Abstract
ObjectiveTo examine the efficacy and safety of the therapeutic regimen using oral and intravenous l-arginine for pediatric and adult patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).MethodsIn the presence and absence of an ictus of stroke-like episodes within 6 h prior to efficacy assessment, we correspondingly conducted the systematic administration of oral and intravenous l-arginine to 15 and 10 patients with MELAS in two, 2-year, prospective, multicenter clinical trials at 10 medical institutions in Japan. Subsequently, patients were followed up for 7 years. The primary endpoint in the clinical trial of oral l-arginine was the MELAS scale, while that for intravenous l-arginine was the improvement rates of headache and nausea/vomiting at 2 h after completion of the initial intravenous administration. The relationships between the ictuses of stroke-like episodes and plasma arginine concentrations were examined.ResultsOral l-arginine extended the interictal phase (p = 0.0625) and decreased the incidence and severity of ictuses. Intravenous l-arginine improved the rates of four major symptoms—headache, nausea/vomiting, impaired consciousness, and visual disturbance. The maximal plasma arginine concentration was 167 μmol/L when an ictus developed. Neither death nor bedriddenness occurred during the 2-year clinical trials, and the latter did not develop during the 7-year follow-up despite the progressively neurodegenerative and eventually life-threatening nature of MELAS. No treatment-related adverse events occurred, and the formulations of l-arginine were well tolerated.ConclusionsThe systematic administration of oral and intravenous l-arginine may be therapeutically beneficial and clinically useful for patients with MELAS.
Highlights
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), a clinical phenotype of mitochondrial encephalomyopathies [1,2,3] and first reported by Pavlakis et al [4], is a progressively neurodegenerative and eventually life-threatening mitochondrial disorder that causes anatomohistopathological and clinical findings (e.g., A3243G point mutation in mtDNA, ragged red fibers, and stroke-like episodes)
The present research has integrated the pooled data from two small-sized clinical trials of oral and l-arginine in Japanese patients with MELAS that did not adopt the “placebocontrolled design”, because (1) strong ethical concerns were elicited by MELAS a miserable mitochondrial disease that could cause irreversible brain damage so severe as leading to bedriddenness after one ictus only in patients who would have received placebo and (2) impossibility of obtaining informed consent from candidate patients to accept a 50% probability of receiving placebo despite such a horrible feature of the disease under the current universal health insurance system in Japan, based on which the institutional review board at the participating sites necessarily led to abandon the initially designed randomized placebo-controlled trial
Our results afford clinical evidence on the therapeutic regimen of l-arginine therapy that is enough to satisfy the “unmet desire [18]” of pediatricians and neurologists around the world who are daily dedicated to the treatment of patients with MELAS
Summary
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), a clinical phenotype of mitochondrial encephalomyopathies [1,2,3] and first reported by Pavlakis et al [4], is a progressively neurodegenerative and eventually life-threatening mitochondrial disorder that causes anatomohistopathological and clinical findings (e.g., A3243G point mutation in mtDNA, ragged red fibers, and stroke-like episodes). MELAS has the estimated prevalence rate of 10–15 cases per 100,000 persons [5], and our 5-year, nationwide, multicenter, prospective cohort study in Japan [6] identified MELAS as the most common clinicopathologic type of mitochondrial disorders and indicated the following facts: the mortality rates from sudden death were 17.6% (3/17) and 33.3% (1/3) among 20 deaths in 58 patients with juvenile-onset MELAS (< 18 years) and 38 patients with adult-onset MELAS (≥ 18 years), respectively; and juvenile-onset MELAS was associated with a significantly higher mortality and more rapid disease progression than adult-onset MELAS, with a greater risk of renal failure an increasingly recognized clinical feature of mitochondrial cytopathies [7]. L-Arginine therapy has been suggested to be beneficial for patients with MELAS [6, 9,10,11,12,13,14,15].
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