Background: Current hypotheses on pathophysiology of restless legs syndrome (RLS) implicate iron as a cofactor in dopamine synthesis. Vitamin B12 also plays an important role in dopamine synthesis, but its role in the pathogenesis of RLS has not been studied. We hypothesize that Vitamin B12 deficiency can potentially reduce the synthesis of dopamine and thus RLS may be an early manifestation of this deficiency. Aims: To  measure serum vitamin B12 levels in patients with RLS and assess the response of RLS to its replacement. Methods and Material: To test this a Prospective, Open Label, Non­Randomized clinical Study was conducted. Fasting serum Vitamin B12 levels were measured in 44 consecutive patients who fulfilled the International RLS study group criteria. The response of RLS to dopamine agonists and to additional Vitamin B12 replacement therapy in those with low B12 levels, was measured. Results: Low serum Vitamin B12 levels (<211 pg/mL) were detected in 45% of patients with RLS. Those with normal B12 levels had a longer duration of symptoms, female preponderance and greater likelihood of positive family history. They were more likely to have a relapse of RLS symptoms after withdrawing dopamine agonists. Those with low vitamin B12 levels had shorter duration of illness, no gender preference, no family history and could be rapidly weaned off dopamine agonists without worsening of RLS symptoms, after B12 supplementation. None of the patients with low vitamin B12 levels had classical manifestations of B12 deficiency. Conclusion: As a significant number of our patients with RLS have low Vitamin B12 levels and respond well to its replacement, we propose that RLS may be an early neurological manifestation of vitamin B12 deficiency. 

Keywords: Restless Leg Syndrome; Vitamin B12 Deficiency; Clinical Manifestation