LAUSR

OBJECTIVE Stroke management in the context of primary mitochondrial disease is clinically challenging and the best treatment options for patients with stroke-like episodes remain uncertain. We sought to perform a systematic review on the safety and efficacy of L-arginine use in the acute and prophylactic management of stroke-like episodes in patients with mitochondrial disease. METHODS The systematic review was registered in PROSPERO (CRD42020181230). We searched six databases from inception - 15/01/2021: MEDLINE, Embase, Scopus, Web of Science, CINAHL and ClinicalTrials.gov. Original articles and registered trials available, in English, reporting L-arginine use in the acute or prophylactic management of stroke-like episodes in patients with genetically confirmed mitochondrial disease were eligible for inclusion.Data on safety and treatment response were extracted and summarized by multiple observers. Risk of bias was assessed by the methodological quality of case reports, case series and a risk-of-bias checklist for non-randomized studies. Quality of evidence was synthesized using the Oxford Centre for Evidence-Based Medicine Levels of Evidence and Grade of Recommendations. The predetermined main outcome measures were clinical response to L-arginine treatment, adverse events, withdrawals, and deaths (on treatment and/or during follow up), as defined by the author. RESULTS Thirty-seven articles met inclusion [0=randomised controlled trials (RCTs); 3 open-label; 1 retrospective cohort; 33 case reports/case series] (N = 91 patients; 86% m.3243A>G). In the case reports, 54% of patients reported a positive clinical response to acute L-arginine, of which 40% were concomitantly treated with AEDs. Improved headache at 24-hours was the greatest reported benefit in response to IV L-arginine in the open-label trials (31/39, 79%). Of 15/48 patients (31%) who positively responded to prophylactic L-arginine, AEDs were either used (7/15) or unreported (8/15). Moderate adverse events were reported in the follow-up of both IV and oral L-arginine treatment and 11 patients (12%) died during follow up or while on prophylactic treatment. CONCLUSION The available evidence is of poor methodological quality and classified as Level 5. IV and/or oral L-arginine confers no demonstrable clinical benefit in either the acute or prophylactic treatment of MELAS, with more robust controlled trials required to assess its efficacy and safety profile.