ISCHEMIC STROKE / CLASSIFICATION AND ETIOLOGY

MELAS

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes

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

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 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

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

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

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)

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%)

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

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

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

Content available only for logged-in subscribers (registration will be available soon)

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