ISCHEMIC STROKE / CLASSIFICATION AND ETIOLOGY

MELAS

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes

Created 10/05/2023, last revision 12/05/2023

Definition

MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a mitochondrial multisystem disease primarily affecting the nervous system and muscles
- one of the most common mitochondrial diseases, with an estimated incidence of 1 in 4000
- both genders are equally affected, but only women can pass the condition
presents in children or young adults (onset in a wide range of 2 -40 years) as episodes of migraine-like headache, encephalopathy, myopathy, and focal neurological deficits
several MELAS-associated point mutations were described
- 80% are caused by the 3243A>G mutation in the MTTL1 gene in mitochondrial DNA encoding tRNALeu
- most cases show maternal inheritance, but rarely more than 1 family member can be found with classic MELAS
histopathologic examination of the brain shows spongiform encephalopathy, characterized by necrosis, neuronal loss, gliosis, and microcystic formations (status spongiosus) in the cortex
calcifications in the basal ganglia are present in almost half of the cases

children with MELAS often have normal early psychomotor development until the onset of symptoms between the ages of 2 and 10
infantile onset is possible with growth retardation and progressive deafness

The presence of at least two of the three additional criteria is required to confirm the diagnosis:

The disease usually manifests at the end of the 1st decade of life (ranging from 2 to 40 years of age)

myopathy initially presents as exercise intolerance or proximal muscle weakness
mild progressive external ophthalmoplegia (PEO) may occur (much more pronounced in Kears-Seyre)

the most common and usually initial symptom is a migraine-like headache with vomiting (90%)
epileptic seizures (85%)
- focal or generalized with no syndrome-specific semiology or EEG findings
- higher rates of drug-resistance epilepsy are reported
“stroke-like” episodes are often accompanied by headaches and epileptic seizures
- hemiparesis, aphasia, and cortical visual defects (hemianopsia or cortical blindness); stroke-like episodes result in gradual impairment of neurologic function
  deficits from each progressively
- attacks resemble ischemic vascular events but do not correspond to typical vascular territories
encephalopathy with mental retardation occurs in > 50% of cases
- encephalopathy may be exacerbated by valproate, which is used as an antiepileptic drug or for migraine prophylaxis
sensorineural hearing loss (25%)

elevated resting lactate in serum and CSF with a dramatic increase after exercise
increased CSF protein
genetic testing
- screening for mtDNA mutations can be performed from blood leukocytes or muscle tissue
- genetic evaluation from blood should be done first to eliminate the need for muscle biopsy in most cases

muscle biopsy
- histochemical examination of muscle shows typical “ragged red” fibers on SDH and trichrome staining
- in contrast to KSS and MERRF, only a minimum of fibers are COX-negative
- the specific histochemical feature of MELAS is evidence of SDH-positive vessels due to the mitochondrial proliferation
- ultrastructural examination confirms mitochondrial proliferation and mitochondrial morphological abnormalities

brain CT/MRI
- multifocal infarct-like cortical lesions with disrespect to known vascular territories and initial preference for the posterior brain regions (occipital or parietal lobes)
  - cerebellum, basal ganglia, and thalamus may also be involved
  - MRI findings may fluctuate or resolve more quickly than typical stroke, and the ADC is not always decreased and may instead be increased or show mixed signal
- cerebral atrophy
- calcifications in the basal ganglia, mainly in elderly patients (50%)
MR spectroscopy – elevated lactate peak in affected and even unaffected brain areas

ECG – possible signs of preexcitation or partial block
- much less common and less pronounced than in KSS
EMG – myopathic pattern

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effective causal treatment to stop disease progression is not known; supportive measures (social worker assistance, physical and occupational therapy) are essential to improve the quality of life
partial effect of coenzyme Q10, riboflavin, has been described
L-Arginine shows promising results [Koga, 2006]
- IV administration attenuates the severity of symptoms when used in acute attacks (e.g., status epilepticus); dosage is adjusted according to arginine levels (ref. interval 45-130 umol/L) – ARDEAELYTOSOL 21% + 500mg Glu 5% 20 mL/h [Toribe, 2007] (Coga, 2018)
- oral L-arginine 4x1g per day prolongs the interval between stroke-like attacks (AHA/ASA 2021)
epileptic seizures respond favorably to antiepileptic drugs (be careful about valproate encephalopathy)

a progressive disease that worsens after “stroke-like” episodes
the prognosis is variable; death may occur in the first decades of life, especially with early clinical manifestations
death is usually caused by cardiopulmonary failure or a malignant course of status epilepticus