MELAS – Mitochondrial Encephalomyopathy, Lactic Acidosis, Strokelike Episodes Overview of MELAS

MELAS – Mitochondrial Encephalomyopathy, Lactic Acidosis, Strokelike Episodes Overview of MELAS

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Patients with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) have strokelike events that are acute in onset, often transient, and occasionally associated with a febrile illness. The vascular territories of focal brain lesions and the prior medical history of these patients differ substantially from those of typical patients with stroke.

This syndrome is due to point or microdeletion mutations in mitochondrial DNA; as in all diseases with mitochondrial transmission, the disease is inherited via the ovum and hence always from the mother. Mitochondrial DNA is 10 times more prone to mutation than somatic DNA. Since both normal mitochondria and abnormal mitochondria may be present in tissues, the clinical presentation can be heterogeneous. Cardiomyopathy due to mitochondrial disease may produce typical cardioembolic strokes in some patients.

MELAS is a complicated, multisystem disease. Since the symptoms, signs, and acute clinical presentations are so varied and the disease is relatively rare, the disease is misdiagnosed frequently. Although MELAS remains a largely untreatable condition, prevention and management of medical complications may prolong survival, adding to the benefit of establishing a diagnosis.

Although classic features are seen on muscle biopsy, a negative muscle biopsy does not rule out this disease. Without a clear pattern of signs and symptoms, the clinical suspicion may be insufficient to prompt genetic analysis.

A multidisciplinary team approach is needed in the diagnosis and further care of patients with MELAS. Genetic testing and counseling should be offered to family members.

For more information on stroke, see Hemorrhagic Stroke and Ischemic Stroke.

For patient education information, see the Stroke Center, as well as Stroke.

An epidemiologic study in northern Finland found the prevalence of the A3243G MELAS mutation (responsible for 80% of cases) to be 16.3 per 100,000. In certain groups of stroke patients, such as those younger than 50 years, the prevalence of mitochondrial disease has been reported to be as high as 22%. Some mitochondrial mutations may give rise to “overlap” syndromes, which present with clinical features of more than one disease entity.

Males and females appear equally affected. Patients have normal early development and usually present in childhood with recurrent migraine-like headaches and vomiting. Typically, patients present with strokelike episodes by 40 years of age; however, strokelike episodes may present as early as the teens.

Patients present early with seemingly benign problems such as migraines; later, they may develop the full gamut of conditions that define the syndrome. The neurological dysfunction increases with increased age.

Seizures may become uncontrollable; dementia and other psychiatric disorders may supervene. Multiple strokes in different vascular territories may occur.

Early death is a common outcome. The reported ages of death range from 10 to 35 years of age, but patients alive in their 50s also have been described. Most deaths are due to medical complications; a few are a result of status epilepticus. [1]

When relatively young patients without common risk factors for ischemic stroke present with strokelike episodes and lesions that cross vascular boundaries, MELAS should be considered. Other points in favor of MELAS include previous migraine headaches, vomiting, acidotic episodes, or unexplained neurologic/psychiatric disorders.

Patients with MELAS typically have normal early development, followed by migraine-like headaches, focal or generalized seizures, growth retardation, hearing loss, [2] limb weakness, exercise intolerance, and strokelike episodes.

The cerebral lesions favor the posterior regions of the hemispheres, with hemianopia and cortical blindness appearing more frequently than hemiparesis.

Individual strokelike episodes may be followed by a complete recovery, but residual deficits and/or a progressive encephalopathy generally appear eventually.

Some of the common presentations include the following:

History of migraine along with vomiting

Cognitive deficits

Psychiatric problems

Seizures

Hearing loss

Diabetes [3]

The physical findings listed below are nonspecific. When the abnormalities occur together, MELAS should be considered, especially when a remitting-relapsing history is obtained. The physical findings include the following:

Short stature

Muscle weakness

Cognitive and psychiatric problems (eg, learning difficulties, dementia, psychosis, personality disorders)

Aphasia

Cortical blindness

Hemianopia

Hearing loss

Hemiparesis

Ataxia

Seizures or myoclonus

Tremor

MELAS is a mitochondrial genetic disease. At least 30 different point mutations have been associated with MELAS. The most common defect, present in 80% of patients, is a point mutation at nucleotide position 3243 in the transfer RNA for leucine. A number of other point mutations and double point mutations have also been associated with MELAS. [4]

Several case reports have suggested that valproic acid, an antiepileptic drug used also in migraine and psychiatric disorders, may exacerbate symptoms of MELAS. Apparently, valproic acid also may unmask a previously undiagnosed condition of MELAS.

Metabolic and vascular mechanisms have both been suggested as causes of the strokelike episodes in MELAS. According to the metabolic hypothesis, a defect exists in neuronal oxidative metabolism, with resulting mismatch between perfusion and metabolism. Perfusion may be normal, but the electron-transport chain defects of the mitochondria result in decreased ATP production, leading to neuronal death.

Magnetic resonance (MR) spectroscopic studies have shown that lactic acidosis may be increased, leading to neuronal toxicity in patients undergoing strokelike episodes. Cell death, however, does not explain the resolution of lesions by MRI or the remitting-relapsing nature of the disease.

An alternative hypothesis suggests that the abnormal mitochondria in endothelial and smooth muscle cells of blood vessels cause impaired autoregulation. Abnormal nitric oxide metabolism in endothelial cells is believed to be the underlying reason for the impaired autoregulation. Blood vessels in the brain and the muscle are affected preferentially by the abnormal autoregulation compared with other tissues.

Currently, whether the above mechanisms are independent processes or both jointly responsible for the pathology is unclear. Various imaging modalities have shown that the focal brain lesions in MELAS are unlike typical ischemic strokes. Specifically, the lesions are associated with increased blood flow, hyperemia, and vasogenic edema, rather than focal ischemia.

MELAS is a complicated, multisystem disease. Since the symptoms, signs, and acute clinical presentations are so varied and the disease is relatively rare, the disease is misdiagnosed frequently.

The differential diagnosis of the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) includes the following:

Basilar Artery Thrombosis

Cerebral Venous Thrombosis

Childhood Migraine Variants

Inherited Metabolic Disorders

Metabolic Disease & Stroke: Methylmalonic Acidemia

Metabolic Disease & Stroke: Propionic Acidemia

Metabolic Myopathies

Migraine Headache

Moyamoya Disease

Multiple Sclerosis

Posterior Cerebral Artery Stroke

If the history and physical findings are suggestive of MELAS, lactic acid and pyruvate may be used as screening tests, after first eliminating the more common causes of lactic acidosis, such as tissue hypoxic-ischemic injury, hyperglycemia, and hypoglycemia. The more uncommon amino acid and fatty acid metabolic disorders also need to be considered.

Characteristics of lactic acidosis in MELAS are somewhat unique. Arterial lactate and pyruvate are high and cerebrospinal fluid (CSF) lactate also may be high. Lactate and pyruvate may increase substantially with exercise. Lactate/pyruvate ratio may be increased.

The increased lactate-to-pyruvate ratio is observed in the face of a normal O2 saturation, as opposed to tissue-injury lactic acidosis in which the increased ratio is associated with decreased O2 saturation.

Mitochondrial DNA analysis is now available commercially from several sources to identify the mutations responsible for this disease. The local laboratory director may need to be consulted regarding the specific vendor to be used.

In around 80% of cases, the responsible point mutation is at position 3243 of the nucleotide sequence. Close to 8% are at position 3271. A number of additional point mutations, double point mutations, and one 4-base pair deletion mutation have also been described.

CT scan of the head may demonstrate areas of low attenuation that do not correspond to vascular territories and that may be transient, predominantly in the temporoparietal and occipital cortices and subjacent white matter. Basal ganglia calcification and generalized atrophy also are seen.

MRI studies show hyperintense T2 lesions predominantly in the gray and subcortical white matter in the temporal, parietal, and occipital lobes. Lesions spare the deep white matter and cross vascular boundaries. Basal ganglia calcifications and atrophy also are reported. Generalized cerebral atrophy is frequent. Serial MRI studies often demonstrate lesion resolution, differentiating these lesions from typical ischemic strokes. [5]

By using MR spectroscopy, several groups have shown that lactic acid levels in the brain parenchyma and ventricles may be increased during the acute phase of the disease and in chronic lesions. [6, 7]

Findings of noninvasive and cerebral angiographic studies are generally normal or show focal capillary blush or early venous filling in affected cortical regions.

Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) studies have been reported variably to show normal or increased (and occasionally diminished) cerebral blood flow to regions structurally abnormal on CT scan and MRI. [8] Metabolic PET studies demonstrate focally deranged metabolic states.

Electroencephalography is often performed when seizures are a concern. This is especially necessary in MELAS, since patients occasionally have intractable status epilepticus as a terminal condition.

Electrocardiography may reveal preexcitation or incomplete heart block.

Echocardiography may demonstrate cardiomyopathy.

Muscle biopsy demonstrates ragged red fibers on modified Gomori trichrome stain in at least 85% of cases. Ragged red fibers, common to MELAS, myoclonic epilepsy with ragged red fibers (MERRF), [9] Kearns-Sayer, and overlap syndromes, reflect proliferation of abnormal mitochondria under the sarcolemma. Negative muscle biopsy findings do not preclude consideration of this syndrome.

Pathologic examination of brain tissues demonstrates multiple cortical and subjacent white matter ischemic regions, spongiform degeneration of cortex, and calcium deposition in capillary walls of the globus pallidus.

Endothelial and smooth muscle cells of pial arterioles and small arteries exhibit increased numbers of structurally abnormal mitochondria, and capillary lumens are narrowed due to endothelial hypertrophy.

A number of agents have been tried experimentally in patients with MELAS. Trials of coenzyme Q10, [10] idebenone, dichloroacetate, cytochrome c, L-carnitine, L-arginine, [11] and various B vitamins all have been reported in small groups of patients as short- and long-term treatments.

A number of studies have claimed success by both biochemical and clinical measures with each of these agents. Lack of long-term follow-up and the natural history of remission of lesions, however, hamper accurate evaluation of these drugs. Dichloroacetate has recently been subjected to a double-blind randomized controlled evaluation for efficacy in patients with MELAS, and current recommendations are not to use this agent.

levels of coenzyme Q10 are not reduced in patients suffering from MELAS; its therapeutic benefit is presumed to be due to the increase in production of ATP at the inner mitochondrial membrane. Some success with use of coenzyme Q10 at a dose of 4 mg/kg/day has been reported. Idebenone (an analogue of coenzyme Q10) has been used in a few patients. [12]

Both intravenous formulations and oral formulations of dichloroacetate have been used in the acute treatment of strokelike episodes, as well as in long-term prophylaxis of stroke in patients with MELAS. The possible therapeutic effect of dichloroacetate was thought to be mediated via reduction in lactate levels in blood and brain. [13] Reductions in brain lactate levels reported in earlier studies were inferred from MR spectroscopic readings, PET analysis of isolated brain regions, and estimates of total lactate levels in CSF.

A double-blind randomized trial sought to show improvement in Global Assessment of Treatment Efficacy (GATE) Score with oral dichloroacetate treatment. [14] GATE was based on a combination of neurological examination, neuropsychological assessment, Karnofsky score, and event inventory (eg, seizure, stroke, headaches). No difference in outcomes was noted between treatment and placebo arms. There were also no differences in venous and CSF lactate levels.

MR spectroscopic and MRI studies did not show any differences between dichloroacetate-treated patients and placebo-treated patients. A significant increase was seen in peripheral nerve toxicity leading to discontinuation of the treatment regimen in patients treated with dichloroacetate. Subjects in both arms of the trial were also given thiamine, coenzyme Q10, L-carnitine, and alpha-lipoic acid supplementation. [14]

Repeated intravenous injections of cardiochrome have been reported to produce similar biochemical and clinical improvement, in terms of decreased number of strokelike episodes. Cardiochrome, a combination of cytochrome c and vitamins B-1 and B-2, may increase the effectiveness of the electron transport chain of the inner mitochondrial membrane. [15]

A report of 15 patients with MELAS who were treated with L-arginine for 2 years showed improved flow-mediated vasodilatory response. [16]

Valproic acid should not be used as an antiepileptic. Its detrimental effect on mitochondria has been reported to exacerbate seizures and to precipitate strokelike episodes in patients with MELAS.

The general supportive care measures used in acute stroke syndromes also should be followed. Death in patients with MELAS is usually the result of cardiac failure, pulmonary embolus, or renal failure. Status epilepticus can occasionally be fatal; seizures should be treated aggressively.

A neurologist, adult or pediatric, should be consulted for diagnosis and care of a patient with strokelike episodes, seizures, and encephalopathy.

Advice on the proper handling and processing of a muscle biopsy should be sought from a pathologist or neuromuscular disease specialist.

If psychosis is present, the patient may benefit from psychiatric consultation.

Poststroke rehabilitation needs are best addressed through consultations with a physical therapist, occupational therapist, speech-language pathologist, and rehabilitation specialist (neurologist or physiatrist).

Transfer to a tertiary care center with multispecialty facilities is appropriate for patients suspected of having MELAS, particularly if muscle biopsy and MRI facilities are not readily available for diagnosis.

Immediate life-threatening issues, such as acidosis, seizures, pulmonary embolus, and cardiac arrhythmias, may need to be addressed locally prior to transfer.

Serious medical complications, such as cardiac failure, pulmonary embolus, renal failure, and aspiration pneumonia, require emergency treatment.

Progressive neurological deficits, with a tendency to relapses and remissions, characterize the typical course of MELAS. Most patients die by the fourth decade of medical complications. Some patients have survived into the sixth decade.

Klopstock T, Jaksch M, Gasser T. Age and cause of death in mitochondrial diseases. Neurology. 1999 Sep 11. 53(4):855-7. [Medline].

Hoptasz M, Szczucinski A, Losy J. Heterogeneous phenotypic manifestations of maternally inherited deafness associated with the mitochondrial A3243G mutation. Case report. Neurol Neurochir Pol. 2014. 48(2):150-3. [Medline].

Tzen CY, Thajeb P, Wu TY, et al. Melas with point mutations involving tRNALeu (A3243G) and tRNAGlu(A14693g). Muscle Nerve. 2003 Nov. 28(5):575-81. [Medline].

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Abe K, Yoshimura H, Tanaka H, et al. Comparison of conventional and diffusion-weighted MRI and proton MR spectroscopy in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like events. Neuroradiology. 2004 Feb. 46(2):113-7. [Medline].

Peng NJ, Liu RS, Li JY. Increased cerebral blood flow in MELAS shown by Tc-99m HMPAO brain SPECT. Neuroradiology. 2000 Jan. 42(1):26-9. [Medline].

Demarest ST, Whitehead MT, Turnacioglu S, Pearl PL, Gropman AL. Phenotypic analysis of epilepsy in the mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes-associated mitochondrial DNA A3243G mutation. J Child Neurol. 2014 Sep. 29(9):1249-56. [Medline].

Abe K, Matsuo Y, Kadekawa J, et al. Effect of coenzyme Q10 in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): evaluation by noninvasive tissue oximetry. J Neurol Sci. 1999 Jan 1. 162(1):65-8. [Medline].

Koga Y, Ishibashi M, Ueki I, et al. Effects of L-arginine on the acute phase of strokes in three patients with MELAS. Neurology. 2002 Mar 12. 58(5):827-8. [Medline].

Ikejiri Y, Mori E, Ishii K. Idebenone improves cerebral mitochondrial oxidative metabolism in a patient with MELAS. Neurology. 1996 Aug. 47(2):583-5. [Medline].

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Kaufmann P, Engelstad K, Wei Y, et al. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology. 2006 Feb 14. 66(3):324-30. [Medline].

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Koga Y, Akita Y, Junko N, Yatsuga S, Povalko N, Fukiyama R. Endothelial dysfunction in MELAS improved by l-arginine supplementation. Neurology. 2006 Jun 13. 66(11):1766-9. [Medline].

Pitchaiah Mandava, MD, PhD Assistant Professor, Department of Neurology, Baylor College of Medicine; Consulting Staff, Department of Neurology, Michael E DeBakey Veterans Affairs Medical Center

Pitchaiah Mandava, MD, PhD is a member of the following medical societies: American Academy of Neurology, Stroke Council of the American Heart Association

Disclosure: Nothing to disclose.

Thomas A Kent, MD Professor and Director of Stroke Research and Education, Department of Neurology, Baylor College of Medicine; Chief of Neurology, Michael E DeBakey Veterans Affairs Medical Center

Thomas A Kent, MD is a member of the following medical societies: American Academy of Neurology, Royal Society of Medicine, Stroke Council of the American Heart Association, American Neurological Association, New York Academy of Sciences, Sigma Xi

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Howard S Kirshner, MD Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center

Howard S Kirshner, MD is a member of the following medical societies: Alpha Omega Alpha, American Neurological Association, American Society of Neurorehabilitation, American Academy of Neurology, American Heart Association, American Medical Association, National Stroke Association, Phi Beta Kappa, Tennessee Medical Association

Disclosure: Nothing to disclose.

Helmi L Lutsep, MD Professor and Vice Chair, Department of Neurology, Oregon Health and Science University School of Medicine; Associate Director, OHSU Stroke Center

Helmi L Lutsep, MD is a member of the following medical societies: American Academy of Neurology, American Stroke Association

Disclosure: Medscape Neurology Editorial Advisory Board for: Stroke Adjudication Committee, CREST2; Executive Committee for the NINDS-funded DEFUSE3 Trial; Physician Advisory Board for Coherex Medical.

Jeffrey L Saver, MD, FAHA, FAAN Professor of Neurology, Director, UCLA Stroke Center, University of California, Los Angeles, David Geffen School of Medicine

Jeffrey L Saver, MD, FAHA, FAAN is a member of the following medical societies: American Academy of Neurology, American Heart Association, American Neurological Association, National Stroke Association

Disclosure: Received the university of california regents receive funds for consulting services on clinical trial design provided to covidien, stryker, and lundbeck. from University of California for consulting.

MELAS – Mitochondrial Encephalomyopathy, Lactic Acidosis, Strokelike Episodes Overview of MELAS

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