Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes

David Goldemund M.D.
Updated on 14/01/2024, published on 10/05/2023


  • 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 on the condition to their children
  • 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 have been described
    • most common is the 3243A>G mutation in the MTTL1 gene in mitochondrial DNA encoding tRNALeu
    • most cases show maternal inheritance
  • 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  Calcifications in basal ganglia

Clinical presentation

  • children with MELAS often have normal early psychomotor development until the onset of symptoms between the ages of 2 and 10
  • infant onset is possible with growth retardation and progressive deafness
  • “stroke-like” episodes before the age of 40
  • encephalopathy (with epileptic seizures and/or dementia)
  • mitochondrial myopathy with ragged-red fibers and lactic acidosis

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

  • normal early development
  • periodic cephalea
  • periodic vomiting

The disease usually manifests at the end of the first 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) MELAS with external ophtalmoplegia

Encephalopathy, stroke-like episodes

  • 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-resistant 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
    • attacks resemble ischemic vascular events, but they 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%)

Systemic symptoms

  • small figure
  • retinal pigmentary degeneration – a progressive loss of vision due to damage to the retina
  • cardiomyopathy and cardiac conduction disorders
  • diabetes mellitus
  • hirsutism
  • nephropathy
  • chronic fatigue

Diagnostic evaluation

Laboratory tests

  • 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
Calcifications in basal ganglia
Typical MRI lesions in MELAS
Typical MRI lesions in MELAS


Other methods

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

Differential diagnostics

  • other causes of stroke in young persons under age 40
  • other mitochondrial disorders:
    • MERFF (Myoclonus epilepsy associated with ragged red fibers)
      • hearing loss
      • visual disturbance secondary to optic atrophy
      • characteristic myoclonic seizures
    • Kearn-Sayre
      • chronic progressive external ophthalmoplegia
      • atypical retinitis pigmentosa
      • retinal pigmentary degeneration
      • more pronounced cardiac manifestation
    • Leigh syndrome
      • primarily affects infants and young children ( 3 months to 2 years; rarely, it can occur in teenagers and adults
      • generalized weakness, lack of muscle tone
      • episodes of lactic acidosis, which can lead to impairment of respiratory and kidney function
  • vasculitis
  • CADASIL (subcortical lesions, external capsule, and temporal poles)
    • CADASIL is caused by mutations in the NOTCH3 gene, which encodes a protein involved in the development of blood vessels
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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
  • a partial effect of coenzyme Q10, riboflavin, has been described
  • L-arginine shows promising results   [Koga, 2006]
    • IV administration reduces 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  (Lekoubou, 2011) (AHA/ASA 2021)
  • idebenone
    • a synthetic analog of coenzyme Q10 that acts as an antioxidant and has the potential to improve mitochondrial oxidative metabolism
    • further investigation through clinical studies is required
  • epileptic seizures respond favorably to antiepileptic drugs (beware of valproate encephalopathy)


  • MELAS is a progressive disease that tends to worsen following each “stroke-like” episode
    • these episodes cause cumulative damage to the brain over time
    • while the severity and frequency of episodes can vary among individuals, MELAS typically follows a progressive course
  • the prognosis varies depending on the severity of symptoms and age of onset; death may occur in the first decades of life, especially in early clinical manifestations
  • death is usually caused by cardiopulmonary failure or a malignant course of status epilepticus
  • the average lifespan for people with MELAS is reduced, but many people with MELAS live into their 40s or 50s

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