Abstract
Based on the hypothesis that mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) are caused by impaired vasodilation in an intracerebral artery, the authors evaluated the effects of administering l-arginine, a nitric oxide precursor. Patients were administered l-arginine intravenously at the acute phase or orally at the interictal phase. l-Arginine infusions significantly improved all strokelike symptoms, suggesting that oral administration within 30 minutes of a stroke significantly decreased frequency and severity of strokelike episodes.
Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) is a maternally inherited, multisystem mitochondrial disorder.1 The primary cause of strokelike episodes in young patients with MELAS, whether mitochondrial cytopathy, angiopathy, or both, remains controversial. Based on the hypothesis that strokelike episodes in MELAS are caused by segmental impairment of vasodilation in intracerebral arteries, we administered l-arginine by IV administration during the acute phase of strokelike episodes and by oral administration during the interictal phase.
Methods.
Patients.
We studied 24 patients referred to the hospital with MELAS diagnosed according to clinical, muscle pathologic, and genetic studies and 72 healthy control subjects (table 1). Patients with congenital anomalies, sepsis, IV hyperalimentation, diabetes mellitus, cardiac failure, or a bedridden state were excluded from this study.
Table 1 Baseline characteristics of the patients with MELAS and controls
Study design.
All patients or patients’ parents gave written informed consent, and the l-arginine study protocol was approved (Kurume University IRB no. 9715). The study design was chosen because of patients’ availability and finances did not permit a balanced, randomized design involving multiple centers. Our strokelike episodes fulfilled the criteria that patients have migraine headache, vomiting, convulsion, and transient blindness with brain image suggesting focal brain abnormality. Twenty-four patients with a total of 34 strokelike episodes took part in this study of l-arginine versus placebo, following a previously described protocol.2 The severity of a strokelike attack (convulsion, cortical blindness, hemiparesis, or abnormality in brain images associated with headache and vomiting) was similar when either l-arginine or placebo was administered.
Six patients were treated by oral administration of l-arginine to prevent strokelike episodes. Four to 24 g of l-arginine (Arugi U, Ajinomoto Pharma; 0.15 to 0.3 g/kg/d) were given orally for 18 months. Patients were monitored clinically and biochemically as described previously once every 2 weeks. When patients were admitted to the hospital with a strokelike episode, the following symptoms were scored: headache (present: 1, none: 0), vomiting (present: 1, none: 0), teichopsia (present: 1, none: 0), convulsion (present: 1, none: 0) and hemiparesis (present: 1, none; 0).3 For each admission during the study period, these scores were summed as the severity score for the stroke. Frequency of admission was taken to be the frequency of strokelike episodes. Severity and frequency were related to time as number and month and were compared between periods 18 months before and after oral administration of l-arginine in the same patient.
Analysis of amino acids, asymmetric dimethylarginine (ADMA),4 nitric oxide (NOx),5 cyclic guanosine monophosphate (cGMP)6 were measured using described methods.
Analysis.
Plasma concentrations of amino acids, NOx, and ADMA in patients in the acute or interictal phase of MELAS were compared with those in controls using unpaired t tests, with Bonferroni corrections for outlying values. Concentrations of l-arginine, l-citrulline, NOx, ADMA, and cGMP in plasma obtained before, 30 minutes after, and 24 hours after l-arginine infusion were compared with those in controls using paired t tests. Statistical analysis of clinical improvement was performed using Fisher’s exact test. Frequency and severity of strokelike episodes in six patients with MELAS after long-term oral l-arginine supplementation were compared with those in the same patients without supplementation using a nonparametric Mann–Whitney U test. All data are presented as means ± SD. p Values of 0.05 or less were considered to indicate significance.
Results.
Baseline characteristics of the 24 patients and 72 controls are shown in table 1. Mean plasma concentrations of l-arginine and l-citrulline were lower in both acute (l-arginine: 47 ± 13 μmol/L; l-citrulline: 23 ± 10 μmol/L) (p < 0.01) and interictal phases (l-arginine: 84 ± 26 μmol/L; l-citrulline: 26 ± 10 μmol/L) (p < 0.01) of MELAS than in controls (l-arginine: 108 ± 28 μmol/L; l-citrulline: 35 ± 9 μmol/L). Concentrations of l-arginine in the acute phase were also significantly lower than in the interictal phase, whereas those of l-citrulline did not show a significant phase-related change. NOx concentrations were lower in the acute phase (24 ± 10 μmol/L) (p < 0.01) of MELAS than in controls (45 ± 30 μmol/L), whereas in the interictal phase (91 ± 44 μmol/L) (p < 0.01), they were higher than in controls. Conversely, concentrations of ADMA did not significantly differ between controls and acute phase, although the ADMA/l-arginine ratio was higher in the acute phase (0.011 ± 0.004) (p < 0.01) than in the controls (0.005 ± 0.001) or in the interictal phase (0.005 ± 0.001).
Symptoms and biochemical measurements after l-arginine therapy in the acute phase of strokelike episodes in MELAS are shown in table 2 and the figure. After administration of l-arginine, all symptoms suggesting stroke dramatically improved. No adverse effects occurred, except headache, when l-arginine was infused too rapidly in two patients. With treatment, concentrations of lactate and pyruvate, l-arginine, l-citrulline, NOx, cGMP, and ADMA returned to interictal-phase concentrations within 24 hours.
Table 2 Effects of l-arginine on the clinical symptoms in acute phase of MELAS
Figure. Plasma concentrations of l-arginine, l-citrulline, nitric oxide (NOx), cyclic guanosine monophosphate (cGMP), lactate, and asymmetric dimethylarginine (ADMA) before and after l-arginine therapy in the acute phase of strokelike episodes in MELAS. Data represent mean ± SD (μmol/L) (n = 24). *p < 0.05; **p < 0.01 vs values before l-arginine therapy. ns = not significant. Filled circles show biochemical analysis after l-arginine therapy. Open squares show biochemical analysis after administration of placebo.
After oral l-arginine supplementation, the frequency and severity of symptoms caused by the stroke had decreased dramatically. Frequency of strokelike episodes after treatment (0.09 ± 0.09) (p < 0.05) decreased compared with before supplementation (0.78 ± 0.42). The severity score after treatment (0.17 ± 0.18) (p < 0.05) was also lower than before supplementation (2.04 ± 0.34). After l-arginine supplementation, no patient with MELAS had a major strokelike attack, including hemiconvulsion or hemiparesis, but only headache or teichopsia. Plasma concentrations of l-arginine in patients with MELAS ranged from 82 to 120 μmol/L (mean ± SD 92 ± 17 μmol/L) after initiation of l-arginine supplementation.
Discussion.
l-Arginine, which plays an important role in endothelium-dependent vascular relaxation, was significantly lower in both the acute and interictal phases of MELAS than in control subjects. Why plasma l-arginine is decreased in the acute phase of MELAS remains to be elucidated. We analyzed the correlation in all amino acids and found that the decrease of l-arginine in the acute phase is not influenced by urea cycle activities but may be caused by endothelial dysfunction (data not shown). A low l-arginine concentration and a relatively high ADMA concentration may predispose to strokelike episodes in MELAS. Impairment of endothelial function associated with relatively increased ADMA concentrations is reversed by IV l-arginine.7 Consistent with these data, l-arginine infusion improved the ischemic process during the acute phase of MELAS.
Focal cerebral hyperemia has been reported in MELAS.8 Although the underlying mechanisms are incompletely understood, hyperemia is thought to reflect vasodilation caused by local metabolic acidosis in the area of the infarct or by the foci of periodic epileptiform discharge.9 Because the above studies were performed several days or several weeks after the onset of a strokelike episode, secondarily induced NOx production generated by inducible NOx synthase in the injured region may alter evidence of the primary pathophysiologic abnormality. In an analysis of SPECT findings in young patients with MELAS at a very early stage of strokelike episodes (within 3 hours after onset), we found hypoperfusion in the region affected by the strokelike episode. We cannot explain conclusively why our findings differ from those reported by neurologists treating adults. If the sites of angiopathy in MELAS most likely include small cerebral arteries, arterioles, and capillaries, small infarcts would be expected rather than the large confluent region of infarction described in many reports of MELAS. l-Arginine is an important precursor of NOx, which may reduce ischemic damage in the acute phase of focal brain ischemia by increasing microcirculation in the cerebral blood flow. The symptoms improved earliest, and magnetic resonance spectroscopy abnormality was minimal when l-arginine was given during the acute phase of strokelike episodes in MELAS.10
We evaluated the effects of oral l-arginine supplementation on long-term occurrence of strokelike episodes. The frequency and severity of clinical symptoms of strokelike episodes decreased without serious adverse effects. Prophylactically treated patients with MELAS have not had major strokelike attacks such as hemiconvulsion and hemiparesis. Headache and teichopsia have occurred.
References
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