With interest we read the article by Chen about a 52yo female with diabetes and end-stage renal disease (ESRD), requiring hemodialysis, who experienced sudden onset fever, delir, elevated lactate, and epilepsy being initially diagnosed as herpes simplex encephalitis (HSE) [1]. Surprisingly, work up for lactic acidosis revealed mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome due to the variant m.3243A>G [1]. The study has a number of shortcomings. 

The first shortcoming is that no heteroplasmy rates in any affected or non-affected tissue were provided. Knowing heteroplasmy rates is crucial for interpreting the phenotype, for predicting the further disease trajectory and the outcome of this patient, and for genetic counselling [2]. 

The second shortcoming is that first degree relatives were not systematically investigated for clinical manifestations of a mitochondrial disorder (MID) and for the presence or absence of the m.3243A>G variant. Knowing the phenotype and genetic background of first degree relatives is crucial for assessing the intrafamilial phenotypic heterogeneity, for assessing the variability of heteroplasmy rates within a family, and for genetic counselling [3].

Third, the patient received valproic acid (VPA) despite the diagnosis MELAS. From VPA it is well known that it is potentially mitochondrion-toxic [4]. In patients carrying POLG1 variants even fatalities from acute liver failure have been reported [5]. After recording periodic lateralised epileptiform discharges (PLEDS) [1], VPA was replaced by levetiracetam (LEV), upon which EEG abnormalities disappeared completely [1]. Improvement of the EEG activity upon discontinuation of VPA suggests that VPA exhibited indeed a mitochondrion-toxic effect.

A fourth shortcoming is that it was not discussed if progression and deterioration of the phenotype had been favoured by the long-term use of sirolimus or tacrolimus. From sirolimus it is well known that it can be muscle toxic and may go along with myopathy [6]. From tacrolimus it is well known that it may cause mitochondrial dysfunction and apoptosis [7], which can be improved by application of antioxidants [8]. Since transplantation entails immunosuppression, and since immunosuppression is potentially mitochondrion-toxic, transplantation in MID patients must be considered carefully. 

A fifth shortcoming is that no reference limits for the reported figures were provided, why interpretation of the results remains vague. 

A sixth shortcoming is that the patient did not receive nitric-oxide (NO) precursors for the first stroke-like lesion (SLL). It is conceivable that application of NO-precursors after the first SLL in a left lateral temporal distribution, might have prevented the development of the second SLL. Oral NO-precursors have been shown beneficial even for preventing the recurrence of a SLL [9]. 

We do not agree that the patient had a late-onset MELAS syndrome [1]. Since the patient had short stature since early childhood, experienced renal dysfunction at young age, and hypoacusis since age 35y [1], the index patient manifested with MELAS much earlier than anticipated. Patients of short stature should generally raise the suspicion of a MID, since growth hormone deficiency is a frequent feature of MIDs,

HSE should be delineated from a SLL in MELAS not only by application of imaging studies but rather by investigations of the CSF. CSF investigations most likely can differentiate these two entities. We do not agree that patients with suspected HSE and MELAS should receive antiviral medication until MELAS is excluded. Even anti-viral agents can be mitochondrion-toxic [10]. 

We do not agree with the notion that progression of the SLL is “unique” as mentioned in the discussion [1]. On the contrary, spreading and regression are typical features of a SLL. Missing in table 1 are the lactate levels.

Overall, this interesting case report has a number of shortcomings which need to be addressed before drawing conclusions as those provided. Immunosuppressants as well as antiviral agents should be applied with caution in MID patients.