This is the first case report in which dc-MEP was successfully recorded in a 12-year-old neurologically immature patient using remimazolam. Intraoperative neurophysiological monitoring used for supratentorial surgery has been investigated mainly for adults, despite recording myogenic MEP as a valuable safety measure in complex intracranial surgery when the lesion is in proximity to the motor cortex and fibers [9]. However, the parameters for cortical stimulation need to be adjusted in young children and infants due to their central nervous system immaturity [10]. Age significantly impacts cortical development; Eyre et al. indicated that a higher stimulation threshold to elicit a motor response is necessary for children up to 16 years old [11]. Furthermore, the decreased interhemispheric transmission time of evoked potential along with increasing age from 7 to 17 years reported by Hagelthorn et al. suggests that increasing corpus callosal myelination during late childhood integrates functional connection across the midline [12]. Spinal cord motor pathways also require a prolonged period of maturation. Unlike other pathways, the corticospinal tracts (CSTs) undergo a protracted period of myelogenesis and synaptogenesis; the diameters of corticospinal axons do not reach full myelination until the age of 16 [13]. Nezu et al. estimated that electrophysiologic maturity of the CSTs innervating the hand muscles is completed by the age of 13 [14]. Moreover, direct cortical stimulation is sometimes required in supratentorial surgeries because the stimulating electrodes in tc-MEP, placed overlapping the motor areas on the scalp, could interfere with the surgical field. Therefore, much lower current intensities than transcranial electrical stimulation are adopted for direct motor cortex stimulation. Notably, the titration of remimazolam infusion and the adjustment of monitoring conditions in our case were complicated. However, a recent report on pediatric supratentorial surgeries showed that dc-MEP was more sensitive than tc-MEP in predicting postoperative motor decline despite the patients being aged 3–207 months [15]. The fact that persistent loss of MEP response for more than 5 min results in postoperative motor deficit [2] also encourages us to find more reliable and effective conditions for motor potential monitoring, even if the patient is not neurologically matured.
MEP is sensitive to neurological conditions, the extent of myelination of corticospinal pathways, and anesthesia techniques. Clinically recommended doses of opioids, such as fentanyl or remifentanil, have little impact on MEPs [16]; however, the anesthesia plan must be carefully considered because the choice of anesthetic affects the likelihood of a false-positive result. In order to record reliable MEPs, total intravenous anesthesia with propofol, rather than inhalational agents, is recommended in children over 6 years old [17]. Propofol has advantages over other intravenous agents, such as ketamine or midazolam; it exhibits higher suitability for EEG changes to the depth of anesthesia, and a well-established target-controlled infusion system can precisely control propofol concentration. Nevertheless, propofol involves a potential risk for propofol infusion syndrome (PRIS), originally found in children but has become often reported in adults even within the recommended limits [18]. The demand for an alternative anesthesia regimen for the ketamine-based technique in children younger than 6 years old [17] and propofol dose-dependent suppression of MEP amplitude [19] are of significant concern. Considering the effects of physiological variables during MEP, a significant decrease in systemic arterial pressure caused by propofol seems inferior to remimazolam. Doi and colleagues revealed that hypotensive events were more frequent with propofol than with remimazolam during all phases of the anesthesia. The requirement for vasopressors was greater for propofol than for remimazolam [20]. Further research is still required to determine propofol safety in pediatric cases with severe anaphylaxis to eggs and allergic reactions to peanut or soy [4]. In this pediatric case, we avoided propofol due to the patient’s history of egg allergy and decided to administrate remimazolam. The clinical use of remimazolam is increasing worldwide. This case report demonstrates that dc-MEP recording under remimazolam anesthesia is possible even if the patient’s neurological development is not maturated.
Remimazolam has some issues that should be addressed. First, the reliability of frontal EEG-derived index alteration is still controversial [21], despite the good correlations between the BIS value, and the effects of propofol, midazolam, and isoflurane on the level of consciousness and recall were evident [22]. The EEG effects of benzodiazepines are predominantly a monotonic beta activation, especially in frontal areas, and these effects map to higher EEG-derived indices to estimate the anesthesia depth [23]. In contrast to the current pediatric case, previous tc-MEP reports of young and elderly patients showed that relatively higher remimazolam infusion rates were required for successful MEP recording [6, 7]. In neurosurgery, stimulating intensities should be minimized to the least possible extent to circumvent false-positive signals that result from the stimuli reaching the skull base [16]; this is the most significant difference from tc-MEP, which is frequently used in spine surgery. Certain indicators to estimate the level of remimazolam anesthesia are required to make the minimum infusion rate compatible with avoiding intraoperative awareness. Long-term benzodiazepine use for seizure control, frequently observed among patients with intracranial legions, is another concern; otherwise, the patient might show remimazolam tolerance [24], and reversal with flumazenil may cause a seizure. Thus, at present, eliminating the incidences of intraoperative hypotension or PRIS is the most rational reason for considering remimazolam-based anesthesia for pediatric supratentorial surgery under MEP monitoring.
The present case report had some limitations. First, it is still unclear whether remimazolam suppresses dc-MEP responses. A previous report could not find any dose-dependent effects of remimazolam on tc-MEP [6], though several reports indicated the progressive suppression of tc-MEP with the increase of midazolam dose [25, 26]. In our case, a successful dc-MEP recording was obtained with a reduced remimazolam infusion. Second, the pharmacological differences between midazolam and remimazolam on MEP are considered clinically important, but this study could not investigate these differences based on the experience of a single case handled with remimazolam anesthesia. Further studies are needed to address these limitations.
