l -Arginine in Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes

Abstract

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.

A 47-Year-Old Man Presenting With Seizures and Prior Stroke

“…[25][26][27] A recent systematic review demonstrated a limited benefit of Larginine, suggesting that stroke-like episodes may be epileptic in nature requiring ASM treatment. 28 VPA should be avoided in patients with mitochondrial disease due to the risk of hepatic dysfunction and the possibility of a decline in mitochondrial function. 26,27 In resource-limited settings such as Peru, availability, accessibility, and affordability of neurodiagnostic testing are limited.…”

A clinical approach to diagnosis and management of mitochondrial myopathies

“…There is a paucity of randomized controlled trials and difficulty in measuring clinical outcomes to evaluate the efficacy of such regimens. For example, a systematic review of 37 articles on the use of l-arginine in MELAS showed no demonstrable clinical efficacy, but the studies were assessed to be of poor methodologic quality [ 68 ]. Nonetheless, such regimens have good safety profiles and reasonable acceptance and relatively easy applicability.…”

Management of noncytotoxic extravasation injuries: A focused update on medications, treatment strategies, and peripheral administration of vasopressors and hypertonic saline

“…7 It has also been studied for the prophylaxis and treatment of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in children and young adults with mixed results. 70 Properties of intravenous arginine include a pH 5.6 and an osmolarity 950 mOsm/L. 7 Infusions of arginine are known to be associated with venous irritation and several extravasations of arginine have been reported…”

“…Arginine is an essential amino acid that can be administered intravenously as a diagnostic agent to test for growth hormone production in pediatric patients and several other indications including metabolic alkalosis and genetic urea cycle disorders 7 . It has also been studied for the prophylaxis and treatment of mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes (MELAS) in children and young adults with mixed results 70 . Properties of intravenous arginine include a pH 5.6 and an osmolarity 950 mOsm/L 7 …”