Takehiko Morimoto

Electroencephalographic Study of Rat Hyperthermic Seizures

Summary: The behavior and EEG of rat hyperthermic convulsions was studied. We found that a long run of high‐voltage slow waves without convulsions, high‐voltage irregular activity consisting of spikes and waves with intermittent myoclonus, and rapid spike and wave bursts accompanied by generalized clonic convulsions occurred sequentially. This behavioral and EEG activity is analogous to human febrile convulsions and supports the usefulness of this model for studies of human febrile convulsions. Rats frequently showed arrest of locomotion concurrently with paroxysmal EEG theta bursts before development of generalized convulsions. We speculate that this paroxysmal activity is a type of seizure discharge.

Pathogenic Role of Glutamate in Hyperthermia‐Induced Seizures

Summary: Hyperthermia induces seizures in both humans and rodents, but the underlying mechanism remains unknown. The present study showed that hyperthermia, causing rapid increase in body temperature, increases the concentration of glutamate (Glu) released into a cortical perfusate before onset of seizures in rats and that this increase in Glu concentration correlated with a decrease in seizure threshold temperature. These results indicate that increased cortical extracellular Glu induced by hyperthermia contributes to onset of seizures. The same mechanism may be involved in clinical seizures induced by fever in patients with febrile convulsions or epilepsy.

Epileptic seizures precipitated by constant light, movement in daily life, and hot water immersion.

Summary: We describe a patient with epilepsy characterized by eyelid myoclonous, which often evolved into complex partial seizures, hemiconvulsions, or generalized convulsions. The Outstanding feature was that seizures became markedly more frequent on exposure to light, movement in daily life, and hot watr immersion. the patient was highly susceptible to seizures under constant light, but the dopamine level in the cerebrospinal fluid was quite low, and administration of levodopa transiently suppressed the seizures.

Clinical study of epilepsy with severe febrile seizures and seizures induced by hot water bath.

We followed five cases with severe febrile seizures (FS) with early onset and seizures induced by hot water bath, indicating severe myoclonic epilepsy in infancy (SME) or the peripheral form of SME. These cases, however, had far better clinical courses than that of SME or the peripheral form of SME. These cases were characterized by: (a) severe FS with early onset and seizures induced by hot water bath; (b) a lack of myoclonic seizures; (c) no psychomotor deterioration; (d) no underlying disorders or signs of brain insult on neurologic and laboratory examination; (e) relatively successful seizure control; (f) none of the severe EEG abnormalities seen in SME and the peripheral form of SME; and (g) a positive family history of convulsive disorders.

The pathogenic role of the NMDA receptor in hyperthermia-induced seizures in developing rats

Hyperthermia-induced seizures (HS) in rats have been used as a model of febrile seizures. Activation of the N-methyl-D-aspartate (NMDA) receptor by increased extracellular glutamate (Glu) in the cortex during hyperthermia may be involved in the induction of HS and HS kindling. To confirm this hypothesis, the effects of a potent blocker of the NMDA receptor, MK-801, on the threshold and pattern of HS were evaluated. The threshold temperatures for rats given 0.1 (low dose) and 0.5 (high dose) mg/kg MK-801 (i.p.) for the first time were 41.6 degrees C (39.7-42) (median, range) and 42.0 (41.2-42.0), respectively, which were significantly higher than the 40.5 (39.4-41.2) for rats without MK-801 administration (P < 0.01). The recurrent occurrence of HS suppressed the increase in the threshold temperature with age, and changed the seizure from partial to generalized seizures (HS kindling), whereas these effects of recurrent HS on the threshold and pattern of HS were inhibited by the high dose (0.5 mg/kg) of MK-801. MK-801 blocks HS and HS kindling. The activation of the NMDA receptor during hyperthermia plays an important role in the induction of HS and HS kindling.

The influence of blood gas changes on hyperthermia-induced seizures in developing rats

Fever induces seizures in infants with febrile convulsions or epilepsy. Hyperpnea induced by fever may contribute to the induction of these seizures. In order to examine this possibility, we evaluated the effect of changes in arterial blood gas tension on hyperthermia-induced seizures in developing rats. Electrical seizure discharges were induced by application of infra-red rays on the skull of rats under mechanical ventilation with different respiratory conditions. There was positive correlation between pCO(2) and the seizure threshold (ST) defined as a latency from the start of hyperthermia to the occurrence of seizures: ST (seconds, s) = 2.36 pCO(2) + 0.05 (R(2) = 0.80, P < 0.001). Seizure duration (SD) was longer at lower pCO(2) level: 18 (6-33) (median, range) s at pCO(2) ranging from 23 to 26 mmHg vs. 0 (0-7) s at pCO(2) ranging from 35 to 57 mmHg (P < 0.01). Hypoxia significantly increased ST: 84 (61-100) s at P0(2) ranging from 53 to 76 mmHg vs. 60 (51-72) s at P0(2) ranging from 87 to 131 mmHg (P < 0.01). Hyperoxia prolonged SD: 27 (10-30) s at P02 ranging from 100 to 170 mmHg vs. 9 (0-23) at P0(2) ranging from 53 to 93 mmHg (P < 0.02). Hypocarbia caused by fever-induced hyperpnea probably contributes to the generation of fever-induced seizures.

Interleukin-1β enhances susceptibility to hyperthermia-induced seizures in developing rats

Cytokines have been shown to influence susceptibility to febrile seizures and epilepsy. In this study, the role of interleukin-1beta (IL-1beta) was examined in developing rats. IL-1beta and interleukin-1 receptor antagonist (IL-1ra) were administered to developing rats, and seizures were induced by moist warm air. Twenty male Lewis rats (21-23 days old) were divided into two groups (IL-1beta and saline control groups) and two holes were made in the skull for EEG electrodes. We applied human recombinant IL-1beta intra-nasally 1h before seizures induced by moist warm air. The brain temperature at the appearance of seizure discharges on EEG, and the latency time from the hyperthermia onset until the appearance of seizure discharges on EEG were measured. And the same study using IL-1ra was performed. The median brain temperature for the IL-1beta group, 42.6 degrees C (range: 41.8-43.0), was significantly lower than that for the control, 42.9 (42.3-43.4) (P=0.043). The brain temperature for the IL-1ra group, 43.3 (42.8-43.7), was significantly higher than that for the control, 42.9 (42.2-43.5) (P=0.011), and the latency time for the IL-1ra group, 398s (270-561), was significantly longer than that for the control, 325 (252-462) (P=0.035). These results demonstrate that IL-1beta promotes hyperthermia-induced seizures in developing rats.

MRI in poliomyelitis-like syndrome

We report the MRI findings in a patient with poliomyelitis-like syndrome. MRI demonstrated a lesion extending from the dorsal region of the spons to the upper level of the thoracic spinal cord. The spinal cord was particularly affected in a region involving the bilateral anterior horns. Although its pathology is unknown, the lesion of the spinal cord seemingly reflects the pathological features of this disease.

Hyperthermia-induced seizures with a servo system: Neurophysiological roles of age, temperature elevation rate and regional GABA content in the rat

A servo system including a microwave generator was applied to raise a rats body temperature at a pre-set rate. Using this system the effects of age and the temperature elevation rate upon febrile seizures in rats were studied. The relationship between the brain GABA content and hyperthermia was also studied. From the results of the present study, the seizure occurrence rate was found to be highest at the age of 20 days, brain damage was speculated to be severe after hyperthermia-induced seizures with a slow temperature rise, and the regional GABA concentration in subcortical structures was found to increase during hyperthermia. These data indicate that a servo system with a microwave generator is useful for experimental febrile convulsions, and that GABA neurotransmission in subcortical structures might contribute to feed-back regulation against seizures during hyperthermia.

Adenosine A1 receptor blockage mediates theophylline-associated seizures.

Theophylline‐associated seizures (TAS) often progress to prolonged or treatment‐resistant convulsions. Theophylline is a nonselective adenosine receptor antagonist. Adenosine is an endogenous anticonvulsant that can terminate seizures. Fever and young age have been reported to be risk factors for TAS. To elucidate the mechanism of TAS, we investigated the effect of theophylline and adenosine receptor ligands on hyperthermia‐induced seizures in juvenile rats. The treatment dose of theophylline or control saline was injected intraperitoneally 1 h before hyperthermia‐induced seizures. The seizure threshold in the theophylline group was significantly lower and seizure duration was significantly longer than those in the control group. The addition of a selective adenosine A1 receptor agonist and an adenosine kinase inhibitor completely counteracted the effects of theophylline. Moreover, a selective A1 antagonist caused a significantly longer seizure duration compared with the control. These findings suggest that blockage of the adenosine A1 receptor is the main cause of TAS.