44 Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)
44.1 Case Description
44.1.1 Clinical Presentation
A 26-year-old Chinese male patient was brought to the emergency department with a history of transient nausea and vomiting 3 weeks prior to presentation, which was followed by gradual progressive confusion with a sudden inability to express himself on the day of his arrival to the hospital. On examination, he was somnolent and was found to have dysphasia, dysarthria, and a right homonymous hemianopia.
His past medical history was remarkable for insulin-dependent diabetes mellitus and for the development of gradual hearing loss over the last few months prior to presentation. He had a strikingly short stature, a poor physical tolerance since childhood, and learning difficulties. His family history was noncontributory.
He was admitted for further investigations. During admission, he developed focal occipital seizures with secondary generalization treated with carbamazepine.
44.1.2 Imaging Workup and Investigations
The initial noncontrast enhanced CT of the brain showed multiple hypodense areas within the left occipital, parietal, and temporal lobes (Fig. 44.1).
Subsequent MRI of the brain performed on the same day revealed hyperintensity on T2 fluid-attenuated inversion recovery (FLAIR) imaging in the left parietal, occipital, and temporal lobe (Fig. 44.2a) as well as in the left thalamus with a high signal on diffusion-weighted imaging (DWI; Fig. 44.2b) but without decreased signal on apparent diffusion coefficient (ADC; Fig. 44.2c). Abnormality mainly affected the cortical gray matter with gyral swelling and some subcortical white matter involvement. Contrast-enhanced T1-weighted images showed mild leptomeningeal enhancement in the affected areas (Fig. 44.2d). MR angiography including MR venography was unremarkable (not shown). Note was also made of mild generalized atrophy for age.
MR spectroscopy was obtained. In the region of abnormal signal in the left hemisphere, a double peak was found between 1.2 and 1.4 ppm, in the expected location of lactate (resonates at 1.3 ppm), and inversion of the doublet was seen at a longer echo time (Fig. 44.3). Also in the contralateral nonaffected brain tissue, a lactate peak was found, although less pronounced.
On serum and cerebrospinal fluid (CSF) analysis, lactate was elevated, while infectious workup was negative and electroencephalography (EEG) did not demonstrate ongoing epileptic discharges.
Electrocardiography showed sinus rhythm with Wolff–Parkinson–White conduction abnormality.
On molecular investigations, an A3243G transition was found, which confirmed the diagnosis of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS).
This patient received a metabolic cocktail consisting of idebenone, L-arginine, riboflavin, creatine, and ascorbic acid. He gradually recovered from his strokes and did not develop new stroke-like episodes over a 5-year period. His seizures were well controlled with carbamazepine and he remained stable from a cardiac standpoint.
Mutations in the mitochondrial DNA (mDNA), or in nuclear genes coding for proteins involved in the respiratory chain, may result in mitochondrial dysfunction, which typically affects organs with high-energy requirements such as the brain and skeletal muscles. In mitochondrial diseases, the mutation is not present in all cells and tissues, the so-called heteroplasmy, and the number of mutated cells needs to exceed a certain threshold to become clinically manifest (threshold effect). Even if clinically manifest, the amount of mutant mDNA does not correlate with the severity of the disease. This together with the heteroplasmy and threshold effect makes the diagnosis of mitochondrial diseases challenging. Diagnosis usually relies on a combination of clinical features, biochemical test results, and structural findings on imaging.
The prevalence of mitochondrial disease is higher than previously thought; clinical studies have found a frequency of 9.2/100,000 adults younger than 65 years with clinically manifested mitochondrial disease caused by a mutation in mDNA, making this one of the most common inherited neuromuscular disorders. MELAS is one of the most frequent maternally inherited mitochondrial diseases. In 80% of patients, it is caused by an A to G point mutation at position 3243 in the mDNA in the MT-TL1 gene. There are also other mitochondrial and nuclear DNA mutations associated with MELAS, such as mutations in the POLG (polymerase gamma 1) gene. The A3243G point mutation has a frequency up to 1 in 400 in the general population. The prevalence of manifest disease was found to be 0.2:100,000 in a study from Japan.
44.2.2 Workup and Diagnosis
Symptoms typically manifest before the age of 20 years, and only 1 to 6% of patients present after the age of 40. The disease is progressive and clinical manifestations are diverse, as several organ systems are involved. Patients can present with stroke-like episodes, dementia, epilepsy, lactic acidemia, myopathy, migrainous headaches, sensorineural hearing loss, diabetes mellitus, and short stature caused by growth hormone deficiency. In addition, cardiac diseases such as hypertrophic cardiomyopathy or conduction abnormalities, psychiatric manifestations, cyclic vomiting, peripheral neuropathy, and progressive encephalopathy can be part of this syndrome. The most recent diagnostic criteria for a definitive diagnosis of MELAS require the presence of two category A and two category B criteria. Category A criteria include clinical stroke-like episodes, headache with vomiting, seizures, hemiplegia, cortical blindness/hemianopsia, or an acute focal lesion observed via brain imaging. Category B criteria comprise evidence of mitochondrial dysfunction, high-lactate levels in plasma/CSF or deficiency of mitochondrial-related enzyme activities, mitochondrial abnormalities in muscle biopsy, or definitive gene mutation related to MELAS.
Stroke-like episodes are a hallmark of MELAS; however, the mechanism of these episodes is not well understood. Patients present with acute or subacute focal neurological deficits, typically hemiparesis and visual field defects, which can improve over time. There are three hypotheses to explain the pathophysiology of stroke-like episodes. The first theory is an ischemic vascular mechanism, presumably caused by mitochondrial angiopathy, where cerebral infarcts occur as a result of impaired autoregulation and segmental impairment of vasodilation of the small arteries induced by mitochondrial dysfunction. It remains unknown whether ischemic processes trigger the onset of the stroke-like episodes. The ischemic vascular theory cannot explain some of the features of MELAS, such as continuous spread of the stroke-like lesions and the predominant nature of vasogenic edema. The second hypothesis is the generalized cytopathic theory, wherein a defect in the oxidative phosphorylation pathway causes generalized cytopathy. This would explain why a lactate peak is also found in normal-appearing brain tissue on imaging and the cerebrovascular reserve capacity is spared in MELAS patients. The third hypothesis concerns a nonischemic neurovascular cellular underlying mechanism where neuronal hyperexcitability (i.e., epileptic activity) increases the energy demand, which cannot be delivered due to the oxidative phosphorylation defect.
Examination and Investigations
Findings on examination of patients presenting with stroke-like episodes are dependent on the region of brain involvement, and clinical findings typically correlate with location of abnormality on imaging. Classically, the occipital lobe is affected with or without the involvement of the parietal lobe.
Wolff–Parkinson–White syndrome and conduction block are often identified on an electrocardiogram, and cardiac ultrasound may demonstrate hypertrophic cardiomyopathy that can remain asymptomatic until an advanced stage.
Serum and CSF lactate are increased due to impaired oxidative phosphorylation.
A muscle biopsy can demonstrate ragged red fibers and succinate dehydrogenase reactive vessels. This is not a specific finding for MELAS but indicative of mitochondrial disease.