LAUSR

We read with interest the article by Li et al about three MELAS patients carrying the m.3243A>G mutation who underwent conventional magnetic resonance imaging (MRI), diffusion kurtosis imaging (DKI), 3D arterial spin labeling (ASL) perfusion MRI, and singlevoxel proton MR spectroscopy (MRS). We have the following comments and concerns. We do not agree with the conclusions that regional hyperperfusion indicates a future stroke-like episode (SLE). Cerebral blood flow (CBF) may not only depend on the presence or absence of an acute or chronic SLE but also on the presence or absence of seizures, frequently occurring before, during, or after a SLE. Additionally, migraine-like headache, frequently associated with SLEs, may influence the CBF. Did any of the three presented patients complain about headache when performing the MRI? Did any of the three have peri-episodic seizures? Additionally, the CBF depends on the heteroplasmy rate of an mtDNA mutation. Thus, it is essential to know the heteroplasmy rates in the three presented patients. Since heteroplasmy rates vary greatly between different tissues, heteroplasmy rates should be determined in different tissues, such as hair follicles, buccal cells, blood lymphocytes, fibroblasts, urinary epithelial cells, and muscle. Another argument against hyperperfusion as an indicator for a future SLE is that stroke-like lesions do not conform to a vascular territory. Increased CBF could be simply interpreted as a compensatory mechanism to provide a cerebral region with oxygen or substrates for energy production independent of the respiratory chain. We agree that arteries may be affected by the metabolic defect in mitochondrial disorders (MIDs), resulting in mitochondrial vasculopathy. However, mitochondrial vasculopathy is just one of the speculations to explain the pathophysiology of a SLE. Other speculations have been raised, including that a SLE is triggered by preclinical seizure activity or by regional breakdown of physiologic energy production. There is no definition of the term “preclinical stage.” Do the authors mean the entire interval between two SLEs or do they just mean the minutes, hours, or days before the development of a SLE? In case they mean the latter, how do they know that a SLE is upcoming? How many hours or days before a SLE does hyperperfusion start? We do not agree with the statement that MELAS syndrome is the most common MID. The most common mitochondrial disorder is nonspecific, syndromic MID. MELAS is just the most well-known acronym. There is also a need to differentiate between MIDs in children and adults. In pediatric cases, encephalopathy. muscle hypotonia, lactic acidosis, epilepsy, cardiomyopathy, and psychomotor delay are the most frequently reported features. In adult-onset cases, the predominant phenotypic features include myopathy, peripheral neuropathy, visual failure, sensorineural deafness, cardiac, gastrointestinal, renal, endocrine, or central nervous system (CNS) involvement. Why did patient 2 receive antiepileptic drugs, although no seizures were reported? Overall, this interesting study is preliminary and requires confirmation in a larger cohort. Dependency of CBF on heteroplasmy rate, on the presence of seizures or migraine, on the sympathetic or parasympathetic tone, on drug cocktails (frequently given in MIDs), on age, or gender needs to be further investigated. Currently, it is quite unlikely that increased CBF represents the preclinical stage of a SLE.