MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like syndrome) is
a mitochondrial cytopathy presenting with stroke-like episodes, seizures, dementia,
headache, and vomiting in a child with normal early psychomotor development. Investigation
shows lactic acidosis and/or ragged-red fibers on muscle biopsy.[1] Magnetic resonance imaging (MRI) is pivotal in diagnosis and differentiation from
close mimics. The m.3243A>G pathogenic variant in the mitochondrial gene MT-TL1 is
present in approximately 80% of MELAS.[1] Acute administration of l-arginine attenuates severity of symptoms and regular supplementation reduces further
episodes.[2]
An 8-year-old, developmentally normal boy, born uneventfully to a nonconsanguineous
couple, presented with three episodes of sudden-onset stroke-like episodes. He had
headache, vomiting, blurred vision, slurred speech, unstable gait with preceding fever
during the first and second episodes. During the third episode, he had left focal
seizures and paraesthesia. He also had exercise intolerance. Neurological examination
showed short stature, decreased color vision, unreliable visual fields, dysmetria,
and transient mild left hemiparesis.
On investigation, high plasma lactate with maximum of 57.3mg/dL and raised CPK (creatinine
phosphokinase) with maximum of 343IU/L were noted. Genetic evaluation (whole mitochondrial
genome sequencing) detected a heteroplasmic exonic noncoding variation in the MT-TL1
gene (chrM: 3243A>G; depth: 9550×).
MRI brain, during the first episode, showed diffusion restriction involving left parieto-occipitotemporal
gyri with corresponding regional hyperperfusion on arterial spin labeling (ASL) and
prominent left posterior cerebral artery on magnetic resonance angiography (MRA).
Susceptibility-weighted imaging showed reduced susceptibility ([Fig. 1A–D]). Magnetic resonance spectroscopy (MRS) showed high lactate peak ([Fig. 2D]). During the second episode, MRI showed similar changes in right occipitotemporal
lobe ([Fig. 2A]) with resolution of prior abnormal MRI signals ([Fig. 2C]). During third episode, MRI showed involvement of bilateral postcentral gyri ([Fig. 2B]).
Fig. 1 Restricted diffusion on diffusion-weighted imaging (A), increased perfusion signals on arterial spin labeling (B), reduced susceptibility signals on susceptibility-weighted imaging (C) in left occipital region; relatively prominent left posterior cerebral artery in
magnetic resonance angiography (D) during the first event involving left occipital lobe.
Fig. 2 Fluid-attenuated inversion recovery hyperintensity in right occipital lobe (A) during second event and bilateral postcentral gyri during third event (B). Resolution of signal changes in prior involved areas (C). Magnetic resonance spectroscopy showing inverted lactate peak (D).
He received oral l-arginine 500mg/kg stat and was discharged with oral l-arginine at 300mg/kg/day, coenzyme Q and L-carnitine during all episodes with additional
daily oral L-citrulline (same dose and frequency as l-arginine) during the last episode, following which he remained symptom-free for the
last 6 months.
The diagnosis of MELAS remains challenging, because of its rarity and multisystem
involvement. It has clinically relapsing-remitting episodes with transient fleeting
cortical lesions.[3] MRI aids in diagnosis and differentiation from ischemic stroke. Though mostly vasogenic,
cytotoxic edema has also been reported.[4] Lesions are not confined to vascular territories. Regional hyperperfusion on ASL
indicates compensatory effort to meet demands of affected neurons and increased regional
lactate causing abnormal local vascular permeability or vasodilation, a feature not
seen in ischemic stroke. MRA shows normal or dilated cerebral artery, in contrast
to stenosis or thrombosis in ischemic stroke. Elevated lactate peak on MRS is a feature
seen in both.
Perirolandic cortex involvement in MELAS is an unusual, yet differentiating feature
from vascular infarct in view of its bilaterality. It may be also be seen in hypoxic–ischemic
injury and metabolic encephalopathies in patients with other distinct clinical features.
Other imaging differentials of MELAS include viral encephalitis with predominant involvement
of the limbic system and status epilepticus, usually involving unilateral thalamus
and hippocampus. Vasculitis presents with multifocal strokes with distinct MRA findings.
Other mitochondrial disorders like Leigh syndrome with pronounced brain stem and basal
ganglia involvement or Kearns-Sayre syndrome involving subcortical white matter are
other differentials.
The prompt identification of MELAS in a child with acute onset neurologic deficit
with expeditious neuroimaging aids acute treatment with L-arginine, leading to alleviation
of deficits. It is, therefore, important to exclude other clinical and radiological
mimics of MELAS. Nitric oxide (NO) deficiency contributes to the pathogenesis and
hence use of NO precursors (l-arginine and L-citrulline) alleviates acute symptoms and regular supplementation
results in reduction of further stroke like episodes.[5]
