Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-Like Episodes

Mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes (MELAS) is a maternally inherited mitochondrial disease, most often from the m.3243A>G variant in MT-TL1 (about 80%). Onset is usually before 40 years, with stroke like episodes, seizures, migraine, hearing loss and diabetes.

Pathophysiology. Impaired oxidative phosphorylation, with nitric oxide deficiency and microvascular dysfunction, causes neuronal energy failure and episodes that do not follow arterial territories. Heteroplasmy varies between tissues.

Stroke like episodes (focal deficit, visual field loss, aphasia, headache, seizures, encephalopathy) mainly in posterior brain regions, recurrent migraine like headache, focal and generalised seizures, sensorineural hearing loss, diabetes, short stature, cardiomyopathy, myopathy and exercise intolerance, gastrointestinal dysmotility, renal tubular disease and cognitive decline.

Red flags.

• Status epilepticus or prolonged stroke like episode.
• Lactic acidosis with encephalopathy.
• Cardiomyopathy or heart block.

Serum and CSF lactate raised. MRI shows cortical and subcortical lesions that cross vascular territories, affecting the parieto occipital and temporal regions, with restricted diffusion early and migration over time. MR spectroscopy shows a lactate peak. Blood or urine genetic testing for m.3243A>G (urine sediment is more sensitive than blood), with muscle biopsy for ragged red fibres if negative. ECG, echocardiography, glucose, audiometry and renal function.

Differential diagnosis.

• Ischaemic stroke, herpes encephalitis, epilepsy with postictal change.
• Other mitochondrial diseases (Leigh, MERRF, POLG), CNS vasculitis and hemiplegic migraine.

No treatment cures the condition.

Acute stroke like episode. Treat seizures, correct metabolic derangement, provide fluids and glucose. L-arginine 0.5 g/kg IV (maximum 30 g) over 30 minutes within 3 hours of onset, then 0.5 g/kg daily IV for 3 to 5 days. Prevention: L-arginine 0.15 to 0.3 g/kg daily orally in 3 divided doses, or citrulline 0.15 g/kg three times daily.

Seizures. Levetiracetam 500 to 1500 mg twice daily. Avoid valproate, which impairs mitochondrial function.

Supportive. Coenzyme Q10 (ubiquinol 200 to 400 mg daily) and other supplements have limited evidence. Treat diabetes (avoid metformin, which can raise lactate), hearing loss (cochlear implant), cardiomyopathy and gastrointestinal dysmotility.

Avoid valproate, aminoglycosides, linezolid, propofol infusion for long periods, and fasting.

Monitoring. Yearly ECG, echocardiography, glucose, audiometry and renal function.

Referral and escalation. Refer to mitochondrial disease services and genetics.

Special groups. Genetic counselling is complex because of heteroplasmy. In pregnancy, give specialist care.