deficiency; homocysteine levels may be increased in folate deficiency, classic homocystinuria and renal failure. Patients with proven B12 deficiency should be investigated for causes of secondary deficiency. These include pernicious anaemia, gastric and intestinal malabsorption, pancreatic insufficiency, malnutrition and various drugs including alcohol and proton pump inhibitors. The Schilling test, which involves oral administration of radiolabelled B12 alongside intramuscular non-radiolabelled B12 loading to assess gastric absorption, has been superseded by the combination of commercially available antibody measurement, the ease of B12 replacement and concerns regarding exposure to radiolabelled pharmaceuticals.

Current UK guidelines state that all patients with neurological manifestations of B12 deficiency should receive parenteral therapy.1 Parenteral therapy has the added benefit of improved adherence and monitoring. However, some evidence suggests that high dose oral therapy (2000 μg daily) may be an alternative parental therapy (1000 μg every 3 days for 1 month, then monthly).3 This trial had only four patients in each arm and we clearly need further evidence before considering oral treatment for patients with neurological manifestations of deficiency. In patients with neurological manifestations of vitamin B12 deficiency, standard initial treatment is 1000 μg intramuscularly 3 times/week for 2 weeks, followed by 1000 ug intramuscularly on alternate days for up to 3 weeks or until there is no further improvement.1 Maintenance therapy is 1000 μg every 3 months. If an underlying cause of deficiency is found treatment can be reviewed once it is addressed. Folate levels should be checked alongside vitamin B12 levels, and if there is a coexisting folate deficiency this should be corrected alongside vitamin B12 replacement.

Our patient had no detectable reversible cause for her B12 deficiency; given that her diet was restricted over the long term to highly processed foods this was may have been the cause. The haematology team reviewed her as an inpatient and discussed with her local team; neither haematology team felt that further investigations were needed to look for the cause of her B12 deficiency. Her neurological symptoms stabilised following intensive parental therapy, and have improved following rehabilitation. We do not know whether her long-standing depression and anxiety related to B12 deficiency or not. Without a reversible cause and with clear neurological dysfunction, she continues on high dose replacement for the foreseeable future.

Key points

  • Patients in whom there is a strong clinical suspicion of vitamin B12 deficiency should have their serum methylmalonic acid levels (with or without plasma homocysteine) measured; high serum methylmalonic acid indicates vitamin B12 deficiency even with normal serum vitamin B12.

  • There is a wide range of neurological and non-neurological manifestations of vitamin B12 deficiency, some of which are relatively non-specific.

  • When there is evidence of neurological manifestations of vitamin B12 deficiency then high dose parenteral replacement should be used; there is insufficient evidence at present to support high dose oral replacement.

  • All patients with proven vitamin B12 deficiency should be investigated for causes of secondary deficiency.

Acknowledgments

The authors thank Dr Tina Good for her assistance with the MRI images.

References

View Abstract

Footnotes

  • Contributors DA was the consultant responsible for the care of the patient. RD was the specialist registrar on the team. RD drafted the manuscript with input from DA. All authors approved the final manuscript for submission.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed. The paper was reviewed by Robin Lachmann, London UK.

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