Mitochondrial Encephalomyopathy With Lactic Acidosis and Strokelike Episodes Presenting Before 50 Years of Age: When a Stroke Is Not Just a Stroke

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is one of the most common maternally inherited mitochondrial diseases. However, its pleomorphic clinical manifestations and the fact that the maternal relatives carrying the same mutation may be asymptomatic or only oligosymptomatic makes the diagnosis sometimes elusive.

A man in his 50s presented with a 5-year history of stepwise loss of executive and somatosensory functions in relation to what was interpreted as 2 previous stroke episodes. He had no vascular risk factors apart from mild dyslipidemia.

The first strokelike episode, when he was in his late 40s, presented with left homonymous hemianopsia. Head computed tomographic scan depicted a right parieto-occipital lesion compatible with recent ischemic stroke. Diagnostic workup in another hospital failed to provide an etiology. Brain magnetic resonance imaging 6 months later showed no evidence of the previous lesion and identified an asymptomatic right temporal lesion, suggestive of low-grade astrocytoma. The right temporal lesion was not apparent on magnetic resonance imaging 6 months later. Years later, he presented with sudden-onset aphasia, visual deficit, and behavior changes, and there was a new left parieto-temporo-occipital lesion on magnetic resonance imaging. Magnetic resonance angiography was normal.

When he first came to our attention, there was severe executive dysfunction with multiple higher mental function changes and urinary incontinence. He was taking risperidone, memantine, valproate, aspirin, and dipyridamole.

Echocardiography and cervical and transcranial Doppler ultrasonography were normal, and metabolic causes of reversible dementia were excluded. Brain magnetic resonance imaging was obtained at this point (Figure 1) and showed features highly suggestive of a metabolic disorder. Laboratory workup results subsequently found lactacidemia (lactic acid level, 35.01 mg/dL; normal range <19.8 mg/dL [to convert to micromoles per liter, multiply by 0.111]) and raised cerebrospinal fluid lactate (48.29 mg/dL; normal range, <27 mg/dL [to convert to micromoles per liter, multiply by 0.111]). Electroencephalogram recording showed frequent epileptiform discharges in the posterior regions.

The diagnosis of mitochondrial disease was confirmed with a deltoid muscle biopsy showing ragged-red fibers on modified Gomori trichrome stain, strongly succinate deshydrogenase-positive blood vessels, and some citocrome c oxidase–negative fibers. We further studied the MTTL1 mitochondrial gene and identified the point mutation m3242 A>G (in heteroplasmy as described in Figure 2).

We prescribed aspirin, 100 mg/day, and arginine, 60 mg/day, and we minimized the iatrogenic cognitive symptoms, discontinuing valproate, memantine, and risperidone and replaced them with low-dose quetiapine.

The diagnosis of mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS) syndrome is sometimes elusive owing to the phenomenon of heteroplasmy.¹ We could hypothesize that the low level of mutated mitochondrial DNA in blood leukocytes of our patient justifies its late presentation and oligosymptomatic picture, but we have no knowledge of the percentage of mutated mitochondrial DNA in the symptomatic tissue in this patient, namely central nervous system neurons and possibly central nervous system blood vessels.²

The greatest difficulty in diagnosing MELAS syndrome in this patient was the low level of suspicion. However, the absence of a satisfying etiology for strokelike episodes in a relatively young man with barely any vascular risk factors should have encouraged further study. Ultimately, it was the neuroimaging characteristics of evanescent lesions, highly suggestive of a metabolic disorder, that put us on the right track.³

The pathophysiology of strokelike episodes remains to be clarified. A previous group,⁴ reporting a case of MELAS syndrome with elderly-onset strokelike episodes, hypothesized that it could be the absence of strongly succinate deshydrogenase–positive blood vessels and evidence of vascular affection that justified the delay in symptoms. Our case does not support this hypothesis, given that there were strongly succinate deshydrogenase–positive blood vessels in this patient’s muscle biopsy, despite the late onset of the strokelike episodes.

The diagnostic criteria for MELAS syndrome require stroke-like episodes before 40 years of age, encephalopathy (seizures or dementia), and either blood lactic acidosis or the presence of ragged-red fibers in skeletal muscle biopsy. However, the amount of publications reporting cases that do not conform to such criteria keeps growing, as previously noted.⁵ Our patient is proof of the need for a new level of suspicion in what concerns mitochondrial diseases, given that he spent 5 years without a proper diagnosis and was exposed to the iatrogenic effects of probably unnecessary medications.

Corresponding Author: Cláudia Marques Matos, MD, MSc, Serviço de Neurologia, Hospital de São João, Alameda Prof Hernâni Monteiro, Porto, Portugal 4200–319 (marques.matos.claudia@gmail.com).

Published Online: March 7, 2016. doi:10.1001/jamaneurol.2015.5061.

Conflict of Interest Disclosures: None reported.

Additional Contributions: We acknowledge Laura Vilarinho, PhD, from the Newborn Screening Unit at the Medical Genetics Institute of the Portuguese National Institute of Health, who performed the genetic analysis and provided the corresponding images, and Maria Matos, MSc, Business Administration at the Católica-Lisbon School of Business and Economics, for postprocessing all images included in the manuscript. They did not receive compensation for their work.