We read with interest the article by Perez-Cruz et al. [1] about a 46 years old male with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome [1]. Initially, immune encephalitis was suspected why the patient underwent brain biopsy and received steroids without benefit (Pérez-Cruz, E. et al., 2022). Work-up for MELAS revealed basal ganglia calcification, two stroke-like lesions in a right temporal and the left temporo-occipital distribution, lactic acidosis in the serum and cerebrospinal fluid (CSF) and the mtDNA variant m.3243A>G in MT-TL1 [1]. Immuno-nutrition, a so called mitochondrial cocktail, together with anti-seizure drugs (ASDs) was initiated, this time with a beneficial effect [1]. The study is appealing but raises concerns that need to be discussed.
 

It is not comprehensible why initially immune encephalitis was suspected and why work-up for it was initiated and why the patient received ex juvantibus steroids [1]. The patient was of short stature, had a previous history of diabetes, hearing impairment, tinnitus, partial complex seizures (left leg, visual hallucinations, unconsciousness, secessus), quadruparesis and had elevated lactate in the serum and the cerebrospinal fluid (CSF) on admission [1]. Additionally, cerebral CT revealed bilateral basal ganglia calcification, which is a typical feature of mitochondrial disorders on cerebral imaging [2]. Furthermore, echocardiography revealed systolic dysfunction, frequently observed in patients with a mitochondrial disorder and cardiac involvement [3]. Patients with immune encephalitis usually do not develop lactic acidosis in the serum or CSF unless they experience seizures. We should know why nonetheless immune encephalitis was suspected and why brain biopsy had been carried out and why steroids were given. Steroids can be harmful to patients with a mitochondrial disorder, particularly in patients with Kearns-Sayre syndrome [4]. Application of steroids is particularly critical in diabetic patients. Brain biopsy is an invasive diagnostic measure with a high risk of complications, such as infection, bleeding or seizures.
 

Missing is the heteroplasmy rate of the m.3243A>G variant and the tissue in which heteroplasmy was determined. Knowing heteroplasmy rates in various different tissues is crucial for assessing the phenotypic spectrum, progression and outcome of MELAS patients and for genetic counselling.
 

Missing is the information if the variant m.3243A>G was inherited from the mother of if it occurred spontaneously. Since three quarters of the MELAS patients inherit the culprit mutation from their mothers [5], it is essential to know if the index patient’s mother was clinically affected or if she carried the m.3243A>G variant as well. Furthermore, we should know if other first degree relatives were clinically affected or carried the culprit variant as well.
 

MELAS should not be diagnosed upon the Hirano criteria [6], which stem form 1992 and require the triad of encephalopathy, lactic acidosis and stroke-like episodes (SLEs) but rather according to the Japanese criteria [7]. The Japanese criteria have been published in 2012 and require the presence of more subtle phenotypic features and the presence of a causative mutation.
 

There is a discrepancy between the history of hearing loss and tinnitus two months prior to admission and the normal status of cranial nerves on clinical neurologic exam. We should be told if the patient was hearing normally or not on admission.
 

MELAS is associated with permanent or episodic lactic acidosis in the majority of the cases [8]. We should be told why the patient nonetheless received metformin during 7 months since evolvement of diabetes prior to admission. Missing is the HbA1c value.
 

The authors described a hyperintense lesion on fluid attenuated inversion recovery (FLAIR) in the “cerebellar lobe” [1]. We should be told if it was the right or left lobe and if this lesion was also hyperintense on Diffusion-Weighted Imaging (DWI). Is it conceivable that this lesion met the criteria for being classified as a SLL?
 

Though nutritional and lifestyle modifications may have a temporary beneficial effect on the disease course [9], MELAS is usually a progressive disease from which patients die prematurely. From none of the compounds usually administered to MELAS patients is a long-term benefit documented by prospective studies with a double blind placebo-controlled design. L-carnitine will be beneficial only in case of confirmed carnitine deficiency. Since mitochondrial disorders, including MELAS, are highly sensitive to drugs, compounds with a mitochondrion- toxic effect should be avoided. This is particularly the case for certain ASDs, such as phenytoin, carbamazepin, valproic acid and barbituric acid [9].
 

Though the patient underwent muscle biopsy, no results of this investigation were presented [1]. We should be told if any morphological abnormalities of the mitochondria were found, if immune histochemistry revealed COX-deficient fibers or if there were SDH hyper-reactive fibers. Were ragged-red fibers detected upon the Gomori stain? It would be also interesting to know if the variant m.3243A>G was detected in muscle and if the heteroplasmy rate was higher as compared with other tissues.
 

Overall, the interesting study has several limitations which challenge the results and their interpretation. Addressing these issues would strengthen the conclusions and could be more educative. Patients with a mitochondrial disorder should not receive mitochondrion-toxic drugs. Patients in whom a mitochondrial disorder is suspected should not undergo brain biopsy. Treatment of MELAS currently remains symptomatic and supportive.

Ethical Approval
Ethical approval was in accordance with ethical guidelines. The study was approved by the institutional review board.