Metabolomics by magnetic resonance spectroscopy may not sufficiently explain “brain fog” in neuro-COVID

Dear Editor,
We eagerly read the article by Sklinda et al. about a prospective study of 11 patients with post-COVID-19 “brain fog” by means of magnetic resonance spectroscopy (MRS) and the following neuropsychological batteries: Addenbrooke’s cognitive examination III (ACE-III), the Rey complex figure test (RCFT), the California verbal learning test (CVLT), the Trail Making Test (TMT), the Wechsler adult intelligence scale (WAIS), and the hospital and anxiety depression scale (HADS), after an undetermined time after onset of the infection [1]. It was found that the Lac/Cr ratio was decreased and that the Glx/Cr ratio was increased on MRS in COVID patients with “brain fog” [1]. The study is very interesting but raises concerns that require discussion.
The main limitation of the study is that the term “brain fog” is not well defined and is generally a vague description that includes various different conditions, such as impaired consciousness, cognitive dysfunction, memory decline, concentration difficulty, disorientation, trouble finding words, decreased fluency of speech, dizziness, confusion, delirium, deficits in executive functions, impaired episodic and visuo-spatial memory, dysfunctional memory processing, non-convulsive epileptic state, depression, anxiety, hallucinations, multitasking problem, reduced ability of meeting activities of daily living (ADLs), and even sleep disorders. Accordingly, it is quite likely that the 11 included patients experienced variable deficits, constituting an inhomogeneous cohort.
A further limitation is that the various causes of “brain fog” were not entirely encountered in the 11 patients. Particularly, we should know the results of cerebral MRI, with regard to the statement that the study also aimed at investigating the macroscopic status of the brain in patients with “brain fog” [1]. Knowing the results of the MRI investigation is crucial because many of the cerebral manifestations of neuro-COVID can clinically manifest with “brain fog”. These include stroke, bleeding, immune encephalitis, meningitis, acute, disseminated encephalomyelitis (ADEM), posterior reversible encephalopathy syndrome (PRES), venous sinus thrombosis (VST), multiple sclerosis (MS), neuromyelitis optica (NMO), cerebral vasculitis, and reversible cerebral vasoconstriction syndrome (RCVS).
Some key characteristics of the study population are missing. We should know the current medication the 11 patients were taking at...


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