Effects of drugs on the initiation and maintenance of status epilepticus induced by administration of pilocarpine to lithium-pretreated rats

The ability of various drugs to prevent the onset of status epilepticus induced by administration of the muscarinic agonist, pilocarpine, to lithium-pretreated rats was determined. Motor limbic seizures and status epilepticus occurred in 100% of rats administered pilocarpine (30 mg/kg, s.c.) 20 h after pretreatment with lithium (3 meq/kg, i.p.). The latency to spike activity and to status epilepticus was 20 +/- 1 min and 24 +/- 1 min, respectively. Atropine, diazepam, phenytoin, carbamazepine, phenobarbital, paraldehyde, and L-phenylisopropyladenosine (L-PIA) prevented all phases of seizure activity induced by lithium/pilocarpine treatment. The initiation of status epilepticus was significantly prolonged by pretreatment with sodium valproate. These findings indicate that the seizures induced by administration of lithium and pilocarpine accurately model generalized tonic-clonic epilepsy. The anticonvulsant activity of L-PIA was prevented by prior treatment with the adenosine antagonist, theophylline. The latency to spike and seizure activity was decreased by theophylline, indicating that endogenous adenosine may have a tonic inhibitory influence on cholinergic neurons. Atropine, diazepam, phenobarbital, phenytoin, sodium valproate, L-PIA, and carbamazepine did not interrupt seizure activity when administered 60 min after pilocarpine (approximately 35 min after initiation of status epilepticus). When rats were administered paraldehyde at this time, status epilepticus was rapidly terminated and all rats survived. Thus, status epilepticus induced by lithium and pilocarpine provides a seizure model that is not responsive to conventional anticonvulsants.     

Antiepileptic drugs combined with high‐frequency electrical stimulation in the ventral hippocampus modify pilocarpine‐induced status epilepticus in rats

Purpose: To evaluate the effects of high‐frequency electrical stimulation (HFS) in both ventral hippocampi, alone and combined with a subeffective dose of antiepileptic drugs, during the status epilepticus (SE) induced by lithium‐pilocarpine (LP). Methods: Male Wistar rats, stereotactically implanted in both ventral hippocampi, were injected with pilocarpine (30 mg/kg, i.p.) 24 h after lithium (3 mEq/kg) administration. One minute following pilocarpine injection, HFS (pulses of 60 μs width at 130 Hz at subthreshold intensities and applied during 3 h) was applied alone or combined with subeffective doses of antiepileptic drugs. Results: HFS alone reduced the incidence of severe generalized seizures. This effect was not evident when HFS was combined with phenytoin (33.3 mg/kg, i.p.). HFS combined with diazepam (0.41 mg/kg, i.p.) or phenobarbital (10 mg/kg, i.p.) reduced the incidence of severe generalized seizures and mortality rate, and augmented the latency to first forelimb clonus, generalized seizure, and status epilepticus (SE). When combined with gabapentin (46 mg/kg, i.p.), HFS reduced the incidence of severe generalized seizures, enhanced latency to SE, and decreased mortality rate. Discussion: Subeffective doses of antiepileptic drugs that increase the γ‐aminobutyric acid (GABA)ergic neurotransmission may represent a therapeutic tool to augment the HFS‐induced anticonvulsant effects.     

Review: cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: a novel experimental model of intractable epilepsy

High-dose treatment with pilocarpine hydrochloride, a cholinergic muscarinic agonist, induces seizures in rodents following systemic or intracerebral administration. Pilocarpine seizures are characterized by a sequential development of behavioral patterns and electrographic activity. Hypoactivity, tremor, scratching, head bobbing, and myoclonic movements of the limbs progress to recurrent myoclonic convulsions with rearing, salivation, and falling, and status epilepticus. The sustained convulsions induced by pilocarpine are followed by widespread damage to the forebrain. The amygdala, thalamus, olfactory cortex, hippocampus, neocortex, and substantia nigra are the most sensitive regions to epilepsy-related damage following convulsions produced by pilocarpine. Spontaneous seizures are observed in the long-term period following the administration of convulsant doses of pilocarpine. Developmental studies show age-dependent differences in the response of rats to pilocarpine. Seizures are first noted in 7-12 day-old rats, and the adult pattern of behavioral and electroencephalographic sequelae of pilocarpine is seen in 15-21-day-old rats. During the third week of life the rats show an increased susceptibility to the convulsant action of pilocarpine relative to older and younger animals. The developmental progress of the convulsive response to pilocarpine does not correlate with evolution of the brain damage. The adult pattern of the damage is seen after a delay of 1-2 weeks in comparison with the evolution of seizures and status epilepticus. The susceptibility to seizures induced by pilocarpine increases in rats aged over 4 months. The basal ganglia curtail the generation and spread of seizures induced by pilocarpine. The caudate putamen, the substantia nigra, and the entopeduncular nucleus govern the propagation of pilocarpine-induced seizures. The antiepileptic drugs diazepam, clonazepam, phenobarbital, valproate, and trimethadione protect against pilocarpine-induced convulsions, while diphenylhydantoin and carbamazepine are ineffective. Ethosuximide and acetazolamide increase the susceptibility to convulsant action of pilocarpine. Lithium, morphine, and aminophylline also increase the susceptibility of rats to pilocarpine seizures. The pilocarpine seizure model may be of value in designing new therapeutic approaches to epilepsy.     

Experimental secondarily generalized convulsive status epilepticus induced by D,L-homocysteine thiolactone

Secondarily generalized convulsive status epilepticus was induced by intraperitoneal (i.p.) injection of D,L-homocysteine thiolactone to rats with actively epileptogenic cobalt lesions in motor cortex. This induced focal motor seizures which secondarily generalized. Control animals not treated with antiepileptic drugs had a mean of 18.3 generalized convulsions over a mean period of 103.8 min. Electrographic patterns seen during status epilepticus are described and are very similar to those seen during human status epilepticus. Phenytoin, phenobarbital, diazepam and lorazepam were all effective in arresting the generalized seizures when given i.p. after the second such seizure. Efficacy was serum drug concentration dependent. Concentrations effective in arrest of generalized seizures in this model are similar to those reported to be effective in the treatment of human status epilepticus. Diazepam ED50s for control of generalized tonic-clonic seizures and for arrest of all seizure activity were determined.     

NMDA receptor antagonists and limbic status epilepticus: a comparison with standard anticonvulsants

Status epilepticus (SE) evolves through several stages when untreated. The later stages of SE are less responsive to standard anticonvulsants and may require general anesthesia to suppress seizures. Antagonists acting at the N-methyl-D-aspartate (NMDA) subclass of glutamate (excitatory) receptors have been demonstrated to exert antiepileptic activity in some seizure models. We report experiments performed to determine if NMDA receptor antagonists are effective in stopping seizures in the late stages of SE. A model of limbic SE induced by 90 min of 'continuous' electrical stimulation of the hippocampus in rats was employed. Three NMDA receptor antagonists, one 'competitive' (CPP) and two 'non-competitive' (ketamine and MK-801), were compared to 3 standard antiepileptic drugs (diazepam, phenobarbital, and phenytoin) for their ability to suppress seizures at a physiologically defined stage of SE. All NMDA receptor antagonists, diazepam and phenobarbital were effective in suppressing behavioral and electrographic seizures for varying periods of time. Phenytoin had no effect on SE. Ketamine and MK-801 induced a paradoxical enhancement of electrographic seizures that preceded SE suppression. We believe that NMDA-receptor antagonists offer a novel approach for treating the late stages of SE.     

Time-dependent decrease in the effectiveness of antiepileptic drugs during the course of self-sustaining status epilepticus

An animal model of self-sustaining status epilepticus (SSSE) induced in rats by brief intermittent perforant path stimulation (PPS) was examined with regard to the effects of two conventional antiepileptic drugs, diazepam and phenytoin. Thirty or sixty minutes PPS induced SSSE characterized by continuous behavioral and electrographic seizures lasting for hours. Both diazepam (10 mg/kg i.v.) and phenytoin (50 mg/kg i.v.) prevented the establishment of SSSE when administered 10 min prior to PPS. The injection of diazepam to seizing animals, 10 min after the end of 30 min PPS, was significantly less effective than pretreatment in attenuating SSSE. Administration of diazepam after 60 min PPS was characterized by a further decrease of its efficacy. Phenytoin was effective in aborting SSSE when injected 10 min after 30 min PPS. However, its efficacy was vastly decreased if injected 40 min after 30 min PPS, or 10 min after 60 min PPS. It is concluded that antiepileptic drugs, while highly effective in blocking the induction of SSSE, failed to affect its maintenance. SSSE induced by PPS is an advantageous animal model of refractory status epilepticus, which may be used in preclinical studies of novel antiepileptic drugs.     

Prise en charge d’un état de mal épileptique de l’enfant (nouveau-né exclu)

Convulsive status epilepticus in childhood is a life threatening condition with serious risk of neurological sequelae which constitutes a medical emergency. Clinical and experimental data suggest that prolonged seizures can have immediate and long-term adverse consequences on the immature and developing brain. So the child who presents with a continuous generalized convulsive seizure lasting greater than five minutes should be promptly treated. The outcome is mainly determined by the underlying etiology, age and duration of status epilepticus. In children the mortality from status epilepticus ranges from 3 to 5% and the morbidity is two-fold higher. Mortality and morbidity are highest with status epilepticus associated with central nervous system infections, which is the most important cause of status epilepticus. There are few evidence-based data to guide management decisions for the child with status epilepticus. Immediate goals are stabilization of airways, breathing and circulation and termination of seizures. Benzodiazepines remain the first-line drugs recommended for prompt termination of seizures. As intravenous lorazepam is not available in France, we suggest clonazepam as the best choice for initial therapy. Rectal diazepam or buccal midazolam remain important options. Intravenous phenytoin/fosphenytoin and phenobarbital are the second-line drugs. Phenytoin is being increasingly substituted by fosphenytoin, but pediatric data are scarce and fosphenytoin is not authorized for use in France below five years old. In children, phenytoin is often preferred to phenobarbital, even though no comparative studies have demonstrated a better efficacy. To manage status epilepticus refractory to a benzodiazepine and administration of phenytoin and/or phenobarbital, many pediatricians today prefer high-dose midazolam infusion rather than thiopental to minimize serious side effects from barbiturate anesthesia. There is no benefit/risk ratio to support the use of propofol for children with refractory status epilepticus.     

Successful management of refractory neonatal seizures with midazolam

Seizures are indicative of underlying neurologic dysfunction in neonates. Repeated seizures may be deleterious to the brain even without disturbances of ventilation or perfusion. First-line antiepileptic drugs such as phenobarbital and phenytoin are not very effective in controlling seizures in neonates. Rapid control of status epilepticus with midazolam has been demonstrated in 2 previous studies with complete clinical and electrographic response in neonates who did not respond to phenobarbital and phenytoin. We report our experience with 3 neonates with status epilepticus. Seizures in all 3 neonates did not respond to phenobarbital and phenytoin but responded to midazolam infusion. Midazolam may be considered a safe and effective antiepileptic drug in refractory neonatal seizures of diverse etiologies.     

Amplitude-integrated electroencephalography in patients with acute encephalopathy with refractory, repetitive partial seizures

We report amplitude-integrated EEG findings in two children with acute encephalopathy with refractory, repetitive partial seizures. Both patients had a febrile illness one week before the onset of seizure. They had reduction of consciousness and repetitive seizures refractory to first-line antiepileptic drugs. Seizure frequency rapidly increased and evolved into status epilepticus. Continuous seizure monitoring with amplitude-integrated EEG revealed frequent subclinical seizures which were missed by direct observation. In addition, the site of origin of seizures was multifocal, and seizure foci shifted from one hemisphere to the other. Their seizures were controlled after an administration of high-dose phenobarbital. Continuous seizure monitoring with amplitude-integrated EEG will contribute to correct estimation of seizure burden and efficacy of antiepileptic drugs in children with acute encephalopathy with refractory, repetitive partial seizures.     

Influence of levetiracetam on the anticonvulsant efficacy of conventional antiepileptic drugs against audiogenic seizures in DBA/2 mice

Levetiracetam (LEV, [S]-alpha-ethyl-2-oxo-1-pyrrolidine acetamide) is a new antiepileptic that has been used as adjunctive therapy to treat patients with intractable epilepsy. Systemic administration of levetiracetam (2.5-30 mg/kg, intraperitoneally (i.p.)) was able to produce a dose-dependent decrease in DBA/2 audiogenic seizure severity score. In combination with conventional antiepileptic drugs, levetiracetam, 5mg/kg, i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of some antiepileptic drugs studied against sound-induced seizures in DBA/2 mice. The degree of potentiation induced by levetiracetam was greater, approximately twice, for carbamazepine, diazepam, felbamate, topiramate, gabapentin, and valproate, less for lamotrigine, phenobarbital and phenytoin. This increase was associated with a comparable impairment in motor activity; however, the therapeutic index of combined treatment of antiepileptic drugs with levetiracetam was more favourable than the combination with saline with the exception of lamotrigine, phenytoin and phenobarbital. Since levetiracetam did not significantly influence the total and free plasma and the brain levels of antiepileptics studied. In addition, levetiracetam did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, levetiracetam showed an additive anticonvulsant effect when administered in combination with some classical anticonvulsants, most notably carbamazepine, diazepam, felbamate, gabapentin, topiramate and valproate, implicating a possible therapeutic relevance of such drug combinations.     

Choice and administration sequence of antiepileptic agents for status epilepticus and frequent seizures in children

We investigated the sequence of the administration, the efficacy and the safety of antiepileptic drugs (AED) given intravenously for the treatment of status epilepticus and frequent seizures in children. Our institute has a recommended sequence of AED administration for treatment of status epilepticus: the first-line agent is diazepam (0.3 - 0.5 mg/kg administered intravenously, once or twice). The second-line drugs include midazolam (0.15 - 0.4 mg/kg intravenously, once or twice, and if necessary, followed by continuous infusion at 0.06 - 0.18 mg/kg/hour), lidocaine (1 - 2 mg/kg intravenously, once or twice, and if necessary, followed by continuous infusion at 2 - 4 mg/kg/hour) and phenytoin (10 - 20 mg/kg, infused slowly). For those patients who previously experienced a seizure which was refractory to diazepam but responsive to the second-line agent, it was recommended to use the second-line agent as a first-line agent. When seizures were refractory to the first and second-line agents, thiopental was administered (3 - 10 mg/kg intravenously, and if necessary, followed by continuous infusion at 2 -5 mg/kg/hour). The etiologies of 177 occasions of status epilepticus and frequent seizures were categorized into two groups:epilepsy (n = 95) and situation-related seizures (n = 82). Situation-related seizures included febrile seizures (n = 44), acute encephalopathy/encephalitis (n = 31) and benign infantile convulsions (n = 7). The ages of the patients ranged from 0.1 to 18.4 years (average +/- SD:3.69 +/- 3.15 years). Diazepam was administered as the first-line drug on 157 of 177 occasions (88.7%). On 116 occasions the second-line agents were administered. Midazolam and lidocaine were injected as the second-line agent on 54 (46.6%), and on 33 (28.4%) occasions, respectively, although both midazolam and lidocaine injections were off-label use for seizure control in Japan. Thiopental was used as the third to fifth-line agent. Effective ratios (effective occasions/total occasions) of each drug were the following: thiopental 19/21 (90.4%), midazolam 57/99 (57.6%), lidocaine 25/60 (41.7%), phenytoin 16/41 (39.0%), diazepam 59/164 (36.0%). Thiopental was statistically more effective than midazolam, lidocaine, diazepam or phenytoin (p < 0.01), and midazolam was statistically more effective than diazepam (p < 0.01) or phenytoin (p < 0.05). Administration of thiopental caused complications more frequently than the other agents (p < 0.01): The complications by thiopental were severe in some cases requiring intratracheal intubations and artificial ventilation. From the viewpoint of both efficacy and safety, midazolam should be recommended as one of the first-line agents for status epilepticus.     

Age- and region-specific effects of anticonvulsants and bumetanide on 4-aminopyridine-induced seizure-like events in immature rat hippocampal-entorhinal cortex slices

Purpose: Seizure‐like events (SLEs) induced by 4‐aminopyridine in rat organotypic slices cultures, which are prepared early after birth, are resistant to standard antiepileptic drugs. In this study we tested the hypothesis that pharmacoresistance may be an intrinsic property of the immature brain. Methods: Frequently recurring SLEs presumably representing status epilepticus were induced by 4‐aminopyridine in acute rat hippocampal–entorhinal cortex slices obtained from postnatal day 3–19 (P3–P19), and the effects of carbamazepine, phenytoin, valproic acid, and phenobarbital were examined. In addition, bumetanide was tested, which blocks the Na⁺‐K⁺‐2Cl⁻ (NKCC1) cotransporter, and also acetazolamide, which blocks the carbonic anhydrase and thereby the accumulation of bicarbonate inside neurons. Results: The efficacy of all antiepileptic drugs in blocking SLEs was dependent on postnatal age, with low efficacy in P3–P5 slices. Antiepileptic drugs suppressed SLEs more readily in the medial entorhinal cortex (ECm) than in the CA3. In P3–P5 slices, valproic acid and phenobarbital increased both tonic and clonic seizure‐like activities in the CA3, whereas phenytoin and carbamazepine blocked tonic‐like but prolonged clonic‐like activity. In P3–P5 slices, bumetanide often blocked SLEs in the CA3, but was not as effective in the ECm. Like with other antiepileptic drugs, the seizure‐suppressing effects of acetazolamide increased with postnatal age. Conclusion: We conclude that pharmacoresistance may be inherent to very immature tissue and suggest that expression of the NKCC1 cotransporter might contribute to pharmacoresistance.     

Anticonvulsant sensitivity of absence seizures in the tottering mutant mouse

Homozygous tottering mice (tg, autosomal recessive) exhibit frequent spontaneous "absence" seizures accompanied by bilaterally synchronous spike-and-wave or polyspike electrocorticographic discharges. In adult tottering mice, the antiepileptic effects of a single dose of ethosuximide, diazepam, phenobarbital, or phenytoin were assessed using continuous electrocorticographic recording to monitor seizure incidence. The dose chosen for each drug was selected to correspond to an effective antiepileptic dose in standard murine models. Ethosuximide, 150 mg/kg, diazepam, 1.4 mg/kg, and phenobarbital, 25 mg/kg were effective against absence seizures. In contrast, phenytoin at 5, 10, 30, or 60 mg/kg produced no significant reduction in the incidence of absence seizures. These results suggest that absence seizures in the tottering mutant may represent a relatively specific pharmacological model for the identification of drugs effective for clinical absence epilepsy, and emphasize the potential value of this new model for the study of fundamental mechanisms of absence of epilepsy and the actions of antiepileptic drugs.     

Pharmacokinetics and Clinical Use of Benzodiazepines in the Management of Status Epilepticus

Summary: Benzodiazepines are potent and effective drugs for the management of acute seizures and status epilepticus. Lorazepam, diazepam, and clonazepam have been the most widely studied of the benzodiazepines in the treatment of status epilepticus. In 47 studies of these drugs involving 1,455 patients, lasting control of status epilepticus was achieved in 79% of the patients. None of these benzodiazepines is clearly superior to another for the effective control of status epilepticus. Differences in pharmacokinetic parameters, therefore, will influence the choice of drug. All three benzodiazepines are lipid-soluble and enter the brain within seconds to minutes after intravenous administration. Diazepam, however, is very lipid-soluble and highly protein-bound and thus has a very large volume of distribution of unbound drug. As a result, the effective duration of action of diazepam in status epilepticus is only 20 to 30 min, whereas that of lorazepam, which has a much smaller volume of distribution of unbound drug, is at least several hours after a single intravenous injection. This allows the orderly administration of an antiepileptic drug for long-term seizure control after status epilepticus has been controlled. For this reason, lorazepam is preferable for the initial management of status epilepticus. Continuous intravenous infusion of diazepam has been used successfully in the management of some patients with status epilepticus refractory to initial treatment.     

Antiepileptic treatment against clustered seizures in benign partial epilepsy in infancy

We performed detailed review of clinical course of clustered seizures in patients with benign partial epilepsy in infancy in order to determine the optimal treatment during the acute period. We retrospectively investigated the details of antiepileptic treatment for clustered seizures in 20 patients with benign partial epilepsy in infancy. The temporal course of seizures and the use of antiepileptic drugs were investigated in each patient. Drugs were judged as effective when seizure cessation was achieved after administration of the drug. As the first drug, diazepam/bromazepam was effective in 14% and phenobarbital in 60%. As the second drug, diazepam/bromazepam was effective in 13% and phenobarbital in 40%. As the third drug, phenobarbital was effective in 56%. The efficacy rate of the first dose of phenobarbital was relatively higher than that of diazepam/bromazepam. Persistence of seizures after treatment was relatively shorter and the number of seizures after treatment was relatively smaller in patients treated with PB as the first 2 drugs. In conclusion, the efficacy of diazepam/bromazepam or phenobarbital was insufficient for the cessation of clustered seizures in benign partial epilepsy in infancy.     

Uncoupling of EEG-clinical neonatal seizures after antiepileptic drug use

A prospective study of the efficacy of seizure cessation by phenobarbital versus phenytoin administration utilized both clinical and electroencephalographic expressions of seizure behaviors. The phenomenon of uncoupling was defined as the persistence of electrographic seizures despite the suppression of >or=50% clinical seizures after either one or both antiepileptic drugs use. Fifty-nine neonates (25 to 43 weeks estimated gestational age) with electrically-confirmed seizures were assigned to either of two drugs and continuously monitored over a 24-hour period. Nine of the fifty-nine patients had only electrographic seizure expression both before and after drug administration. Of the remaining 50 patients who had both electrical and clinical seizure expression before treatment, 24 infants responded to the first choice of an antiepileptic drug with no further seizures. Fifteen of the remaining 26 infants (58%) with persistent seizures after treatment had uncoupling of electrical and clinical expressions of seizures; no difference in the uncoupling effect was noted for neonates who were treated with either antiepileptic drug or based on prematurity or gender. Serial electroencephalographic monitoring helps document continued electrographic seizure expression after antiepileptic drug use, following complete or partial suppression of clinical seizure behaviors.     

New insights from the use of pilocarpine and kainate models

Local or systemic administration of pilocarpine and kainate in rodents leads to a pattern of repetitive limbic seizures and status epilepticus, which can last for several hours. A latent period follows status epilepticus and precedes a chronic phase, which is characterized by the occurrence of spontaneous limbic seizures. These distinct features, in a single animal preparation, of an acute damage induced by status epilepticus, a silent interval between injury and the onset of spontaneous seizures, and a chronic epileptic state have allowed antiepileptic drug (AED) studies with different purposes, (a) in the acute phase, identification of compounds with efficacy against refractory status epilepticus and/or neuroprotection against damage induced by sustained seizures; (b) in the latent period, identification of agents with a potential for preventing epileptogenesis and/or against seizure-induced long-term behavioral deficits and (c) in the chronic phase, testing drugs effective against partial and secondarily generalized seizures. Studies on pilocarpine and kainate models have pointed out that some AEDs or other compounds exert an antiepileptogenic effect. The analogy of the latent phase of pilocarpine and kainate models with the acquisition of amygdala kindling should encourage testing of drugs that have proved to suppress the evolution of amygdala kindling. Drug testing in the chronic phase should not address only the suppression of secondarily generalized motor seizures. Most of current tools used to quantify spontaneous seizure events need to be coupled to electrophysiology and more sophisticated systems for recording and analyzing behavior.     

Substantia nigra regulates action of antiepileptic drugs

The cholinergic agonist pilocarpine triggers sustained limbic seizures in rodents. Pilocarpine seizures were blocked by systemic administration of benzodiazepines, barbiturates, valproate and trimethadione, while diphenylhydantoin did not affect, and ethosuximide increased the susceptibility of rats to such seizures. This pattern of action antiepileptic drugs is characteristic for pilocarpine seizures and different from other rodent models of epilepsy. Although the anatomical substrates in the forebrain involved in the expression of anticonvulsant activity are unknown, the basal ganglia are believed to be essential for the motor expression of pilocarpine seizures. Bilateral microinjections into the substantia nigra, a major output station of the basal ganglia, of midazolam (ED₅₀ 38.5 nmol; range 29–52 nmol), phenobarbital (ED₅₀ 16 nmol; range 7–39 nmol) and trimethadione (ED₅₀ 30 nmol; range 16–56 nmol) protected rats against pilocarpine seizures (380 mg/kg i.p.). Diphenylhydantoin (up to 100 nmol) remained inactive, while ethosuximide (ED₅₀ 38 nmol; range 22–65.5 nmol) reduced the threshold for pilocarpine seizures, converting subconvulsant doses of pilocarpine (200 mg/kg i.p.) into convulsant ones. The profiles of action of antiepileptic drugs on pilocarpine seizures were similar following intranigral and systemic administration. These observations suggest that the substantia nigra may mediate some actions of antiepileptic drugs.     

Therapie des generalisierten tonisch-klonischen Status epilepticus im Erwachsenenalter

If continuous seizure activity lasts longer than 5 minutes generalized tonic-clonic seizures require prompt treatment, if significant morbidity and mortality are to be avoided. The mortality varies (mean: 20%) depending on patient age and etiology. Control of status epilepticus is achieved by benzodiazepines in about 80% of cases: Lorazepam is recommended due to its longer-acting effects on the central nervous system. To maintain the anticonvulsive effect phenytoin is usually administered intravenously. Fosphenytoin (not approved in Germany) has advantages over phenytoin, because it can be given three times more rapidly and produces fewer side effects. The IV use of valproic acid in status epilepticus seems to be promising, but needs further evaluation. There is no generally accepted treatment protocol for the therapy of persistent seizure activity lasting more than 60 minutes (i.e., refractory status epilepticus). Usually phenobarbital, or general anesthesia with thiopental or pentobarbital are treatment recommendations. In recent reports, the administration of midazolam or propofol proved to be effective and well-tolerated.     

Childhood epilepsy: Management in resource-limited setting

Objective:

To optimize the use of phenobarbital and/or phenytoin as frontline drugs for treatment of childhood epilepsy.

Design:

Before-and -after study.

Setting:

Epilepsy clinic at paediatric OPD, Sassoon General Hospital, Pune.

Materials and Methods:

Epilepsy is a condition in which seizures are triggered recurrently from within the brain. For epidemiological classification purpose epilepsy is considered to be present when two or more unprovoked seizures occur at an interval greater than twenty four hours apart. Seizures were classified as generalized and partial seizures, with underlying etiology investigated with EEG, CT scan in majority of the patients. Follow - up rate, seizure - control and antiepileptic drugs used among 151 children enrolled as on 31 March 2005 were compared with 106 children with new onset epilepsy enrolled as on February 2006. Eight children with breakthrough convulsion after a seizure free period of five to eighteen months were followed up after injection vitamin D. Nineteen children with poor control of seizures receiving polytherapy with newer antiepileptic drugs were assessed with frontline antiepileptic medication of phenobarbital and/or phenytoin. Serum calcium, phosphorus, alkaline phosphatase were done in seventy two consecutive children with seizure disorder.

Results:

During post protocol period good seizure control was achieved in 84.8% as against 80.7% and use of phenobarbital and/or phenytoin increased to 65.11% from 22.87%. Of the 8 cases with breakthrough seizures seven remained seizure free after vitamin D administration and with no dose enhancement of AED medications of the nineteen. Children receiving polytherapy thirteen children could be successfully switched to phenobarbital and/or phenytoin. Forty four (61%) children had hypocalcemia (less than 9 mg%), fifty seven (79%) children had raised alkaline phosphatase levels (more than 270 IU).

Comments:

Phenobarbital and/or phenytoin have been found to be effective frontline AED. Periodic administration of vitamin D plays a supportive role.