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Recommendations for the Management of Strokelike Episodes in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes

Recommendations for the Management of Strokelike Episodes in Patients With Mitochondrial... Abstract Importance Strokelike episodes are a cardinal feature of several mitochondrial syndromes, including mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS). Recent advances in the understanding of the pathophysiologic mechanisms of strokelike episodes in MELAS have led to improved treatment options. Observations Current understanding of the cause of strokelike episodes in MELAS and present recommendations to assist in the identification and treatment of patients with MELAS who present with stroke are presented. Mounting evidence points toward a benefit of the nitric oxide precursors, arginine, to both prevent and reduce the severity of strokes in patients with MELAS. Conclusions and Relevance Although much information is still needed regarding the appropriate dosing and timing of arginine therapy in patients with MELAS, urgent administration of nitric oxide precursors in patients with MELAS ameliorates the clinical symptoms associated with strokelike episodes. Introduction Mitochondrial encephalomyopathies are a complex group of disorders with multisystem involvement that have a wide range of biochemical and genetic defects. Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) is one of the better described mitochondrial encephalomyopathies, with a prevalence as frequent as 1 in 6000 people.1,2 Although the most common cause of MELAS is a missense mitochondrial DNA (mtDNA) mutation (m.3243A>G) in the MT-TL1 gene (OMIM 590050) encoding 1 of the 2 mitochondrial transfer RNAs for leucine, tRNALeu(UUR),3,4 MELAS can also be caused by multiple other mtDNA mutations and mutations in nuclear genes, such as POLG (OMIM 174763). Common symptoms of MELAS include muscle weakness, easy fatigability, endocrinopathies, gastrointestinal dysmotility, sensorineural hearing loss, diabetes mellitus, headaches, seizures, dementia, and strokelike episodes.5 Strokelike Episodes Strokelike episodes are the cardinal feature of MELAS and often the primary reason for diagnosis. The hallmark of strokelike episodes in MELAS is the lack of conformation of ischemic regions to the typical vascular territories seen in classic thrombotic or embolic strokes6 (Figure 1). Although recovery from strokelike episodes in MELAS is typically rapid and complete early in the disease, once the first strokelike episode occurs, a patient’s neurologic status continues to deteriorate, resulting in disability and premature death.7 Strokelike episodes present clinically with variable neurologic symptoms, including seizures, headaches, altered mental status, focal weakness, visual loss, sensory loss, dysarthria, and ataxia. Magnetic resonance imaging of the acute strokelike events reveals high signal on diffusion-weighted imaging8,9 with corresponding high signal on T2-weighted and fluid-attenuated inversion recovery sequences. Apparent diffusion coefficient signal of the affected regions may be increased, decreased, or mixed, suggesting coexistence of cytotoxic (low apparent diffusion coefficient) and vasogenic (high apparent diffusion coefficient) edema within a strokelike lesion in patients with MELAS.10 The affected areas typically involve the cortex and subjacent white matter, with sparing of the deep white matter. Acute changes may fluctuate, migrate, or even disappear completely during the acute to subacute phase.11 Magnetic resonance spectroscopy can detect the presence of lactate within the infarction and in other unaffected regions of the brain.12 As early as 1996, Wang et al13 found impaired vasodilation of cerebral blood vessels in patients with MELAS. There is now mounting evidence that the strokelike episodes in MELAS result, at least in part, from impaired oxidative phosphorylation within the cerebral vasculature, producing impaired vasodilation (secondary to a mitochondrial angiopathy) and cytotoxic damage (secondary to a mitochondrial cytopathy).14,15 The mitochondrial cytopathy produces cytotoxic edema through increased glycolysis, lactate production, and reactive oxygen species; reduced glucose oxidation, mitochondrial membrane potential fluctuations, and adenosine triphosphate production; impaired nicotinamide adenine dinucleotide response; and disrupted calcium homeostasis.16 Coexisting with the mitochondrial cytopathy is a mitochondrial angiopathy.14,15 Endothelial and smooth muscle cells of cerebral arterioles and capillaries have a proliferation of abnormal mitochondria.14,15,17 These regions have smooth muscle cell dysfunction and impaired regulation of blood flow,18 producing a segmental vasodilatation defect and subsequent vasogenic edema. Clinical Evaluation and Management Appropriate identification of patients at risk for MELAS is important and those with MELAS should receive immediate clinical evaluation. The eAppendix in the Supplement provides a proposed protocol for the management of strokelike episodes in patients with MELAS. Nitric Oxide Metabolism Within the cerebral endothelial smooth muscle cells, nitric oxide binds to guanylate cyclase, converting guanosine triphosphate to cyclic guanosine monophosphate. This process leads to relaxation of the smooth muscle cells (endothelium) and vasodilation of blood vessels (Figure 2). Nitric oxide has a strong affinity for cytochrome c oxidase, and the endothelial and smooth muscle cells in patients with MELAS have excess cytochrome c oxidase activity,19 which results in increased nitric oxide binding and lower availability of nitric oxide in the endothelial and smooth muscle cells. Hemodynamic and metabolic stress enhances nitric oxide recruitment further, again decreasing circulating nitric oxide levels. Lack of nitric oxide results in vasoconstriction, hypoxemia, and the strokelike episodes seen in patients with MELAS.20 Arginine Endothelium-dependent vascular relaxation is mediated by the enzyme endothelial nitric oxide synthase, which converts l-arginine to nitric oxide (Figure 2). In 2006, Koga et al21 noted that patients with MELAS had significantly low levels of l-arginine during the acute phase of their strokelike episodes. Through a series of follow-up studies, Koga et al22 revealed the effectiveness of arginine in decreasing the severity of strokelike symptoms, reducing the frequency of strokelike episodes, enhancing microcirculatory dynamics, and reducing tissue injury in patients with MELAS. Although, to our knowledge, no randomized clinical trials have been performed, the evidence presented is compelling and has led to the wide implementation of arginine use for the treatment of acute strokelike episodes and prevention of strokelike episodes in patients with MELAS. In 2015, Parikh et al23 published a consensus statement from the Mitochondrial Medicine Society on the diagnosis and management of mitochondrial disease. This review includes recommendations regarding the use of arginine in the management of acute strokelike episodes in patients with MELAS. The current review summarizes and expands on those recommendations. Citrulline Citrulline also acts as a nitric oxide precursor, and hypocitrullinemia has been observed in patients with MELAS.19 Short-term citrulline supplementation raises nitric oxide production to a greater extent than arginine because of the significant increase in de novo arginine synthesis associated with citrulline supplementation24; thus, in addition to arginine, administration of citrulline has the potential for therapeutic use in MELAS. Controlled studies that assessed the effects of citrulline supplementation on clinical aspects of MELAS are needed to support its use as a therapeutic modality. Short-term Therapy Patients with known MELAS who present with any symptoms suggestive of a metabolic stroke should receive a loading dose of intravenous arginine hydrochloride. Although the optimal dose has not been defined, a bolus of 0.5 g/kg given within 3 hours of symptom onset is recommended. Imaging may be helpful to determine whether an acute strokelike episode is occurring; however, arginine treatment should not be delayed for imaging. Normal saline boluses should be given intravenously to maintain cerebral perfusion, and the patient should be given dextrose-containing fluids as soon as possible to reverse ongoing or impending catabolism (even in the setting of euglycemia). If the clinical presentation is altered mental status, patients should immediately undergo electroencephalography to assess for subclinical (nonconvulsive) status epilepticus because this is a common cause of altered mental status in patients with MELAS. Ongoing Therapy After the initial arginine bolus, an additional 0.5 g/kg should be administered as a continuous infusion for 24 hours for the next 3 to 5 days. Although there is no clinical evidence on how long to continue the maintenance dose of arginine, most mitochondrial specialists recommend continuing treatment for at least 3 days. If clinical symptoms persist at 3 days, performing imaging again to evaluate for stroke progression and continuing the arginine therapy for a total of 5 days should be considered. Patients may be transitioned to oral l-arginine at a 1-to-1 dose once swallowing safety is ensured and they are able to tolerate oral intake. Prophylaxis Once a patient with MELAS has experienced a first stroke, arginine should be administered prophylactically to reduce the risk of recurrent strokelike episodes. A daily dose of 0.15 to 0.30 g/kg administered orally in 3 divided doses is recommended. Conclusions Although much information is still needed regarding the appropriate dosing and timing of arginine therapy in patients with MELAS, mounting evidence points toward a marked benefit of arginine to prevent and reduce the severity of strokes in patients with this condition. Section Editor: David E. Pleasure, MD. Back to top Article Information Accepted for Publication: December 28, 2015. Corresponding Author: Mary Kay Koenig, MD, The University of Texas Medical School at Houston, 6410 Fannin St, UTPB 732, Houston, TX 77030 (Mary.K.Koenig@uth.tmc.edu). Published Online: March 7, 2016. doi:10.1001/jamaneurol.2015.5072. Author Contributions: Drs Koenig and Goldstein had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: All authors. Acquisition, analysis, or interpretation of data: Koenig, Goldstein. Drafting of the manuscript: Koenig, Emrick, Karaa, Korson, Parikh. Critical revision of the manuscript for important intellectual content: Koenig, Emrick, Karaa, Scaglia, Parikh, Goldstein. Administrative, technical, or material support: Koenig, Karaa, Goldstein. Study supervision: Koenig, Scaglia, Parikh, Goldstein. Conflict of Interest Disclosures: None reported. References 1. Chinnery PF, Johnson MA, Wardell TM, et al. The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol. 2000;48(2):188-193.PubMedGoogle ScholarCrossref 2. Majamaa K, Moilanen JS, Uimonen S, et al. Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. Am J Hum Genet. 1998;63(2):447-454.PubMedGoogle ScholarCrossref 3. Goto Y, Nonaka I, Horai S. A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990;348(6302):651-653.PubMedGoogle ScholarCrossref 4. Goto Y, Horai S, Matsuoka T, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation. Neurology. 1992;42(3, pt 1):545-550.PubMedGoogle ScholarCrossref 5. Ciafaloni E, Ricci E, Shanske S, et al. MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol. 1992;31(4):391-398.PubMedGoogle ScholarCrossref 6. Koga Y, Povalko N, Nishioka J, Katayama K, Yatsuga S, Matsuishi T. Molecular pathology of MELAS and l-arginine effects. Biochim Biophys Acta. 2012;1820(5):608-614.PubMedGoogle ScholarCrossref 7. Hirano M, Pavlakis SG. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts. J Child Neurol. 1994;9(1):4-13.PubMedGoogle ScholarCrossref 8. Ohshita T, Oka M, Imon Y, et al. Serial diffusion-weighted imaging in MELAS. Neuroradiology. 2000;42(9):651-656.PubMedGoogle ScholarCrossref 9. Ito H, Mori K, Harada M, et al. Serial brain imaging analysis of stroke-like episodes in MELAS. Brain Dev. 2008;30(7):483-488.PubMedGoogle ScholarCrossref 10. Stoquart-Elsankari S, Lehmann P, Périn B, Gondry-Jouet C, Godefroy O. MRI and diffusion-weighted imaging followup of a stroke-like event in a patient with MELAS. J Neurol. 2008;255(10):1593-1595.PubMedGoogle ScholarCrossref 11. Koga Y, Povalko N, Nishioka J, Katayama K, Kakimoto N, Matsuishi T. MELAS and l-arginine therapy: pathophysiology of stroke-like episodes. Ann N Y Acad Sci. 2010;1201:104-110.PubMedGoogle ScholarCrossref 12. Castillo M, Kwock L, Green C. MELAS syndrome: imaging and proton MR spectroscopic findings. AJNR Am J Neuroradiol. 1995;16(2):233-239.PubMedGoogle Scholar 13. Wang XL, Sim AS, Badenhop RF, McCredie RM, Wilcken DEL. A smoking-dependent risk of coronary artery disease associated with a polymorphism of the endothelial nitric oxide synthase gene. Nat Med. 1996;2(1):41-45.PubMedGoogle ScholarCrossref 14. Ohama E, Ohara S, Ikuta F, Tanaka K, Nishizawa M, Miyatake T. Mitochondrial angiopathy in cerebral blood vessels of mitochondrial encephalomyopathy. Acta Neuropathol. 1987;74(3):226-233.PubMedGoogle ScholarCrossref 15. Kishi M, Yamamura Y, Kurihara T, et al. An autopsy case of mitochondrial encephalomyopathy: biochemical and electron microscopic studies of the brain. J Neurol Sci. 1988;86(1):31-40.PubMedGoogle ScholarCrossref 16. Jahangir Tafrechi RS, Svensson PJ, Janssen GMC, Szuhai K, Maassen JA, Raap AK. Distinct nuclear gene expression profiles in cells with mtDNA depletion and homoplasmic A3243G mutation. Mutat Res. 2005;578(1-2):43-52.PubMedGoogle ScholarCrossref 17. Koga Y, Nonaka I, Kobayashi M, Tojyo M, Nihei K. Findings in muscle in complex I (NADH coenzyme Q reductase) deficiency. Ann Neurol. 1988;24(6):749-756.PubMedGoogle ScholarCrossref 18. Lax NZ, Pienaar IS, Reeve AK, et al. Microangiopathy in the cerebellum of patients with mitochondrial DNA disease. Brain. 2012;135(pt 6):1736-1750.PubMedGoogle ScholarCrossref 19. Naini A, Kaufmann P, Shanske S, Engelstad K, De Vivo DC, Schon EA. Hypocitrullinemia in patients with MELAS: an insight into the “MELAS paradox.” J Neurol Sci. 2005;229-230:187-193.PubMedGoogle ScholarCrossref 20. Vos MH, Lipowski G, Lambry JC, Martin JL, Liebl U. Dynamics of nitric oxide in the active site of reduced cytochrome c oxidase aa3. Biochemistry. 2001;40(26):7806-7811.PubMedGoogle ScholarCrossref 21. Koga Y, Akita Y, Junko N, et al. Endothelial dysfunction in MELAS improved by l-arginine supplementation. Neurology. 2006;66(11):1766-1769.PubMedGoogle ScholarCrossref 22. Koga Y, Akita Y, Nishioka J, et al. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology. 2005;64(4):710-712.PubMedGoogle ScholarCrossref 23. Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015;17(9):689-701.PubMedGoogle ScholarCrossref 24. El-Hattab AW, Hsu JW, Emrick LT, et al. Restoration of impaired nitric oxide production in MELAS syndrome with citrulline and arginine supplementation. Mol Genet Metab. 2012;105(4):607-614.PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Neurology American Medical Association

Recommendations for the Management of Strokelike Episodes in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes

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Publisher
American Medical Association
Copyright
Copyright © 2016 American Medical Association. All Rights Reserved.
ISSN
2168-6149
eISSN
2168-6157
DOI
10.1001/jamaneurol.2015.5072
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Abstract

Abstract Importance Strokelike episodes are a cardinal feature of several mitochondrial syndromes, including mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS). Recent advances in the understanding of the pathophysiologic mechanisms of strokelike episodes in MELAS have led to improved treatment options. Observations Current understanding of the cause of strokelike episodes in MELAS and present recommendations to assist in the identification and treatment of patients with MELAS who present with stroke are presented. Mounting evidence points toward a benefit of the nitric oxide precursors, arginine, to both prevent and reduce the severity of strokes in patients with MELAS. Conclusions and Relevance Although much information is still needed regarding the appropriate dosing and timing of arginine therapy in patients with MELAS, urgent administration of nitric oxide precursors in patients with MELAS ameliorates the clinical symptoms associated with strokelike episodes. Introduction Mitochondrial encephalomyopathies are a complex group of disorders with multisystem involvement that have a wide range of biochemical and genetic defects. Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) is one of the better described mitochondrial encephalomyopathies, with a prevalence as frequent as 1 in 6000 people.1,2 Although the most common cause of MELAS is a missense mitochondrial DNA (mtDNA) mutation (m.3243A>G) in the MT-TL1 gene (OMIM 590050) encoding 1 of the 2 mitochondrial transfer RNAs for leucine, tRNALeu(UUR),3,4 MELAS can also be caused by multiple other mtDNA mutations and mutations in nuclear genes, such as POLG (OMIM 174763). Common symptoms of MELAS include muscle weakness, easy fatigability, endocrinopathies, gastrointestinal dysmotility, sensorineural hearing loss, diabetes mellitus, headaches, seizures, dementia, and strokelike episodes.5 Strokelike Episodes Strokelike episodes are the cardinal feature of MELAS and often the primary reason for diagnosis. The hallmark of strokelike episodes in MELAS is the lack of conformation of ischemic regions to the typical vascular territories seen in classic thrombotic or embolic strokes6 (Figure 1). Although recovery from strokelike episodes in MELAS is typically rapid and complete early in the disease, once the first strokelike episode occurs, a patient’s neurologic status continues to deteriorate, resulting in disability and premature death.7 Strokelike episodes present clinically with variable neurologic symptoms, including seizures, headaches, altered mental status, focal weakness, visual loss, sensory loss, dysarthria, and ataxia. Magnetic resonance imaging of the acute strokelike events reveals high signal on diffusion-weighted imaging8,9 with corresponding high signal on T2-weighted and fluid-attenuated inversion recovery sequences. Apparent diffusion coefficient signal of the affected regions may be increased, decreased, or mixed, suggesting coexistence of cytotoxic (low apparent diffusion coefficient) and vasogenic (high apparent diffusion coefficient) edema within a strokelike lesion in patients with MELAS.10 The affected areas typically involve the cortex and subjacent white matter, with sparing of the deep white matter. Acute changes may fluctuate, migrate, or even disappear completely during the acute to subacute phase.11 Magnetic resonance spectroscopy can detect the presence of lactate within the infarction and in other unaffected regions of the brain.12 As early as 1996, Wang et al13 found impaired vasodilation of cerebral blood vessels in patients with MELAS. There is now mounting evidence that the strokelike episodes in MELAS result, at least in part, from impaired oxidative phosphorylation within the cerebral vasculature, producing impaired vasodilation (secondary to a mitochondrial angiopathy) and cytotoxic damage (secondary to a mitochondrial cytopathy).14,15 The mitochondrial cytopathy produces cytotoxic edema through increased glycolysis, lactate production, and reactive oxygen species; reduced glucose oxidation, mitochondrial membrane potential fluctuations, and adenosine triphosphate production; impaired nicotinamide adenine dinucleotide response; and disrupted calcium homeostasis.16 Coexisting with the mitochondrial cytopathy is a mitochondrial angiopathy.14,15 Endothelial and smooth muscle cells of cerebral arterioles and capillaries have a proliferation of abnormal mitochondria.14,15,17 These regions have smooth muscle cell dysfunction and impaired regulation of blood flow,18 producing a segmental vasodilatation defect and subsequent vasogenic edema. Clinical Evaluation and Management Appropriate identification of patients at risk for MELAS is important and those with MELAS should receive immediate clinical evaluation. The eAppendix in the Supplement provides a proposed protocol for the management of strokelike episodes in patients with MELAS. Nitric Oxide Metabolism Within the cerebral endothelial smooth muscle cells, nitric oxide binds to guanylate cyclase, converting guanosine triphosphate to cyclic guanosine monophosphate. This process leads to relaxation of the smooth muscle cells (endothelium) and vasodilation of blood vessels (Figure 2). Nitric oxide has a strong affinity for cytochrome c oxidase, and the endothelial and smooth muscle cells in patients with MELAS have excess cytochrome c oxidase activity,19 which results in increased nitric oxide binding and lower availability of nitric oxide in the endothelial and smooth muscle cells. Hemodynamic and metabolic stress enhances nitric oxide recruitment further, again decreasing circulating nitric oxide levels. Lack of nitric oxide results in vasoconstriction, hypoxemia, and the strokelike episodes seen in patients with MELAS.20 Arginine Endothelium-dependent vascular relaxation is mediated by the enzyme endothelial nitric oxide synthase, which converts l-arginine to nitric oxide (Figure 2). In 2006, Koga et al21 noted that patients with MELAS had significantly low levels of l-arginine during the acute phase of their strokelike episodes. Through a series of follow-up studies, Koga et al22 revealed the effectiveness of arginine in decreasing the severity of strokelike symptoms, reducing the frequency of strokelike episodes, enhancing microcirculatory dynamics, and reducing tissue injury in patients with MELAS. Although, to our knowledge, no randomized clinical trials have been performed, the evidence presented is compelling and has led to the wide implementation of arginine use for the treatment of acute strokelike episodes and prevention of strokelike episodes in patients with MELAS. In 2015, Parikh et al23 published a consensus statement from the Mitochondrial Medicine Society on the diagnosis and management of mitochondrial disease. This review includes recommendations regarding the use of arginine in the management of acute strokelike episodes in patients with MELAS. The current review summarizes and expands on those recommendations. Citrulline Citrulline also acts as a nitric oxide precursor, and hypocitrullinemia has been observed in patients with MELAS.19 Short-term citrulline supplementation raises nitric oxide production to a greater extent than arginine because of the significant increase in de novo arginine synthesis associated with citrulline supplementation24; thus, in addition to arginine, administration of citrulline has the potential for therapeutic use in MELAS. Controlled studies that assessed the effects of citrulline supplementation on clinical aspects of MELAS are needed to support its use as a therapeutic modality. Short-term Therapy Patients with known MELAS who present with any symptoms suggestive of a metabolic stroke should receive a loading dose of intravenous arginine hydrochloride. Although the optimal dose has not been defined, a bolus of 0.5 g/kg given within 3 hours of symptom onset is recommended. Imaging may be helpful to determine whether an acute strokelike episode is occurring; however, arginine treatment should not be delayed for imaging. Normal saline boluses should be given intravenously to maintain cerebral perfusion, and the patient should be given dextrose-containing fluids as soon as possible to reverse ongoing or impending catabolism (even in the setting of euglycemia). If the clinical presentation is altered mental status, patients should immediately undergo electroencephalography to assess for subclinical (nonconvulsive) status epilepticus because this is a common cause of altered mental status in patients with MELAS. Ongoing Therapy After the initial arginine bolus, an additional 0.5 g/kg should be administered as a continuous infusion for 24 hours for the next 3 to 5 days. Although there is no clinical evidence on how long to continue the maintenance dose of arginine, most mitochondrial specialists recommend continuing treatment for at least 3 days. If clinical symptoms persist at 3 days, performing imaging again to evaluate for stroke progression and continuing the arginine therapy for a total of 5 days should be considered. Patients may be transitioned to oral l-arginine at a 1-to-1 dose once swallowing safety is ensured and they are able to tolerate oral intake. Prophylaxis Once a patient with MELAS has experienced a first stroke, arginine should be administered prophylactically to reduce the risk of recurrent strokelike episodes. A daily dose of 0.15 to 0.30 g/kg administered orally in 3 divided doses is recommended. Conclusions Although much information is still needed regarding the appropriate dosing and timing of arginine therapy in patients with MELAS, mounting evidence points toward a marked benefit of arginine to prevent and reduce the severity of strokes in patients with this condition. Section Editor: David E. Pleasure, MD. Back to top Article Information Accepted for Publication: December 28, 2015. Corresponding Author: Mary Kay Koenig, MD, The University of Texas Medical School at Houston, 6410 Fannin St, UTPB 732, Houston, TX 77030 (Mary.K.Koenig@uth.tmc.edu). Published Online: March 7, 2016. doi:10.1001/jamaneurol.2015.5072. Author Contributions: Drs Koenig and Goldstein had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: All authors. Acquisition, analysis, or interpretation of data: Koenig, Goldstein. Drafting of the manuscript: Koenig, Emrick, Karaa, Korson, Parikh. Critical revision of the manuscript for important intellectual content: Koenig, Emrick, Karaa, Scaglia, Parikh, Goldstein. Administrative, technical, or material support: Koenig, Karaa, Goldstein. Study supervision: Koenig, Scaglia, Parikh, Goldstein. Conflict of Interest Disclosures: None reported. References 1. Chinnery PF, Johnson MA, Wardell TM, et al. The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol. 2000;48(2):188-193.PubMedGoogle ScholarCrossref 2. Majamaa K, Moilanen JS, Uimonen S, et al. Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. Am J Hum Genet. 1998;63(2):447-454.PubMedGoogle ScholarCrossref 3. Goto Y, Nonaka I, Horai S. A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990;348(6302):651-653.PubMedGoogle ScholarCrossref 4. Goto Y, Horai S, Matsuoka T, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation. Neurology. 1992;42(3, pt 1):545-550.PubMedGoogle ScholarCrossref 5. Ciafaloni E, Ricci E, Shanske S, et al. MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol. 1992;31(4):391-398.PubMedGoogle ScholarCrossref 6. Koga Y, Povalko N, Nishioka J, Katayama K, Yatsuga S, Matsuishi T. Molecular pathology of MELAS and l-arginine effects. Biochim Biophys Acta. 2012;1820(5):608-614.PubMedGoogle ScholarCrossref 7. Hirano M, Pavlakis SG. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts. J Child Neurol. 1994;9(1):4-13.PubMedGoogle ScholarCrossref 8. Ohshita T, Oka M, Imon Y, et al. Serial diffusion-weighted imaging in MELAS. Neuroradiology. 2000;42(9):651-656.PubMedGoogle ScholarCrossref 9. Ito H, Mori K, Harada M, et al. Serial brain imaging analysis of stroke-like episodes in MELAS. Brain Dev. 2008;30(7):483-488.PubMedGoogle ScholarCrossref 10. Stoquart-Elsankari S, Lehmann P, Périn B, Gondry-Jouet C, Godefroy O. MRI and diffusion-weighted imaging followup of a stroke-like event in a patient with MELAS. J Neurol. 2008;255(10):1593-1595.PubMedGoogle ScholarCrossref 11. Koga Y, Povalko N, Nishioka J, Katayama K, Kakimoto N, Matsuishi T. MELAS and l-arginine therapy: pathophysiology of stroke-like episodes. Ann N Y Acad Sci. 2010;1201:104-110.PubMedGoogle ScholarCrossref 12. Castillo M, Kwock L, Green C. MELAS syndrome: imaging and proton MR spectroscopic findings. AJNR Am J Neuroradiol. 1995;16(2):233-239.PubMedGoogle Scholar 13. Wang XL, Sim AS, Badenhop RF, McCredie RM, Wilcken DEL. A smoking-dependent risk of coronary artery disease associated with a polymorphism of the endothelial nitric oxide synthase gene. Nat Med. 1996;2(1):41-45.PubMedGoogle ScholarCrossref 14. Ohama E, Ohara S, Ikuta F, Tanaka K, Nishizawa M, Miyatake T. Mitochondrial angiopathy in cerebral blood vessels of mitochondrial encephalomyopathy. Acta Neuropathol. 1987;74(3):226-233.PubMedGoogle ScholarCrossref 15. Kishi M, Yamamura Y, Kurihara T, et al. An autopsy case of mitochondrial encephalomyopathy: biochemical and electron microscopic studies of the brain. J Neurol Sci. 1988;86(1):31-40.PubMedGoogle ScholarCrossref 16. Jahangir Tafrechi RS, Svensson PJ, Janssen GMC, Szuhai K, Maassen JA, Raap AK. Distinct nuclear gene expression profiles in cells with mtDNA depletion and homoplasmic A3243G mutation. Mutat Res. 2005;578(1-2):43-52.PubMedGoogle ScholarCrossref 17. Koga Y, Nonaka I, Kobayashi M, Tojyo M, Nihei K. Findings in muscle in complex I (NADH coenzyme Q reductase) deficiency. Ann Neurol. 1988;24(6):749-756.PubMedGoogle ScholarCrossref 18. Lax NZ, Pienaar IS, Reeve AK, et al. Microangiopathy in the cerebellum of patients with mitochondrial DNA disease. Brain. 2012;135(pt 6):1736-1750.PubMedGoogle ScholarCrossref 19. Naini A, Kaufmann P, Shanske S, Engelstad K, De Vivo DC, Schon EA. Hypocitrullinemia in patients with MELAS: an insight into the “MELAS paradox.” J Neurol Sci. 2005;229-230:187-193.PubMedGoogle ScholarCrossref 20. Vos MH, Lipowski G, Lambry JC, Martin JL, Liebl U. Dynamics of nitric oxide in the active site of reduced cytochrome c oxidase aa3. Biochemistry. 2001;40(26):7806-7811.PubMedGoogle ScholarCrossref 21. Koga Y, Akita Y, Junko N, et al. Endothelial dysfunction in MELAS improved by l-arginine supplementation. Neurology. 2006;66(11):1766-1769.PubMedGoogle ScholarCrossref 22. Koga Y, Akita Y, Nishioka J, et al. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology. 2005;64(4):710-712.PubMedGoogle ScholarCrossref 23. Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015;17(9):689-701.PubMedGoogle ScholarCrossref 24. El-Hattab AW, Hsu JW, Emrick LT, et al. Restoration of impaired nitric oxide production in MELAS syndrome with citrulline and arginine supplementation. Mol Genet Metab. 2012;105(4):607-614.PubMedGoogle ScholarCrossref

Journal

JAMA NeurologyAmerican Medical Association

Published: May 1, 2016

Keywords: arginine,acidosis, lactic,melas syndrome,mitochondrial encephalomyopathies,nitric oxide therapy,mitochondria,cerebrovascular accident,nitric oxide,ischemic stroke

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