N-acetylcysteine aggravates seizures while improving depressive-like and cognitive impairment comorbidities in the WAG/Rij rat model of absence epilepsy.

N-acetylcysteine (NAC) is an antioxidant with some demonstrated efficacy in a range of neuropsychiatric disorders. NAC has shown anticonvulsant effects in animal models. NAC effects on absence seizures are still not uncovered, and considering its clinical use as a mucolytic in patients with lung diseases, people with epilepsy are also likely to be exposed to the drug. Therefore, we aimed to study the effects of NAC on absence seizures in the WAG/Rij rat model of absence epilepsy with neuropsychiatric comorbidities. The effects of NAC chronic treatment in WAG/Rij rats were evaluated on: absence seizures at 15 and 30 days by EEG recordings and animal behaviour at 30 days on neuropsychiatric comorbidities. Furthermore, the mechanism of action of NAC was evaluated by analysing brain expression levels of some possible key targets: the excitatory amino acid transporter 2, cystine-glutamate antiporter, metabotropic glutamate receptor 2, the mechanistic target of rapamycin and p70S6K as well as levels of total glutathione. Our results demonstrate that in WAG/Rij rats, NAC treatment significantly increased the number and duration of SWDs, aggravating absence epilepsy while ameliorating neuropsychiatric comorbidities. NAC treatment was linked to an increase in brain mGlu2 receptor expression with this being likely responsible for the observed absence seizure-promoting effects. In conclusion, while confirming the positive effects on animal behaviour induced by NAC also in epileptic animals, we report the aggravating effects of NAC on absence seizures which could have some serious consequences for epilepsy patients with the possible wider use of NAC in clinical therapeutics.

Uric acid and allopurinol aggravate absence epileptic activity in Wistar Albino Glaxo Rijswijk rats.

Uric acid has a role in several physiological and pathophysiological processes. For example, uric acid may facilitate seizure generalization while reducing uric acid level may evoke anticonvulsant/antiepileptic effects. Allopurinol blocks the activity of xanthine oxidase, by which allopurinol inhibits catabolism of hypoxanthine to xanthine and uric acid and, as a consequence, decreases the level of uric acid. Although the modulation of serum uric acid level is a widely used strategy in the treatment of certain diseases, our knowledge regarding the effects of uric acid on epileptic activity is far from complete. Thus, the main aim of this study was the investigation of the effect of uric acid on absence epileptic seizures (spike-wave discharges: SWDs) in a model of human absence epilepsy, the Wistar Albino Glaxo/Rijswijk (WAG/Rij) rat. We investigated the influence of intraperitoneally (i.p.) injected uric acid (100 mg/kg and 200 mg/kg), allopurinol (50 mg/kg and 100 mg/kg), a cyclooxygenase 1 and 2 (COX-1 and COX-2) inhibitor indomethacin (10 mg/kg) and inosine (500 mg/kg) alone and the combined application of allopurinol (50 mg/kg) with uric acid (100 mg/kg) or inosine (500 mg/kg) as well as indomethacin (10 mg/kg) with uric acid (100 mg/kg) and inosine (500 mg/kg) with uric acid (100 mg/kg) on absence epileptic activity. We demonstrated that both uric acid and allopurinol alone significantly increased the number of SWDs whereas indomethacin abolished the uric acid-evoked increase in SWD number. Our results suggest that uric acid and allopurinol have proepileptic effects in WAG/Rij rats.

Guanosine may increase absence epileptic activity by means of A2A adenosine receptors in Wistar Albino Glaxo Rijswijk rats.

The non-adenosine nucleoside guanosine (Guo) was demonstrated to decrease quinolinic acid(QA)-induced seizures, spontaneously emerged absence epileptic seizures and lipopolysaccharide(LPS)-evoked induction of absence epileptic seizures suggesting its antiepileptic potential. It was also described previously that intraperitoneal (i.p.) injection of 20 and 50mg/kg Guo decreased the number of spike-wave discharges (SWDs) in a well investigated model of human absence epilepsy, the Wistar Albino Glaxo Rijswijk (WAG/Rij) rats during 4th (20mg/kg Guo) and 3rd as well as 4th (50mg/kg Guo) measuring hours. Guanosine can potentially decrease SWD number by means of its putative receptors but absence epileptic activity changing effects of Guo by means of increased extracellular adenosine (Ado) cannot be excluded. An increase in the dose of i.p. injected Guo is limited by its low solubility in saline, therefore, we addressed in the present study whether higher doses of Guo, diluted in sodium hydroxide (NaOH) solution, have more potent antiepileptic effect in WAG/Rij rats. We confirmed that i.p. 50mg/kg Guo decreased but, surprisingly, i.p. 100mg/kg Guo enhanced the number of SWDs in WAG/Rij rats. Combined i.p. injection of a non-selective Ado receptor antagonist theophylline (5mg/kg) or a selective Ado A2A receptor (A2AR) antagonist SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) (1mg/kg) and a cyclooxygenase 1 and 2/COX-1 and COX-2 inhibitor indomethacin (10mg/kg) with 100mg/kg Guo decreased the SWD number compared to i.p. 100mg/kg Guo alone. The results suggest that i.p. 100mg/kg Guo can increase SWD number by means of the adenosinergic system.

Modulatory effects of inosine, guanosine and uridine on lipopolysaccharide-evoked increase in spike-wave discharge activity in Wistar Albino Glaxo/Rijswijk rats.

We showed previously that the number of spike-wave discharges (SWDs) was increased after intraperitoneal (i.p.) injection of lipopolysaccharide (LPS), inosine (Ino) and muscimol alone whereas i.p. guanosine (Guo), uridine (Urd), bicuculline, theophylline and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801) alone decreased the SWD number in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. These drugs may exert their effects on absence epileptic activity mainly via proinflammatory cytokines-evoked increase in cortical excitability (such as LPS), GABAergic system (LPS, Ino, Urd, muscimol and bicuculline), glutamatergic system (LPS, Guo and MK-801) and adenosinergic system (LPS, Ino, Guo, Urd and theophylline). Both GABAergic system and glutamatergic system are involved in the pathomechanism of absence epilepsy, the LPS-evoked increase in absence epileptic activity and the pro- or antiepileptic effects of non-adenosine (non-Ado) nucleosides Ino, Guo and Urd. Moreover, Ino, Guo and Urd have modulatory effects on inflammatory processes. Thus, we investigated whether Ino, Guo and Urd have also modulatory influence on LPS-evoked increase in SWD number using two different concentrations of each nucleoside in WAG/Rij rats. We demonstrated that Ino dose-dependently aggravated whereas Guo and Urd attenuated the LPS-evoked increase in SWD number. Our results suggest that different nucleosides have diverse effects on LPS-induced changes in absence epileptic activity.

Absence seizures associated with efavirenz initiation.

Efavirenz, used in treating pediatric human immunodeficiency virus infection, has central nervous system side effects. We report on a 5-year-old girl with perinatally acquired human immunodeficiency virus infection, presenting with new onset absence seizures after starting treatment with efavirenz. Plasma efavirenz values were above therapeutic range. The child was homozygous for the CYP2B6-516T/T genotype, which is associated with poor efavirenz clearance. Seizures abated after efavirenz discontinuation.

[Seizure exacerbation caused by antiepileptic drugs]. / Anfallsforverring forårsaket av antiepileptika.

BACKGROUND: In certain types of epilepsy, antiepileptic drugs can exacerbate the disease instead of improving it. MATERIAL AND METHODS: This review is based on a non-systematic literature search in Medline for the time-period 1990-2007, and our own clinical experience. RESULTS AND INTERPRETATION: As a consequence of treatment with antiepileptic drugs, patients with epilepsy may have more frequent and severe seizures of the type they had before, but also new seizure types or patterns, and even series of seizures or status epilepticus. Both old and new antiepileptic drugs may exacerbate seizures, but carbamazepine-induced generalized seizures (such as absence and myoclonic) are best documented. More than one pathophysiological mechanism is probably involved in drug-related exacerbation of seizures, such as sedative and pro-convulsive effects of high serum levels, drug-associated encephalopathy, and a paradoxical pharmacodynamic effect. Accurate epilepsy- and seizure classification is important in the treatment of all types of epilepsy. Atypical absences are sometimes mistaken for complex partial seizures. Such patients may be given drugs with a narrow spectrum such as sodium channel blockers (e.g. carbamazepine, phenytoin, oxcarbazepine) or GABAergic agents (e.g. vigabatrin, tiagabine) with an increased risk of seizure exacerbation. Those at greatest risk of experiencing drug-related seizure exacerbation are learning-disabled patients, children with severe epileptic encephalopathies, those with high seizure frequency and several seizure types, and those using polytherapy.

Delayed absence seizure: a complication of intrathecal fluorescein injection. A case report and literature review.

Intrathecal fluorescein injection has a long history of use by surgeons to determine the exact site of a cerebrospinal fluid (CSF) leak from the skull base. This method, however accurate, is not without complications. We present a case of grand mal and absence seizure after intrathecal fluorescein injection and discuss the possible aetiological factors. We also review the articles in the diagnostic methods for the CSF rhinorrhoea and the complications of the intrathecal fluorescein injection.

Refractory atypical absence seizures in rat: a two hit model.

Medically refractory seizure disorders in children usually have malignant neurodevelopmental outcomes and often are associated with the presence of congenital cortical dysplasias in the brain. To date, there are no animal models of these disorders by which to test hypotheses of pathogenesis or to screen novel drugs for antiepileptic activity. In rats, treatment with the antimitotic agent methylazoxymethanol acetate (MAM) on gestational day (G) 15 produces a neuronal migration disorder similar to the cortical dysplasias seen in human brain. We sought to produce chronic, recurrent, medically refractory seizures by administration of the cholesterol biosynthesis inhibitor AY-9944 (AY) during postnatal development in rats exposed prenatally to MAM. Prenatal MAM and postnatal AY treatments resulted in spontaneous, recurrent atypical absence seizures that were characterized by bilaterally synchronous slow spike-and-wave discharges (SWD) with a frequency of 6 Hz. The MAM-AY-induced seizures were refractory to ethosuximide, sodium valproate, and the GABABR antagonist CGP 35348, and were exacerbated by carbamazepine. Histological examination of brains from MAM-treated rats showed hippocampal heterotopias, in addition to atrophy and abnormalities of cortical lamination. The MAM-AY-treated rat represents a reproducible model of refractory atypical absence seizures in children with brain dysgenesis.

Hormonal regulation of atypical absence seizures.

A time course study that examined the effects of the female estrous cycle on the chronic slow spike-and-wave discharges (SSWDs), gamma-aminobutyric B receptor (GABA(B)R) binding, and GABA(B)R protein expression was conducted in Long Evans hooded rats treated during development with a cholesterol synthesis inhibitor AY9944 (AY). In addition, a pharmacological study using the hormones progesterone, 17 beta-estradiol, mifepristone (intracellular progesterone receptor antagonist), tamoxifen (intracellular estrogen receptor antagonist), and allopregnanolone (progesterone metabolite) was performed to determine their effects on AY-induced seizures. The data indicate that there is a significant increase in both the duration of SSWD and GABA(B)R binding in the AY model, during the proestrus stage of the estrous cycle, the stage during which the levels of progesterone are at their highest. No changes in GABA(B)R1a or R2 protein levels were observed. In addition, the administration of both progesterone and allopregnanolone exacerbated seizures in the AY model, whereas 17 beta-estradiol attenuated the SSWD duration. Neither mifepristone nor tamoxifen blocked the effects of progesterone and 17 beta-estradiol, respectively, on SSWD duration in the AY model, suggesting that these two sex hormones are working in a manner independent of their intracellular receptors. These data suggest an important role for steroid hormones in the regulation and maintenance of AY-induced atypical absence seizures.

A case of atypical absence seizures induced by leuprolide acetate.

We report a case of a 13-year-old female with atypical absence seizures induced by prolonged administration of long-acting leuprolide acetate (LA). This patient had brain involvement resulting from chemotherapy and radiotherapy for a medulloblastoma. At 13 years of age, administration of long-acting LA was started. After the third dose of long-acting LA, atypical absence seizures appeared. After discontinuing long-acting LA, the seizures stopped without administration of any antiepileptic drugs. However, 2 years, 6 months later, the same seizures again appeared. On the basis of the findings of endocrinologic investigations and the reported data of pharmacokinetics of LA, we speculate that her seizures were induced by LA and that the seizures were associated with the presence of brain damage in the patient. Care should therefore be taken when using long-acting LA or other gonadotropin-releasing hormone analogues for pediatric patients with diffuse brain damage.

Bicuculline-induced rhythmic EEG episodes: gender differences and the effects of ethosuximide and baclofen treatment.

PURPOSE: There are gender differences in the expression of seizures. We tested rhythmic EEG episodes induced by low doses of bicuculline in rats for gender differences. To verify the validity of these discharges as a model of absence seizures in both male and female rats, we tested the antiabsence drug ethosuximide (ESM) and a gamma-aminobutyric acid (GABA(B))-receptor agonist, baclofen, which may exacerbate absence seizures. METHODS: Adult rats of both sexes were used. Under general anesthesia, EEG electrodes were implanted over frontal and occipital cortex, and some females were ovariectomized. After recovery, male, intact female rats, and female rats ovariectomized and ovariectomized rats with estradiol replacement were compared for occurrence of rhythmic EEG episodes (approximately 6 cycles/ s) induced by 2.5 mg/kg of bicuculline, s.c. Because of gender differences in sensitivity to bicuculline, further pharmacologic effects of ESM (125 and 250 mg/kg, i.p.) and baclofen (2 mg/kg, i.p.) were tested separately in male (3.0 mg/kg of bicuculline), and female (2.5 mg/kg of bicuculline) rats. RESULTS: After the identical dose of bicuculline, s.c., male and female rats differed in the incidence of rhythmic episodes and in the latency to onset of the first as well as the generalized episode. Female rats with natural or exogenous estrogens (but not ovariectomized rats) developed EEG episodes more often than did males, and this effect could be attributed to the presence of estrogens. ESM pretreatment suppressed the episodes, whereas baclofen enhanced their occurrence, as well as the total duration of episodes without gender-specific differences. CONCLUSIONS: The study demonstrates gender differences (related probably to the presence of circulating estrogens) in the susceptibility of rats to develop rhythmic EEG episodes induced by threshold doses of bicuculline. This activity has some features of an acute absence seizure model.

Early activation of inhibitory neurons in the thalamic reticular nucleus during focal neocortical seizures.

The neurons of the thalamic reticular nucleus are among the main targets of corticothalamic projections and their vulnerability in pathological conditions is well established. The present experiments aimed at the description and immunocytochemical characterization of the neurons of the thalamic reticular nucleus activated in neocortical seizures. Focal seizures were induced by the topical application of isotonic, isohydric 4-aminopyridine solution to the sensorimotor neocortex of adult, anesthetized Wistar rats. The animals were perfused with fixative after 1 and 2 h of recorded seizure activity. Coronal plane vibratome sections were incubated with cocktails of polyclonal c-fos and monoclonal parvalbumin antisera. Labeled cells in the thalamic reticular nucleus were counted and related to total cell counts. Neurons and neuropil showed strong parvalbumin immunoreactivity. Double-stained sections revealed that 55.32% of the parvalbumin-positive cell population expressed c-fos protein in their cell nuclei at the end of the 1 h seizure period. This ratio decreased to 43.5% following 2 h seizure. Labeled cells, although less in number were also observed in the contralateral thalamic reticular nucleus. Since parvalbumin labels GABAergic cells, it is tempting to speculate that this activation of intrathalamic inhibiton might exert an important anticonvulsant protection on other thalamic nuclei.

Fos oncoprotein expression in the rat forebrain following muscimol-induced absence seizures.

Fos oncoprotein expression is a marker of neuronal activation following seizures. Here, using this method we examined the anatomical locations of muscimol-induced absence seizures in the rat forebrain. Six hours after a systemic injection of muscimol a massive Fos immunoreactivity appeared in the olfactory system, retrosplenial cortex and paraventricular thalamic nucleus, whereas other cortical areas contained low level of Fos expression. These results provide the first functional morphological evidence suggesting that these forebrain structures with Fos expression may play an important role in the pathophysiology of muscimol-induced absence seizures.

[EEG changes during sedation with gamma-hydroxybutyric acid]. / EEG-Veränderungen unter Sedierung mit gamma-Hydroxybuttersäure (GHB).

Gamma-hydroxybutyric acid (GHB) is a naturally occurring transmitter in the mammalian brain, related to sleep regulation and possibly to energy balance in diving or hibernating animals. It has been used for almost 35 years as an intravenous agent for induction of anaesthesia and for long-term sedation. Its convincing pharmacological properties, without serious adverse effects on circulation or respiration, are compromised by its unpredictable duration of action. This is not a major problem with long-term sedation during ICU treatment. GHB has been used with good results for sedation of patients with severe brain injury, where it compares favourably with barbiturates. In animal studies, it seems to possess a protective action against hypoxia on a cellular and whole organ level. However, in some experimental animals GHB has been shown to produce seizure-like activities, and the compound is being used to produce absence-like seizures. GHB has been used in our ICU for years to provide adequate sedation for patients under controlled ventilation or for patients fighting the respirator during spontaneous respiration. No serious side effects were observed in these patients, while in some patients under haemodialysis hypernatraemia and metabolic alkalosis developed; both were reversible after discontinuation of GHB and restriction of additional sodium input (Somsanit, the commercially available GHB preparation in Germany, contains 9.2 mmol sodium/g; the daily dose averages 20-40 g GHB, i.e. 180-370 mmol sodium). PATIENTS AND METHODS. In 31 patients after major abdominal surgery, sedation was established with GHB 50 mg/kg BW injected via perfusion pump over a 20-min period. No centrally acting medication had been given for at least 2 h. A computer-based multichannel EEG system (CATEEM, MediSyst, Linden) was used, allowing for fast Fourier transformation, spectral analysis and topographical brain mapping. EEG during induction of sedation was followed after a baseline EEG (10 min) had been recorded. Patients receiving long-term sedation were studied daily for an additional 15-min period. Corresponding well to the clinical findings, EEG pattern changed to a slow delta-theta or delta-only rhythm within 10 min of the start of injection. Alpha and beta power decreased, while delta activity exhibited an increase. All changes were most obvious in frontal and central areas of the brain. In about one out of three patients, a burst--suppression pattern developed. Since automatic processing of EEG may fail to detect special patterns like the looked-for 3/s spikes and waves, the raw EEG was analysed visually by an expert neurologist. Both processed and conventionally analysed EEG were free of any seizure-like electrical activity. CONCLUSION. We conclude that animal data may not apply to the use of GHB in humans, provided the dose is limited to the clinical needs. GHB is used in clinical practice in doses twice as high, or even higher, than the one we use for induction, without obvious side effects. However, the suppression of theta rhythm we observed in about half of the patients studied may indicate that even less than 50 mg/kg BW might be sufficient for adequate sedation.

Neurological manifestations of baclofen withdrawal.

Baclofen is a central nervous system agent that is commonly used for the treatment of muscle spasticity in spinal cord injury patients. Acute withdrawal of this medication can induce the development of neurological symptoms, including seizure disorder, psychosis, hallucinations and visual disturbances. We report 3 cases of acute central nervous system symptoms that developed in spinal cord injury patients. Each patient had been chronically maintained on a baclofen regimen to control muscle spasticity. Symptoms developed shortly after baclofen therapy was interrupted following genitourinary surgery. It is important that urologists become familiar with the symptomatology of baclofen withdrawal, the methods of its prevention and the appropriate therapy should the syndrome develop.

Exacerbation of typical absence seizures by progesterone.

Variation of seizure frequency during the menstrual cycle has been attributed in part to an antiepileptic action of progesterone reducing seizure frequency during the luteal phase, but studies have not distinguished patients with primary generalized, secondary generalized and absence epilepsies. We describe a patient whose absence seizure frequency increased when she was administered progesterone. This indicates that, in contrast to secondarily generalized seizures, progesterone may exacerbate absence seizures.

Seizures and cortical dysfunction following high-dose cisplatin administration in children.

Four of eight children with advanced neuroblastoma treated with a rapid delivery high dose intensity cisplatin based regimen developed acute neurological toxicity. Three had seizures and one developed transient blindness. In the absence of other causes it seems probable that high dose cisplatin (200 mg/m2) as a continuous infusion over five days followed 10 days later by 80 mg/m2 infused over 48 hours was responsible. Other risk factors included an associated deterioration in renal function and neutropenia related fever.

Fos expression in GHB-induced generalized absence epilepsy in the thalamus of the rat.

Using the model of gamma-hydroxybutyrate (GHB)-induced generalized absence epilepsy, the present work investigated the distribution of fos oncoprotein expression in the rat thalamus with fos antibody immunohistochemistry. Thirty minutes after absence-like seizures, some fos-immunoreactive cell nuclei were found in bilateral thalamic paraventricular nuclei (PV). After a further 30 min, a massive bilateral induction of fos was observed in the lateral habenular nucleus (LHb), the PV, the rhomboid thalamic nucleus, and the intralaminar nuclei of the thalamus. These results suggest that the LHb and the midline and intralaminar thalamic nuclei may very likely be involved in the pathophysiology of absence seizures.

An unusual pelvic tumor with benign glandular, sarcomatous, and Wilms' tumor-like components.

We present a pelvic tumor occurring in a 23 year old woman in which a Wilms' tumor-like element was predominant. The presence of a benign glandular component surrounded by small spindle and round malignant cells paralleled that encountered in adenosarcoma of the uterine body and cervix. The possible histogenesis is discussed. Clinically the recurrent tumor showed evidence of a response to chemotherapy. Treatment was complicated by petit mal seizures, for which adriamycin was responsible. The patient exhibited no evidence of disease 22 months after the first operation.

Petit mal and grand mal seizures produced by toluene or benzene intoxication in the cat.

Motor incoordination, euphoria and hallucinations are symptoms reported for humans voluntarily intoxicated by industrial solvents. An epileptic-like consciousness impairment has also been noted. The present paper describes a technique used for the experimental study of solvent intoxication in which toluene and benzene can be applied directly into the trachea of freely moving cats with chronically implanted electrodes. This technique permits the control of solvent dose and time of exposure. Results showed a 3 Hz spike-wave activity in the gyrus cinguli recording with both toluene or benzene intoxication. Furthermore, benzene inhalation produced generalized tonic-clonic seizures. These effects were dose-related. However, a sensitization period was essential for the development of such alterations, and effects showed a tendency to shortening through chronic exposures. These alterations were correlated with behavioral disturbances such as nodding, twitching and apparent hallucinations. Results are discussed regarding the sensitization period, the optimal peak of effects, and the period of tolerance development relevant to an earlier found amygdalar activation that could be correlated with other methods inducing experimental seizures, such as repetitive stimulation of the brain (kindling).