Combination Of Antiepileptic Drugs Research Articles

Sibling response to initial antiepileptic medication predicts treatment success

ObjectiveA recent study focusing on a response to antiepileptic drugs (AED) among siblings for epilepsy showed a similar response among epileptic siblings to specific AEDs or AED combinations. Currently, however, family history of treatment response to AEDs is not readily employed in deciding which initial medication to use when treating patients with epilepsy. We tested the hypothesis that sibling response to initial AED predicts treatment success. MethodsPresumed siblings were identified from a single-center database of patients diagnosed with epilepsy by matching last name, address, and name of parent(s). We identified 28 sibling pairs and two sibling trios with epilepsy. Seventeen of these sibling pairs were started on the same initial AED, with 15 sibling pairs having the same type of epilepsy. The remaining 11 pairs were started on a different initial AED, with 8 of these sibling pairs having the same type of epilepsy. Subjects with seizure freedom for a period of ≥1year were classified as a “responder”. ResultsWhen at least one of the sibling pair responded to an initial AED, the proportion of the other siblings also responding to the initial AED was significantly higher if the siblings were treated with the same AED (8/11) compared to siblings who were treated with different AED (1/10) (Fisher’s exact test, p-value=0.0075). SignificanceThese findings suggest that sibling response to initial AED is predictive of the success of AED therapy. This study is limited by a small cohort and retrospective design. Future, larger prospective studies are needed to reproduce and further validate these findings.

Thalamic and cerebellar hypermetabolism and cortical hypometabolism during absence status epilepticus

We report on a 17-year-old girl with absence status epilepticus who developed recurrent motionless confusional state and continuous generalised 3–4 Hz rhythmic delta waves on electroencephalogram (EEG). The patient had...

Combination therapy of levetiracetam and gabapentin against nonconvulsive seizures induced by penetrating traumatic brain injury.

Posttraumatic seizures are a medical problem affecting patients with traumatic brain injury. Yet effective treatment is lacking owing to the limitations of antiepileptic drugs (AEDs) applicable to these patients. In this study, we evaluated the dose-response efficacy of levetiracetam (12.5-100.0 mg/kg) and gabapentin (1.25-25.0 mg/kg) administered either individually or in pairs at fixed-dose ratios as a combination in mitigating posttraumatic nonconvulsive seizures induced by severe penetrating ballistic-like brain injury (PBBI) in rats. Seizures were detected by continuous electroencephalogram (EEG) monitoring for 72 hours postinjury. Animals were treated twice per day for 3 days by intravenous injections. Both levetiracetam (25-100 mg/kg) and gabapentin (6.25-25 mg/kg) significantly reduced PBBI-induced seizure frequency by 44% to 73% and 61% to 69%, and seizure duration by 45% to 64% and 70% to 78%, respectively. However, the two drugs manifested different dose-response profiles. Levetiracetam attenuated seizure activity in a dose-dependent fashion, whereas the beneficial effects of gabapentin plateaued across the three highest doses tested. Combined administration of levetiracetam and gabapentin mirrored the more classic dose-response profile of levetiracetam monotherapy. However, no additional benefit was derived from the addition of gabapentin. Furthermore, isobolographic analysis of the combination dose-response profile of levetiracetam and gabapentin failed to reach the expected level of additivity, suggesting an unlikelihood of favorable interactions between these two drugs against spontaneously occurring posttraumatic seizure activities at the particular set of dose ratios tested. This study was the first attempt to apply isobolographic approach to studying AED combination therapy in the context of spontaneously occurring posttraumatic seizures. Despite the failure to achieve additivity from levetiracetam and gabapentin combination, it is important to recognize the objectivity of the isobolographic approach in the evaluation of AED combination therapy against seizures directly associated with brain injuries.

Clinical features of limbic encephalitis with LGI1 antibody.

ObjectiveThe objective of this study was to analyze the clinical manifestation, course, evolution, image manifestation, and treatments of LGI1 limbic encephalitis (LE).Patients and methodsStudies confirmed that LE with the complex antibody of voltage-gated potassium channels is LGI1 LE. Since then, LE cases have been reported. In this study, 10 typical LE cases were searched in PubMed. These cases and one additional case, which we reported herein, were retrospectively analyzed.ResultsAll the patients suffered from recent memory deterioration. The following cases were observed: eight with faciobrachial dystonic seizures (FBDS), six with different kinds of epileptic seizures (four complex partial seizures, one myoclonus seizure, and one generalized tonic–clonic seizure), four with FBDS and different kinds of epileptic seizures at the same time, five with mental disorders (one visual hallucination, one paranoia, one depression, one anxiety, and one dysphoria), five with hyponatremia, and two with sleep disorder. The brain MRI of nine patients revealed abnormalities in the mediotemporal lobe and the hippocampus. The LGI1 antibodies in the blood and/or cerebrospinal fluid (CSF) were positive. The content of the CSF protein of two patients increased slightly. The tumor marker of all the patients was normal, but capitate myxoma was detected in the combined pancreas duct of one patient. Gamma globulin and hormone treatments were administered to nine patients. Of these patients, six received a combination of antiepileptic drugs. The clinical symptoms of all the patients improved.ConclusionLGI1 LE is an autoimmune encephalitis whose clinical manifestations are memory deterioration, FBDS, epileptic seizure, mental disorders, and hyponatremia. Brain MRI shows that this autoimmune disease mainly involves the mediotemporal lobe and the hippocampus. This condition can also be manifested with other autoimmune encephalitis cases but can be rarely associated with tumors. After patients with LGI1 LE receive gamma globulin and hormone treatments, their clinical prognosis is good.

Nonketotic hyperglycemia-related epileptic seizures

ObjectiveTo investigate nonketotic hyperglycemia (NKH)-related epileptic clinical features and pathogenesis, and improve the diagnosis and treatment.MethodsClinical data, including the clinical manifestations, laboratory tests, imaging studies and other information, of 13 patients with hyperglycemia-related epilepsy in our department were retrospectively analyzed.ResultsBlood glucose levels of the 13 patients when admitted to the hospital ranged between 24.7-34.6 mmol/L (average 28.3 mmol/L), their plasma osmolality ranged between 290–332 mOsm/L (average 308 mOsm/L), and their ketone results were negative. Among them, seven had convulsions, 4 had upper limbs and facial twitching, and 2 had bust twitch. Imaging findings could not detect accountable lesions related to seizures. EEG mainly showed spikes, slow waves, and scattered sharp slow waves. Insulin combined short-term antiepileptic drugs, allowed the epilepsy to be effectively controlled without recurrence.InterpretationPatients with episodes of NKH epilepsy increased significantly with hyperglycemia. Raising awareness of the disease, early diagnosis, and very early lowering the hyperglycemia levels, can effectively control the seizures. Lowering blood glucose is an effective way to control blood glucose levels.

Lennox-Gastaut Syndrome: A Prospective Follow-up Study.

Objectives:Lennox–Gastaut syndrome is a catastrophic epileptic encephalopathy. In Lennox–Gastaut syndrome, seizures are resistant to pharmacological treatment. In this prospective study, we evaluated the clinical features, neuroimaging, and response to treatment.Materials and Methods:Forty-three consecutive newly diagnosed patients of Lennox–Gastaut syndrome were enrolled in the study. Baseline clinical assessment included seizure semiology, seizure frequency, electroencephalography, and neuroimaging. Patients were treated with combinations of preferred antiepileptic drugs (sodium valproate [VPA], clobazam [CLB], levetiracetam [LVT], lamotrigine [LMT], and topiramate [TPM]). Patients were followed for 6 months. The outcome was assessed using modified Barthel index.Results:Tonic and generalized tonic-clonic forms were the most common seizures types. Features suggestive of hypoxic-ischemic encephalopathy (37.2%) were most frequent neuroimaging abnormality. Neuroimaging was normal in 32.6% of patients. With a combination valproic acid (VPA), CLB, and LVT, in 81.4% of patients, we were able to achieve >50% reduction in seizure frequency. Eleven (25.58%) patients showed an improvement in the baseline disability status.Conclusions: A combination of VPA, CLB, and LVT is an appropriate treatment regimen for patients with Lennox–Gastaut syndrome.

Adverse effects & drug load of antiepileptic drugs in patients with epilepsy: Monotherapy versus polytherapy.

Background & objectives:Although the need for a combination of antiepileptic drugs (AEDs) in the treatment of epilepsy is well justified, but an associated increase in adverse effects (AEs) lends a restriction to polytherapy. The aim of this study was to evaluate AEs and drug load (prescribed daily dose/defined daily doses) of AEDs in patients with epilepsy (PWE).Methods:Consecutive PWEs attending Epilepsy clinic in a tertiary care hospital in New Delhi, India, were enrolled in the study. Demographic variables, such as age, gender, diagnosis, age at onset of seizures, frequency of seizures, use of all AEDs and adverse event profile (AEP) score were noted. Routine laboratory tests including lipid profile, fasting blood glucose, haematological parameters and liver and kidney function tests were done.Results:A total of 697 consecutive patients were included in this study. Of them, 64.4 per cent were male; mean age was 29.6 ± 10.6 yr. Generalized seizures and focal seizures were recorded in n=386 (55.4%) and n=311 (44.6%), respectively. Monotherapy and polytherapy with two and greater than or equal to three AEDs were prescribed in 264 (37.9%), 243 (34.9%) and 190 (27.2%) patients, respectively. The average AED load, duration of treatment as well as AEP score were found to be significantly higher in combination of greater than or equal to three AEDs as compared to both monotherapy and combination of two AEDs, whereas no significant difference was observed between monotherapy and combination of two AEDs. Patients on monotherapy were in good control of seizures as compared to polytherapy. There was no significant change in biochemical parameters between the groups.Interpretation & conclusions:Polytherapy with combination of greater than or equal to three AEDs was associated with higher AEs and lower seizure control as compared to both monotherapy and combination of two AEDs. AEs did not correlate with AED load, seizure type, gender and age of the patients but were associated with both numbers of AEDs as well as seizure frequency in PWE.

An investigation of the characteristics of outpatients with epilepsy and antiepileptic drug utilization in a multicenter cross-sectional study in China.

This study aimed to describe the distribution of seizure types, clinical characteristics, and antiepileptic drug (AED) utilization in patients with epilepsy visiting tertiary hospitals in China. This was an observational, cross-sectional epidemiology study conducted at 11 tertiary hospitals across China from May 2014 to November 2014. A total of 1603 patients, of either sex or any age with confirmed diagnosis of epilepsy, visiting outpatient clinics at tertiary hospitals were screened and enrolled. Demographics, seizure types, frequency, etiologies, comorbidities, and current AED therapy were analyzed using descriptive statistics. Overall, the majority (n=1201; 74.9%) of patients were adults (16-59years of age), and the mean (SD) age was 27.5 (15.9) years. A total of 989 (61.7%) patients had partial seizures, and 653 (40.7%) had generalized seizures. The majority experienced monthly (n=663) or yearly (n=625) seizures, with 2.7seizures/month or 2.9seizures/year, respectively. The most commonly reported symptomatic etiologies were traumatic brain injury, encephalitis, and stroke, whereas the most common comorbidities were sleep disorder, headache, anxiety, and depression. Overall, monotherapy was used in 54.1% of patients, while 30.6% of patients used dual therapy. The most commonly prescribed monotherapy for patients with partial seizures was oxcarbazepine (25.9%), while that for patients with generalized seizures was valproic acid (38.9%), and the most common AED combination was valproic acid and lamotrigine. Overall, valproic acid was the most commonly prescribed AED as monotherapy and combination therapy. Findings from this study provide extensive information on clinical characteristics and utilization of AEDs in Chinese patients with epilepsy which may help physicians make well-informed clinical decisions.

Association between antiepileptic drug dose and long-term response in patients with refractory epilepsy.

Seizures in patients with medically refractory epilepsy remain a substantial clinical challenge, not least because of the dearth of evidence-based guidelines as to which antiepileptic drug (AED) regimens are the most effective, and what doses of these drugs to employ. We sought to determine whether there were regions in the dosage range of commonly used AEDs that were associated with superior efficacy in patients with refractory epilepsy. We retrospectively analyzed treatment records from 164 institutionalized, developmentally disabled patients with refractory epilepsy, averaging 17years of followup per patient. We determined the change in seizure frequency in within-patient comparisons during treatment with the most commonly used combinations of 12 AEDs, and then analyzed the response to treatment by quartile of the dose range for monotherapy with carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), or phenytoin (PHT), and the combination LTG/VPA. We found that of the 26 most frequently used AED regimens, only LTG/VPA yielded superior efficacy, similar to an earlier study. For the monotherapies, patients who were treated in the lowest quartile of the dose range had significantly better long-term reduction in seizure frequency compared to those treated in the 2nd and 3rd quartiles of the dose range. Patients with paired exposures to CBZ in both the lowest quartile and a higher quartile of dose range experienced an increase in seizure frequency at higher doses, while patients treated with LTG/VPA showed improved response with escalation of LTG dosage. We conclude that in this population of patients with refractory epilepsy, LTG/VPA was the most effective AED combination. The best response to AEDs used in monotherapy was observed at low dosage. This suggests that routine exposure to maximally tolerated AED doses may not be necessary to identify those patients with drug-resistant seizures who will have a beneficial response to therapy. Rather, responders to a given AED regimen may be identified with exposure to low AED doses, with careful evaluation of the response to subsequent titration to identify non-responders or those with exacerbation of seizure frequency at higher doses.

Anti-Epileptic Drug Combination Efficacy in an In Vitro Seizure Model - Phenytoin and Valproate, Lamotrigine and Valproate.

In this study, we investigated the relative efficacy of different classes of commonly used anti-epileptic drugs (AEDs) with different mechanisms of action, individually and in combination, to suppress epileptiform discharges in an in vitro model. Extracellular field potential were recorded in 450 μm thick transverse hippocampal slices prepared from juvenile Wistar rats, in which “epileptiform discharges” (ED’s) were produced with a high-K+ (8.5 mM) bicarbonate-buffered saline solution. Single and dual recordings in stratum pyramidale of CA1 and CA3 regions were performed with 3–5 MΩ glass microelectrodes. All drugs—lamotrigine (LTG), phenytoin (PHT) and valproate (VPA)—were applied to the slice by superfusion at a rate of 2 ml/min at 32°C. Effects upon frequency of ED’s were assessed for LTG, PHT and VPA applied at different concentrations, in isolation and in combination. We demonstrated that high-K+ induced ED frequency was reversibly reduced by LTG, PHT and VPA, at concentrations corresponding to human therapeutic blood plasma concentrations. With a protocol using several applications of drugs to the same slice, PHT and VPA in combination displayed additivity of effect with 50μM PHT and 350μM VPA reducing SLD frequency by 44% and 24% individually (n = 19), and together reducing SLD frequency by 66% (n = 19). 20μM LTG reduced SLD frequency by 32% and 350μM VPA by 16% (n = 18). However, in combination there was a supra-linear suppression of ED’s of 64% (n = 18). In another independent set of experiments, similar results of drug combination responses were also found. In conclusion, a combination of conventional AEDs with different mechanisms of action, PHT and VPA, displayed linear additivity of effect on epileptiform activity. More intriguingly, a combination of LTG and VPA considered particularly efficacious clinically showed a supra-additive suppression of ED’s. This approach may be useful as an in vitro platform for assessing drug combination efficacy.

Anti-Epileptic Drug Prescription in a Psychiatric Hospital Outpatient Clinic in Southeast Nigeria

The optimum control of seizures requires adequate dosing of appropriately selected anti-epileptic medications. The availability of AEDs in Nigeria is limited and this constrains the prescription latitude of clinicians. This study was conducted to describe the prescribing pattern of anti-epileptic drugs in the outpatient service of a psychiatric facility in southeast Nigeria. The case records of the epileptic patients attending the outpatient clinic of a psychiatric hospital were retrieved, reviewed and data abstracted with a prepared proforma. The information extracted include age, sex, marital status, residence, type of seizure and anti-seizure medications prescribed, frequency of administration and dosage among other variables. Of the 178 patients whose prescriptions and case records were assessed, males constituted 62.9% and females 37.1%. Most of the patients were single (78.1%) and the group had a mean age of 25.6 ± 10.9 years. Generalized tonic-clonic seizures predominated (61.2%) among the seizure types, whilst complex partial seizure type was identified in 35.4% of the patients. Patient diagnosis relied heavily on the use of clinical description alone. About 92.7% of the patients were treated with monotherapy, whereas 7.3% received two anti-epileptic drug combinations. Carbamazepine was the most frequently prescribed drug, and was utilized in the treatment of 87.9% of patients receiving monotherapy and 92.3% of individuals receiving two drug combinations. Adjunctive medications like benzodiazepines were rarely utilised to improve the effect of the AEDs. The patients that received polytherapy could only be distinguished from those that received monotherapy by higher frequency of epileptic auras and higher mean dose of AEDs per day. The predominant use of monotherapy is in accordance with the treatment recommendations and needs to be encouraged. The greater use of carbamazepine is probably related to its perceived benefits in the control of behavioural symptoms.

META ANALYSIS OF ANTIEPILEPTIC DRUGS INDUCED CHOREOATHETOSIS IN PAEDIATRIC PATIENTS

BACKGROUND: The safety profile of anti-epileptic drugs (AEDs) is an important consideration for the regulatory bodies, owners and prescribing clinicians. Meta-analysis has increasingly been used to identify adverse effects of drugs. Efficacy studies are often too small to reliably assess risks that become important when a medication is in widespread use, so meta-analysis, which is a statistically efficient way to pool evidence from similar studies, seems like a natural approach. The safety profile of drugs is an important consideration and it affects clinicians’ decisions to prescribe specific AED(s), as serious adverse effects can lead to chronic complications or even death. Less serious, but nonetheless important, adverse effects can significantly impact quality of life, leading to systematic illness which may increase the overall cost of treatment METHODS: An electronic search was performed in using Pubmed,Paediatric journals of Neurology, MEDLINE etc. RESULTS: The literature search identified 30 unduplicated papers. Of these 11 papers were excluded by reading the abstracts and titles. Another 10 papers were excluded after reading their complete text. We selected 9 papers which comprised of case studies and observational studies. CONCLUSION: The combination of different antiepileptic drugs has resulted in drug induced choreoathetosis. A particular increased risk was seen with combinations that have phenytoin and lamotrigine. This could be due to an additive or a synergistic effect on central dopaminergic pathways.

Drug therapy of epileptic seizures among adult epileptic outpatients of University of Gondar Referral and Teaching Hospital, Gondar, North West Ethiopia.

ObjectiveThe aim of this study was to assess the practice of pharmacotherapy of epilepsy and its treatment outcomes in adult epileptic outpatients at the University of Gondar Referral and Teaching Hospital, Gondar, North West Ethiopia.MethodsAn institution based, retrospective cross-sectional study was conducted from the medical charts of 336 adult epileptic patients at the outpatient epileptic clinic of Neurology Department of University of Gondar Teaching Hospital from May 2014 to April 2015. Reviewing follow-up information from the medical charts was used to evaluate antiepileptic drug (AED) prescribing patterns and treatment outcome. Data were collected by using data collection format and analyzed using SPSS software version 16.ResultsThe most common type of seizure diagnosed was generalized tonic–clonic seizure (n=245, 72.91%). Monotherapy with an AED accounted for 80.35% of the cases, whereas dual therapy and polytherapy with three AED combinations accounted for 16.37% and 3.28%, respectively. The most frequently prescribed AED was phenobarbitone (62.47%) followed by carbamazepine (17.91%). From the total epileptic cases, 277 (82.4%) had well-controlled seizure status in the last three consecutive months.ConclusionMost of the patients were maintained by monotherapy, and largely this was by the older antiepileptic drug, phenobarbitone. Considering the development of pharmacotherapy of epilepsy and other patient related factors, the standard treatment guideline for Ethiopia needs to be revised periodically.

Additive interactions between retigabine and oxcarbazepine in the chimney test and the model of generalized tonic-clonic seizures in mice

Summary Introduction. Patients with pharmacoresistant epilepsy are usually treated with two or more antiepileptic drugs (AEDs). The search for therapeutically efficacious AED combinations is still a challenging issue for clinicians and epileptologists throughout the world. Aim. To determine the interaction profile for the combination of retigabine (RTG) and oxcarbazepine (OXC) in both, the model of tonic-clonic seizures, the maximal electroshock (MES)-induced seizure model and chimney test (motor performance) in adult male albino Swiss mice. Methods. Isobolographic analysis (type I) was applied to characterize interactions for the combination of RTG with OXC with respect to its anticonvulsant and acute side (neurotoxic) effects, as determined in the MES and chimney tests, respectively. Results. The combination of RTG with OXC at the fixed-ratios of 1:3, 1:1 and 3:1 produced additive interactions in the MES test in mice. Similarly, the combination of RTG with OXC at the fixed-ratio of 1:1 produced additive interaction with a tendency towards sub-additivity in the chimney test in mice. Measurement of total brain concentrations of both AEDs revealed that RTG did not affect total brain concentrations of OXC and inversely, OXC had no impact on RTG’s total brain concentrations, confirming pharmacodynamic interaction between the drugs. Conclusions. The additive pharmacodynamic interactions in both the MES and chimney tests in mice were observed for the combination of RTG with OXC.

Seizure control as a new metric in assessing efficacy of tumor treatment in low-grade glioma trials.

Patients with low-grade glioma frequently have brain tumor-related epilepsy, which is more common than in patients with high-grade glioma. Treatment for tumor-associated epilepsy usually comprises a combination of surgery, anti-epileptic drugs (AEDs), chemotherapy, and radiotherapy. Response to tumor-directed treatment is measured primarily by overall survival and progression-free survival. However, seizure frequency has been observed to respond to tumor-directed treatment with chemotherapy or radiotherapy. A review of the current literature regarding seizure assessment for low-grade glioma patients reveals a heterogeneous manner in which seizure response has been reported. There is a need for a systematic approach to seizure assessment and its influence on health-related quality-of-life outcomes in patients enrolled in low-grade glioma therapeutic trials. In view of the need to have an adjunctive metric of tumor response in these patients, a method of seizure assessment as a metric in brain tumor treatment trials is proposed.

Effects of antiepileptic drugs on the serum folate and vitamin B12 in various epileptic patients.

Epilepsy is a common neurodegenerative disease with an increasing morbidity. Clinical treatment of epilepsy includes symptomatic treatment, etiological treatment, surgery and prevention. The aim of the present study was to determine the effects of antiepileptic drugs (AEDs) on serum folate and vitamin B12 in various epileptic patients, and to examine the correlation between these effects and secondary cerebrovascular events. A total of 68 epileptic patients, diagnosed between May 2012 and May 2014, were included in the present study. The study included 8 cases of autonomic seizures, 10 cases of absence seizures, 13 cases of complex partial seizures, 28 cases of generalized tonic-clonic seizures, and 9 cases of simple partial seizures. The patients received appropriate AED treatment according to the characteristics of epileptic seizure and the treatment guidance. The differences in the serum levels of folate and vitamin B12 in these patients, and the differences in the secondary cerebrovascular events in these patients after 1 year follow-up were analyzed. The difference in the AEDs used by various epileptic patients was statistically significant (P<0.05). The proportion of AED monotherapy in the autonomic seizure group and petit mal group was highest, and the proportion of two AED in combination with the psychomotor seizure, grand mal and simple partial seizure groups was highest. The serum levels of folate and vitamin B12 in these patients following treatment were significantly lower than those prior to treatment (P<0.05). The differences in the serum levels of folate and vitamin B12 in these groups following treatment were not statistically significant (P>0.05). The difference in the incidence of cerebrovascular events in these groups at follow up was not statistically significant (P>0.05). The multifactorial logistic regression analysis revealed that the serum levels of folate and vitamin B12 were the independent risk factors for epilepsy with secondary cerebrovascular events [folate: odds ratio (OR)=0.536, P=0.039; vitamin: OR=0.382, P=0.041]. In conclusion, various AEDs may decrease the serum levels of folate and vitamin B12 and affect the secondary cerebrovascular events in various epileptic patients. Thus, regular supplementation of folate and vitamin B12 may be an option.

Prevalence of Different Combinations of Antiepileptic Drugs and CNS Drugs in Elderly Home Care Service and Nursing Home Patients in Norway.

Introduction. Antiepileptic drugs (AEDs) are used to treat different conditions in elderly patients and are among the drug classes most susceptible to be involved in drug-drug interactions (DDI). The aim of the study was to describe and compare use of AEDs between home care service and nursing home patients, as these patients are not included in nationwide databases of drug utilization. In the combined population, we investigate DDI of AEDs with other central nervous system- (CNS-) active drugs and DDIs involving AEDs in general. Materials and Methods. Point-prevalence study of Norwegian patients in home care services and nursing homes in 2009. At the patient level, we screened for different DDIs involving AEDs. Results. In total, 882 patients (7.8%) of 11,254 patients used AEDs and number of users did not differ between home care services and nursing homes (8.2% versus 7.7%). In the combined population, we identified 436 potential DDIs in 45% of the patients. Conclusions. In a large population of elderly, home care service and nursing home patients do not differ with respect to exposure of AEDs but use more AEDs as compared to the general population of similar age. The risk of DDIs with AEDs and other CNS-active drugs should be taken into consideration and individual clinical evaluations are assessed in this population.

Antiepileptic drug combinations not involving valproate and the risk of fetal malformations.

To investigate the relationship between antiepileptic drug (AED) polytherapy in pregnant women and the risk of fetal malformations as prescribing practice changed, with valproate being used less often and at lower doses. Specifically, the risks associated with two of the most common AEDs included in polytherapy over recent years, levetiracetam and topiramate, were examined. An observational cohort study in which malformation rates were analyzed in 1,461 pregnancies exposed to AED monotherapy, and in 484 exposed to antiepileptic drug combinations, from the Australian Register of Antiepileptic Drugs in Pregnancy over a 15-year period (1999-2014). Fetal malformation rates had fallen over time in monotherapy pregnancies, but increased in polytherapy pregnancies, despite decreasing use and lower dosages of valproate. The rise in polytherapy malformation rates began around 2005 when levetiracetam and topiramate use began to increase. Excluding pregnancies involving valproate exposure, malformation rates were higher in the remaining polytherapy pregnancies as compared with the monotherapy ones (6.90% vs. 3.64%; odds ratio [OR] 1.96, 95% confidence interval [CI] 1.14-3.39). Malformation rates were similar in polytherapy pregnancies whether or not levetiracetam was included (7.14% vs. 8.38%), but were higher in polytherapy pregnancies involving topiramate (14.94% vs. 6.55%: OR 2.507, 95% CI 1.23-5.10). Logistic regression showed that topiramate in polytherapy had a positive dose relationship with teratogenicity risk (p = 0.025). The malformation risk associated with AED polytherapy depends on the specific drugs involved. Topiramate, when used as part of AED polytherapy that did not include valproate, was associated with a dose-related increased risk of fetal malformations.

Focal interictal epileptiform discharges in idiopathic generalized epilepsy

Are idiopathic generalized epilepsies (IGEs) truly generalized? Do IGEs representa continuum or rather distinct syndromes? Focal changes in the electroencephalography (EEG) have been reported inIGEs. The aim of this work is to investigate focal interictal epileptiform discharges (IEDs) in IGEs, and their relation to clinical variables. Forty-one IGE patients (classified according to ILAE, 2001) were recruited from a tertiary center (age 23±10.938years). Their files were reviewed and they were subjected to clinical examination and interictal EEG. Patients with focal IEDs were compared to those without focal IEDs. Nine patients had juvenile myoclonic epilepsy (JME) and 32 had idiopathic epilepsy with generalized tonic-clonic seizures only (EGTCSA). Focal IEDs were found in 20 patients, mostly in the frontal (45.5%) and temporal (31.8%) distribution. Patients with focal IEDs were treated witha larger number of combined antiepileptic drugs (AEDs) (p value=0.022). No significant difference was found between the two groups regarding age, sex, age at onset, epilepsy syndrome, seizure frequency, family history, AEDs used (sodium valproate and carbamazepine) and their doses. Seventeen EGTCSA patients had focal IEDs. They were treated with larger number of combined AEDs (p value=0.0142). No significant difference was found between the EGTCSA patients with and those without focal IEDs regarding age, sex, age at onset, seizure frequency, family history and AEDs doses. Caution must be applied in the interpretation of interictal focal IEDs. These focal changes may be related to prognosis, however this needs further investigation.

Synergism of perampanel and zonisamide in the rat amygdala kindling model of temporal lobe epilepsy.

Anticonvulsive monotherapy fails to be effective in one third of patients with epilepsy resulting in the need for polytherapy regimens. However, with the still limited knowledge, drug choices for polytherapy remain empirical. Here we report experimental data from a chronic epilepsy model for the combination of perampanel and zonisamide, which can render guidance for clinical studies and individual drug choices. The anticonvulsant effects of the combination of perampanel and zonisamide were evaluated in a rat amygdala kindling model. Furthermore, the potential for motor impairment was evaluated. The type of interaction was quantitatively assessed based on isobolographic analysis. When administered alone, zonisamide dose-dependently increased the afterdischarge threshold in fully kindled rats. Moreover, data confirmed efficacy of perampanel to inhibit seizure initiation and progression with an impact on propagation of activity from the focus. Pronounced threshold increases were observed following administration of a constant zonisamide dosage combined with different doses of perampanel. Isobolographic analysis of drug responses, which is based on individual drug dose-effect data, revealed a synergistic interaction substantiating the high efficacy of the combination. Furthermore, rotarod data indicated that the combination has a favorable tolerability profile when zonisamide is coadministered with low doses of perampanel. Plasma concentration analysis argued against a pharmacokinetic interaction as a basis for the synergism. The findings clearly indicate a pronounced synergistic anticonvulsant effect for the combination of the noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist perampanel with zonisamide, which modulates voltage-sensitive sodium channels and T-type calcium currents. Consequently, polytherapy using these two antiepileptic drugs might be efficacious for clinical management of partial-onset seizures. The findings indicate that the impact of dose ratios on tolerability needs be taken into account. With regard to conclusions about the extent of the synergism and its implications further antiepileptic drug combinations need to be evaluated allowing direct comparison.