Peripheral Neuropathy, B12 deficiency

Numb : Part 1
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Diagnosis and reasoning

Peripheral neuropathy is one of the most common complications of type 2 diabetes mellitus - and at first glance, this patient's history is highly suggestive of this diagnosis. The examination provides further evidence in support by revealing the presence of background retinopathy (indicating that microvascular disease is present). In addition, the symmetric large fibre (vibration, proprioception) and small fibre (pain) sensory neuropathy is suggestive of diabetic distal symmetric polyneuropathy (DSP). However, this very straightforward line of thought is thrown into disarray by a single finding: the preservation of ankle reflexes. Loss of ankle reflexes is the cardinal feature of diabetic DSP - an alternative diagnosis should always be considered when this is not present. Note that the differential diagnosis of distal polyneuropathy is a literal can of worms. However, his age and the fact that certain etiologies are more common in diabetics can be used to prioritize the list of diagnoses. Thus, uremia, hypothyroidism and nutritional deficiencies should probably be considered initially, as should the possibility of a paraproteinemia. Uremic neuropathy is typically encountered in advanced renal disease, and can be ruled out here by the absence of suggestive clinical findings and normal creatinine level. In addition, he is clinically euthyroid, with normal TSH levels, excluding hypothyroidism. Paraproteinemias cannot be excluded via clinical findings alone. However the normal ESR and serum electrophoresis are strong evidence in the negative. Vitamin B12 and Folate deficiency are the most common nutritional deficiencies giving rise to peripheral neuropathy. These too cannot be be excluded clinically - serum levels should be estimated. This reveals the presence of significantly reduced vitamin B12 levels. Note that a low serum B12 level does not always imply vitamin B12 deficiency, as between 20% to 40% of such elderly people have normal methylmalonic acid and homocysteine levels (indicating normal metabolism). However, there is general agreement that a vitamin B12 level less than 100 pg/ml can be assumed as being diagnostic of deficiency. Thus, the diagnosis appears to be peripheral neuropathy secondary to vitamin B12 deficiency. While vitamin B12 deficiency is classically associated with a megaloblastic anemia, it should be kept in mind that the development of neuropathy often precedes this. Thus, the normal full blood count of this patient in no way excludes this diagnosis. Note also that a myriad of conditions can give rise to vitamin B12 deficiency - he needs further investigation in this direction. Play the case "Numb - part 2" (coming next week) to find out the causative etiology ! Regardless of etiology, what is unambiguous is that he is vitamin B12 depleted. Vitamin B12 supplementation should be commenced as soon as any remaining diagnostic investigations have been performed. In addition, due to the loss of protective sensation, it is essential to provide proper foot protection. Gabapentin is indicated in patients with painful peripheral neuropathy. Folate supplementation is unnecessary in view of the normal serum folate level.


Vitamin B12 (cobalamin) is an essential nutrient which acts as a coenzyme in many intermediate metabolic processes. In the nervous system, vitamin B12 deficiency causes demyelination followed by axonal degeneration and neuronal death; this may affect the peripheral nervous system, posterior and lateral columns of the spinal cord, and even the cerebrum. Isolated peripheral neuropathy (which the remainder of this discussion focuses on) is a relatively uncommon manifestation of vitamin B12 deficiency; it is mainly encountered in elderly patients with comorbidities, or in those undergoing chronic treatment with drugs known to cause B12 deficiency. The first symptom is typically a sensation of cold, numbness, or tightness in the tips of the toes and then in the fingertips. Poor joint position and vibration sense are early examination findings. At the time of presentation, half of patients have absent ankle reflexes with relative hyperreflexia at the knees. The plantars are initially flexor, but become extensor later on. A Hoffman sign may also be present. As the disease progresses, ascending loss of pinprick, light touch, and temperature sensation occurs. Note that the legs are affected before the arms, and rarely are all limbs affected simultaneously. Abnormal evoked potentials are the first electrodiagnostic finding, and may be present even in asymptomatic patients with a normal neurologic examination. Subsequently, a length dependent motor and sensory polyneuropathy develops. Similar to other patients with vitamin B12 deficiency, vitamin B12 supplementation is a fundamental aspect of therapy. In this respect, it should be noted that while parenteral B12 has been the standard treatment protocol for many years, current evidence suggests that the oral route is also effective, avoiding the discomfort and cost associated with injections. Treatment measures specific to patients with isolated peripheral neuropathy include physical therapy and occupational therapy to improve gait, balance, and limb function. In addition, the importance of proper foot care and footwear cannot be overemphasized.

Take home messages

  1. Peripheral neuropathy in patients with diabetes should not be indiscriminately attributed to microvascular disease.
  2. Peripheral neuropathy secondary to vitamin B12 deficiency may precede the development of anemia.
  3. Low vitamin B12 levels do not necessarily imply vitamin B12 deficiency; nor do normal vitamin B12 levels always exclude deficiency.
  4. Oral vitamin B12 is efficacious in the treatment of these patients, and avoids the cost and discomfort of parenteral therapy.

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  1. Efficacy of oral cobalamin (vitamin B12) therapy: Expert Opin Pharmacother, 2010
  2. Neurologic Manifestations of Vitamin B12 Deficiency: NEJM, 2003
  3. Rare sensory and autonomic disturbances associated with vitamin B12 deficiency: Journal of the Neurological Sciences, Dec 2009
  4. Reversible isolated sensory axonal neuropathy due to cobalamin deficiency: Muscle and Nerve, March 2012
  6. Vitamin B12 Deficiency: AFP, 2003
  7. Vitamin B12 Deficiency: Centers for Disease Control, 2009,