What are the causes of stroke in a patient with a history of MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) syndrome?

Causes of Stroke in MELAS Syndrome

In patients with MELAS syndrome, strokes are not caused by traditional vascular mechanisms like atherosclerosis or thromboembolism, but rather by metabolic stroke resulting from mitochondrial dysfunction leading to angiopathy, energy failure in cerebral vasculature, and nitric oxide deficiency. 1, 2

Primary Pathophysiologic Mechanisms in MELAS

The stroke-like episodes in MELAS are fundamentally different from typical strokes:

• Mitochondrial angiopathy: Energy deficiency stimulates mitochondrial proliferation in smooth muscle and endothelial cells of small blood vessels, leading to impaired blood perfusion in the microvasculature 2

• Impaired mitochondrial energy production: The m.3243A>G mutation (most common in MELAS) results in defective mitochondrial translation and protein synthesis, causing insufficient ATP generation to meet cerebral metabolic demands 2, 3

• Nitric oxide deficiency: This contributes significantly to the vascular complications and stroke-like episodes characteristic of MELAS 2

• Metabolic stroke before age 40: These are not true ischemic infarcts but rather metabolic crises that mimic stroke, occurring in brain regions with high metabolic demands 1

Distinguishing MELAS Strokes from Traditional Stroke Etiologies

Critical pitfall: Do not apply standard stroke classification systems to MELAS patients. Unlike typical strokes:

• NOT caused by large-vessel atherosclerosis: Traditional mechanisms (20% of general strokes) do not apply 1

• NOT caused by small-vessel disease/lacunar infarcts: Despite appearing similar, MELAS lesions are metabolic, not due to arteriolosclerosis from hypertension or diabetes 1, 4

• NOT caused by cardiogenic embolism: The 20% cardioembolic mechanism seen in typical strokes is not the primary pathology 1

• Lesions do NOT respect vascular territories: MRI changes in MELAS are not confined to single arterial distributions, a key distinguishing feature 5

Clinical Diagnostic Criteria for MELAS-Related Stroke

To establish MELAS as the stroke etiology, three invariant criteria must be present:

1. Stroke-like episode before age 40 years 6
2. Encephalopathy with seizures, dementia, or both 6
3. Lactic acidosis, ragged-red fibers on muscle biopsy, or both 6

Secure the diagnosis with at least two additional features:

• Normal early development 6
• Recurrent headache 6
• Recurrent vomiting 6

Associated Multisystem Manifestations

MELAS affects metabolically active organs beyond the brain:

• Neurologic: Seizures (most prevalent manifestation in children, mean presentation age 8.1 years), dementia, myopathy 2, 5
• Cardiac: Cardiomyopathy, conduction defects 2, 3
• Endocrine: Diabetes mellitus, short stature 2, 3
• Auditory: Hearing impairment 2
• Other: Gastrointestinal disturbances 3

Genetic Confirmation and Heteroplasmy Considerations

Important caveat: Blood testing alone may miss the diagnosis:

• The m.3243A>G mutation in MT-TL1 gene is most common but not universal 2, 3
• Heteroplasmy varies considerably between tissues; muscle biopsy may be required if blood testing is negative despite high clinical suspicion 5
• Not all patients with clinical MELAS have the typical mtDNA point mutation, and some with the mutation have different clinical syndromes 6
• Blood heteroplasmy is higher in tissues other than blood in most cases 5

Rare Associated Phenomenon

• Crossed cerebellar diaschisis (CCD): Hypoperfusion and edema in the cerebellar hemisphere contralateral to a cerebral lesion can occur, representing decreased metabolism due to disrupted fiber tract connections 7

This represents a fundamentally metabolic rather than vascular etiology requiring completely different management approaches than traditional stroke mechanisms. 1, 2