Resistance to phenobarbital extends to phenytoin in a rat model of temporal lobe epilepsy

PURPOSE: Most patients who are resistant to the first antiepileptic drug (AED) treatment are also resistant to a treatment with a second or third AED, indicating that patients who have an inadequate response to initial treatment with AEDs are likely to have refractory epilepsy. Animal models of refractory epilepsy are important tools to study mechanisms of AED resistance and develop new treatment strategies for counteracting resistance. We have recently described a rat model of temporal lobe epilepsy (TLE), in which spontaneous recurrent seizures (SRS) develop after a status epilepticus induced by sustained electrical stimulation of the basolateral amygdala. Prolonged treatment of epileptic rats with phenobarbital (PB) resulted in two subgroups, PB responders and PB nonresponders. METHODS: In the present study we examined if rats with PB-resistant seizures are also resistant to phenytoin (PHT), using continuous EEG/video recording of spontaneous seizures. RESULTS: First, a new group of 15 epileptic rats was produced and selected by treatment with PB into responders (8 rats) and nonresponders (6 rats), respectively. During subsequent treatment with PHT, the doses of PHT had to be individually adjusted for each rat to avoid toxicity. Treatment with PHT led to complete seizure control in two animals and a >50% reduction of seizure frequency in three other rats, which were considered PHT responders. In nine of the remaining rats, PHT did not exert any clear anticonvulsant effect, so that these rats were considered nonresponders. Plasma levels of PHT did not differ significantly between responders and nonresponders. When comparing the PB and PHT nonresponder groups, five of the six PB-resistant rats (83%) were also resistant to PHT, demonstrating that rats that have an inadequate response to initial treatment with PB are likely to be also resistant to treatment with a second AED. CONCLUSIONS: The AED-resistant rats of our model meet the definition of pharmacoresistance in animal models, that is, persistent seizure activity not responding to at least two AEDs at maximum tolerated doses. This new model of pharmacoresistant TLE may be useful in the targeted development of new therapies for refractory epilepsy.     

Chronic focal epilepsy induced by microinjection of tetanus toxin into the cat motor cortex.

The tetanus toxin model of epilepsy, involving direct microinjection of toxin into the mammalian brain, has a number of advantages relative to other chronic models. However, chronic seizure foci have been confined primarily to the hippocampus. In the present study, 5 cats received total doses of 7.5-22.5 ng of tetanus toxin applied to the left primary motor cortex through an epidural cannula. After 2-18 days, all 5 cats exhibited similar persistent epileptiform syndromes. Three distinct types of spontaneous seizures were noted: focal motor seizures of variable complexity, focal motor seizures with secondary generalization, and epilepsia partialis continua. All cats required anticonvulsant therapy. Simple focal motor seizures, which predominated, were electrographically characterized by 3-5 Hz spike-sharp wave activity, originating in the left motor cortex, associated with contralateral shoulder and forepaw clonus and jacksonian spread. Electrographic activity quickly spread to ipsilateral neocortical structures, and in longer episodes to the cingulate gyri. Seizure foci were still active as long as 37 days after toxin injection. Light microscopic damage attributable to the toxin was absent. These experiments further generalized the tetanus toxin model and confirmed its advantages.     

Chronic Semichronic Limbic Epilepsy Produced by Microinjection of Tetanus Toxin in Cat Hippocampus

We describe an animal preparation in which a semichronic or chronic limbic epileptiform syndrome can be produced reliably by unilateral microinjection of tetanus toxin in cat ventral hippocampus. Injections were given at 1-week intervals until abnormal EEG activity was observed. After two to five injections, the animals abruptly began to exhibit intermittent spikes and subclinical discharges that soon gave way to spontaneous and recurrent behavioral seizures which gradually increased in frequency, duration, and severity in the next 12-48 h. Anticonvulsant therapy (phenobarbital, PB) was required within the first 3 days of the syndrome, since life-threatening generalized tonic-clonic seizures (GTCS) and status epilepticus would develop if the animal were left untreated. If severe seizures were prevented by antiepileptic drugs (AEDs) there was complete remission of the syndrome and repeat injection was necessary to reinitiate seizures. Animals that experienced severe seizures or that were reinjected after remission developed a chronic seizure syndrome and could be maintained with AEDs for long times (greater than 1 year) without significant debilitation. Although early spikes and subclinical discharges were typically focal to ipsilateral limbic sites, initial seizures appeared explosively in the form of a high-amplitude, high-frequency discharge, which often had an apparently bilateral limbic onset. On the other hand, chronic seizures had much more gradual onset and spread, often consisting of periodic sharp waves or low-amplitude sinusoidal discharge that was more clearly focal to ipsilateral limbic sites. Throughout the syndrome, ictal behavioral manifestations were highly stereotyped and very comparable to those described by other investigators in studies of clinical and experimental limbic epilepsy. All animals exhibited signs of independent contralateral involvement during the syndrome, ranging from independent contralateral spikes to subclinical discharges with a clear contralateral onset. None of the animals exhibited structural lesions on histologic examination at the level of light microscopy.     

Symptomatology of Epileptic Seizures in the First Three Years of Life

PURPOSE: Few data are available concerning symptomatology of epileptic seizures in infants. METHODS: We reviewed 296 videotaped seizures from 76 patients aged 1-35 months (mean, 15.1 months) who underwent video-EEG monitoring at our institution from 1988 to 1998. Seizure symptomatology was first classified based on observable behavioral and motor manifestations and then correlated with ictal EEG. RESULTS: Four seizure types accounted for 81% of all seizures seen in this group: epileptic spasms (24%), clonic seizures (20%), tonic seizures (17%), and hypomotor seizures (20%; characterized by arrest or significant decrease of behavioral motor activity with indeterminate level of consciousness). The remaining seizures included small numbers of myoclonic, atonic, and versive seizures. All 12 focal motor seizures and all five versive seizures were associated with focal EEG seizure patterns, seen in the contralateral hemisphere in all but one patient with versive seizures. Generalized motor seizures (clinically generalized at onset) were accompanied either by focal (19 of 51; 37%) or generalized (32 of 51; 63%) EEG seizures. Hypomotor seizures also were associated with focal (14 of 20; 70%) or generalized (six of 20; 30%) EEG seizures. Four patients with generalized epileptic spasms had generalized EEG seizures in the setting of focal epilepsy based on neuroimaging, interictal EEG, and in two cases also on postresection seizure freedom. Seizure types not seen in this age group included auras, seizures with prominent automatisms (except in one case), and classic generalized tonic-clonic seizures. CONCLUSIONS: The repertoire of seizure manifestation in the first 3 years of life appears to be limited. In infants, focal motor seizures are reliably associated with focal EEG seizures in the contralateral hemisphere, whereas generalized motor and hypomotor clinical seizures may be either focal or generalized on EEG. Epileptic spasms may be seen in focal as well as generalized epilepsies. Video-EEG monitoring and neuroimaging may be critical for clarifying the focal or generalized nature of the epilepsy in infants.     

Neocortical seizure termination by focal cooling: temperature dependence and automated seizure detection

PURPOSE: The therapy for focal neocortical epilepsy remains suboptimal. We have, therefore, worked to develop techniques to cool small regions of the neocortical surface for seizure mapping and, ultimately, for long-term suppression of focal seizures. METHODS: We induced focal neocortical seizures in halothane-anesthetized rats by the microinjection of 4-aminopyridine (4-AP) into the motor cortex. The dura over the injection site was cooled with a Peltier device, and the temperature at the interface between dura and Peltier was measured with a thermocouple. In some experiments, seizures were automatically detected by a computer program that activated the Peltier device. RESULTS: Monopolar EEG indicated that our seizures were focal and suppressed when cooling was applied directly over the injection site. The threshold temperature required to observe any reduction in seizure duration was 24 degrees C. The temperature gradient across the cooled neocortex was sharp, with the temperature increasing to 31 degrees C at 4 mm below the Peltier, which was cooled to 20 degrees C. Automatic seizure detection reduced the total seizure duration from 43.4 +/- 33.6 s to 5.6 +/- 5.3 s. CONCLUSIONS: Cooling terminates neocortical seizures when applied very close to the epileptogenic focus. The threshold for seizure termination (24 degrees C) may be lower than the threshold for termination of normal cortical activity, suggesting that this technique will not dissociate the anticonvulsant effect of cooling from the disruption of normal behavior. However, when coupled with automatic seizure detection, focal cooling remains an attractive option for development as a treatment for focal epilepsy.     

Antiepileptic effect of gap-junction blockers in a rat model of refractory focal cortical epilepsy

PURPOSE: Epilepsy is the most common serious neurologic disease, and current treatments are ineffective for or=1 h before drug infusion and for >or=3 h afterward. No ill effects were observed. RESULTS: An immediate and marked reduction in percentage of seizure time was seen in rats receiving carbenoxolone (baseline, 69.4%+/- 7.0% (SEM); maximum effect, 9.3%+/- 3.5%, p 相似文献   

Anticonvulsant properties of the novel nootropic agent nefiracetam in seizure models of mice and rats

PURPOSE: Nefiracetam (NEF) is a novel pyrrolidone-type nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognition-enhancing effects. The present study focused on the anticonvulsant effect of NEF and its potential for antiepileptic therapy. METHODS: The anticonvulsant properties of NEF were investigated in experimental seizure models of mice and rats, compared with levetiracetam (LEV) and other standard antiepileptic drugs [AEDs; zonisamide (ZNS), phenytoin (PHT), carbamazepine (CBZ), valproic acid (VPA), diazepam (DZP), and ethosuximide (ESM)]. With reference to standard programs for evaluating potential AEDs, the study included the traditional maximal electroshock seizure and subcutaneous chemoconvulsant (pentylenetetrazole, bicuculline, picrotoxin, strychnine, or N-methyl-D-aspartate) seizure tests and two threshold models (the increasing-current electroshock seizure test and intravenous pentylenetetrazole seizure threshold test). Neurotoxic activities were examined with the rotarod test and traction test. RESULTS: NEF inhibited electroshock-induced seizures at nontoxic doses, whereas it had no effect on seizures chemically induced by pentylenetetrazole, bicuculline, picrotoxin, strychnine, or N-methyl-D-aspartate. The anticonvulsant spectrum of NEF paralleled that of ZNS, PHT, and CBZ. The anticonvulsant efficacy of NEF was comparable with that of ZNS and less potent than that of PHT, CBZ, and DZP. However, the safety margin of NEF was superior to that of ZNS, CBZ, VPA, and DZP. LEV showed only slight anticonvulsant effects in threshold models, and it was not effective in conventional screening models. CONCLUSIONS: These results suggest that NEF has distinct anticonvulsant spectrum and mechanisms from those of LEV. NEF is an orally active and safe AED, and it possesses a potential for antiepileptic therapy.     

Anticonvulsant efficacy of topiramate in phenytoin-resistant kindled rats

PURPOSE: We evaluated the anticonvulsant efficacy of topiramate (TPM), a structurally novel antiepileptic drug (AED), in amygdala kindled rats that had been preselected with respect to their response to phenytoin (PHT). METHODS: Anticonvulsant response was tested by determining the afterdischarge threshold (ADT; i.e., a sensitive measure for drug effects on focal seizure activity). By repeated testing with the PHT prodrug fosphenytoin (FOS) three groups of kindled rats were separated: rats in which consistent anticonvulsant effects were obtained (PHT responders), rats that showed no anticonvulsant response (PHT nonresponders), and rats with variable responses (variable PHT responders). The latter, largest group was used to evaluate at which doses and pretreatment times TPM exerted significant anticonvulsant effects on ADT. For this purpose, TPM was tested at four doses (20, 40, 80, 160 mg/kg i.p.) and two pretreatment times (1 and 4 h). The most effective treatment protocol was then used for TPM testing in PHT responders and nonresponders. RESULTS: TPM proved to be an effective AED in the kindling model. At 40 mg/kg, significant ADT increases were obtained after both 1 and 4 h after administration. In addition to the effect on focal seizure threshold, seizure severity and duration recorded at ADT were decreased by TPM, indicating that this drug acts on both seizure threshold and seizure spread. In PHT nonresponders, TPM significantly increased ADT, which is in line with its proven efficacy in patients with refractory partial epilepsy in whom phenytoin has failed. However, TPM was more efficacious in increasing ADT in PHT responders than in nonresponders, substantiating that the difference between these groups of kindled rats extends to other AEDs. Repeated testing of kindled rats with TPM indicated that, similar to PHT, there are individual kindled rats without anticonvulsant response to TPM (i.e., TPM nonresponders). CONCLUSIONS: The data of this study substantiate that PHT nonresponders are a unique model for the search of new AEDs with improved efficacy in refractory partial epilepsy.     

Epileptiform syndrome in rats produced by injecting tetanus toxin into the hippocampus.

An epileptiform syndrome in rats produced by injecting small doses (a few (mouse)LD50) of tetanus toxin into the hippocampus is described. The animals had intermittent seizures, with at least a superficial resemblance to human epilepsy, for some weeks but they eventually recovered. They were hyperkinetic for several weeks after the injection of toxin, and showed intermittent aggressive behaviour. Control animals which received similar injections of tetanus toxin first neutralised with antitoxin did not have seizures, and their behaviour appeared normal. EEG recordings showed characteristic seizure activity. Histological examination of the site of injection showed very little morphological damage.     

Current trends in electroencephalography

Several recent articles re-emphasize the value of clinical electrophysiology: in localizing epileptogenesis, predicting effectiveness of epilepsy surgery, and disclosing a mechanism of benign Rolandic epilepsy of childhood.A review of the role of EEG in the diagnosis of epilepsy indicated that epileptiform activity will appear in 50% of initial awake recordings of adults with epilepsy and in 85% of subjects undergoing two recordings. This contrasts with the appearance of spikes in only 4 of 1000 normal persons. Several studies focused on the value of electroencephalography in extratemporal epilepsy: 62% of patients with neocortical epilepsy had at least one localizing ictal EEG; occipital and temporal neocortical seizures were localized in a greater proportion than frontal or parietal attacks. Interictal spikes, if unifocal, always arose from the epileptogenic region in a study of their seizure localizing value. Such congruence augured for better seizure control by focal resection in two studies reviewed herein.Studies indicating the value of interictal temporal lobe spikes and scalp-recorded seizures in lateralising a temporal seizure focus are reviewed. One study found EEG to be slightly more reliable for lateralization of temporal epileptogenesis than MRI.In patients with benign Rolandic seizures, enhanced motor evoked potentials (MEPs) were obtained from transcranial magnetic stimulation when this was applied 50-80 msec after electrical stimulation of the thumb whereas this interval inhibited the MEP in normal subjects. This suggests that afferent cutaneous input abnormally and synchronously activates a large population of sensory neurons; such activation is subsequently transmitted to the motor cortex to produce the focal spikes in this condition.Finally, advances in non-invasive technology have redefined and limited the need for invasive monitoring in children with intractable seizure disorders.     

Inter-individual variation in the anticonvulsant effect of phenobarbital in the pilocarpine rat model of temporal lobe epilepsy

Despite a large therapeutic arsenal of old and new antiepileptic drugs (AEDs), there remains a substantial unmet need for the patients with refractory (AED-resistant) epilepsy. Animal models of refractory epilepsy are needed for at least two goals; (1) better understanding of the mechanisms underlying resistance to AEDs, and (2) development of more efficacious AEDs for patients with refractory seizures. It is only incompletely understood why two patients with seemingly identical types of epilepsy and seizures may respond differently to the same AED. Prompted by this well-known clinical phenomenon, we tested whether epileptic rats from the same epilepsy model respond differently to AEDs and previously discovered phenobarbital (PB) responsive and resistant animals in groups of rats in which epilepsy had been induced by sustained electrical stimulation of the basolateral amygdala (BLA). In the present study, we used the same approach for the widely used pilocarpine model of temporal lobe epilepsy. Epileptic rats from this model were continuously video/EEG monitored over seven consecutive weeks, starting with a predrug control period of two weeks, then two weeks of daily treatment with PB at maximum tolerated doses, and finally a postdrug control period of three weeks. In those rats that were included in response selection, 50% did not adequately respond to PB, whereas PB significantly decreased seizure frequency and severity in another 50% of the animals. Responders and nonresponders did not differ in predrug seizure frequency, PB plasma levels or hippocampal neurodegeneration, but behavioral differences were observed in anxiety models. These findings demonstrate that in the pilocarpine model, similar to epilepsy patients, epileptic rats differ in their response to an AED, which is most likely due to as yet unknown genetic factors.     

SECTION D: NEUROSURGERY & NEUROPATHOLOGY

Comparison of surgical and medical treatment for partial epilepsy. Medical and social implications of the treatment
Procedures in Pediatric Epilepsy Surgery
The possible need for intra-cranial EEG in surgery for temporal lobe epilepsy
Consistency of lateralisation in intracranial record-ings of seizures of temporal lobe origin
Comparison of lateralising capability of 99Tc^m HM-PAO-SPECT, neuropsychology, interictal and ictal EEG in the pre-surgical evaluation of patients with intractable epilepsy
Convergence of CT/MRI, "FDG-PET, intracarotid amobarbital procedure and D.EEG in presurgical evaluation of refractory partial epilepsy
Surgery for epilepsy in the United Kingdom
Anterior 2/3 callosotomy for the treatment of in-tractable epilepsy
Pre-surgical EEG evaluation
A simplified technique for epidural recording of epi-leptiform activity and seizure patterns
Discrepancy between interictal and ictal EEG-find-ings - the use of subdural electrodes may solve the problem
Temporal mesiolimbic versus temporal neocortical complex partial seizures; electroclinical correlates recorded by combined depth and subdural electrodes
Verifying electrical dipole localization in patients with epilepsy undergoing depth EEG recordings in the presurgical evaluation of intractable epilepsy
A current dipole tracing method locating interictal epileptiform activity in patients with focal epilepsy
PET-studies on distribution of glia in patients with focal epilepsy
Relationship of pre-operative neuropsychological test to the sodium amytal test - results on an empiri-cal study
Amygdalohippocampectomy in complex partial epi-lepsy     

Localizing and lateralizing features of auras and seizures

The symptomatology of auras and seizures is a reflection of activation of specific parts of the brain by the ictal discharge, the location and extent of which represent the symptomatogenic zone. The symptomatogenic zone is presumably, though not necessarily, in close proximity to the epileptogenic zone, the area responsible for seizure generation, the complete removal or disconnection of which is necessary for seizure freedom. Knowledge about the symptomatogenic zone in focal epilepsy is acquired through careful video/EEG monitoring and behavioral correlation of seizures and electrical stimulation studies. Ictal symptomatogy provides important lateralizing and/or localizing information in the presurgical assessment of epilepsy surgery candidates. As the initial symptoms of epileptic seizures, many types of auras have highly significant localizing or lateralizing value. Similarly, motor signs during focal and secondary generalized seizures, language manifestations, and autonomic features offer reliable clues to the delineation of the epileptogenic zone. Some focal epilepsies (e.g., neocortical temporal lobe epilepsy, insular lobe epilepsy, temporal-plus epilepsies, and parieto-occipital lobe epilepsy) generate seizure manifestations that mimic temporal lobe epilepsy, potentially contributing to surgical failure. To optimize surgical outcome, careful interpretation of ictal symptomatology in conjunction with other components of the presurgical evaluation is required.     

When antiepileptic drugs aggravate epilepsy

Paradoxically, an antiepileptic drug (AED) may aggravate epilepsy. The number of AEDs is steadily increasing, and the occurrence of paradoxical aggravation will probably become a frequent problem. The overall status of the patient treated for epilepsy can be altered due to maladjustment to the diagnosis of epilepsy, to unwanted side-effects, to overdosage and to the occurrence of tolerance. However, the main mechanism of aggravation is the occurrence of an inverse pharmacodynamic effect. The specific effect of the AED is such that it controls epilepsy in most cases and increases seizures in other cases. Idiopathic generalised epilepsies (IGE) are particularly prone to pharmacodynamic aggravation: typical absences are constantly increased by carbamazepine (CBZ), vigabatrin, tiagabine, gabapentin, while phenytoin (PHT) is less aggravating. Juvenile myoclonic epilepsy is often aggravated by CBZ, less constantly by PHT and other AEDs. Generalised tonic-clonic seizures found in IGEs may respond to AEDs that aggravate the other seizure types. In symptomatic generalised epilepsies, patients have often several seizure types that respond differently to AEDs: myoclonias are generally aggravated by the same drugs that aggravated IGEs; tonic seizures in the Lennox-Gastaut syndrome respond to CBZ, which may however aggravate atypical absences. In severe myoclonic epilepsy of infancy, there is a nearly constant aggravating effect of lamotrigine. In some patients with benign rolandic epilepsy, a clear aggravation may be produced by CBZ, with occurrence of negative myoclonias, atypical absences, drop attacks, and at the maximum evolution into a state of electrical status epilepticus during sleep. It is much more difficult to pinpoint specific pharmacological sensitivity in other focal epilepsies, but aggravation clearly occurs. When treating epilepsy, the clinician should act according to seizure type, or, better, to epilepsy type. Patients are usually aware of aggravation before their doctors: we should listen carefully whenever they express a 'dislike' for an AED.     

Inhibition of the multidrug transporter P-glycoprotein improves seizure control in phenytoin-treated chronic epileptic rats

PURPOSE: Overexpression of multidrug transporters such as P-glycoprotein (P-gp) may play a significant role in pharmacoresistance, by preventing antiepileptic drugs (AEDs) from reaching their targets in the brain. Until now, many studies have described increased P-gp expression in epileptic tissue or have shown that several AEDs act as substrates for P-gp. However, definitive proof showing the functional involvement of P-gp in pharmacoresistance is still lacking. Here we tested whether P-gp contributes to pharmacoresistance to phenytoin (PHT) by using a specific P-gp inhibitor in a model of spontaneous seizures in rats. METHODS: The effects of PHT on spontaneous seizure activity were investigated in the electrical post-status epilepticus rat model for temporal lobe epilepsy, before and after administration of tariquidar (TQD), a selective inhibitor of P-gp. RESULTS: A 7-day treatment with therapeutic doses of PHT suppressed spontaneous seizure activity in rats, but only partially. However, an almost complete control of seizures by PHT (93 +/- 7%) was obtained in all rats when PHT was coadministered with TQD. This specific P-gp inhibitor was effective in improving the anticonvulsive action of PHT during the first 3-4 days of the treatment. Western blot analysis confirmed P-gp upregulation in epileptic brains (140-200% of control levels), along with approximately 20% reduced PHT brain levels. Inhibition of P-gp by TQD significantly increased PHT brain levels in chronic epileptic rats. CONCLUSIONS: These findings show that TQD significantly improves the anticonvulsive action of PHT, thus establishing a proof-of-concept that the administration of AEDs in combination with P-gp inhibitors may be a promising therapeutic strategy in pharmacoresistant patients.     

Epilepsy in hypothalamic hamartoma: clinical and EEG features

Hypothalamic hamartoma (HH) is a congenital malformation of the hypothalamus that may be asymptomatic or manifest with precocious puberty or seizures. Gelastic seizures often begin early in life, even in the newborn period, being manifest by frequent attacks of inappropriate laughter resulting from seizure activity in the HH. The scalp electroencephalogram (EEG) is often normal in children with gelastic seizures, such that the diagnosis of epilepsy and the finding of a HH are often delayed. In a proportion of children with HH, there is an epileptic progression, in which complex partial seizures with frontal, temporal, and lateralized clinical features appear, usually with the appearance of focal slowing and epileptiform activity on the interictal EEG. Further progression may ensue with the appearance of tonic or atonic drop attacks, generalized tonic-clonic seizures, and epileptic spasms; rarely, infantile spasms may be the presenting seizure type. With the appearance of generalized seizures, the interictal EEG shows bilaterally synchronous and generalized epileptiform activity, often in abundance. The mechanism of this evolution is incompletely understood but neocortical seizure propagation and secondary epileptogenesis are believed to be important. Paralleling the development of the focal and generalized electroclinical manifestations in children with HH is usually slowing of development and the appearance of behavioral problems. Fortunately, many of these neurologic manifestations can be arrested, or reversed, with effective surgical treatment directed at the HH.     

Levetiracetam monotherapy for primary generalised epilepsy.

PURPOSE: To evaluate the efficacy of levetiracetam in cases of refractory primary generalised epilepsy. METHODS: Three patients with refractory primary generalised epilepsy were treated with levetiracetam monotherapy; one with absence seizures, myoclonic jerks and generalised tonic-clonic (GTC) seizures one with myoclonic jerks and GTC seizures, and one with only GTC seizures. All three patients had generalised spike wave on the EEG and had failed at least three antiepileptic drugs (AEDs) before trying levetiracetam. RESULTS: All three patients tolerated levetiracetam well and became seizure free for at least 6 months. Therapeutic doses of levetiracetam ranged from 1250 to 3000 mg/day. CONCLUSION: Levetiracetam, a new AED with a novel mechanism(s) of action, should be considered for patients with refractory primary generalised epilepsy.     

Efficacy and Adverse Effects of Established and New Antiepileptic Drugs*

Summary: Antiepileptic drug (AED) selection is based primarily on efficacy for specific seizure types and epileptic syndromes. However, efficacy is often similar for the different AEDs, and other properties such as adverse effects, pharmacokinetic properties, and cost may also be of importance. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the AED of choice is valproate (VPA). Secondarily generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single AED or combination of AEds. The AEDs of choice for absence seizures are ethosuximide (ESM) and VPA. For control of primary generalized tonic-clonic seizures, any of the other major AEDs can be effective. If VPA cannot be prescribed, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), or primidone (PRM) may be effective, but ESM or a benzodiazepine (BZD) must be added to control associated absence or myoclonic seizures. The AEDs of first choice for partial epilepsies with partial and secondarily generalized tonic-clonic seizures are CBZ and PHT. Increasing evidence suggests that VPA is a good alternative when CBZ and PHT fail. PB and PRM are second-choice selections because of adverse effects. A combination of two of the five standard AEDs may be necessary to treat intractable seizures, but no studies have been done to indicate an optimal combination. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, alcoholic epilepsy, and status epilepticus require specific AED treatment. Ultimately, AED selection must be individualized. No “drug of choice” can be named for all patients. The expected efficacy for the seizure type, the importance of the expected adverse effects, the pharmacokinetics, and the cost of the AEDs all must be weighed and discussed with the patient before a choice is made. A number of new AEDs with unique mechanisms of action, pharmacokinetic properties, and fewer adverse effects hold important promise of improved epilepsy treatment.     

Insights into the tetanus toxin model of early-onset epilepsy from long-term video monitoring during anticonvulsant therapy

Video monitoring studies were undertaken to determine if the anticonvulsant, carbamazepine (CBZ), could prevent seizures in infant rats that had been intrahippocampally injected with tetanus toxin (TNTX). In control rats, seizure frequency peaked 5-6 days after injection and rapidly declined by postinjection day 9. Twice-daily CBZ treatments dramatically suppressed behavioral seizures for 7 days. However, despite increasing the dosage of CBZ, rats experienced more behavioral seizures during the second week after TNTX injection. Paradoxically, tetanus-toxin-injected control rats had very few seizures at this time. Results not only suggest that this TNTX model may be useful in screening drugs for treating intractable focal epilepsy of infancy but also provide some insight into the processes that may contribute to the rapid decline in behavioral seizure frequency that occurs during the acute phase of epileptogenesis in this model.     

Outpatient sleep recording during antiepileptic drug monotherapy

The effects of sleep and sleep deprivation on epilepsy are well known, but the effects of seizures and antiepileptic drugs (AEDs) on sleep have been less well studied. We recorded nocturnal sleep in 17 patients receiving antiepileptic monotherapy with ambulatory cassette EEG devices. Twelve patients had complex partial seizures and five had tonic-clonic convulsions. Two patients' seizures were largely nocturnal, and no seizures occurred during sleep recording. Five patients each were taking phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA), and two were taking clonazepam (CZP), all with therapeutic serum levels and no toxic symptoms. Total sleep time was reduced, wakefulness increased, and sleep latency prolonged in partial seizures as compared with generalized epilepsy. REM sleep was reduced and its latency decreased in partial seizure patients. Both groups had decreased slow wave sleep; that of partial seizure patients was decreased more markedly. PHT increased sleep latency and decreased sleep time, and CBZ increased awakening and diminished slow wave and REM sleep. Patients taking VPA had slight reduction in slow wave sleep; those taking CPZ had decreased sleep and REM latencies. Epilepsy may affect nocturnal sleep, and the effects of partial and generalized seizure disorders may be different. AEDs may also have differential effects on nighttime sleep. These may prove important in the long-term management of epileptic patients.