L-arginine and mitochondrial encephalomyopathy, lactic acidosis and stroke- like episodes (MELAS): a systematic review

Background Stroke-like episodes are a neurological emergency associated with MELAS syndrome. Recovery from stroke-like episodes occurs over a variable time period (hours to weeks) and no rigorous natural history studies of the condition have been undertaken. Despite this, L-arginine has been adopted as both acute treatment and prophylaxis. We sought to systematically evaluate the evidence for L-argi- nine use. Methods We searched 5 databases published between inception and 15/01/2021. The inclusion criteria were 1) use of L-arginine in acute or chronic management of stroke-like episodes; 2) genetically confirmed mitochondrial disease. GRADE was used to assess the quality of evidence. Prospero registra- tion: CRD42020181230. Results Of 3,541 articles identified, 37 were eligible (3 open-label, 1 retrospective cohort, and 33 case reports). All studies were rated as very low-quality evidence. Open-label trials reported clinical response based on the subjective improvement of symptoms within 24 hours of treatment. Thirty-seven patients received L-arginine acutely in other studies. Clinical response was reported over variable time points (27/37); though confounders such as anticonvulsants (19/37) were not considered. Efficacy of chronic L-arginine supplementation cannot be established in most studies. Conclusion Evidence for the use of L-arginine in MELAS syndrome is poor, and is associated with a high risk of bias. yi.ng@ncl.ac.uk 19