Changes in B12, MMA, and Homocysteine Linked to Peripheral Neuropathy

The researchers investigated how low levels of B vitamins were associated with peripheral neuropathy and the effect of vitamin treatment on symptoms of pain.

According to results of a systematic review and meta-analysis, patients with peripheral neuropathy (PN) were more likely to have elevated methylmalonic acid (MMA) concentrations and homocysteine levels and depleted vitamin B12 levels regardless of the disease believed to have caused the PN. These results were published in the European Journal of Neurology.

Researchers searched publication databases through September 2018 for studies of neuropathy that included plasma or serum assessment for metabolites. This analysis included observational (n=46) and interventional (n=7) studies of patients with PN.

Among the observational studies, reduced plasma vitamin B12 levels were observed among 2948 patients with PN compared with 9432 control group participants. The pooled estimate for lowered levels of vitamin B12 was 1.51 (95% CI, 1.23-1.84) with moderate heterogeneity (I2, 43.3%; P =.003) and no publication bias (P =.065).

The relationship between PN and B12 levels was significant among European (pooled estimate, 1.66; 95% CI, 1.20-2.31; I2, 13.4%; P =.314) and North American studies (pooled estimate, 1.55; 95% CI, 1.14-2.10; I2, 44.8%; P =.053) but not among Asian studies (pooled estimate, 1.43; 95% CI, 0.87-2.36; I2, 63.5%; P =.003).

MMA concentrations were elevated in 827 patients with PN compared with concentrations in 1492 control group participants (pooled estimate, 2.53; 95% CI, 1.39-4.60; I2, 63.8%; P =.005) but with significant publication bias (P =.033).

Homocysteine levels were elevated in 1047 patients with PN compared with 4763 control group participants (pooled estimate, 3.48; 95% CI, 2.01-6.04; I2, 70.6%; P <.001) with no publication bias (P =.276).

Among the interventional studies, the odds ratio (OR) for improvement of NP symptoms after vitamin B12 supplementation was 1.36 (95% CI, 0.66-2.79; I2, 28.9%). Significant symptom improvement was observed with vitamin B1 supplementation (OR, 5.34; 95% CI, 1.87-15.19; I2, 64.6%; P =.059).

These findings may have been biased by the discrepant definitions of vitamin B12 markers.

These data indicated patients with PN had altered plasma vitamin levels, MMA concentrations, and homocysteine levels — all are potential therapeutic targets.

Disclosure: An author declared an affiliation with the pharmaceutical industry. Please refer to the original article for a full list of authors’ disclosures.


Stein J, Geisel J, Obeid R. Association between neuropathy and B-vitamins; a systematic review and meta-analysis. Eur J Neurol. Published online February 22, 2021. doi:10.1111/ene.14786