Ketamine (KET) is a noncompetitive N-Methyl-D-aspartate (NMDA) receptor antagonist that was developed in the 1960s. Corssen et al. (1) reported that the corticothalamic system is suppressed while the limbic system is activated in cats using KET, thus, KET is referred to as a “dissociative anesthetic.” In veterinary medicine, KET is generally used for restraint, sedation, and analgesia. In addition to these applications, KET has been recently used to control refractory (GABAergic drugs-resistant) status epilepticus (RSE) in dogs (2). However, studies on the effects of KET on epilepsy are inconsistent, with reports stating that KET has antiseizure effects (3, 4), while other reports state that KET induces seizure activity (5).

Electroencephalography (EEG) is one of the most important diagnostic tools in epilepsy and has also attracted attention for detecting the epileptogenic zone for both seizure classification and epilepsy surgery (6, 7). However, in the veterinary field, especially in cats, EEG usage is not prevalent. As one factor of this, EEG in cats with high-density coats and hard scalps requires strict sedation and immobilization for electrode placement and stable recording. Some studies have reported the use of sedatives, typically medetomidine (MED) or the enantiomer of MED, dexmedetomidine, to perform scalp EEG in dogs and cats (8–10). MED and dexmedetomidine produce sedative and analgesic effects enough for EEG recording and can be rapidly antagonized by the administration of atipamezole (11, 12). Therefore, MED or dexmedetomidine is preferred for EEG recording in animals. In a canine EEG study with MED, dogs with severe seizures had a predominantly higher incidence of interictal epileptiform discharges (IEDs) than control dogs (13). However, there are cases in which IED cannot be detected in actual EEG measurements, even if the patient has epilepsy, and repeated EEG testing is recommended depending on the case (14). However, because of the burdens associated with EEG in animals, including the administration of sedatives, an agent that is safe and does not interfere with IED detection would be ideal.

In previous studies, we reported familial spontaneous epileptic cats (FSECs) with suspected genetic epilepsy. FSECs have spontaneous focal limbic seizures with or without evolving to generalized tonic-clonic seizures (GTCS), and, therefore, are classified as temporal lobe epilepsy (TLE) (15–21). The epileptogenic zone of FSECs is presumed to exist in the hippocampus or amygdala, which are parts of the limbic system, or both based on the previous evaluations of symptomatogenic, irritative, seizure-onset, structurally abnormal, and functional deficit zones (22).

Although feline EEG using KET was examined in the past (4, 5, 23–26), to our knowledge, there are no reports of such studies conducted in cats with spontaneous TLE. Therefore, we hypothesized that the use of KET, which stimulates the limbic system and inhibits the cortex, in EEG in cats with TLE would increase the number of IEDs. To verify this hypothesis, we conducted scalp EEG in healthy and TLE cats after the sole administration of KET or MED (study 1). Then, according to the results from study 1, we evaluated the effect of KET after sedation with MED on scalp EEG in cats with TLE (study 2).

In this study, we investigated the effects of intramuscular KET alone or intravenous KET under MED sedation on scalp EEG in healthy cats and cats with TLE. There were no significant differences in the incidence of IEDs between MED and KET nor between MED and MED-KET. In a previous report, KET suppressed focal seizures in 6 of 16 cats with epileptogenic focus produced by penicillin, and it did not affect IEDs in 10 cats (4). On the other hand, studies using KET in baboons have reported generalized IED activation in the scalp EEG (28). In the present study, the incidence of IEDs tended to be depressed by both KET alone and MED-KET in both control and TLE groups. Taking into account the previous study that KET suppressed the corticothalamic system and activated the limbic system (1), the trend in decreasing the incidence of IEDs in the present study may suggest that KET has an inhibitory effect on the corticothalamic system in cats. Although there were no statistically significant differences to support these trends in the present analysis, one factor may be the exclusion of individuals who did not have sufficient EEG records, especially with respect to the administration of KET alone.

In the TLE group, clinical seizures were observed in all cats after the administration of KET alone. The KET-induced seizure in 5 of 6 TLE cats was similar to their habitual seizures, i.e., limbic seizure to generalization (see Table 1 for details). In addition, a subclinical seizure was observed in one TLE cat (No. 7) after the administration of KET following MED sedation, the onset of which coincided with the regions with the highest incidence of IEDs. Although the mechanism by which KET induces seizures has not been elucidated, these facts suggest that KET activated the limbic system, which is the epileptogenic zone of TLE cats in this study. In addition, the three cats (Nos. 1, 2, and 18) that had clinical seizures induced by KET in both studies had a higher seizure frequency (12, 19, and 14 per year, respectively) than the others. Thus, whether the epileptogenic zone is activated with KET administration may depend on seizure frequency.

In the adult human, the detection rate of epileptic discharges is reported to be approximately 50% on the initial examination and increases to approximately 80%–90% with repeated testing (29). However, unlike humans, EEG in cats always requires immobilization using sedatives or anesthetics, and few EEGs are repeated. In addition, a recently developed ambulatory EEG system for dogs and humans may not be adopted for cats due to the nature of felines and the size and weight of the equipment. In this situation, capturing clinical seizure onset during a single scalp EEG is often difficult, depending on the individual’s seizure frequency. A previous report suggested that low doses of KET may lower seizure thresholds within minutes of administration in people with a predisposition to focal epilepsy (30). Considering that we were able to capture seizures after KET administration compared to MED alone in the present study, KET administration may be useful for determining the epileptogenic zone.

In both studies of KET administration alone (study 1) and KET administration after MED (study 2), the generalized slow wave was observed in both TLE and control groups. Quantitative analysis showed that the delta band on background activity in both TLE and control groups was significantly increased, while other bands were significantly decreased in most areas. In a study with cats, electrocorticogram changes during KET administration under general anesthesia with ether were reported to occur in a dose-dependent manner, with doses below 5 mg/kg causing generalized beta activity and doses above 5 mg/kg causing alternating bursts of polyspike-slow waves and high-potential synchronous beta waves (4). In humans, low doses of KET were reported to cause the EEG to show fast oscillations in the high beta and low gamma, and that the slow oscillations exhibited by KET were more irregular than the slow oscillations caused by propofol and dexmedetomidine (31). That report also suggested that the beta and gamma oscillations were caused by KET’s preference for NMDA receptors on inhibitory interneurons, which, in turn, increased cerebral metabolic rate, cerebral blood flow, and hallucinations (31). However, in the present study, we did not observe beta oscillations, and, in the quantitative analysis of study 2, beta oscillations were clearly reduced and a visually recognizable generalized slowing (2–5 Hz) was observed in many cats after KET administration. The slow waves observed in study 1 may be due to cortical inhibition by KET, and the lack of fast oscillations as reported in the past (under anesthesia) may be due to insufficient immobilization by KET alone, which may have masked these fast oscillations. The reason why beta oscillations were reduced in study 2 and slow waves were observed in more individuals than in study 1 (6/10 vs. 18/22) may be due to cortical inhibition by KET and the pre-administration of MED. High-voltage and low-frequency activity expressed as delta and theta rhythms have been reported as MED-induced background activity in cats (9). In addition, it has been reported that intraperitoneal administration of MED and KET in rats increases low-frequency bands with only minor changes in the high-frequency bands (32). The KET-induced higher frequency band activity has been reported to be associated with increased cerebral metabolic rate and cerebral blood flow by inhibiting NMDA receptors, as described above, while alpha-2 agonist (MED) has been reported to decrease cerebral blood flow (33). Therefore, fast oscillations in the high beta and low gamma may have been suppressed in the present study.

In previous studies in normal cats or feline experimental models receiving KET, KET was administered under anesthesia, and changes in EEG were investigated (4, 5, 23–26). One of these reports evaluated the effect of KET on IEDs in the penicillin-induced seizure model of cats; however, quantitative evaluation has not been conducted (4). Another study reported that 5 of 22 (23%) healthy cats administered an anesthetic dose of KET (20 mg/kg IM) showed limbic seizures evolving to GTCS (23). However, to the best of our knowledge, there is no report of KET administration in cats with naturally occurring TLE so far. In the present study, we used cats with naturally occurring TLE to assess background activity, the presence of seizure activity, and the quantitative of IEDs under KET-induced sedation. We consider that the results of the present study provide important consideration for the use of KET in cats in the veterinary clinical setting.

We recognize there are several limitations to the present study. First, in the comparison of IEDs between KET and MED, most of the IED counts for KET in the TLE group were conducted in post-ictal EEG measurements because of a seizure induced immediately after KET administration. It is known that postictal generalized EEG suppression (PGES) occurs immediately after an epileptic seizure (34). PGES are generally observed more frequently in convulsive seizures than in focal seizures, but reports on the frequency of occurrence and duration are very inconsistent (35). Therefore, PGES may have occurred after KET-induced seizures and reduced the number of IED in the present study. Second, we considered the dose variation of agents to obtain sufficient sedation for EEG recording as a possible reason for the variability in the results of this study. Although KET can produce dose-dependent EEG changes as mentioned above (4), the dose of KET alone in this study was at the upper limit of a typical sedation dose because it was intended to sedate sufficiently for measuring EEG and to avoid respiratory depression. Therefore, the large dose variability among individuals may have particularly affected the analysis. Because of individual differences in sedative effects, the administration of KET alone may result in a time lag or inadequate sedation before an EEG measurement can be performed. If the time lag between the administration and EEG measurement was significant, a subclinical seizure may have been missed. To confirm the acute effects of KET immediately after administration, as in this study, simultaneous administration of a sedative such as MED may be necessary. Alternatively, EEG under intubation should be considered, given the possibility of respiratory depression. When an anesthetic dose of KET was administered, we expected that the reported bursts of polyspike-slow waves (i.e., elevated beta and delta bands) would be observed (4). However, in recent years, it suggested that the administration of KET under appropriate respiratory control might suppress EEG activity (36). Therefore, if appropriate respiratory management is performed after the administration of KET, a remarkable alteration in the power spectrum may be observed. Further investigation of the dose-depend effect of KET on EEG is necessary. Third, the fact that many cats included in the present study were older, and that there was a wide variation in seizure frequency prior to inclusion may have contributed to the variability in the results. An EEG study using two groups of cats divided according to age under sedation with MED reported that older cats had significantly higher relative power in the theta, alpha, and beta bands and lower in the delta band than younger cats (9). Thus, in our MED-KET study, the significant increase in the delta band might have been more pronounced in our older cats than in a young cat population.

In the present study, MED produced more stable sedation than KET alone in cats with TLE, and EEG measurements were feasible. Furthermore, KET is easy to induce seizures in cats with TLE. Therefore single-use KET as a sedative for EEG is not recommended from the results of this study. However, we would suggest that KET may be useful to activate seizure activities on EEG under MED sedation. This will be a critical tool to obtain ictal EEG for detecting the epileptogenic zone (irritative or seizure-onset zones). Although the combination of MED and KET has long been used as an anesthetic induction in veterinary medicine (11), caution will be needed for feline patients with a history of seizures. Recently, KET has received increasing attention in the management of RSE (2). However, our results emphasize that “Do not use ketamine as first line for treatment of status epilepticus (or seizure management)” and “use ketamine after confirmation of GABAergic/benzodiazepine-resistant (refractory) status epilepticus.” Whether KET is an anti-seizure or pro-seizure medication, the present results indicate that KET has a proconvulsant feature for interictal cats with TLE and/or high seizure frequency.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This study, including care and maintenance of the FSEC colony, healthy, and epileptic cats genetically unrelated to FSECs, was reviewed and approved by the Animal Care and Use Committee of Nippon Veterinary and Life Science University (accession Nos. 2020K-3, 2021K-2, 2022K-2; the principal investigator is DH).

SM, RA, and DH designed this study. SM and RA conducted experiments, data acquisition, and analyses. SM wrote the draft of the manuscript and performed statistics. SM and YY performed data visualization. YH, YY, and DH performed editing of the draft. All authors contributed to the article and approved the submitted version.

This study was partially supported by the Science Research Promotion Fund (grant numbers 2022-16 and 2023-18) from the Promotion and Mutual Aid Corporation for Private School of Japan (PMAC).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.