Cefepime, a fourth-generation cephalosporin with a beta-lactam ring, acts as a GABAA receptor antagonist. Cefepime-induced encephalopathy (CIE), diagnosed in 15% of patients treated with cefepime in the intensive care unit, is frequently overlooked.
We noticed that patients with CIE experienced similar clinical manifestations and characteristic electroencephalography (EEG) waveforms. We aimed to reproduce these characteristic EEG waveforms and investigate the pathogenesis of CIE via computer simulation.
Three patients with CIE were retrospectively documented by a single-center consultation-liaison team during a two-year study period. In all the cases, the patients refused medication/examination and showed signs of overt pain, palilalia, and a much greater deterioration in eye and verbal responses than in their motor responses. These symptoms might have been misdiagnosed as a psychogenic condition. We hypothesized that the clinical manifestations were related to GABAergic dysfunction. To define the characteristic EEG waveforms presented by all three patients, we coined the term, "triphasic wave-like generalized periodic discharges with a high negative component (Tri-HNC, pronounced, Try-high-neck)".
Computer simulation using neural mass modeling (basically mean-field model) reproduced the characteristic features of Tri-HNC, the recovery course on EEG, and the individual differences in pharmacological intervention. The simulation also suggested that auto-inhibition (synaptic inputs from interneuron to interneuron) dysregulation contributed to the generation of Tri-HNC. We believe that there is a common pathophysiologic basis of excitatory/inhibitory imbalance due to GABAergic dysfunction and that Tri-HNC can be its experimental phenotype.
Given the rapid progress of basic neuroscience, enabling psychiatrists to make clinical observations, particularly with respect to psychopathology and pharmacology, and to extract homogeneous subgroups from heterogeneous patients may yield useful insights; moreover, it may promote effective patient care.
<Authors' abstract>
Characteristic EEG Waveform, Tri-HNC, in Cefepime-induced Encephalopathy Due to Excitatory/inhibitory Imbalance
1 Department of Neuropsychiatry, Tokyo Metropolitan Tama Medical Center
2 Department of Cellular Neurobiology, Graduate School of Medicine, The University of Tokyo
3 Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo
4 Department of Child Neuropsychiatry, Graduate School of Medicine, The University of Tokyo
5 Department of Earth and Planetary Sciences, School of Science, Tokyo Institute of Technology
2 Department of Cellular Neurobiology, Graduate School of Medicine, The University of Tokyo
3 Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo
4 Department of Child Neuropsychiatry, Graduate School of Medicine, The University of Tokyo
5 Department of Earth and Planetary Sciences, School of Science, Tokyo Institute of Technology
Psychiatria et Neurologia Japonica
122: 3-10, 2020
<Keywords:cefepime-induced encephalopathy (CIE), GABAergic neurons, computational psychiatry, computer simulation, translational research>