Effects of piracetam alone and in combination with antiepileptic drugs in rodent seizure models

Summary. The nootropic drug piracetam was investigated in various experimental models of epilepsy. Generally, piracetam exhibits no or only moderate anticonvulsant properties against generalized tonic or clonic seizures. However, in many cases it did increase the anticonvulsant effectiveness of conventional antiepileptics, as shown in the maximal electroshock seizure (MES) threshold test, the traditional MES test or in DBA/2 mice. A pharmacokinetic interaction does not seem to be responsible for this effect. In lethargic mice, a model of absence seizures, piracetam significantly decreased the incidence and duration of spike-wave discharges. Furthermore, in the cobalt-induced focal epilepsy model piracetam reduced the number of spikes/min and in the hippocampal stimulation model it increased the anticonvulsant potency of phenobarbital and phenytoin after single and repeated administration. In conclusion, the well tolerated piracetam itself did not show marked anticonvulsant effects in most screening tests, however, its co-medication with antiepileptic drugs improved seizure protection in various models which may bear potential clinical significance.     

Activity profile of pregabalin in rodent models of epilepsy and ataxia

Pregabalin (Lyrica) is a novel amino acid compound that binds with high affinity to the alpha2-delta (alpha2-delta) auxiliary protein of voltage-gated calcium channels. In vivo, it potently prevents seizures, pain-related behaviors and has anxiolytic-like activity in rodent models. The present studies were performed to determine the profile of pregabalin anticonvulsant activity in a variety of mouse and rat models. In the high-intensity electroshock test, pregabalin potently inhibited tonic extensor seizures in rats (ED50 = 1.8 mg/kg, PO), and low-intensity electroshock seizures in mice. It prevented tonic extensor seizures in the DBA/2 audiogenic mouse model (ED50 = 2.7 mg/kg, PO). Its time course of action against electroshock induced seizures in rats roughly followed the pharmacokinetics of radiolabeled drug in the brain compartment. At higher dosages (ED50 1= 31 mg/kg, PO), pregabalin prevented clonic seizures from pentylenetetrazole in mice. In a kindled rat model of partial seizures, pregabalin prevented stages 4-5 behavioral seizures (lowest effective dose = 10 mg/kg, IP), and also reduced the duration of electrographic seizures. Pregabalin was not active to prevent spontaneous absence-like seizures in the Genetic Absence Epilepsy in Rats from Strasbourg (GAERS) inbred Wistar rat strain. Pregabalin caused ataxia and decreased spontaneous locomotor activity at dosages 10-30-fold higher than those active to prevent seizures. These findings suggest that pregabalin has an anticonvulsant mechanism different from the prototype antiepileptic drugs and similar to that of gabapentin except with increased potency and bioavailability. In summary, our results show that pregabalin has several properties that favor treatment of partial seizures in humans.     

Radiosurgery for epilepsy: clinical experience and potential antiepileptic mechanisms

Stereotactic radiosurgery, well established in the noninvasive treatment of focal lesions that are otherwise difficult to access through open surgery, is an emerging technology in the treatment of focal epileptic lesions. Recent studies suggest that seizures from hypothalamic hamartomas and mesial temporal lobe epilepsy remit at clinically significant rates with radiosurgery, but large variations among different studies have raised questions about appropriate treatment protocols and mechanisms. Proposed anticonvulsant mechanisms include neuromodulatory effects or ischemic necrosis of epileptic tissue. An ongoing trial that directly compares efficacy, morbidities, and cost of radiosurgery versus open surgery for mesial temporal lobe epilepsy is underway.     

Neurobehavioral consequences of stressor exposure in rodent models of epilepsy

Both normal, non-epileptic as well as seizure-prone rodents exhibit a spectrum of anxiogenic-like behaviors in response to stressor exposure. Comparative analysis reveals that the same set of emotionality dependent measures is sensitive to both stress reactivity in normal rodents as well as stress hyperreactivity typically seen in seizure-prone rodents. A variety of unconditioned, exploratory tasks reflect global sensitivity to stressor exposure in the form of behavioral inhibition of locomotor output. Moreover, well chosen stressors can trigger de novo seizures with or without a history of seizure incidence. Seizures may be elicited in response to stressful environmental stimuli such as noxious noises, tail suspension handling, or home cage disturbance. Stress reactivity studies in rodents with a genetic predisposition to seizures have yielded important clues regarding brain substrates that mediate seizure ontogeny and modulate ictogenesis. Brains of seizure susceptible rodents reflect elevated content of the stress-related neuropeptide, corticotropin-releasing factor (CRF) in several nuclei relative to non-susceptible controls and neutralization of brain CRF attenuates seizure sensitivity. Findings outlined in this review support a diathesis-stress hypothesis in which behavioral- and neuro-pathologies of genetically seizure susceptible rodents arise in part due to multifaceted hyperreactivity to noxious environmental stimuli.     

Lecture: profile of risks and benefits of new antiepileptic drugs in brain tumor-related epilepsy

In patients with brain tumor, seizures are the onset symptom in 20-40% of the patients, while a further 20-45% of the patients will present them during the course of the disease. These data are important when considering the choice of antiepileptic drugs for this particular patient population, because brain tumor-related epilepsy (BTRE) is often drug resistant, has a strong impact on the quality of life and weighs heavily on public health expenditures. In brain tumor patients, the presence of epilepsy is considered as the most important risk factor for long-term disability. For this reason, the problem of the proper administration of medications and their potential side effects is of great importance, because good seizure control can significantly improve the patient's psychological and relational sphere. In these patients, new generation drugs such as gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, topiramate, and zonisamide are preferred, because they have fewer drug interactions and cause fewer side effects. Among the recently marketed drugs, lacosamide has demonstrated promising results and should be considered as a possible treatment option. Therefore, it is necessary to develop a customized treatment plan for each patient with BTRE, whose goals are complete seizure control, minimal or no side effects, and elimination of cognitive impairment and/or psychosocial problems.     

Use of chronic epilepsy models in antiepileptic drug discovery: the effect of topiramate on spontaneous motor seizures in rats with kainate-induced epilepsy

Summary:  Purpose: Potential antiepileptic drugs (AEDs) are typically screened on acute seizures in normal animals, such as those induced in the maximal electroshock and pentylenetet-razole models. As a proof-of-principle test, the present experiments used spontaneous epileptic seizures in kainate-treated rats to examine the efficacy of topiramate (TPM) with a repeated-measures, crossover protocol.
Methods: Kainic acid was administered in repeated low doses (5 mg/kg) every hour until each Sprague–Dawley rat experienced convulsive status epilepticus for >3 h. Six 1-month trials (n = 6–10 rats) assessed the effects of 0.3–100 mg/kg TPM on spontaneous seizures. Each trial involved six pairs of TPM and saline-control treatments administered as intraperitoneal injections on alternate days with a recovery day between each treatment day. Data analysis included a log transformation to compensate for the asymmetric distribution of values and the heterogeneous variances, which appeared to arise from clustering of seizures.
Results: A significant effect of TPM was observed for 12 h (i.e., two 6-h periods) after a 30-mg/kg injection, and full recovery from the drug effect was complete within 43 h. TPM exerted a significant effect at doses of 10, 30, and 100 mg/kg, and the effects of TPM (0.3–100 mg/kg) were dose dependent.
Conclusions: These data suggest that animal models with spontaneous seizures, such as kainate- and pilocarpine-treated rats, can be used efficiently for rapid testing of AEDs with a repeated-measures, crossover protocol. Furthermore, the results indicate that this design allows both dose–effect and time-course-of-recovery studies.     

Neuropeptides and the social brain: potential rodent models of autism

Conducting basic scientific research on a complex psychiatric disorder, such as autism, is a challenging prospect. It is difficult to dissociate the fundamental neurological and psychological processes that are disturbed in autism and, therefore, it is a challenge to discover accurate and reliable animal models of the disease. Because of their role in animal models of social processing and social bonding, the neuropeptides oxytocin and vasopressin are strong candidates for dysregulation in autism. In this review, we discuss the current animal models which have investigated oxytocin and vasopressin systems in the brain and their effects on social behavior. For example, mice lacking the oxytocin gene have profound deficits in social processing and social recognition, as do rats lacking vasopressin or mice lacking the vasopressin V1a receptor (V1aR). In another rodent model, monogamous prairie voles are highly social and form strong pair bonds with their mates. Pair bonds can be facilitated or disrupted by perturbing the oxytocin and vasopressin systems. Non-monogamous vole species that do not pair bond have different oxytocin and V1aR distribution patterns in the brain than monogamous vole species. Potential ties from these rodent models to the human autistic condition are then discussed. Given the hallmark disturbances in social function, the study of animal models of social behavior may provide novel therapeutic targets for the treatment of autism.     

Predicting antiepileptic drug response in children with epilepsy

In clinical practice, after diagnosis and when treatment has begun, it is important to predict as soon as possible which children will become seizure-free and which are likely to develop medically intractable seizures. This article summarizes factors predicting seizure remission in childhood-onset epilepsy treated with antiepileptic drugs (AEDs). Sustained seizure remission can be expected in over 90% of idiopathic epilepsies of childhood and in neurologically normal children with epilepsy having infrequent seizures showing early remission after starting treatment with AEDs. Even in the presence of symptomatic etiology of epilepsy--focal seizures and syndromes; high seizure frequency prior to or during treatment; seizure clustering; and poor or delayed response to first adequate drug therapy--up to 60% of children with treated epilepsy are able to enter long-term remission. However, remission can be expected in only 30% or less of those with catastrophic epilepsies of childhood.     

The benefits of antiepileptic drug (AED) blood level monitoring to complement clinical management of people with epilepsy

IntroductionSome argue that there is no evidence to support the use of antiepileptic drug (AED) blood level monitoring when treating people with epilepsy (PWE). This paper identifies how AED monitoring can be invaluable in such treatment.Specific examples

• (i)Compliance: Antiepileptic drug blood levels often confirm noncompliance rather than adequate seizure control, confirming subtherapeutic levels in PWE attending hospitals due to seizures. Routine monitoring of AED levels may prevent breakthrough seizures by identifying noncompliance and instituting heightened compliance measures before experiencing breakthrough seizures without modifying dosages. For PWE attending hospitals due to seizures, loading with the AED shown to be subtherapeutic may be all that is required.
• (ii)Cluster seizures and status epilepticus: When using long-acting AEDs to complement benzodiazepines, blood level monitoring confirms that an adequate dosage was given and, if not, a further bolus can be administered with further monitoring. This is particularly useful when using rectal administration of AEDs.
• (iii)Polypharmacy: Polypharmacy provokes drug interactions in which case AED monitoring helps in differentiating adequate dosing, offending AED with toxicity and free level measuring benefits when total levels are unhelpful.
• (iv)Generic substitution: Generic AEDs can fluctuate considerably from a parent compound, and even a parent compound, sourced from an alternative supplier, may have altered bioavailability for which blood level monitoring is very useful.

ConclusionsWhile therapeutic blood level monitoring is not a substitute for good clinical judgment, it offers a valuable adjunct to patient care.     

Using anxiolytics in epilepsy: neurobiological,neuropharmacological and clinical aspects

Anxiety disorders represent a common psychiatric comorbidity in patients with epilepsy, affecting prognosis and quality of life. However, they are still underdiagnosed and undertreated. In clinical practice, a number of compounds are currently used as anxiolytics, with benzodiazepines being the most popular. Other drug classes, especially antiepileptic drugs, are increasingly prescribed for the treatment of anxiety. This article discusses the neurobiological targets and basic neuropharmacological aspects of anxiolytics in order to give the reader clear insight into their activity and mechanism of action. Clinical data regarding the treatment of anxiety in both adults and children with epilepsy are also summarised, emphasising the need for further studies.     

Effect of topiramate on the anticonvulsant activity of conventional antiepileptic drugs in two models of experimental epilepsy

PURPOSE: The objective of this study was to evaluate the interaction of the novel antiepileptic drug (AED), topiramate (TPM), with conventional AEDs against amygdala-kindled seizures in rats and pentylenetetrazol-induced convulsions in mice. METHODS: Experiments were performed on mice and fully kindled rats. In pentylenetetrazol test, the chemoconvulsant was used at its CD97 dose of 105 mg/kg, producing clonic seizures in 97% of mice. Adverse effects were evaluated with the chimney test and passive avoidance task. Plasma levels of AEDs were measured with immunofluorescence. RESULTS: TPM at 20 mg/kg exerted a significant anticonvulsant effect as regards seizure and afterdischarge durations in amygdala-kindled seizures in rats, being ineffective at lower doses. Coadministration of TPM (10 mg/kg) with valproate (VPA; at a subtherapeutic dose of 50 mg/kg) resulted in essential reductions of seizure and afterdischarge durations. TPM (10 mg/kg) combined with carbamazepine (CBZ; at a subtherapeutic dose of 15 mg/kg) significantly increased afterdischarge threshold, simultaneously decreasing the remaining seizure parameters (duration or severity of seizures and afterdischarge duration). TPM (10 mg/kg) given with phenobarbital (PB; 15 mg/kg) markedly shortened seizure severity and seizure and afterdischarge durations. Combinations of TPM with diphenylhydantoin (PHT) were ineffective against kindled seizures in rats. TPM combined with VPA and PB did not alter their plasma levels, but its combination with CBZ resulted in an increased free plasma CBZ concentration. TPM (10 and 20 mg/kg) alone and its combinations with conventional AEDs affected neither motor coordination nor long-term memory, evaluated in the chimney and passive avoidance tests, respectively, in rats. In pentylenetetrazol-evoked convulsions in mice, TPM (175 and 200 mg/kg) showed anticonvulsant effects per se. Moreover, TPM (at its subtherapeutic dose of 150 mg/kg), significantly potentiated the anticonvulsant action of ethosuximide (ESM), but not that of VPA, PB, or clonazepam (CZP) against pentylenetetrazol-induced seizures. Either TPM alone (150 mg/kg) or its combination with ESM did not result in significant undesired effects. CONCLUSIONS: The experimental data indicate that except for PHT, the combinations of TPM with conventional AEDs are beneficial against amygdala-kindled seizures in rats. In the pentylenetetrazol test, this novel AED potentiated only the protection offered by ESM.     

Bone consequences of epilepsy and antiepileptic medications

Childhood and adolescence are critical periods of skeletal mineralization. Peak bone mineral density achieved by the end of adolescence determines the risk for later pathological fractures and osteoporosis. Chronic disease and medication often adversely affect bone health. Epilepsy is one of the most common neurological conditions occurring in persons under the age of 21. Epilepsy may affect bone in a number of ways. Restrictions of physical activity imposed by seizures, cerebral palsy or other coexisting comorbidities adversely affect bone health. It has been observed that treatment with phenytoin and phenobarbital can be associated with rickets. More recently, established agents such as carbamazepine and valproate have been shown to be associated with decreased bone mineral density. The literature related to bone health in pediatric epilepsy is reviewed.     

Strategies to prevent overtreatment with antiepileptic drugs in patients with epilepsy

Overtreatment is defined here as an unnecessary and excessive drug load in the management of epilepsy leading to a suboptimal risk-to-benefit balance. Pharmacological overtreatment can often be prevented by deciding and counselling carefully about the need for antiepileptic drugs (AEDs) given the limitations of current AEDs. Although AEDs will reduce the incidence of seizures, they have no demonstrated ability to prevent epilepsy in patients at risk or to modify the course of epilepsy in patients following the first seizure. In addition, starting AEDs may not be necessary for control of epileptic seizures induced by precipitation or predisposing factors or for benign epilepsies with rare or mild seizures. Start monotherapy with the chosen first-line AED, initially at low doses titrating up to the low maintenance dose. Avoid drug loading (except for emergency treatment). If seizures continue, titrate to the limit of tolerability which will however, achieve additional seizure control in approximately 20% of patients. If, as in many patients, dosing to the limit of tolerability is not beneficial, the dose should be reduced. Switching to an average dose of another first line AED is another option to prevent overtreatment. Avoid drug overload during add-on therapy by slowly reducing the dose of the first drug in patients having adverse effects, ideally by an amount that the patient does not experience any further adverse effects, if possible, before adding another drug. If the patient does not benefit unequivocally from two-drug therapy within 3 months (and approximately 75% will not benefit), slowly transfer to monotherapy of the second drug and start with a newly chosen AED for add-on. To counteract the propensity to overmedication in chronic epilepsy is not easy. Great benefits, without loss of seizure control, are often gained by slowly reducing the overall drug load.     

Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy

PurposePsychiatric and behavioral side effects (PBSEs) are common, undesirable effects associated with antiepileptic drug (AED) use. The objective of the study was to compare the PBSE profiles of older and newer AEDs in a large specialty practice-based sample of patients diagnosed with epilepsy.MethodsAs part of the Columbia and Yale AED Database Project, we reviewed patient records including demographics, medical history, AED use, and side effects for 4085 adult patients (age: 18 years) newly started on an AED regimen. Psychiatric and behavioral side effects were determined by patient or physician report in the medical record, which included depressive mood, psychosis, anxiety, suicidal thoughts, irritability, aggression, and tantrum. Significant non-AED predictors of PBSE rate were first determined from 83 variables using logistic regression. Predictors were then controlled for in the comparison analysis of the rate of PBSEs and intolerable PBSEs (PBSEs that led to dosage reduction or discontinuation) between 18 AEDs.ResultsPsychiatric and behavioral side effects occurred in 17.2% of patients and led to intolerability in 13.8% of patients. History of psychiatric condition(s), secondary generalized seizures, absence seizures, and intractable epilepsy were associated with increased incidence of PBSE. Levetiracetam (LEV) had the greatest PBSE rate (22.1%). This was statistically significant when compared with the aggregate of the other AEDs (P < 0.001, OR = 6.87). Levetiracetam was also significantly (P < 0.001) associated with higher intolerability rate (17.7%), dose decreased rate (9.4%), and complete cessation rate (8.3%), when compared with the aggregate of the other AEDs. Zonisamide (ZNS) was also significantly associated with a higher rate of PBSE (9.7%) and IPBSE (7.9%, all P < 0.001). On the other hand, carbamazepine (CBZ), clobazam (CLB), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OXC), phenytoin (PHT), and valproate (VPA) were significantly associated with a decreased PBSE rates (P < 0.001). Carbamazepine, GBP, LTG, PHT, and VPA were also associated with lower IPBSE rates when compared individually with the aggregate of other AEDs. All other AEDs were found to have intermediate rates that were not either increased or decreased compared with other AEDs. When each AED was compared to LTG, only CBZ had a significantly lower PBSE rate. The main limitations of this study were that the study design was retrospective and not blinded, and the AEDs were not randomly assigned to patients.ConclusionsPsychiatric and behavioral side effects occur more frequently in patients taking LEV and ZNS than any other AED and led to higher rates of intolerability. Lower PBSE rates were seen in patients taking CBZ, CLB, GBP, LTG, OXC, PHT, and VPA. Our findings may help facilitate the AED selection process.     

Psychiatric and behavioral side effects of the newer antiepileptic drugs in adults with epilepsy

ObjectivePsychiatric/behavioral side effects (PSEs) are common in patients taking antiepileptic drugs (AEDs). The objective of the study described here was to compare the PSE profiles of the newer AEDs.MethodsWe examined the charts of 1394 adult outpatients seen at the Columbia Comprehensive Epilepsy Center who had taken one of the newer AEDs. We compared the rate of AED-related PSEs in patients newly started on the newer AEDs both before and after controlling for non-AED predictors of PSEs.ResultsOverall, 221 of 1394 (16%) patients experienced PSEs. The average rate of AED-related PSEs for a single AED was 8.4%, with 6.1% resulting in dosage change and 4.3% resulting in AED discontinuation. Significantly fewer PSEs were attributed to gabapentin (n = 160, 0.6% incidence, P < 0.001) and lamotrigine (n = 547, 4.8% incidence, P < 0.001), and significantly more PSEs were attributed to levetiracetam (n = 521, 15.7% incidence, P < 0.001; 8.8% discontinued LEV because of PSEs). Vigabatrin, felbamate, and oxcarbazepine were associated with similarly low rates of PSEs in many analyses but with fewer of patients. Tiagabine was associated with high PSE rates (similar to those for levetiracetam), but was used much less commonly at our center. Intermediate rates of PSEs were attributed to topiramate and zonisamide (both nonsignificant). Psychiatric history was the most significant nondrug predictor of AED-related PSEs (PSEs occurred in 23% of patients with a psychiatric history vs 12% of patients without such a history, P < 0.001). The relative rates of AED-related PSEs were similar when controlling for non-AED predictors and when analyzing only patients on monotherapy.ConclusionsThere are significant differences between the newer AEDs in terms of their PSE profiles. Patients taking levetiracetan experience significantly more PSEs than average, and patients taking gabapentin and lamotrigine experience significantly fewer PSEs. Even with the medication with the highest rate of PSEs (levetiracetam), less than 10% of patients discontinued it because of PSEs. A past psychiatric condition is the most significant nondrug predictor of AED-related PSEs.