7-nitroindazole differentially affects the anticonvulsant activity of antiepileptic drugs against amygdala-kindled seizures in rats

PURPOSE: The objective of this study was to evaluate the interaction of the preferential brain nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI), with conventional antiepileptic drugs (AEDs) against amygdala-kindled seizures in rats. METHODS: Experiments were performed on fully kindled rats. Adverse effects were evaluated with the rotorod test, which assesses motor coordination, and the passive-avoidance task, which assesses memory. Plasma levels of AEDs were measured by immunofluorescence. RESULTS: 7-NI (up to 100 mg/kg) failed to modify seizure parameters. However, it reduced the severity and duration of kindled seizures when coadministered with otherwise ineffective doses of carbamazepine (CBZ) (10-20 mg/kg) or phenobarbital (PB) (20 mg/kg). Combinations of 7-NI with valproate (VPA), diphenylhydantoin (DPH), or clonazepam (CLO) were not protective. L-Arginine (500 mg/kg) did not reverse the seizure-suppressing interactions between 7-NI and the conventional AEDs. The combinations of 7-NI and CBZ or PB did not impair performance in the rotorod test. Coadministration of 7-NI with CBZ did not affect long-term memory, and 7-NI given with PB didn't affect the mnemonic effect of PB. Finally, 7-NI did not affect the free plasma levels of CBZ or PB. CONCLUSIONS: Pharmacokinetic interactions do not seem to account for the anticonvulsant effects of 7-NI combined with CBZ or PB. Central nitric oxide (NO) is possibly not involved in the synergism between 7-NI and these AEDs.     

Dissociation of the immunoreactivity of synaptophysin and GAP-43 during the acute and latent phases of the lithium-pilocarpine model in the immature and adult rat

RATIONALE: Lithium-pilocarpine-induced status epilepticus (SE) generates neuronal lesions in the limbic forebrain, cerebral cortex and thalamus that lead to circuit reorganization and spontaneous recurrent seizures. The process of reorganization in regions with neuronal damage is not fully clarified. METHODS: In the present study, we evaluated by immunohistochemistry the early reorganization during the latent period with two neuronal markers, synaptophysin and growth-associated protein 43 (GAP-43) in rats subjected to SE at PN21 and as adults. RESULTS: Synaptophysin immunoreactivity increased between 24 h and 3 weeks post-SE in regions with severe and rapidly occurring neuronal loss, namely thalamus, amygdala, piriform and entorhinal cortices. GAP-43 expression decreased at 1 and 3 weeks in the same regions. The immunoreactivity of synaptophysin and GAP-43 increased in the inner molecular layer of dentate gyrus from 24 h after SE, and decreased in the outer molecular layer from 72 h after SE. These changes likely result from the death of hilar neurons and the reduction of the input from the entorhinal cortex. In 21-day-old rats that experience less SE-induced neuronal loss, increased immunoreactivity of synaptophysin was only found in piriform and entorhinal cortex while no changes occurred in GAP-43 expression. CONCLUSION: These findings suggest that there is an age-related relation between the extent and rapidity of the process of neuronal death and the expression of these markers. Synaptophysin appears to be a more sensitive marker of plasticity induced by SE than GAP-43.     

Frontal lobe tumoral epilepsy: clinical,neurophysiologic features and predictors of surgical outcome

PURPOSE: To review the clinical, neurophysiologic features and surgical outcomes in patients with frontal lobe tumors and chronic intractable seizures. METHODS: Medical records of patients with intractable epilepsy who underwent resection or stereotactic biopsy of frontal lobe tumor (confirmed by surgical pathology) seen between 1985 and 1999 at Yale University School of Medicine Epilepsy Center were reviewed for age at diagnosis, age at onset of seizures, delay between seizure onset and tumor diagnosis, types and frequencies of seizures, EEG results, use of anticonvulsants, extent of surgery, pathological diagnosis, and tumor recurrence. RESULTS: Thirty-seven patients were included. Mean age at seizure onset was 31.6 years, and at tumor diagnosis was 36.2 years. Mean duration between onset of seizures and tumor diagnosis was 6.1 years. Seventeen patients had auras. Seizure frequency averaged 7.6 seizures per week, with 58% of patients having more than one seizure type. All patients used anticonvulsants, with 90% eventually using polytherapy. All patients eventually underwent at least one surgical procedure. Only 13 (35.1%) patients were class I. Twelve (32.4%) patients were class II, seven (18.9%) class III, and five (13.5%) class IV. No statistically significant differences were seen between good and poor long-term seizure outcome in relation to specific tumor pathology, seizure types, or type of resection. CONCLUSIONS: Long-term surgical outcomes in tumoral frontal lobe epilepsy are more favorable than those in nontumoral intractable frontal lobe epilepsy (65% class I or II) and less favorable than those in other tumoral epilepsy (overall, 70% class I). Frontal location of intracranial neoplasm may predict a less favorable long-term epilepsy prognosis than tumoral epilepsy in general, an observation for which several explanations are proposed.     

Toxocara canis and lead alter consummatory behavior in mice

Ingestion of palatable and unpalatable solutions was measured in adult mice to which had been administered the common parasite of the dog, Toxocara canis alone, or in combination with lead. In addition, response to hot plate and susceptibility to electroconvulsive seizure were also measured. Results from the palatability test indicated that either lead or Toxocara may alter the mouse's mode of interacting with its environment. However, the two agents in combination interacted in their effects on consummatory behavior. Results from the hot plate and ECS measures were less clear with respect to how lead and/or Toxocara influence temperature reactivity and seizure susceptibility. Histological examination of the CNS in parasite infected animals revealed Wallerian Type degeneration of fiber pathways including the corpus callosum, olfactory tract, and cerebellar penduncles.     

Hemicranial Volume Deficits in Patients with Temporal Lobe Epilepsy With and Without Hippocampal Sclerosis

Summary: Purpose: In patients with refractory temporal lobe epilepsy, studies have suggested volume deficits measured by MRI of brain structures outside the epileptogenic hippocampus. Hippocampal sclerosis (HS) is a frequent, but not obligate, finding in such patients. The present study examines the influence of the presence of HS on quantitative magnetic resonance imaging (MRI) measurements.
Methods: We analyzed 47 patients and 30 controls by quantitative MRI, including intracranial volume (ICV), hemicranial volume, hippocampal volume (HCV), and T₂relaxometry. MRI results were compared with histological findings in the resected temporal lobe.
Results: Histology documented HS in 35 patients (HS group) and other findings in 12 patients (no-HS group). In both groups, the hemicranial volume ipsilateral to the epileptogenic focus was significantly smaller than on the contralateral side (p <0.004). The HCV on both sides was smaller in the HS group compared with patients without HS (p ≥ 0.004). Unilateral hippocampal atrophy and increased T, value were found in 71% of patients with HS, and bilaterally normal HCV and T, value were found in 67% of patients without HS.
Conclusions: The smaller hemicranial volume on the focus side, irrespective of the presence or absence of HS suggests a different pathogenic mechanism for the additional hemicranial volume deficit, compared to HS itself. The contralateral HCV deficit depends on the presence of HS, indicating a pathogenic connection between damage to both hippocampi.     

Competitive NMDA-Receptor Antagonists, LY 235959 and LY 233053, Enhance the Protective Efficacy of Various Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice

Purpose: The objective of this study was to evaluate an interaction of two competitive N-methyl-D-aspartate (NMDA)-receptor antagonists, LY 235959 [(-)-3R,4aS,6R,8aR-6-(phosphonomethyl)-decahydroiso-quinoline-3-carboxylic acid; 50.5 mgikg] or LY 233053 [cis-(±)-4–[(2H-tetrazol-5–yl) methyl] piperidine-2-carboxylic acid; 5 mg/kg] with carbamazepine, diphenylhydantoin, phenobarbital, or valproate magnesium against maximal electroshock-induced convulsions in mice. Methods: Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the end point) delivered by a Hugo-Sachs stimulator (Type 221, Freiburg, FRG). Adverse effects were evaluated in the chimney test (motor performance) and passive-avoidance task (long-term memory). Plasma levels of antiepileptic drugs were measured by immunofluorescence. Results: Both LY 235959 and LY 233053 (=0.5 and 5 mg/kg, respectively) did not influence the electroconvul sive threshold but potentiated the anticonvulsant action of all antiepileptics studied. The combined treatment of LY 233053 (5 mg/kg) with carbamazepine, diphenylhydan-toin, or phenobarbital (providing a 50% protection against maximal electroshock) resulted in the impairment of long-term memory. No adverse effects were observed with combinations of LY 235959 with these antiepileptics. The combined treatment of valproate with either LY 235959 or LY 233053 was superior to valproate alone, as regards motor impairment, but not the impairment of long-term memory. Neither NMDA-receptor antagonist elevated the total plasma levels of antiepileptic drugs studied. Conclusions: It may be concluded that NMDA-receptor blockade leads to the enhanced anticonvulsive action of conventional antiepileptics against maximal electroshock-induced seizures. A pharmacokinetic interaction does not seem probable.     

The role of interleukin-1 in seizures and epilepsy: A critical review

Interleukin-1 (IL-1) has a multitude of functions in the central nervous system. Some of them involve mechanisms that are related to epileptogenesis. The role of IL-1 in seizures and epilepsy has been investigated in both patients and animal models. This review aims to synthesize, based on the currently available literature, the consensus role of IL-1 in epilepsy.Three lines of evidence suggest a role for IL-1: brain tissue from epilepsy patients and brain tissue from animal models shows increased IL-1 expression after seizures, and IL-1 has proconvulsive properties when applied exogeneously. However, opposing results have been published as well. More research is needed to fully establish the role of IL-1 in seizure generation and epilepsy, and to explore possible new treatment strategies that are based on interference with intracellular signaling cascades that are initiated when IL-1 binds to its receptor.     

Postictal increase in T-wave alternans after generalized tonic-clonic seizures

Purpose: Sudden unexpected death in epilepsy (SUDEP) occurs most frequently in people with chronic uncontrolled epilepsy. Tonic–clonic seizures are a well‐recognized risk factor for SUDEP. T‐wave alternans (TWA) is a novel independent marker of risk of sudden cardiac death and cardiovascular mortality. The aim of this study was to determine if the level of TWA in patients with epilepsy differed after complex‐partial and secondary generalized tonic–clonic seizures (sGTCS). Methods: Electrocardiography (ECG) and electroencephalography (EEG) data from patients with drug‐resistant focal epilepsy who had both complex partial and sGTCS during video‐EEG telemetry were retrospectively reviewed. Periictal TWA, heart rate (HR), and heart rate variability (HRV) were analyzed. Key Findings: ECG and EEG data of 16 patients (31.6 ± 8.7 years, nine male) with focal epilepsies were analyzed. sGTCS led to a postictal increase in TWA for 15 min as well as a higher postictal HR and decreased postictal HRV for the whole observation time of 30 min. There was no significant association between postictal TWA or HR and seizure duration or duration of the tonic–clonic phase. Significance: Our study demonstrates that derangements in autonomic function and TWA are highly prevalent after sGTCS in patients with chronic uncontrolled epilepsy. Further studies are warranted to investigate the value of TWA for risk stratification in epilepsy patients for sudden cardiac death and SUDEP.     

Incidence of hyponatraemia and hyponatraemic seizures in severe respiratory syncytial virus bronchiolitis

AIM: To document the incidence and early evolution of hyponatraemia (serum sodium < 136 mmol l(-1)) associated with respiratory syncytial virus (RSV) bronchiolitis in infants requiring intensive care. METHODS: In a retrospective review over two winter seasons, 130 infants were admitted with confirmed RSV infection, of whom 39 were excluded because of either pre-existing risk factors for hyponatraemia: diuretic therapy (n = 14), cardiac disease (n = 10), renal disease (n = 2) or lack of admission sodium data (n = 13). RESULTS: The incidence of admission hyponatraemia in the remaining infants (median age 6 wk) was 33% (30/91), with 11% (10/91) exhibiting a serum sodium less than 130 mmol l(-1) . Hyponatraemic and normonatraemic infants were of a similar age (median 6 vs 7 wk, p = 0.82). With fluid restriction and diuretic therapy, the incidence of hyponatraemia at 48 h had decreased to 3.3%, odds ratio 0.07 (95% confidence interval 0.02-0.24, p < 0.001). Four infants (4%) suffered hyponatraemic seizures at admission (sodium 114-123 mmol l(-1)); three had received hypotonic intravenous fluids at 100-150 ml kg(-1) d(-1) before referral to intensive care. All four were managed successfully with hypertonic (3%) saline, followed by fluid restriction, resulting in immediate termination of seizure activity and normalization of serum sodium values over 48 h. CONCLUSION: Hyponatraemia is common among infants with RSV bronchiolitis presenting to intensive care. Neurological complications may occur and fluid therapy in vulnerable infants should be tailored to reduce this risk.