Current insight into MELAS: Clinical perspectives and multimodal MRI.

Abstract

We Thank Finsterer and Zarrouk-Mahjoub for their comments and concerns regarding our article. We have carefully read the letter “Regional cerebral hyperperfusion: a biomarker of upcoming stroke-like episodes?,” which states that cerebral blood flow (CBF) may not be specific to a stroke-like episode (SLE) in MELAS, but may also relate with seizures and headache. We agree with it. The three patients in our study had no active neurologic symptoms. MELAS is the most common maternally inherited mitochondrial disorder (MID). SLEs present with migraine-like headaches, seizures, cortical blindness, muscle weakness, and sensory hearing loss.1 Migraine-like headaches and seizures are frequent symptoms of SLEs. We do not agree with excluding them from SLEs and assuming they frequently occur before, during, or after an SLE. Additionally, we disagree with the statement that CBF depends on the heteroplasmy rate of mtDNA mutation. The m.3243A>G in the MT-TL1 gene is the most common mutation associated with MELAS. It is a heteroplasmic mutation, with mutant and wildtype mtDNA occurring at varying percentages in different organs of an individual.2 Thresholds of heteroplasmy percentage vary in organs harboring the mutation. Although a positive correlation between CBF of frontal cortex with blood mutant mtDNA was reported in three MELAS patients,3 the relationship between mutation loading, thresholds, clinical manifestations, and imaging parameters remains unclear. Mutation loading was tested in our three patients, but not emphasized. We agree that stroke-like lesions (SLLs) do not conform to a vascular territory. It is a remarkable imaging feature to distinguish from ischemic stroke, but we do not agree with this as evidence against hyperperfusion as an indicator for a future SLE. Focal hyperperfusion was identified as an imaging hallmark in acute encephalopathy of MELAS.4 Dilation of cerebral arteries and increased microvascular permeability in lesion territories could be major causes of hyperfusion,5 implicating mitochondrial angiopathy as a crucial mechanism rather than a compensation for energy failure. A pathological study confirmed vascular abnormalities including thinning vessel wall, capillary COX-deficiency, increased gap widening between endothelial contact points and breakdown of the blood–brain barrier throughout the cerebellum in patients with mitochondrial DNA disease.6 Therefore, mitochondrial angiopathy may occur during both the acute phase and the interictal phase. Energy failure (mitochondrial cytopathy) and seizure activity (neuronal hyperexcitability) could trigger and exacerbate the episodes attack. Cocktail therapy is administrated in intermittent periods to prevent recurrent attacks. Coenzyme Q10, L-carnitine, idebenone, multivitamins, and oral L-arginine are supplements for treatment. Additionally, antiepilepsy drugs treat both intermittent and stroke-like episodes. That is why antiepileptic drugs were administered to patient 2. Early diagnosis and intervention are critical for MELAS treatment. Although preclinical features and imaging markers have yet to be elucidated, some sensitive tools for predicting SLEs during intermittent interval periods were explored. Eight cases have so far reported that the arterial spin labeling and magnetic resonance spectroscopy technique could be helpful in detecting latent lesions 2 days to 5 months before a recurrent attack4, 7-9 (Table 1). Whether all hyperperfused abnormalities signify potential SLLs remains uncertain. Specific predictable imaging biomarkers will be further investigated in a large-cohort study. Supported by National Natural Science Foundation of China (No. 81301203, 81401035).