ABSTRACT
BACKGROUND: Nonconvulsive status epilepticus (NCSE) is a frequent disorder in neurocritical care and diagnosing it can be challenging. NCSE patients often show altered pupil function, but nature and extent may vary. Infrared pupillometry allows detection of subtle changes of pupil function. The neurological pupil index (NPi) is considered a surrogate marker of global pupil function which is supposed to be independent of absolute parameters such as the pupil diameter. OBJECTIVE: Cross-sectional observational study to assess whether NPi is altered in NCSE. METHODS: 128 consecutive adult emergency patients who had experienced a suspected seizure, have not reached their prior functional level regarding level of consciousness, mental status or focal deficits, had no obvious clinical signs of status epilepticus and had an EEG indication as determined by the treating clinician for exclusion of NCSE were examined by routine EEG and pupillometry. Exclusion criteria were ocular comorbidity (n = 21) and poor EEG quality (n = 4). Pupillometry was performed once directly before the beginning of EEG recording. NCSE diagnosis (no NCSE, possible NCSE and confirmed NCSE) was established according to Salzburg consensus criteria blinded to pupillometry results. Group comparison was performed for right NPi, left NPi, lowest NPi of both sides (minNPi) and the absolute difference of both sides (diffNPi) applying non-parametric testing. In post-hoc analysis, receiver operating characteristics (ROC) of NCSE diagnosis (combined confirmed NCSE and possible NCSE) were performed for minNPi and diffNPi. RESULTS: From 103 patients included in the final analysis, 5 (4.9%) had confirmed NCSE, 7 (6.8%) had possible NCSE. Right NPi (p = 0.002), left NPi (p < 0.001) and minNPi (p < 0.001) were significantly lower in "confirmed NCSE" and "possible NCSE" compared to "no NCSE"; diffNPi was significantly higher in "confirmed NCSE" and "possible NCSE" compared to "no NCSE" (p < 0.001). There was no significant difference of minNPi and diffNPi between "confirmed NCSE" and "possible NCSE". ROC analysis showed an optimal cut-off of minNPi for NCSE diagnosis of 4.0 (AUC = 0.93, 95% CI 0.86-0.99). Optimal ROC analysis cut-off of diffNPi for NCSE diagnosis was 0.2 (AUC = 0.89, 95% CI 0.80-0.99). CONCLUSIONS: NPi was significantly reduced and the difference between left and right NPi was significantly higher in confirmed NCSE. An NPi < 4.0 on either side as well as an NPi difference of both sides > 0.2 may be potential indicators of NCSE. Infrared pupillometry may be a helpful diagnostic tool in the assessment of NCSE and should be studied further in larger populations.
Subject(s)
Electroencephalography , Status Epilepticus , Adult , Cross-Sectional Studies , Humans , ROC Curve , Seizures , Status Epilepticus/diagnosisABSTRACT
Central nervous system (CNS) inflammation involves the generation of inducible cytokines such as interferons (IFNs) and alterations in brain activity, yet the interplay of both is not well understood. Here, we show that in vivo elevation of IFNs by viral brain infection reduced hyperpolarization-activated currents (Ih) in cortical pyramidal neurons. In rodent brain slices directly exposed to type I IFNs, the hyperpolarization-activated cyclic nucleotide (HCN)-gated channel subunit HCN1 was specifically affected. The effect required an intact type I receptor (IFNAR) signaling cascade. Consistent with Ih inhibition, IFNs hyperpolarized the resting membrane potential, shifted the resonance frequency, and increased the membrane impedance. In vivo application of IFN-ß to the rat and to the mouse cerebral cortex reduced the power of higher frequencies in the cortical electroencephalographic activity only in the presence of HCN1. In summary, these findings identify HCN1 channels as a novel neural target for type I IFNs providing the possibility to tune neural responses during the complex event of a CNS inflammation.
Subject(s)
Cerebral Cortex/physiology , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/physiology , Interferon Type I/physiology , Neurons/physiology , Potassium Channels/physiology , Animals , Blotting, Western , Cerebral Cortex/cytology , Computer Simulation , Cytokines/physiology , Electroencephalography , Electrophysiological Phenomena/physiology , HEK293 Cells , Humans , Immunohistochemistry , Interferon Type I/biosynthesis , Interferon-beta/pharmacology , Male , Mice, Inbred C57BL , Neocortex/cytology , Neocortex/metabolism , Neocortex/physiology , Nerve Net/cytology , Nerve Net/physiology , Patch-Clamp Techniques , Rats , Real-Time Polymerase Chain Reaction , Receptors, Interferon/physiology , Signal Transduction/physiology , TransfectionABSTRACT
Hyperpolarization-activated cyclic nucleotide-gated ion channels (HCN) are key determinants of CNS functions. Here we describe an increase in hyperpolarization-activated current (I(h)) at the beginning of whole-cell recordings in rat layer 5 cortical neurons. For a closer investigation of this I(h) increase, we overexpressed the predominant layer 5 rat subunit HCN1 in HEK293 cells. We characterized the resulting I(h) in the cell-attached and whole-cell configurations. Breaking into whole-cell configuration led to about a 30% enhancement of rat HCN1-mediated I(h) accompanied by a depolarizing shift in voltage dependence and an accelerated time course of activation. This current enhancement is not species specific; for human HCN1, the current similarly increases in amount and kinetics. Although the changes were bound to cytosolic solution exchange, they were independent of cAMP, ATP, GTP, and the phosphate group donor phosphocreatine. Together, these data provide a characterization of heterologous expression of rat HCN1 and suggest that cytosolic contents suppress I(h). Such a mechanism might constitute a reserve in h-channel function in vivo.