Abstract
Status epilepticus (SE) and cluster seizures (CS) are common occurrences in veterinary neurology and frequent reasons of admission to veterinary hospitals. With prolonged seizure activity, gamma amino-butyric acid (GABA) receptors (GABAa receptors) become inactive, leading to a state of pharmacoresistance to benzodiazepines and other GABAergic medications, which is called refractory status epilepticus (RSE). Prolonged seizure activity is also associated with overexpression of N-methyl-D-aspartic (NMDA) receptors. Rodent models have shown the efficacy of ketamine (KET) in treating RSE, and its use has been reported in one canine case of RSE. Boluses of KET 5 mg/kg IV have become the preferred treatment for RSE in our hospital. A retrospective study was performed to evaluate and report our experience with KET IV bolus to treat prolonged and/or repeated seizure activity in cases of canine CS, SE, and RSE. A total of 15 dogs were retrieved, for 20 hospitalizations and 28 KET IV injections over 3 years. KET IV boluses were used 12 times for RSE (9 generalized seizures, 3 focal seizures) and KET terminated the episode of RSE 12/12 times (100%); however, seizures recurred 4/12 times (33%) within ≤6 h of KET IV bolus. When used for CS apart from episodes of RSE, KET IV bolus was associated with termination of the CS episode only 4/14 times (29%). Only 4/28 (14%) KET IV boluses were associated with adverse effects imputable only to the use of KET. One dog experienced a short, self-limited seizure activity during administration of KET IV, which was most likely related to a pre-mature use of KET IV (i.e., before GABAergic resistance and NMDA receptor overexpression had taken place). This study indicates that KET 5 mg/kg IV bolus may be successful for the treatment of RSE in dogs.
Highlights
The term cluster seizures (CS) refers to the onset of multiple generalized or focal seizures within a 24-h period [1,2,3,4]
The different types of onsets/episodes of seizures treated during hospitalization and KET IV injections were recorded as follows: Refractory status epilepticus (RSE) of generalized seizure: 7 patients/8 hospitalizations/9 injections, RSE of focal seizure: 3 patients/3 hospitalizations/3 injections, Status epilepticus (SE): 7 patients/7 hospitalizations/2 injections, CS: 11 patients/13 onsets/4 injections, and CS–SE: 8 patients/10 hospitalizations/10 injections
The exact duration of the seizure activity could not be accurately specified but rather estimated in most cases due to the limited temporal specificity obtained from the retrospective review of medical records, but all cases of RSE presented with uninterrupted clinical seizure activity for >15 min at a minimum, with at least 5 onsets of RSE lasting for >30 min prior to termination
Summary
The term cluster seizures (CS) refers to the onset of multiple generalized (tonic, clonic, or tonic– clonic) or focal seizures (with or without secondary generalization) within a 24-h period [1,2,3,4]. Status epilepticus and RSE are prolonged ictal events arising from failure of the mechanisms normally responsible for seizure termination. During prolonged seizures in cases of SE/RSE, GABAa receptors are both desensitized and internalized, and the number of activated GABAa receptors on the postsynaptic membrane gradually decreases while the number of inactive GABAa receptors increases, leading to a decreased effect of GABAergic stimulation and resistance to benzodiazepines [14,15,16,17]. Prolonged seizures in cases of SE/RSE lead to a status of pharmacoresistance against the classical AEMs targeting the GABAergic system for seizure termination (e.g., diazepam, midazolam, phenobarbital, propofol) and potential neurotoxicity. While the GABAergic stimulation may appear as a pharmacological dead end during SE, NMDA receptor subunit migration toward the synaptic membrane [19], NMDA receptor activation during sustained neuronal stimulation, and possible glutamate excess due to failure of glial buffering present the NMDA receptors as an ideal therapeutic target
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