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Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes (MELAS)

Summary

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  • MELAS is a rare mitochondrial disorder characterised by encephalopathy, lactic acidosis, and stroke-like episodes
  • Caused by mutations in mitochondrial DNA, most commonly in the MT-TL1 gene
  • Imaging findings include stroke-like lesions not conforming to vascular territories, often in the posterior cerebral regions

Pathophysiology

  • Caused by mutations in mitochondrial DNA, primarily affecting energy production in cells
  • Most common mutation (80% of cases) is A3243G in the MT-TL1 gene
  • Impaired oxidative phosphorylation leads to:
    • Cellular energy deficiency
    • Increased anaerobic metabolism and lactic acid production
    • Neuronal dysfunction and cell death

Demographics

  • Rare disorder with estimated prevalence of 0.18 per 100,000
  • Typically presents in childhood or early adulthood
  • No significant gender predilection
  • Maternal inheritance pattern due to mitochondrial DNA mutation

Diagnosis

  • Clinical presentation:
    • Stroke-like episodes
    • Seizures
    • Headaches
    • Muscle weakness and exercise intolerance
    • Hearing loss
    • Diabetes mellitus
  • Laboratory findings:
    • Elevated serum and CSF lactate levels
    • Elevated serum pyruvate levels
    • Ragged-red fibres on muscle biopsy
  • Genetic testing:
    • Mitochondrial DNA analysis for common mutations

Imaging

  • CT findings:
    • Hypodense lesions in cortical and subcortical regions
    • Calcifications in basal ganglia and cerebral white matter
  • MRI findings:
    • T2/FLAIR hyperintense lesions not conforming to vascular territories
    • Predilection for posterior cerebral regions (occipital, parietal, and temporal lobes)
    • Cortical and subcortical involvement
    • Restricted diffusion in acute lesions
    • Lesions may show contrast enhancement
  • MR Spectroscopy:
    • Elevated lactate peak at 1.3 ppm
    • Decreased N-acetylaspartate (NAA) peak
  • Perfusion imaging:
    • Hyperperfusion in acute lesions

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  • 40-year-old patient presented with acute onset of aphasia.
  • Initial MRI showed cortical and subcortical diffusion-weighted abnormality in the left anterior temporal lobe.
  • On follow-up imaging, this region of signal abnormality and swelling significantly increased. There was both restricted and facilitiated diffusion involving both cortex and subcortical white matter.

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  • A 30-year-old patient presented with a 1 week history of word finding difficulty followed by a seizure.
  • MRI showed cortical diffusion restriction variably affecting the cortex and subcortical white matter of the left cerebral hemisphere.
  • The region of abnormality increased over the 3 weeks.

Treatment

  • No curative treatment available
  • Management focuses on symptom control and supportive care:
    • Anticonvulsants for seizure control
    • L-arginine for acute stroke-like episodes
    • Coenzyme Q10 and other antioxidants as mitochondrial supplements
    • Management of diabetes mellitus and other systemic manifestations
    • Genetic counselling for affected families
  • Avoid valproic acid due to risk of liver failure in mitochondrial disorders
  • Regular monitoring of cardiac, renal, and endocrine function
  • Physical and occupational therapy for muscle weakness and coordination issues

Differential diagnosis

Differential Diagnosis Distinguishing Feature
Stroke Typically affects older patients; vascular territories respected; no lactic acidosis
Multiple Sclerosis Periventricular white matter lesions; no lactic acidosis; oligoclonal bands in CSF
Encephalitis Fever; CSF abnormalities; infectious etiology often identified
Leigh Syndrome Typically affects infants; basal ganglia involvement; brainstem lesions
Wernicke's Encephalopathy History of alcoholism or malnutrition; thiamine deficiency; mammillary body involvement
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) Family history; white matter lesions; no lactic acidosis
Migraine with aura Reversible symptoms; no persistent imaging abnormalities; no lactic acidosis
Posterior Reversible Encephalopathy Syndrome (PRES) Associated with hypertension; typically reversible; parieto-occipital predilection
Brain tumour Mass effect; contrast enhancement; no lactic acidosis (unless high-grade)
Hashimoto's encephalopathy Thyroid antibodies present; responsive to steroids; no lactic acidosis